• Association of Neighborhood-Level Disadvantage With Cerebral and Hippocampal Volume

    Hunt JFV, Buckingham W, Kim AJ, Oh J, Vogt NM, Jonaitis EM, Hunt TK, Zuelsdorff M, Powell R, Norton D, Rissman RA, Asthana S, Okonkwo OC, Johnson SC, Kind AJH, Bendlin BB.

    JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4501. [Epub ahead of print]


    Importance: Identifying risk factors for brain atrophy during the aging process can help direct new preventive approaches for dementia and cognitive decline. The association of neighborhood socioeconomic disadvantage with brain volume in this context is not well known. Objective: To test whether neighborhood-level socioeconomic disadvantage is associated with decreased brain volume in a cognitively unimpaired population enriched for Alzheimer disease risk. Design, Setting, and Participants: This study, conducted from January 6, 2010, to January 17, 2019, at an academic research neuroimaging center, used cross-sectional data on 951 participants from 2 large, ongoing cohort studies of Alzheimer disease (Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center clinical cohort)... [read more]

  • Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age

    Betthauser TJ, Koscik RL, Jonaitis EM, Allison SL, Cody KA, Erickson CM, Rowley HA, Stone CK, Mueller KD, Clark LR, Carlsson CM, Chin NA, Asthana S, Christian BT, Johnson SC.

    Brain. 2020 Jan 1;143(1):320-335. doi: 10.1093/brain/awz378.


    This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging... [read more]


  • Brain glucose metabolism, cognition, and cardiorespiratory fitness following exercise training in adults at risk for Alzheimer’s disease

    Gaitán JM, Boots EA, Dougherty RJ, Oh JM, Ma Y, Edwards DF, Christian BT, Cook DB, Okonkwo OC

    Brain Plasticity. 2019 Dec 26. 5(1): 83-95. doi: 10.3233/BPL-190093


    Aerobic exercise has been associated with reduced burden of brain and cognitive changes related to Alzheimer’s disease (AD). However, it is unknown whether exercise training in asymptomatic individuals harboring risk for AD improves outcomes associated with AD... [read more]

  • Cortical Microstructural Alterations in Mild Cognitive Impairment and Alzheimer's Disease Dementia

    Vogt NM, Hunt JF, Adluru N, Dean DC, Johnson SC, Asthana S, Yu JJ, Alexander AL, Bendlin BB.

    Cereb Cortex. 2019 Dec 13. pii: bhz286. doi: 10.1093/cercor/bhz286. [Epub ahead of print]


    In Alzheimer's disease (AD), neurodegenerative processes are ongoing for years prior to the time that cortical atrophy can be reliably detected using conventional neuroimaging techniques. Recent advances in diffusion-weighted imaging have provided new techniques to study neural microstructure, which may provide additional information regarding neurodegeneration... [read more]

  • Stressful Life Events and Racial Disparities in Cognition Among Middle-Aged and Older Adults

    Zuelsdorff M, Okonkwo OC, Norton D, Barnes LL, Graham KL, Clark LR, Wyman MF, Benton SF, Gee A, Lambrou N, Johnson SC, Gleason CE.

    J Alzheimers Dis. 2019 Dec 6. doi: 10.3233/JAD-190439. [Epub ahead of print]


    BACKGROUND: It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer's and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. OBJECTIVE: We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP). METHODS: Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. RESULTS: African Americans (N = 50) reported more stressful life events than Whites (N = 1,191)... [read more]

  • Association of Cardiovascular and Alzheimer's Disease Risk Factors with Intracranial Arterial Blood Flow in Whites and African Americans

    Clark LR, Norton D, Berman SE, Johnson SC, Bendlin BB, Wieben O, Turski P, Carlsson C, Asthana S, Gleason CE, Johnson HM.

    J Alzheimers Dis. 2019;72(3):919-929. doi: 10.3233/JAD-190645.


    BACKGROUND: Alzheimer's disease (AD) has a higher prevalence among African Americans. Targeting cardiovascular and metabolic risk factors may be potential mechanisms to modify AD risk and address racial/ethnic disparities in AD dementia. OBJECTIVE: This study investigated relationships among cardiovascular and metabolic risk factors, APOE genotype, AD biomarkers, and intracranial arterial blood flow in Whites and African Americans enriched for AD risk. METHODS: 399 cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center completed physical and neuroimaging examinations... [read more]

  • Screening with a high precision blood-based assay for Alzheimer disease

    Bendlin BB, Zetterberg H.

    Neurology. 2019 Aug 1. pii: 10.1212/WNL.0000000000008080. doi: 10.1212/WNL.0000000000008080. [Epub ahead of print]


    ... [read more]

  • Elevated Insulin and Insulin Resistance are Associated with Altered Myelin in Cognitively Unimpaired Middle-Aged Adults

    O'Grady JP, Dean DC 3rd, Yang KL, Canda CM, Hoscheidt SM, Starks EJ, Merluzzi A, Hurley S, Davenport NJ, Okonkwo OC, Anderson RM, Asthana S, Johnson SC, Alexander AL, Bendlin BB.

    Obesity (Silver Spring). 2019 Jul 17. doi: 10.1002/oby.22558. [Epub ahead of print]


    OBJECTIVE: Insulin regulates metabolism and influences neural health. Insulin resistance (IR) and type II diabetes have been identified as risk factors for Alzheimer disease (AD)... [read more]

  • Predicting Risk for Dementia: Is It Ready for the Clinic?

    Johnson SC, Asthana S.

    Am J Psychiatry. 2019 Jul 1;176(7):501-502. doi: 10.1176/appi.ajp.2019.19050520.


    ... [read more]

  • Comparison of different MRI-based morphometric estimates for defining neurodegeneration across the Alzheimer's disease continuum

    Allison SL, Koscik RL, Cary RP, Jonaitis EM, Rowley HA, Chin NA, Zetterberg H, Blennow K, Carlsson CM, Asthana S, Bendlin BB, Johnson SC.

    Neuroimage Clin. 2019 Jun 10;23:101895. doi: 10.1016/j.nicl.2019.101895. [Epub ahead of print]


    BACKGROUND: Several neurodegeneration (N) metrics using structural MRI are used for the purpose of Alzheimer's disease (AD)-related staging, including hippocampal volume, global atrophy, and an "AD signature" composite consisting of thickness or volumetric estimates derived from regions impacted early in AD. This study sought to determine if less user-intensive estimates of global atrophy and hippocampal volume were equivalent to a thickness-based AD signature from FreeSurfer for defining N across the AD continuum (i.e., individuals who are amyloid-positive (A+)). METHODS: Cognitively unimpaired (CU) late middle-aged and older adults, as well as A+ mild cognitive impairment (MCI) and A+ AD dementia individuals, with available CSF and structural MRI scan <1.5 years apart, were selected for the study (n = 325, mean age = 62)... [read more]

  • Arterial spin labeling reveals relationships between resting cerebral perfusion and motor learning in Parkinson's disease

    Barzgari A, Sojkova J, Maritza Dowling N, Pozorski V, Okonkwo OC, Starks EJ, Oh J, Thiesen F, Wey A, Nicholas CR, Johnson S, Gallagher CL.

    Brain Imaging Behav. 2019 Jun;13(3):577-587. doi: 10.1007/s11682-018-9877-1.


    Parkinson's disease (PD) is an age-related neurodegenerative disease that produces changes in movement, cognition, sleep, and autonomic function. Motor learning involves acquisition of new motor skills through practice, and is affected by PD... [read more]

  • Cross-sectional and longitudinal associations between total and regional white matter hyperintensity volume and cognitive and motor function in Parkinson's disease

    Pozorski V, Oh JM, Okonkwo O, Krislov S, Barzgari A, Theisen F, Sojkova J, Bendlin BB, Johnson SC, Gallagher CL.

    Neuroimage Clin. 2019 May 23;23:101870. doi: 10.1016/j.nicl.2019.101870. [Epub ahead of print]


    BACKGROUND: White matter hyperintensities (WMH) are frequently observed on T2-weighted brain magnetic resonance imaging studies of healthy older adults and have been linked with impairments in balance, gait, and cognition. Nonetheless, few studies have investigated the longitudinal effects of comorbid WMH on cognition and motor function in Parkinson's disease. METHODS: The Lesion Segmentation Tool for Statistical Parametric Mapping was used to obtain total lesion volume and map regional WMH probabilities in 29 PD and 42 control participants at two study visits 18 months apart... [read more]

  • KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD

    Erickson CM, Schultz SA, Oh JM, Darst BF, Ma Y, Norton D, Betthauser T, Gallagher CL, Carlsson CM, Bendlin BB, Asthana S, Hermann BP, Sager MA, Blennow K, Zetterberg H, Engelman CD, Christian BT, Johnson SC, Dubal DB, Okonkwo OC.

    Neurology. 2019 Apr 16;92(16):e1878-e1889. doi: 10.1212/WNL.0000000000007323. Epub 2019 Mar 13.


    OBJECTIVE: To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. METHODS: Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aβ burden... [read more]

  • Differential effects of neurodegeneration biomarkers on subclinical cognitive decline

    Merluzzi AP, Vogt NM, Norton D, Jonaitis E, Clark LR, Carlsson CM, Johnson SC, Asthana S, Blennow K, Zetterberg H, Bendlin BB.

    Alzheimers Dement (N Y). 2019 Apr 12;5:129-138. doi: 10.1016/j.trci.2019.02.004. eCollection 2019.


    Introduction: Neurodegeneration appears to be the biological mechanism most proximate to cognitive decline in Alzheimer's disease. We test whether t-tau and alternative biomarkers of neurodegeneration-neurogranin and neurofilament light protein (NFL)-add value in predicting subclinical cognitive decline. Methods: One hundred fifty cognitively unimpaired participants received a lumbar puncture for cerebrospinal fluid and at least two neuropsychological examinations (mean age at first visit = 59.3 ± 6.3 years; 67% female)... [read more]

  • Cardiorespiratory fitness modifies influence of sleep problems on cerebrospinal fluid biomarkers in an at-risk cohort

    Law LL, Sprecher KE, Dougherty RJ, Edwards DF, Koscik RL, Gallagher CL, Carlsson CM, Zetterberg H, Blennow K, Asthana S, Sager MA, Hermann BP, Johnson SC, Cook DB, Bendlin BB, Okonkwo OC

    J Alzheimers Dis. 2019 Apr 1. doi: 10.3233/JAD-180291. [Epub ahead of print]


    BACKGROUND: Previous studies indicate that cardiorespiratory fitness (CRF) and sleep are each favorably associated with Alzheimer's disease (AD) pathophysiology, including reduced amyloid-β (Aβ) and tau pathology. However, few studies have examined CRF and sleep in the same analysis... [read more]

  • Fitness, independent of physical activity is associated with cerebral blood flow in adults at risk for Alzheimer's disease

    Dougherty RJ, Boots EA, Lindheimer JB, Stegner AJ, Van Riper S, Edwards DF, Gallagher CL, Carlsson CM, Rowley HA, Bendlin BB, Asthana S, Hermann BP, Sager MA, Johnson SC, Okonkwo OC, Cook DB.

    Brain Imaging Behav. 2019 Mar 9. doi: 10.1007/s11682-019-00068-w. [Epub ahead of print]


    Patterns of decreased resting cerebral blood flow (CBF) within the inferior temporal gyri, angular gyri, and posterior cingulate are a feature of aging and Alzheimer's disease (AD) and have shown to be predictive of cognitive decline among older adults. Fitness and physical activity are both associated with many indices of brain health and may positively influence CBF, however, the majority of research to date has examined these measures in isolation, leaving the potential independent associations unknown... [read more]

  • Hypertension and obesity moderate the relationship between β-amyloid and cognitive decline in midlife.

    Clark LR, Koscik RL, Allison SL, Berman SE, Norton D, Carlsson CM, Betthauser TJ, Bendlin BB, Christian BT, Chin NA, Asthana S, Johnson SC.

    Alzheimers Dement. 2019 Mar;15(3):418-428. doi: 10.1016/j.jalz.2018.09.008. Epub 2018 Oct 25.


    BACKGROUND: This study tested if central obesity, hypertension, or depressive symptoms moderated the relationship between B-amyloid (AB) and longitudinal cognitive performance in late middle-aged adults enriched for Alzheimer's disease (AD) risk. METHODS: Participants (n = 207; ages = 40-70 years; 73% parental AD) in the Wisconsin Registry for Alzheimer's Prevention study completed 3+ neuropsychological evaluations and a [11C]PiB positron emission tomography scan or lumbar puncture. Linear mixed-effects regression models tested interactions of risk factor x AB x visit age on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores. RESULTS: The relationship between AB and Verbal Learning & Memory decline was moderated by hypertension (X2(1) = 3.85, P = .04) and obesity (X2(1) = 6.12, P = .01); those with both elevated AB and the risk factor declined at faster rates than those with only elevated AB or elevated risk factors... [read more]

  • Association of longitudinal white matter degeneration and cerebrospinal fluid biomarkers of neurodegeneration, inflammation and Alzheimer's disease in late-middle-aged adults

    Racine AM, Merluzzi AP, Adluru N, Norton D, Koscik RL, Clark LR, Berman SE, Nicholas CR, Asthana S, Alexander AL, Blennow K, Zetterberg H, Kim WH, Singh V, Carlsson CM, Bendlin BB, Johnson SC.

    Brain Imaging Behav. 2019 Feb;13(1):41-52. doi: 10.1007/s11682-017-9732-9.


    Alzheimer's disease (AD) is characterized by substantial neurodegeneration, including both cortical atrophy and loss of underlying white matter fiber tracts. Understanding longitudinal alterations to white matter may provide new insights into trajectories of brain change in both healthy aging and AD, and fluid biomarkers may be particularly useful in this effort... [read more]


  • The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer's disease

    Vogt NM, Romano KA, Darst BF, Engelman CD, Johnson SC, Carlsson CM, Asthana S, Blennow K, Zetterberg H, Bendlin BB, Rey FE.

    Alzheimers Res Ther. 2018 Dec 22;10(1):124. doi: 10.1186/s13195-018-0451-2.


    BACKGROUND: Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer's disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease. METHODS: In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer's clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein). RESULTS: CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein). CONCLUSIONS: These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.... [read more]

  • Longitudinal white matter microstructural change in Parkinson's disease

    Pozorski V, Oh JM, Adluru N, Merluzzi AP, Theisen F, Okonkwo O, Barzgari A, Krislov S, Sojkova J, Bendlin BB, Johnson SC, Alexander AL, Gallagher CL.

    Hum Brain Mapp. 2018 Oct;39(10):4150-4161. doi: 10.1002/hbm.24239. Epub 2018 Jun 27.


    Postmortem studies of Parkinson's disease (PD) suggest that Lewy body pathology accumulates in a predictable topographical sequence, beginning in the olfactory bulb, followed by caudal brainstem, substantia nigra, limbic cortex, and neocortex. Diffusion-weighted imaging (DWI) is sensitive, if not specific, to early disease-related white matter (WM) change in a variety of traumatic and degenerative brain diseases... [read more]

  • Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort

    Vesperman CJ, Pozorski V, Dougherty RJ, Law LL, Boots E, Oh JM, Gallagher CL, Carlsson CM, Rowley HA, Ma Y, Bendlin BB, Asthana S, Sager MA, Hermann BP, Johnson SC, Cook DB, Okonkwo OC.

    Alzheimers Res Ther. 2018 Sep 24;10(1):97. doi: 10.1186/s13195-018-0429-0.


    BACKGROUND: Age is the cardinal risk factor for Alzheimer's disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults... [read more]

  • Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia

    Merluzzi AP, Carlsson CM, Johnson SC, Schindler SE, Asthana S, Blennow K, Zetterberg H, Bendlin BB.

    Neurology. 2018 Jul 31;91(5):e436-e443. doi: 10.1212/WNL.0000000000005901. Epub 2018 Jun 29.


    OBJECTIVE: To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. METHODS: In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40])... [read more]

  • The effect of rare variants in TREM2 and PLD3 on longitudinal cognitive function in the Wisconsin Registry for Alzheimer’s Prevention

    Engelman CD, Darst BF, Bilgel M, Vasiljevic E, Koscik RL, Jedynak BM, Johnson SC.

    Neurobiol Aging. 2018 Jun;66:177.e1-177.e5. doi: 10.1016/j.neurobiolaging.2017.12.025. Epub 2017 Dec 29.


    Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer's disease (AD), but their effect on cognitive function is unknown. We examined the effect of these variants on cognitive function in 1449 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of initially asymptomatic adults, aged 36-73 years at baseline, enriched for a parental history of AD... [read more]

  • In vivo characterization and quantification of neurofibrillary tau PET radioligand [18F]MK-6240 in humans from Alzheimer's disease dementia to young controls

    Betthauser TJ, Cody KA, Zammit MD, Murali D, Converse AK, Barnhart TE, Stone CK, Rowley HA, Johnson SC, Christian BT.

    J Nucl Med. 2018 May 18. pii: jnumed.118.209650. doi: 10.2967/jnumed.118.209650. [Epub ahead of print]


    Tau positron emission tomography (PET) imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimer's disease (AD). This work investigates in vivo kinetics, quantification strategies and imaging characteristics of a novel tau PET radioligand [18F]MK-6240 in humans... [read more]

  • Imaging neurodegeneration in Down syndrome: brain templates for amyloid burden and tissue segmentationv

    Lao PJ, Handen BL, Betthauser TJ, Cody KA, Cohen AD, Tudorascu DL, Stone CK, Price JC, Johnson SC, Klunk WE, Christian BT.

    Brain Imaging Behav. 2018 May 11. doi: 10.1007/s11682-018-9888-y. [Epub ahead of print]


    The focus of Alzheimer's disease (AD) neuroimaging research has shifted towards an investigation of the earliest stages of AD pathogenesis, which manifests in every young adult with Down syndrome (DS; trisomy 21) resulting from a deterministic genetic predisposition to amyloid precursor protein overproduction. Due to morphological differences in brain structure in the DS population, special consideration must be given to processing pipelines and the use of normative atlases developed for the non-DS population... [read more]

  • Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau

    Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Gifford K, Bush WS, Chibnik LB, Mukherjee S, De Jager PL, Kukull W, Crane PK, Resnick SM, Keene CD, Montine TJ, Schellenberg GD, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Bennett DA, Schneider JA, Jefferson AL for the Alzheimer’s for the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative

    JAMA Neurol. 2018 May 7. doi: 10.1001/jamaneurol.2018.0821. [Epub ahead of print]


    Importance: The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner... [read more]

  • The recency ratio as predictor of early MCI

    Bruno D, Koscik RL, Woodard JL, Pomara N, Johnson SC

    International Psychogeriatrics. 2018 Apr 18:1-6. doi: 10.1017/S1041610218000467. [Epub ahead of print]


    OBJECTIVES: Individuals with Alzheimer's disease (AD) present poor immediate primacy recall accompanied by intact or exaggerated recency, which then tends to decline after a delay. Bruno et al... [read more]

  • Age-accelerated cognitive decline in asymptomatic adults with CSF β-amyloid

    Clark LR, Berman SE, Norton D, Koscik RL, Jonaitis EM, Blennow K, Bendlin BB, Asthana S, Johnson SC, Zetterberg H, Carlsson CM.

    Neurology. 2018 Mar 9. pii: 10.1212/WNL.0000000000005291. [Epub ahead of print]


    Objective Compare cognitive and hippocampal volume trajectories in asymptomatic middle-aged and older adults with positive CSF markers of β-amyloid (Aβ) or tau to adults without an Alzheimer disease (AD)-associated biomarker profile. Methods Three hundred ninety-two adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimer’s Prevention or Wisconsin Alzheimer’s Disease Research Center) completed a lumbar puncture and at least 2 biennial or annual neuropsychological evaluations... [read more]

  • Proximity to Parental Symptom Onset and Amyloid-β Burden in Sporadic Alzheimer Disease

    Villeneuve S, Vogel JW, Gonneaud J, Pichet Binette A, Rosa-Neto P, Gauthier S, Bateman RJ, Fagan AM, Morris JC, Benzinger TLS, Johnson SC, Breitner JCS, Poirier J; Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) Research Group

    JAMA Neurol. 2018 Feb 26. doi: 10.1001/jamaneurol.2017.5135. [Epub ahead of print]


    Importance: Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms... [read more]

  • Cognitive decline in the middle-aged after surgery and anaesthesia: results from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) cohort

    Bratzke LC, Koscik RL, Schenning KJ, Clark LR, Sager MA, Johnson SC, Hermann BP, Hogan KJ

    Anaesthesia. 2018 Feb 21. doi: 10.1111/anae.14216. [Epub ahead of print]


    Surgery and anaesthesia might affect cognition in middle-aged people without existing cognitive dysfunction. We measured memory and executive function in 964 participants, mean age 54 years, and again four years later, by when 312 participants had had surgery and 652 participants had not... [read more]

  • CSF and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage

    Bettcher, B. M., Johnson, S. C., Fitch, R., Casaletto, K. B., Heffernan, K. S., Asthana, S., Zetterberg, H., Blennow, K., Carlsson, C. M., Neuhaus, J., Bendlin, B. B., & Kramer, J. H.

    Journal of Alzheimer's Disease. 2018;62(1):385-397. doi: 10.3233/JAD-170602.


    Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer's disease (AD) pathology or neuronal damage... [read more]

  • Moderate intensity physical activity associates with CSF biomarkers in a cohort at risk for Alzheimer's disease

    Law LL, Rol RN, Schultz SA, Dougherty RJ, Edwards DF, Koscik RL, Gallagher CL, Carlsson CM, Bendlin BB, Zetterberg H, Blennow K, Asthana S, Sager MA, Hermann BP, Johnson SC, Cook DB, Okonkwo OC.

    Alzheimers Dement (Amst). 2018 Feb 6;10:188-195. doi: 10.1016/j.dadm.2018.01.001. eCollection 2018.


    Introduction: Alzheimer’s disease (AD) is characterized by the presence of amyloid b (Ab) plaques, neurofibrillary tangles, and neurodegeneration, evidence of which may be detected in vivo via cere- brospinal fluid (CSF) sampling. Physical activity (PA) has emerged as a possible modifier of these AD-related pathological changes... [read more]

  • Statistical tests and identifiability conditions for pooling and analyzing multisite datasets

    Zhou HH, Singh V, Johnson SC, Wahba G, Alzheimer's Disease Neuroimaging Initiative

    Proc Natl Acad Sci U S A


    When sample sizes are small, the ability to identify weak (but scientifically interesting) associations between a set of predictors and a response may be enhanced by pooling existing datasets. However, variations in acquisition methods and the distribution of participants or observations between datasets, especially due to the distributional shifts in some predictors, may obfuscate real effects when datasets are combined... [read more]

  • Declines in Connected Language Are Associated with Very Early Mild Cognitive Impairment: Results from the Wisconsin Registry for Alzheimer's Prevention

    Mueller KD, Koscik RL, Hermann BP, Johnson SC, Turkstra LS

    Front Aging Neurosci. 2018 Jan 9;9:437. doi: 10.3389/fnagi.2017.00437. eCollection 2017.


    Changes to everyday spoken language ("connected language") are evident in persons with AD dementia, yet little is known about when these changes are first detectable on the continuum of cognitive decline. The aim of this study was to determine if participants with very early, subclinical memory declines were also showing declines in connected language... [read more]

  • Cognitive Variability Predicts Incident Alzheimer's Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker

    Gleason CE, Norton D, Anderson ED, Wahoske M, Washington DT, Umucu E, Koscik RL, Dowling NM, Johnson SC, Carlsson CM, Asthana S; Alzheimer’s Disease Neuroimaging Initiative.

    J Alzheimers Dis. 2018;61(1):79-89.


    Background:Alzheimer’s disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures... [read more]

  • An Objective Method to Accurately Measure Cardiorespiratory Fitness in Older Adults Who Cannot Satisfy Widely Used Oxygen Consumption Criteria

    Dougherty RJ, Lindheimer JB, Stegner AJ, Van Riper S, Okonkwo OC, Cook DB.

    J Alzheimers Dis. 2018;61(2):601-611.


    Cardiorespiratory fitness (CRF) is routinely investigated in older adults; however, the most appropriate CRF measure to use for this population has received inadequate attention. This study aimed to 1) evaluate the reliability and validity of the oxygen uptake efficiency slope (OUES) as a sub-maximal measurement of CRF; 2) examine demographic, risk-factor, and exercise testing differences in older adults who satisfied standardized criteria for a peak oxygen consumption (V̇O2peak) test compared to those who did not; and 3) determine the difference between directly measured V̇O2peak values and OUES-predicted V̇O2peak values... [read more]

  • Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome

    Lao PJ, Handen BL, Betthauser TJ, Mihaila I, Hartley SL, Cohen AD, Tudorascu DL, Bulova PD, Lopresti BJ, Tumuluru RV, Murali D, Mathis CA, Barnhart TE, Stone CK, Price JC, Devenny DA, Johnson SC, Klunk WE, Christian BT

    J Alzheimers Dis. 2018;61(2):631-644.


    Background:The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer’s disease (AD). Objective:The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD... [read more]

  • Social support and verbal interaction are differentially associated with cognitive function in midlife and older age

    Zuelsdorff ML, Koscik RL, Okonkwo OC, Peppard PE, Hermann BP, Sager MA, Johnson SC, Engelman CD

    Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2017 Dec 15:1-17. [Epub ahead of print]


    Social engagement is associated with healthy aging and preserved cognition. Two dimensions of engagement, verbal interactions and perceived support, likely impact cognition via distinct mechanistic pathways... [read more]


  • The Wisconsin Registry for Alzheimer's Prevention: A review of findings and current directions

    Johnson SC, Koscik RL, Jonaitis EM, Clark LR, Mueller KD, Berman SE, Bendlin BB, Engelman CD, Okonkwo OC, Hogan KJ, Asthana S, Carlsson CM, Hermann BP, Sager MA

    Alzheimers Dement (Amst). 2017 Dec 8;10:130-142. doi: 10.1016/j.dadm.2017.11.007. eCollection 2018.


    The Wisconsin Registry for Alzheimer's Prevention is a longitudinal observational cohort study enriched with persons with a parental history (PH) of probable Alzheimer's disease (AD) dementia. Since late 2001, Wisconsin Registry for Alzheimer's Prevention has enrolled 1561 people at a mean baseline age of 54 years... [read more]

  • Gut microbiome alterations in Alzheimer's disease

    Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE

    Scientific Reports. 2017 Oct 19;7(1):13537


    Alzheimer's disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood... [read more]

  • Characterization of the radiosynthesis and purification of [18F]THK-5351, a PET ligand for neurofibrillary tau

    Betthauser TJ, Ellison PA, Murali D, Lao PJ, Barnhart TE, Furumoto S, Okamura N, Johnson SC, Engle JW, Nickles RJ, Christian BT

    Appl Radiat Isot 2017; 130: 230-237


    ... [read more]

  • Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers

    Casaletto KB, Elahi FM, Bettcher BM, Neuhaus J, Bendlin BB, Asthana S, Johnson SC, Yaffe K, Carlsson C, Blennow K, Zetterberg H, Kramer JH.

    Neurology. 2017; 89: 1782-1788.


    ... [read more]

  • Evaluation of striatonigral connectivity using probabilistic tractography in Parkinson's disease

    Theisen F, Leda R, Pozorski V, Oh JM, Adluru N, Wong R, Okonkwo O, Dean DC 3rd, Bendlin BB, Johnson SC, Alexander AL, Gallagher CL.

    Neuroimage Clin. 2017 Sep 9;16:557-563. eCollection 2017.


    The cardinal movement abnormalities of Parkinson's disease (PD), including tremor, muscle rigidity, and reduced speed and frequency of movements, are caused by degeneration of dopaminergic neurons in the substantia nigra that project to the putamen, compromising information flow through frontal-subcortical circuits. Typically, the nigrostriatal pathway is more severely affected on the side of the brain opposite (contralateral) to the side of the body that manifests initial symptoms... [read more]

  • Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults

    Sprecher KE, Koscik RL, Carlsson CM, Zetterberg H, Blennow K, Okonkwo OC, Sager MA, Asthana S, Johnson SC, Benca RM, Bendlin BB

    Neurology. 2017 Aug 1;89(5):445-453. Epub 2017 Jul 5.


    OBJECTIVE: To determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife. METHODS: We investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention... [read more]

  • Intracranial Arterial 4D Flow in Individuals with Mild Cognitive Impairment is Associated with Cognitive Performance and Amyloid Positivity

    Berman SE, Clark LR, Rivera-Rivera LA, Norton D, Racine AM, Rowley HA, Bendlin BB, Blennow K, Zetterberg H, Carlsson CM, Asthana S, Turski P, Wieben O, Johnson SC.

    J Alzheimers Dis. 2017;60(1):243-252.


    It is becoming increasingly recognized that cerebrovascular disease is a contributing factor in the pathogenesis of Alzheimer's disease (AD). A unique 4D-Flow magnetic resonance imaging (MRI) technique, phase contrast vastly undersampled isotropic projection imaging (PC VIPR), enables examination of angiographic and quantitative metrics of blood flow in the arteries of the Circle of Willis within a single MRI acquisition... [read more]

  • Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer’s Disease

    Dougherty RJ, Schultz SA, Kirby TK, Boots EA, Oh JM, Edwards DF, Gallagher CL, Carlsson CM, Bendlin BB, Asthana S, Sager MA, Hermann BP, Christian BT, Johnson SC, Cook DB, Okonkwo OC.

    Journal of Alzheimer's Disease. 2017;58(4):1089-1097.


    The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention participated in this cross-sectional study... [read more]

  • Insulin resistance is associated with lower intracranial arterial flow and cortical hypoperfusion in cognitively healthy middle-aged adults

    Hoscheidt SM, Kellawan JM, Berman SE, Rivera L, Krause R, Oh JM, Turski P, Carlsson CM, Beeri MS, Asthana S, Rowley HA, Wieben O, Johnson SC, Schrage WG, Bendlin BB

    Journal of Cerebral Blood Flow and Metabolism. 2017 Jun;37(6):2249-2261. doi: 10.1177/0271678X16663214. Epub 2016 Jan 1.


    Insulin resistance (IR) is associated with poor cerebrovascular health and increased risk for dementia. Little is known about the unique effect of IR on both micro- and macrovascular flow particularly in midlife when interventions against dementia may be most effective... [read more]

  • The Preservation of Cognition 1 Yr After Carotid Endarterectomy in Patients With Prior Cognitive Decline

    Dempsey RJ, Jackson DC, Wilbrand SM, Mitchell CC, Berman SE, Johnson SC, Meshram NH, Varghese T, Hermann BP

    Neurosurgery. 2017 Jun 1. doi: 10.1093/neuros/nyx173. [Epub ahead of print]


    BACKGROUND: Vascular cognitive decline is critically important in the course of atherosclerosis and stroke. OBJECTIVE: To explore the hypothesis that carotid endarterectomy (CEA) by removing an unstable plaque may slow the course of vascular cognitive decline in both symptomatic and asymptomatic patients. METHODS: Patients with clinically significant (>60%) carotid stenosis were studied preop and 1 yr post-CEA for clinical symptoms, vascular cognitive decline, instability of carotid plaque-presence of microemboli, brain white matter changes, and medical risk factors. RESULTS: Forty-six percent were classically symptomatic. All patients showed vascular cognitive decline at presentation which correlated with degree of plaque instability... [read more]

  • BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

    Boots EA, Schultz SA, Clark LR, Racine AM, Darst BF, Koscik RL, Carlsson CM, Gallagher CL, Hogan KJ, Bendlin BB, Asthana S, Sager MA, Hermann BP, Christian BT, Dubal DB, Engelman CD, Johnson SC, Okonkwo OC.

    Neurology. 2017 May 30;88(22):2098-2106. doi: 10.1212/WNL.0000000000003980. Epub 2017 May 3.


    OBJECTIVE: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. METHODS: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years)... [read more]

  • Family history and TOMM40 '523 interactive associations with memory in middle-aged and Alzheimer's disease cohorts

    Willette AA, Webb JL, Lutz MW, Bendlin BB, Wennberg AM, Oh JM, Roses A, Koscik RL, Hermann BP, Dowling NM, Asthana S, Johnson SC; Alzheimer's Disease Neuroimaging Initiative

    Alzhimer's & Dementia. 2017 Nov;13(11):1217-1225. doi: 10.1016/j.jalz.2017.03.009. Epub 2017 May 23.


    INTRODUCTION: Family history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa (TOMM40) rs10524523 ('523) poly-T length on memory decline. METHODS: For 912 nonapolipoprotein ε4 middle-aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 '523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed. RESULTS: For FH negative participants, gene-dose preservation of memory and global cognition was seen for "very long" versus "short" carriers... [read more]

  • Use of the Quick Dementia Rating System (QDRS) as an Initial Screening Measure in a Longitudinal Cohort at Risk for Alzheimer's Disease

    Berman SE, Koscik RL, Clark LR, Mueller KD, Bluder L, Galvin JE, Johnson SC.

    JAD Rep. 2017;1(1):9-13. Epub 2017 Apr 28.


    The Quick Dementia Rating System (QDRS) and Clinical Dementia Rating Scale (CDR) assess global cognitive and functional decline. We evaluated whether the shorter QDRS was a valid screen for problems identified by the CDR in individuals with minimal clinical abnormalities... [read more]

  • Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD

    Schultz SA, Boots EA, Darst BF, Zetterberg H, Blennow K, Edwards DF, Koscik RL, Carlsson CM, Gallagher CL, Bendlin BB, Asthana S, Sager MA, Hogan KJ, Hermann BP, Cook DB, Johnson SC, Engelman CD, Okonkwo OC

    Neurology. 2017 Apr 25;88(17):1650-1658. Epub 2017 Mar 24.


    OBJECTIVE: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. METHODS: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses... [read more]

  • Positive affect predicts cerebral glucose metabolism in late middle-aged adults

    Nicholas C, Hoscheidt SM, Clark LR, Racine AM, Berman SE, Koscik RL, Maritza Dowling N, Asthana S, Christian BT, Sager MA, Johnson SC.

    Social Cognitive and Affective Neuroscience. 2017 Apr 11. [Epub ahead of print]


    Positive affect is associated with a number of health benefits; however, few studies have examined the relationship between positive affect and cerebral glucose metabolism, a key energy source for neuronal function and a possible index of brain health. We sought to determine if positive affect was associated with cerebral glucose metabolism in late middle-aged adults (n =134)... [read more]

  • An Examination of Brain Abnormalities and Mobility in Individuals with Mild Cognitive Impairment and Alzheimer's Disease

    Fischer BL, Bacher R, Bendlin BB, Birdsill AC, Ly M, Hoscheidt SM, Chappell RJ, Mahoney JE, Gleason CE

    Front Aging Neurosci. 2017 Apr 5;9:86. eCollection 2017.


    Background: Mobility changes are concerning for elderly patients with cognitive decline. Given frail older individuals' vulnerability to injury, it is critical to identify contributors to limited mobility... [read more]

  • Stemming the Alzheimer tsunami: introduction to the special issue on reserve and resilience in Alzheimer's disease

    Okonkwo OC, Vemuri P.

    Brain Imaging Behav. 2017 Apr;11(2):301-303.


    ... [read more]

  • Microstructural white matter alterations in preclinical Alzheimer's diseasedetected using free water elimination diffusion tensor imaging

    Hoy AR, Ly M, Carlsson CM, Okonkwo OC, Zetterberg H, Blennow K, Sager MA, Asthana S, Johnson SC, Alexander AL, Bendlin BB.

    PLoS One. 2017 Mar 14;12(3):e0173982. eCollection 2017.


    Brain changes associated with Alzheimer's disease (AD) begin decades before disease diagnosis. While β-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction... [read more]

  • Carotid atherosclerotic plaque instability and cognition determined by ultrasound-measured plaque strain in asymptomatic patients with significant stenosis

    Dempsey RJ, Varghese T, Jackson DC, Wang X, Meshram NH, Mitchell CC, Hermann BP, Johnson SC, Berman SE, Wilbrand SM.

    Journal of Neurosurgery. 2017 Mar 10:1-9. [Epub ahead of print]


    OBJECTIVE This article describes the use of ultrasound measurements of physical strain within carotid atherosclerotic plaques as a measure of instability and the potential for vascular cognitive decline, microemboli, and white matter changes. METHODS Asymptomatic patients with significant (> 60%) carotid artery stenosis were studied for dynamic measures of plaque instability, presence of microemboli, white matter changes, and vascular cognitive decline in comparison with normative controls and premorbid state... [read more]

  • Relationships between cardiorespiratory fitness, hippocampal volume, and episodic memory in a population at risk for Alzheimer's disease

    Dougherty RJ, Schultz SA, Boots EA, Ellingson LD, Meyer JD, Van Riper S, Stegner AJ, Edwards DF, Oh JM, Einerson J, Korcarz CE, Koscik RL, Dowling MN, Gallagher CL, Carlsson CM, Rowley HA, Bendlin BB, Asthana S, Hermann BP, Sager MA, Stein JH, Sterling CJ, Okonkwo OC, Cook DB

    Brain and Behavior. 2017 Feb 17;7(3):e00625. eCollection 2017.


    Cardiorespiratory fitness (CRF) has been shown to be related to brain health in older adults. In individuals at risk for developing Alzheimer’s disease (AD), CRF may be a modifiable risk factor that could attenuate anticipated declines in brain volume and episodic memory... [read more]

  • Macrovascular and microvascular cerebral blood flow in adults at risk for Alzheimer’s disease

    Lindsay R. Clark, Sara E. Berman, Leonardo A. Rivera-Rivera, Siobhan M. Hoscheidt, Burcu F. Darst, Corinne D. Engelman, Howard A. Rowley, Cynthia M. Carlsson, Sanjay Asthana, Patrick Turski, Oliver Wieben, and Sterling C. Johnson

    Alzheimers Dement (Amst). 2017 Jan 23;7:48-55. doi: 10.1016/j.dadm.2017.01.002. eCollection 2017.


    Introduction Capillary hypoperfusion is reported in asymptomatic adults at-risk for Alzheimer's disease (AD), but the extent that can be explained by reduced flow in intracranial arteries is unknown. Methods One hundred fifty-five asymptomatic adults enriched for AD risk (mean age 61 years) completed arterial spin labeling (pcASL) and 4D-flow MRI sequences. Voxel-wise regression models investigated the relationship between mean flow in bilateral cerebral arteries and capillary perfusion, and tested potential moderators of this relationship. Results Mean arterial blood flow through middle cerebral arteries (MCAs) and internal carotid arteries was positively associated with perfusion in large cortical clusters (p < .05, false discovery rate corrected)... [read more]

  • Pathway-specific polygenic risk scores as predictors of β-amyloid deposition and cognitive function in a sample at increased risk for Alzheimer’s disease

    Darst, B. F., Koscik, R. L., Racine, A. M., Oh, J. M., Krause, R. A., Carlsson, C. M., Zetterberg, H., Blennow, K., Christian, B. T., Bendlin, B. B., Okonkwo, O. C., Hogan, K. J., Hermann, B. P., Sager, M. A., Asthana, S., Johnson, S. C., & Engelman, C. D.

    Journal of Alzheimer’s Disease. 2017;55(2):473-484.


    Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function... [read more]

  • Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease

    Dean DC 3rd, Hurley SA, Kecskemeti SR, O'Grady JP, Canda C, Davenport-Sis NJ, Carlsson CM, Zetterberg H, Blennow K, Asthana S, Sager MA, Johnson SC, Alexander AL, Bendlin BB.

    JAMA Neurol. 2017 Jan 1;74(1):41-49.


    Importance: The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia... [read more]

  • Chronotropic Response and Cognitive Function in a Cohort at Risk for Alzheimer's Disease

    Law LL, Schultz SA, Boots EA, Einerson JA, Dougherty RJ, Oh JM, Korcarz CE, Edwards DF, Koscik RL, Dowling NM, Gallagher CL, Bendlin BB, Carlsson CM, Asthana S, Hermann BP, Sager MA, Johnson SC, Cook DB, Stein JH, Okonkwo OC.

    J Alzheimers Dis. 2017;56(1):351-359.


    The objective of this study was to examine the association of chronotropic response (CR) and heart rate (HR) recovery- two indices of cardiovascular function within the context of a graded exercise test- with cognitive performance in a cognitively healthy, late-middle-aged cohort at risk for Alzheimer's disease (AD). Ninety participants (age = 63.52±5.86 years; 65.6% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study... [read more]


  • Mild Cognitive Impairment in Late Middle Age in the Wisconsin Registry for Alzheimer's Prevention Study: Prevalence and Characteristics Using Robust and Standard Neuropsychological Normative Data

    Clark LR, Koscik RL, Nicholas CR, Okonkwo OC, Engelman CD, Bratzke LC, Hogan KJ, Mueller KD, Bendlin BB, Carlsson CM, Asthana S, Sager MA, Hermann BP, Johnson SC

    Archives of Clinical Neuropsychology. 2016; 31(7):675–688.


    OBJECTIVE: Detecting cognitive decline in presymptomatic Alzheimer's disease (AD) and early mild cognitive impairment (MCI) is challenging, but important for treatments targeting AD-related neurodegeneration. The current study aimed to investigate the utility and performance of internally developed robust norms and standard norms in identifying cognitive impairment in late middle-age (baseline age range = 36-68; M = 54)... [read more]

  • Intraindividual Cognitive Variability in Middle Age Predicts Cognitive Impairment 8-10 Years Later: Results from the Wisconsin Registry for Alzheimer's Prevention

    Koscik RL, Berman SE, Clark LR, Mueller KD, Okonkwo OC, Gleason CE, Hermann BP, Sager MA, Johnson SC.

    J Int Neuropsychol Soc. 2016 Nov;22(10):1016-1025.


    OBJECTIVES: Intraindividual cognitive variability (IICV) has been shown to differentiate between groups with normal cognition, mild cognitive impairment (MCI), and dementia. This study examined whether baseline IICV predicted subsequent mild to moderate cognitive impairment in a cognitively normal baseline sample. METHODS: Participants with 4 waves of cognitive assessment were drawn from the Wisconsin Registry for Alzheimer's Prevention (WRAP; n=684; 53.6(6.6) baseline age; 9.1(1.0) years follow-up; 70% female; 74.6% parental history of Alzheimer's disease)... [read more]

  • Associations between performance on an abbreviated CogState battery, other measures of cognitive function, and biomarkers in people at risk for Alzheimer’s disease

    Racine AM, Clark LR, Berman SE, Koscik RL, Mueller KD, Norton D, Nicholas CR, Blennow K, Zetterberg H, Jedynak B, Bilgel M, Carlsson CM, Christian BT, Asthana S, Johnson SC

    Journal of Alzheimer’s Disease. 2016 Oct 18;54(4):1395-1408.


    It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer’s disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer’s Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics; traditional paper-based neuropsychological tests as well as a composite cognitive impairment index; cognitive impairment status(determined by consensus review); and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein)... [read more]

  • Connected Language in Late Middle-Aged Adults at Risk for Alzheimer's Disease

    Mueller KD, Koscik RL, Turkstra LS, Riedeman SK, LaRue A, Clark LR, Hermann B, Sager MA, Johnson SC

    J Alzheimers Dis. 2016 Oct 18;54(4):1539-1550.


    Connected language is often impaired among people with Alzheimer’s disease (AD), yet little is known about when language difficulties first emerge on the path to a clinical diagnosis. The objective of this study was to determine whether individuals with psychometric (preclinical) evidence of amnestic mild cognitive impairment (pMCI) showed deficits in connected language measures... [read more]

  • Alterations of Myelin Content in Parkinson's Disease: A Cross-Sectional Neuroimaging Study

    Dean DC 3rd, Sojkova J, Hurley S, Kecskemeti S, Okonkwo O, Bendlin BB, Theisen F, Johnson SC, Alexander AL, Gallagher CL.

    PLoS One. 2016 Oct 5;11(10):e0163774.


    Alterations to myelin may be a core pathological feature of neurodegenerative diseases. Although white matter microstructural differences have been described in Parkinson's disease (PD), it is unknown whether such differences include alterations of the brain's myelin content... [read more]

  • 4D flow MRI for intracranial hemodynamics assessment in Alzheimer's disease

    Rivera-Rivera LA, Turski P, Johnson KM, Hoffman C, Berman SE, Kilgas P, Rowley HA, Carlsson CM, Johnson SC, Wieben O.

    Journal of Cerebral Blood Flow and Metabolism. 2016 Oct;36(10):1718-1730. Epub 2015 Nov 25.


    Cerebral blood flow, arterial pulsation, and vasomotion play important roles in the transport of waste metabolites out of the brain. Impaired vasomotion results in reduced driving force for the perivascular/glymphatic clearance of beta-amyloid... [read more]

  • Reliability of a Novel Social Activity Questionnaire

    Zuelsdorff ML, Koscik RL, Okonkwo OC, Peppard PE, Hermann BP, Sager MA, Johnson SC, Engelman CD

    Journal of Aging and Health. 2016 Oct 1:898264316674812. [Epub ahead of print]


    OBJECTIVE: Social activity is associated with healthy aging and preserved cognition. Such activity includes a confluence of social support and verbal interaction, each influencing cognition through rarely parsed, mechanistically distinct pathways... [read more]

  • Biomarker clusters are differentially associated with longitudinal cognitive decline in late midlife

    Annie M. Racine, Rebecca L. Koscik, Sara E. Berman, Christopher R. Nicholas, Lindsay R. Clark, Ozioma C. Okonkwo, Howard A. Rowley, Sanjay Asthana, Barbara B. Bendlin, Kaj Blennow, Henrik Zetterberg, Carey E. Gleason, Cynthia M. Carlsson, Sterling C. Johnson

    Brain. 2016 Aug;139(Pt 8):2261-74. Epub 2016 Jun 20.


    The ability to detect preclinical Alzheimer’s disease is of great importance, as this stage of the Alzheimer’s continuum is believed to provide a key window for intervention and prevention. As Alzheimer’s disease is characterized by multiple pathological changes, a biomarker panel reflecting co-occurring pathology will likely be most useful for early detection... [read more]

  • Beta-amyloid and cognitive decline in late middle age: Findings from the WRAP study

    Clark, L. R., Racine, A. M., Koscik, R., Okonkwo, O. C., Engelman, C. D., Carlsson, C. M., Asthana, S., Bendlin, B. B., Chappell, R. J., Nicholas, C. R., Rowley, H. A., Oh, J., Hermann, B., Sager, M. A., Christian, B., & Johnson, S. C.

    Alzheimers Dement. 2016 Jul;12(7):805-14.


    INTRODUCTION: The current study investigated the relationship between beta-amyloid (Aβ) and cognition in a longitudinal cohort of late middle-aged participants enriched for Alzheimer’s disease (AD) risk due to parental history of the disease. METHODS: 184 participants (mean age=60; 72% with a parental history of AD) completed a [C-11]PiB positron emission tomography scan and serial cognitive evaluations... [read more]

  • Age-dependent differences in brain tissue microstructure assessed with neurite orientation dispersion and density imaging

    Merluzzi AP, Dean DC 3rd, Adluru N, Suryawanshi GS, Okonkwo OC, Oh JM, Hermann BP, Sager MA, Asthana S, Zhang H, Johnson SC, Alexander AL, Bendlin BB).

    Neurobiol Aging. 2016 Jul;43:79-88.


    Human aging is accompanied by progressive changes in executive function and memory, but the biological mechanisms underlying these phenomena are not fully understood. Using neurite orientation dispersion and density imaging, we sought to examine the relationship between age, cellular microstructure, and neuropsychological scores in 116 late middle-aged, cognitively asymptomatic participants... [read more]

  • Long-term Variability in Glycemic Control Is Associated With White Matter Hyperintensities in APOE4 Genotype Carriers With Type 2 Diabetes

    Livny, A., Ravona-Springer, R., Heymann, A., Priess, R., Kushnir, T., Tsarfaty, G., Rabinov, L., Moran, R., Hoffman, H., Cooper, I., Greenbaum, L., Silverman, J., Sano, M., Johnson, S. C., Bendlin, B. B., & Schnaider Beeri, M.

    Diabetes Care. 2016 Jun;39(6):1056-9. doi: 10.2337/dc15-2331. Epub 2016 Apr 8.


    OBJECTIVE: We assessed whether the apolipoprotein ε4 (APOE4) genotype affects the relationship of variability in long-term glycemic control (measured by HbA1c SD of multiple measurements) with white matter hyperintensities (WMHs) in elderly patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: WMH volume was generated from structural T1 and fluid-attenuated inversion recovery MRI in each subject. The analysis included 124 subjects; 27 (21.8%) had one or more APOE4 alleles. RESULTS: HbA1c variability was associated with significantly higher WMH in APOE4 carriers (r = 0.47, P = 0.03), controlling for age, sex, mean HbA1c, number of follow-up years, and a composite of cardiovascular risk factors, but not in noncarriers (r = -0.04, P = 0.71; P for interaction = 0.050). CONCLUSIONS: The results suggest that the APOE4 genotype affects the relationship of long-term glycemic control with WMH load so that APOE4 carriers may be more vulnerable to the insults of poor control.... [read more]

  • Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults

    Hoscheidt, S. M., Starks, E. J., Oh, J. M., Zetterberg, H., Blennow, K., Krause, R. A., Gleason, C. E., Puglielli, L., Atwood, C. S., Carlsson, C. M., Asthana, S., Johnson, S. C., & Bendlin, B. B.

    J Alzheimers Dis. 2016 Apr 12;52(4):1373-83.


    Background: Type 2 diabetes is associated with an increased risk for Alzheimer’s disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD... [read more]

  • Meeting physical activity recommendations may be protective against temporal lobe atrophy in older adults at risk for Alzheimer's disease

    Dougherty RJ, Ellingson LD, Schultz SA, Boots EA, Meyer JD, Lindheimer JB, Van Riper S, Stegner AJ, Edwards D, Oh JM, Koscik RL, Dowling MN, Gallagher CL, Carlsson CM, Rowley HA, Bendlin BB, Asthana S, Hermann BP, Sager MA, Johnson SC, Okonkwo OC, Cook DB

    Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring (Amst). 2016 Apr 9;4:14-7.


    INTRODUCTION: Physical activity (PA) is associated with brain health in older adults. However, it is unknown whether the current physical activity recommendations (PAR) impart substantive benefit... [read more]

  • The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B

    Lao PJ, Betthauser TJ, Hillmer AT, Price JC, Klunk WE, Mihaila I, Higgins AT, Bulova PD, Hartley SL, Hardison R, Tumuluru RV, Murali D, Mathis CA, Cohen AD, Barnhart TE, Devenny DA, Mailick MR, Johnson SC, Handen BL, Christian BT

    Alzheimers Dement. 2016 Apr;12(4):380-90. Epub 2015 Jun 13.


    INTRODUCTION: In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology. METHODS: PET imaging with carbon 11-labeled Pittsburgh compound B examined the pattern of amyloid-B deposition in 68 nondemented adults with DS (30-53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellar gray matter as the reference region. RESULTS: Multiple linear regression revealed slight but highly significant (corrected P < .05) positive correlations between SUVR and age... [read more]

  • Fornix microstructure and memory performance is associated with altered neural connectivity during episodic recognition

    Ly M, Adluru N, Destiche DJ, Lu SY, Oh JM, Hoscheidt SM, Alexander AL, Okonkwo OC, Rowley HA, Sager MA, Johnson SC, Bendlin BB

    Journal of the International Neuropsychological Society. 2016 Feb;22(2):191-204.


    The purpose of this study was to assess whether age-related differences in white matter microstructure are associated with altered task-related connectivity during episodic recognition.Using functional magnetic resonance imaging and diffusion tensor imaging from 282 cognitively healthy middle-to-late aged adults enrolled in the Wisconsin Registry for Alzheimer's Prevention, we investigated whether fractional anisotropy (FA) within white matter regions known to decline with age was associated with task-related connectivity within the recognition network.There was a positive relationship between fornix FA and memory performance, both of which negatively correlated with age. Psychophysiological interaction analyses revealed that higher fornix FA was associated with increased task-related connectivity amongst the hippocampus, caudate, precuneus, middle occipital gyrus, and middle frontal gyrus... [read more]

  • Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction

    Martin SA, DeMuth TM, Miller KN, Pugh TD, Polewski MA, Colman RJ, Eliceiri KW, Beasley TM, Johnson SC, Anderson RM

    Aging Cell. 2016 Feb 1;15(1):100-10.


    The hippocampus is critical for cognition and memory formation and is vulnerable to age-related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging... [read more]

  • Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease

    Melah KE, Lu SY, Hoscheidt SM, Alexander AL, Adluru N, Destiche DJ, Carlsson CM, Zetterberg H, Blennow K, Okonkwo OC, Gleason CE, Dowling NM, Bratzke LC, Rowley HA, Sager MA, Asthana S, Johnson SC, Bendlin BB

    Journal of Alzheimer's Disease. 2016;50(3):873-86.


    BACKGROUND: The immune response in Alzheimer's disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD... [read more]

  • Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation

    Racine AM, Koscik RL, Nicholas CR, Clark LR, Okonkwo OC, Oh JM, Hillmer AT, Murali D, Barnhart TE, Betthauser TJ, Gallagher CL, Rowley HA, Dowling NM, Asthana S, Bendlin BB, Blennow K, Zetterberg H, Carlsson CM, Christian BT, Johnson SC

    Alzheimers Dement (Amst). 2016;2:27-38.


    INTRODUCTION: Biomarkers are urgently needed for the critical yet understudied preclinical stage of Alzheimer's disease (AD). METHODS: CSF collection, [C-11]PiB amyloid imaging, and MRI were acquired in n=104 cognitively healthy adults enriched with risk for sporadic AD... [read more]

  • Changes in intracranial venous blood flow and pulsatility in Alzheimer's disease: A 4D flow MRI study

    Rivera-Rivera LA, Schubert T, Turski P, Johnson KM, Berman SE, Rowley HA, Carlsson CM, Johnson SC, Wieben O

    J Cereb Blood Flow Metab. 2016 Jan 1:271678X16661340. [Epub ahead of print]


    Cerebral blood flow, arterial pulsation, and vasomotion may be important indicators of cerebrovascular health in aging and diseases of aging such as Alzheimer's disease. Noninvasive markers that assess these characteristics may be helpful in the study of co-occurrence of these diseases and potential additive and interacting effects... [read more]


  • Age-Related Changes in Inter-Network Connectivity by Component Analysis

    La C, Mossahebi P, Nair VA, Bendlin BB, Birn R, Meyerand ME, Prabhakaran V

    Frontiers in Aging Neuroscience. 2015 Dec 24;7:237.


    Healthy aging is associated with brain changes that reflect an alteration to a functional unit in response to the available resources and architecture. Even before the onset of noticeable cognitive decline, the neural scaffolds underlying cognitive function undergo considerable change... [read more]

  • Participation in cognitively-stimulating activities is associated with brain structure and cognitive function in preclinical Alzheimer's disease

    Stephanie A. Schultz, Jordan Larson, Jennifer Oh, Rebecca Koscik, Maritza N. Dowling, Catherine L. Gallagher, Cynthia M. Carlsson, Howard A. Rowley, Barbara B. Bendlin, Sanjay Asthana, Bruce P. Hermann, Sterling C. Johnson, Mark Sager, Asenath LaRue, Ozioma C. Okonkwo

    Brain Imaging and Behavior. 2015 Dec;9(4):729-36.


    This study tested the hypothesis that frequent participation in cognitively-stimulating activities, specifically those related to playing games and puzzles, is beneficial to brain health and cognition among middle-aged adults at increased risk for Alzheimer’s disease (AD). Three hundred twenty-nine cognitively normal, middle-aged adults (age range, 43.2-73.8 years) enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) participated in this study... [read more]

  • Posteromedial hyperactivation during episodic recognition among people with memory decline: findings from the WRAP study

    Nicholas CR, Okonkwo OC, Bendlin BB, Oh JM, Asthana S, Rowley HA, Hermann B, Sager MA, Johnson SC.

    Brain Imaging and Behavior. 2015 Dec;9(4):690-702


    Episodic memory is one of the earliest preclinical symptoms of AD, and has been associated with an upregulation in the BOLD response in the prodromal stage (e.g. MCI) of AD... [read more]

  • Imaging based enrichment criteria using deep learning algorithms for efficient clinical trials in MCI

    Ithapu VK, Singh V, Okonkwo OC, Chappell RJ, Dowling NM, Johnson SC, for the Alzheimer’s Disease Neuroimaging Initiative

    Alzheimer’s and Dementia. 2015 Dec;11(12):1489-99. Epub 2015 Jun 18.


    The mild cognitive impairment (MCI) stage of Alzheimer's disease (AD) may be optimal for clinical trials to test potential treatments for preventing or delaying decline to dementia. However, MCI is heterogeneous in that not all cases progress to dementia within the time frame of a trial and some may not have underlying AD pathology... [read more]

  • Anterior cingulate dopamine turnover and behavior change in Parkinson's disease

    Gallagher, CL, Bell B, Palotti M, Oh J, Christian BT, Okonkwo OC, Sjokova J, Buyan-Dent L, Nickles R, Harding S, Stone C, Johnson SC, Holden J

    Brain Imaging and Behavior. 2015 Dec;9(4):821-7.


    Subtle cognitive and behavioral changes are common in early Parkinson's disease. The cause of these symptoms is probably multifactorial but may in part be related to extra-striatal dopamine levels... [read more]

  • Intracranial Arterial 4D-Flow is Associated with Metrics of Brain Health and Alzheimer’s Disease

    Berman SE, Rivera-Rivera LA, Clark LR, Racine AM, Keevil JG, Bratzke LC, Carlsson CM, Bendlin BB, Rowley HA, Blennow K, Zetterberg H, Asthana S, Turski P, Johnson SC, Wieben O.

    Alzheimer's disease, Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2015 Dec 1; 1(4):420-428.


    INTRODUCTION: While cerebrovascular disease has long been known to co-occur with Alzheimer's disease (AD), recent studies suggest an etiologic contribution to AD pathogenesis. We used 4D-Flow magnetic resonance imaging (MRI) to evaluate blood flow and pulsatility indices in the Circle of Willis... [read more]

  • Occupational complexity and cognitive reserve in a middle-aged cohort at risk for Alzheimer's disease

    Elizabeth A. Boots, Stephanie A. Schultz, Rodrigo P. Almeida, Jennifer M. Oh, Rebecca L. Koscik, Maritza N. Dowling, Catherine L. Gallagher, Cynthia M. Carlsson, Howard A. Rowley, Barbara B. Bendlin, Sanjay Asthana, Mark A. Sager, Bruce P. Hermann, Sterling C. Johnson, Ozioma C. Okonkwo

    Archives of Clinical Neuropsychology. 2015 Nov;30(7):634-42. Epub 2015 Jul 8.


    Higher occupational attainment has previously been associated with increased Alzheimer’s disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole brain atrophy given comparable cognitive function in middle-aged adults at risk for AD... [read more]

  • Cardiorespiratory fitness attenuates the influence of amyloid on cognition

    Stephanie A. Schultz, Elizabeth A. Boots, Rodrigo P. Almeida, Jennifer M. Oh, Jean Einerson, Claudia E. Korcarz, Dorothy F. Edwards, Rebecca L. Koscik, Maritza N. Dowling, Catherine L. Gallagher, Barbara B. Bendlin, Bradley T. Christian, Henrik Zetterberg, Kaj Blennow, Cynthia M. Carlsson, Sanjay Asthana, Bruce P. Hermann, Mark A. Sager, Sterling C. Johnson, James H. Stein, Ozioma C. Okonkwo Schultz, S. A., Boots, E. A., Almeida, R. P., Oh, J. M., Einerson, J., Korcarz, C. E., … Okonkwo, O. C. (2015). Card

    Journal of the International Neuropsychological Society. 2015 Nov; 21(10):841-50.


    Objective: To examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer’s disease (AD). Methods: Sixty-nine enrollees in the Wisconsin Registry for Alzheimer’s Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion... [read more]

  • Amyloid Burden Is Associated With Self-Reported Sleep In Non-Demented Late Middle-Aged Adults

    Sprecher KE, Bendlin BB, Racine AM, Okonkwo OC, Christian BT, Koscik RL, Sager MA, Asthana S, Johnson SC, Benca RM

    Neurobiology of Aging. 2015 Sep;36(9):2568-76. Epub 2015 May 14.


    Midlife may be an ideal window for intervention in Alzheimer's disease (AD). To determine whether sleep is associated with early signs of AD neuropathology (amyloid deposition) in late midlife, we imaged brain amyloid deposits using positron emission tomography with [C-11]Pittsburgh Compound B (PiB), and assessed sleep with the Epworth Sleepiness Scale and the Medical Outcomes Study Sleep Scale in 98 cognitively healthy adults (aged 62.4 ± 5.7 years) from the Wisconsin Registry for Alzheimer's Prevention... [read more]

  • Multi-resolution Statistical Analysis of Brain Connectivity Graphs in Preclinical Alzheimer's Disease

    Kim WH, Adluru N, Chung MK, Okonkwo OC, Johnson SC, Bendlin BB, Singh V

    Neuroimage. 2015 Sep;118:103-17. Epub 2015 May 27.


    There is significant interest, both from basic and applied research perspectives, in understanding how structural/functional connectivity changes can explain behavioral symptoms and predict decline in neurodegenerative diseases such as Alzheimer's disease (AD). The first step in most such analyses is to encode the connectivity information as a graph; then, one may perform statistical inference on various 'global' graph theoretic summary measures (e.g., modularity, graph diameter) and/or at the level of individual edges (or connections)... [read more]

  • Cardiorespiratory fitness is associated with brain structure, cognition, and mood in a middle-aged cohort at risk for Alzheimer's disease

    Elizabeth A. Boots, Stephanie A. Schultz, Jennifer M. Oh, Jordan Larson, Dorothy Edwards, Dane Cook, Rebecca L. Koscik, Maritza N. Dowling, Catherine L. Gallagher, Cynthia M. Carlsson, Howard A. Rowley, Barbara B. Bendlin, Asenath LaRue, Sanjay Asthana, Bruce P. Hermann, Mark A. Sager, Sterling C. Johnson, Ozioma C. Okonkwo

    Brain Imaging and Behavior. 2015 Sep;9(3):639-49.


    Cardiorespiratory fitness (CRF) is an objective measure of habitual physical activity (PA), and has been linked to increased brain structure and cognition. The gold standard method for measuring CRF is graded exercise testing (GXT), but GXT is not feasible in many settings... [read more]

  • Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle-Aged Adults at Risk for Alzheimer Disease

    Willette AA, Bendlin BB, Starks EJ, Birdsill AC, Johnson SC, Christian BT, Okonkwo OC, La Rue A, Hermann BP, Koscik RL, Jonaitis EM, Sager MA, Asthana S

    JAMA Neurology; 2015 Sep 1;72(9):1013-20, In Press


    IMPORTANCE: Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET). OBJECTIVES: To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study, a general community sample enriched for AD parental history... [read more]

  • Verbal Fluency and Early Memory Decline: Results from the Wisconsin Registry for Alzheimer’s Prevention

    Mueller KD, Koscik RL, LaRue A, Clark LR, Hermann BP, Johnson SC, Sager MA

    Archives of Clinical Neuropsychology. 2015 Aug;30(5):448-57. Epub 2015 May 29.


    This study examined the relationship between phonemic and semantic (category) verbal fluency and cognitive status in the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal cohort enriched for family history of Alzheimer's disease. Participants were 283 WRAP subjects (age 53.1[6.5] years at baseline); who had completed three waves of assessment, over ~6 years and met psychometric criteria either for "cognitively healthy" (CH) or for psychometric amnestic mild cognitive impairment (aMCI) using an approach that did not consider fluency scores... [read more]

  • The relationship between carotid artery plaque stability and white matter ischemic injury

    Berman SE, Wang X, Mitchell CC, Kundu B, Jackson DC, Wilbrand SM, Varghese T, Hermann BP, Rowley HA, Johnson SC, Dempsey RJ

    NeuroImage: Clinical. 2015 Aug 22;9:216-22.


    Higher local carotid artery strain has previously been shown to be a characteristic of unstable carotid plaques. These plaques may be characterized by microvascular changes that predispose to intraplaque hemorrhage, increasing the likelihood of embolization... [read more]

  • Statistical Inference Models for Image Datasets with Systematic Variations

    Won Hwa Kim, Barbara B. Bendlin, Moo K. Chung, Sterling C. Johnson, Vikas Singh

    The IEEE Conference on Computer Vision and Pattern Recognition (CVPR), 2015, pp. 4795-4803


    Statistical analysis of longitudinal or cross sectionalbrain imaging data to identify effects of neurodegenerative diseases is a fundamental task in various studies in neuroscience. However, when there are systematic variations in the images due to parameters changes such as changes in the scanner protocol, hardware changes, or when combining data from multi-site studies, the statistical analysis becomes problematic... [read more]

  • Amyloid burden, cortical thickness, and cognitive function in the Wisconsin Registry for Alzheimer’s Prevention

    Benjamin M. Doherty, Stephanie A. Schultz, Jennifer M. Oh, Rebecca L. Koscik, N. Maritza Dowling, Todd E. Barnhart, Dhanabalan Murali, Catherine L. Gallagher, Cynthia M. Carlsson, Barbara B. Bendlin, Asenath LaRue, Bruce P. Hermann, Howard A. Rowley, Sanjay Asthana, Mark A. Sager, Brad T. Christian, Sterling C. Johnson, Ozioma C. Okonkwo

    Alzheimer's & Dementia: DADM. 2015 Jun 1;1(2):160-169.


    There is a growing interest in understanding how amyloid-β (Aβ) accumulation in preclinical Alzheimer’s disease relates to brain morphometric measures and cognition. Existing investigations in this area have been primarily conducted in older cognitively-normal (CN) individuals... [read more]

  • Effect of Cognitive Reserve on Age-Related Changes in Cerebrospinal Fluid Biomarkers of Alzheimer Disease

    Rodrigo P. Almeida, Stephanie A. Schultz, Benjamin P. Austin, Elizabeth A. Boots, N. Maritza Dowling, Carey E. Gleason, Barbara B. Bendlin, Mark Sager, Bruce P. Hermann, Henrik Zetterberg, Cindy Carlsson, Sterling Johnson, Sanjay Asthana, Ozioma C. Okonkwo

    JAMA Neurology. 2015 Jun;72(6):699-706.


    Importance: Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer’s disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology. Objective: In this study, we investigated whether cognitive reserve modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD. Design, Setting, and Participants: Cross-sectional cohort of 268 individuals (211 cognitively normal and 57 cognitively impaired) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed... [read more]

  • On Statistical Analysis of Neuroimages with Imperfect Registration

    Won Hwa Kim, Sathya N. Ravi, Sterling C. Johnson, Ozioma C. Okonkwo, Vikas Singh

    The IEEE International Conference on Computer Vision (ICCV), 2015, pp. 666-674


    A variety of studies in neuroscience/neuroimaging seek to perform statistical inference on the acquired brain image scans for diagnosis as well as understanding the pathological manifestation of diseases. To do so, an important first step is to register (or co-register) all of the image data into a common coordinate system... [read more]

  • A Projection free method for Generalized Eigenvalue Problem with a nonsmooth Regularizer

    Seong Jae Hwang, Maxwell D. Collins, Sathya N. Ravi, Vamsi K. Ithapu, Nagesh Adluru, Sterling C. Johnson, Vikas Singh

    The IEEE International Conference on Computer Vision (ICCV), 2015, pp. 1841-1849


    Eigenvalue problems are ubiquitous in computer vision, covering a very broad spectrum of applications ranging from estimation problems in multi-view geometry to image segmentation. Few other linear algebra problems have a more mature set of numerical routines available and many computer vision libraries leverage such tools extensively... [read more]

  • Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOE ε4 Carriers

    Starks EJ, O’Grady JP, Hoscheidt SM, Racine AM, Carlsson CC, Zetterberg H, Blennow K, Okonkwo OC, Puglielli L, Asthana S, Dowling NM, Gleason CE, Anderson R, Davenport-Sis NJ, DeRungs LM, Sager MA, Johnson SC, Bendlin BB

    Journal of Alzheimer’s Disease. 2015 May 30;46(2):525-33.


    Background: Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer’s disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear.Objective: To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age.Method: Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Aβ 42, P-Tau181, and T-Tau... [read more]

  • Aging, practice effects, and genetic risk in the Wisconsin Registry for Alzheimer’s Prevention

    Jonaitis EM, Koscik RL, La Rue A, Johnson SC, Hermann BP, Sager MA

    Clin Neuropsychol. 2015 May;29(4):426-41 Epub 2015 May 27.


    BACKGROUND: In the last five years, a consensus has developed that Alzheimer's disease (AD) may begin years before overt cognitive impairment. Accordingly, the focus has shifted to identifying preclinical disease in order to match treatments to those most likely to benefit... [read more]

  • Insulin resistance predicts brain amyloid deposition in late middle-aged adults

    Willette AA, Johnson SC, Birdsill AC, Sager MA, Christian B, Baker LD, Craft S, Oh J, Statz E, Hermann BP, Jonaitis EM, Koscik RL, La Rue A, Asthana S, Bendlin BB

    Alzheimers Dement. 2015 May;11(5):504-510.e1. Epub 2014 Jul 17.


    BACKGROUND: Insulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD... [read more]

  • Multi-resolution statistical analysis on graph structured data in Neuroimaging

    Won Hwa Kim, Vikas Singh, Moo K. Chung, Nagesh Adluru, Barbara B. Bendlin, Sterling C. Johnson

    Biomedical Imaging (ISBI), 2015 IEEE 12th International Symposium on , pp.1548-1551, 16-19 April 2015


    Statistical data analysis plays a major role in discovering structural and functional imaging phenotypes for mental disorders such as Alzheimer's disease (AD). The goal here is to identify, ideally early on, which regions in the brain show abnormal variations with a disorder... [read more]

  • Heritability of Cognitive Traits Among Siblings with a Parental History of Alzheimer’s Disease

    Darst BF, Koscik, RL, Hermann BP, La Rue A, Sager MA, Johnson SC, Engelman CD

    Journal of Alzheimer’s Disease, 2015;45(4):1149-55


    Cognitive decline is one of the hallmark features of Alzheimer's disease, but many studies struggle to find strong associations between cognitive function and genetic variants. In order to identify which aspects of cognition are more likely to have a strong genetic component, we assessed the heritability of various cognitive functions related to Alzheimer's disease in 303 initially asymptomatic middle-aged adult siblings with a parental history of Alzheimer's disease from the Wisconsin Registry for Alzheimer's Prevention... [read more]

  • Subjective memory complaints, cortical thinning, and cognitive dysfunction in middle-aged adults at risk for AD

    Stephanie A. Schultz, Jennifer Oh, Rebecca Koscik, Maritza N. Dowling, Catherine L. Gallagher, Cynthia M. Carlsson, Barbara B. Bendlin, Asenath LaRue, Bruce P. Hermann, Howard A. Rowley, Sanjay Asthana, Mark Sager, Sterling C. Johnson, Ozioma C. Okonkwo

    Alzheimer's & Dementia: DADM. 2015 Mar;1(1):33-40.


    Background: Subjective memory complaints (SMCs) represent an individual’s perception of subtle changes in memory in the absence of objective impairment in memory. However, it is not fully known whether persons with SMCs harbor brain alterations related to Alzheimer’s disease (AD) or whether they indeed demonstrate poorer cognitive performance. Methods: Participants were 261 middle-aged adults (mean age=54.30 years) enrolled in the Wisconsin Registry for Alzheimer’s Prevention, a registry of cognitively normal adults at risk for AD... [read more]

  • Understanding Dysphagia in Dementia: The Present and the Future

    Rogus-Pulia N, Malandraki GA, Johnson SC, Robbins JA

    Current Physical Medicine and Rehabilitation Reports. March 2015, Volume 3, Issue 1, pp 86-97


    Dysphagia is common in patients with dementia of varying types and often results in serious health consequences, including malnutrition, dehydration, aspiration pneumonia, and even death. Due to progressive cognitive and functional decline, patients with dementia experience difficulties throughout the eating process which encompasses all aspects of self-feeding and swallowing function... [read more]

  • The mediational effects of FDG hypometabolism on the association between cerebrospinal fluid biomarkers and neurocognitive function

    Dowling NM, Johnson SC, Gleason CE, Jagust WJ; Alzheimer's Disease Neuroimaging Initiative.

    Neuroimage. 2015 Jan 15;105:357-68. Epub 2014 Oct 29.


    Positive cerebrospinal fluid (CSF) biomarkers of tau and amyloid beta42 suggest possible active underlying Alzheimer's disease (AD) including neurometabolic dysfunction and neurodegeneration leading to eventual cognitive decline. But the temporal relationship between CSF, imaging markers of neural function, and cognition has not been described... [read more]

  • A 4D hyperspherical interpretation of q-space

    Pasha Hosseinbor A, Chung MK, Wu YC, Bendlin BB, Alexander AL

    Med Image Anal. 2015 Apr;21(1):15-28


    3D q-space can be viewed as the surface of a 4D hypersphere. In this paper, we seek to develop a 4D hyperspherical interpretation of q-space by projecting it onto a hypersphere and subsequently modeling the q-space signal via 4D hyperspherical harmonics (HSH)... [read more]


  • First-in-Human Evaluation of 18F-Mefway, a PET Radioligand Specific to Serotonin-1A Receptors

    Hillmer AT, Wooten DW, Bajwa AK, Higgins AT, Lao PJ, Betthauser TJ, Barnhart TE, Rowley HA, Stone CK, Johnson SC, Mukherjee J, Christian BT

    Journal of Nuclear Medicine. 2014 Dec;55(12):1973-9.


    The serotonin-1A (5-HT1A) receptor is implicated in an array of neurological and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system... [read more]

  • Canonical Correlation Analysis on Riemannian Manifolds and Its Applications

    Kim HJ, Adluru N, Bendlin BB, Johnson SC, Vemuri BC, Singh V.

    Comput Vis ECCV. 2014; 8690:251-267


    Canonical correlation analysis (CCA) is a widely used statistical technique to capture correlations between two sets of multi-variate random variables and has found a multitude of applications in computer vision, medical imaging and machine learning. The classical formulation assumes that the data live in a pair of vector spaces which makes its use in certain important scientific domains problematic... [read more]

  • Physical Activity Attenuates Age-Related Biomarker Alterations in Preclinical AD

    Ozioma Okonkwo, Stephanie Schultz, Jennifer Oh, Jordan Larson, Dorothy Edwards, Dane Cook, Rebecca Koscik, Catherine L. Gallagher, N. Maritza Dowling, Cynthia Carlsson, Barbara Bendlin, Asenath LaRue, Howard Rowley, Brad Christian, Sanjay Asthana, Bruce Hermann, Sterling Johnson, and Mark Sager

    Neurology. 2014 Nov 4;83(19):1753-60.


    Objective: To examine whether engagement in physical activity might favorably alter the age-dependent evolution of Alzheimer’s disease (AD)-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults. Methods: Three hundred and seventeen enrollees in the Wisconsin Registry for Alzheimer’s Prevention underwent T1 MRI; a subset also underwent PiB-PET (n=186) and FDG-PET (n=152) imaging. Participants’ responses on a self-report measure of current physical activity were used to classify them as either Physically Active or Physically Inactive based on American Heart Association guidelines... [read more]

  • At the crossroads of preclinical AD and normal brain ageing

    Okonkwo, O. C.

    Lancet Neurol. 2014 Oct;13(10):965-6. Epub 2014 Sep 4.


    ... [read more]

  • Cognitive functioning in relation to brain amyloid-β in healthy adults with Down syndrome

    Hartley SL, Handen BL, Devenny DA, Hardison R, Mihaila I, Price JC, Cohen AD, Klunk WE, Mailick MR, Johnson SC, Christian BT.

    Brain. 2014 Sep;137(Pt 9):2556-63. Epub 2014 Jul 2.


    Nearly all adults with Down syndrome show neuropathology of Alzheimer’s disease, including amyloid-β deposition, by their fifth decade of life. In the current study, we examined the association between brain amyloid-β deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30–53 years who did not exhibit symptoms of dementia... [read more]

  • Extracting and summarizing white matter hyperintensities using supervised segmentation methods in Alzheimer’s disease risk and aging studies

    Vamsi Ithapu, Vikas Singh, Christopher Lindner, Benjamin P. Austin, Chris Hinrichs, Cynthia M. Carlsson, Barbara B. Bendlin and Sterling C. Johnson

    Human Brain Mapping. 2014 Aug;35(8):4219-35. Epub 2014 Feb 7.


    Precise detection and quanti cation of white matter hyperintensities (WMH) observed in T2-weighted Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) is of substantial interest in aging, and age related neurological disorders such as Alzheimer's disease (AD). This is mainly because WMH may reflect comorbid neural injury or cerebral vascular disease burden... [read more]

  • A dual-tracer study of extrastriatal 6-[18F]fluoro-m-tyrosine and 6-[18F]-fluoro-L-dopa uptake in Parkinson's disease

    Li CT, Palotti M, Holden JE, Oh J, Okonkwo O, Christian BT, Bendlin BB, Buyan-Dent L, Harding SJ, Stone CK, DeJesus OT, Nickles RJ, Gallagher CL.

    Synapse. 2014 Aug;68(8):325-31. Epub 2014 Apr 22.


    6-[(18)F]-Fluoro-L-dopa (FDOPA) has been widely used as a biomarker for catecholamine synthesis, storage, and metabolism--its intense uptake in the striatum, and fainter uptake in other brain regions, is correlated with the symptoms and pathophysiology of Parkinson's disease (PD). 6-[(18)F]fluoro-m-tyrosine (FMT), which also targets L-amino acid decarboxylase, has potential advantages over FDOPA as a radiotracer because it does not form catechol-O-methyltransferase (COMT) metabolites. The purpose of the present study was to compare the regional distribution of these radiotracers in the brains of PD patients... [read more]

  • Multivariate General Linear Models (MGLM) on Riemannian Manifolds with Applications to Statistical Analysis of Diffusion Weighted Images

    Kim HJ, Adluru N, Collins MD, Chung MK, Bendlin BB, Johnson SC, Davidson RJ, Singh V

    Proc IEEE Comput Soc Conf Comput Vis Pattern Recognit. 2014 Jun 23;2014:2705-2712


    Linear regression is a parametric model which is ubiquitous in scientific analysis. The classical setup where the observations and responses, i.e., (xi , yi ) pairs, are Euclidean is well studied... [read more]

  • Diffeomorphic metric mapping and probabilistic atlas generation of hybrid diffusion imaging based on BFOR signal basis

    Du J, Hosseinbor AP, Chung MK, Bendlin BB, Suryawanshi G, Alexander AL, Qiu A.

    Med Image Anal. 2014 Oct;18(7):1002-14


    We first propose a large deformation diffeomorphic metric mapping algorithm to align multiple b-value diffusion weighted imaging (mDWI) data, specifically acquired via hybrid diffusion imaging (HYDI). We denote this algorithm as LDDMM-HYDI... [read more]

  • Multi-resolutional Shape Features via Non-Euclidean Wavelets: Applications to Statistical Analysis of Cortical Thickness

    Kim WH, Singh V, Chung MK, Hinrichs C, Pachauri D, Okonkwo OC, Johnson SC; Alzheimer's Disease Neuroimaging Initiative.

    Neuroimage. 2014 Jun;93 Pt 1:107-23. Epub 2014 Mar 12.


    Statistical analysis on arbitrary surface meshes such as the cortical surface is an important approach to understanding brain diseases such as Alzheimer's disease (AD). Surface analysis may be able to identify specifi c cortical patterns that relate to certain disease characteristics or exhibit di fferences between groups... [read more]

  • Cerebrospinal fluid sphingolipids, β-amyloid, and tau in adults at risk for Alzheimer's disease

    Mielke MM, Haughey NJ, Bandaru VV, Zetterberg H, Blennow K, Andreasson U, Johnson SC, Gleason CE, Blazel HM, Puglielli L, Sager MA, Asthana S, Carlsson CM

    Neurobiol Aging. 2014 Nov;35(11):2486-94. Epub 2014 May 27.


    Cellular studies suggest sphingolipids may cause or accelerate amyloid-beta (Aβ) and tau pathology but in vivo human studies are lacking. We determined cerebrospinal fluid levels of sphingolipids (ceramides and sphingomyelins), amyloid-beta (Aβ1-42, AβX-38, AβX-40, and AβX-42) and tau (T-tau and p-tau181) in 91 cognitively normal individuals, aged 36-69 years, with a parental history of Alzheimer's disease... [read more]

  • Effect of age and calorie restriction on corpus callosal integrity in rhesus macaques: A fiber tractography study

    Sridharan A, Bendlin BB, Gallagher CL, Oh JM, Willette AA, Alexander AL, Kemnitz JW, Colman RJ, Weindruch RH, Johnson SC

    Neuroscience Letters. 2014 May 21;569:38-42.


    The rhesus macaque exhibits age-related brain changes similar to humans, making an excellent model of normal aging. Calorie restriction is a dietary intervention that reduces age-related comorbidities in short-lived animals, and its effects are still under study in rhesus macaques... [read more]

  • Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer.

    Peng Y, Li M, Clarkson BD, Pehar M, Lao PJ, Hillmer AT, Barnhart TE, Christian BT, Mitchell HA, Bendlin BB, Sandor M, Puglielli L.

    The Journal of Neuroscience


    The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N(ε)-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia... [read more]

  • Midlife measurements of white matter microstructure predict subsequent regional white matter atrophy in healthy adults

    Ly M, Canu E, Xu G, McLaren DG, Oh JM, Dowling NM, Alexander AL, Sager MA, Johnson SC, Bendlin BB

    Human Brain Mapping. 2014 May;35(5):2044-54.


    OBJECTIVES: Although age-related brain changes are becoming better understood, midlife patterns of change are still in need of characterization, and longitudinal studies are lacking. The aim of this study was to determine if baseline fractional anisotropy (FA), obtained from diffusion tensor imaging (DTI) predicts volume change over a 4-year interval. EXPERIMENTAL DESIGN: Forty-four cognitively healthy middle-age adults underwent baseline DTI and longitudinal T1-weighted magnetic resonance imaging. Tensor-based morphometry methods were used to evaluate volume change over time. FA values were extracted from regions of interest that included the cingulum, entorhinal white matter, and the genu and splenium of the corpus callosum. Baseline FA was used as a predictor variable, whereas gray and white matter atrophy rates as indexed by Tensor-based morphometry were the dependent variables. PRINCIPAL OBSERVATIONS: Over a 4-year period, participants showed significant contraction of white matter, especially in frontal, temporal, and cerebellar regions (P < 0.05, corrected for multiple comparisons)... [read more]

  • Randomized denoising autoencoders for smaller and efficient imaging based AD clinical trials

    Ithapu VK, Singh V, Okonkwo O, Johnson SC.

    Med Image Comput Comput Assist Interv. 2014;17(Pt 2):470-8


    There is growing body of research devoted to designing imaging-based biomarkers that identify Alzheimer's disease (AD) in its prodromal stage using statistical machine learning methods. Recently several authors investigated how clinical trials for AD can be made more efficient (i.e., smaller sample size) using predictive measures from such classification methods... [read more]

  • White matter microstructure in late middle-age: effects of Apolipoprotein E4 and parental family history of Alzheimer's disease

    Adluru N, Destiche DJ, Lu SYF, Doran ST, Birdsill AC, Melah KE, Okonkwo OC, Alexander AL, Dowling NM, Johnson SC, Sager MA, Bendlin BB

    NeuroImage: Clinical. 2014 Apr 21;4:730-42. eCollection 2014.


    INTRODUCTION: Little is still known about the effects of risk factors for Alzheimer's disease (AD) on white matter microstructure in cognitively healthy adults. The purpose of this cross-sectional study was to assess the effect of two well-known risk factors for AD, parental family history and APOE4 genotype. METHODS: This study included 343 participants from the Wisconsin Registry for Alzheimer's Prevention, who underwent diffusion tensor imaging (DTI)... [read more]

  • Amyloid burden, neuronal function, and cognitive decline in middle-aged adults at risk for Alzheimer’s disease

    Ozioma C. Okonkwo, Jennifer M. Oh, Rebecca Koscik, Erin Jonaitis, Caitlin A. Cleary, N. Maritza Dowling, Barbara B. Bendlin, Asenath LaRue, Bruce P. Hermann, Todd E. Barnhart, Dhanabalan Murali, Howard A. Rowley, Cynthia M. Carlsson, Catherine L. Gallagher, Sanjay Asthana, Mark A. Sager, Brad T. Christian, Sterling C. Johnson.

    Journal of the International Neuropsychological Society. 2014 Apr;20(4):422-33.


    The relative influence of amyloid burden, neuronal structure and function, and prior cognitive performance on prospective memory decline among asymptomatic late middle-aged individuals at risk for Alzheimer’s disease (AD) is currently unknown. We investigated this using longitudinal cognitive data from 122 middle-aged adults (21 “Decliners” and 101 “Stables”) enrolled in the Wisconsin Registry for Alzheimer’s Prevention who underwent multimodality neuroimaging (11C-Pittsburgh Compound B (PiB), 18F-fluorodeoxyglucose (FDG), and structural/functional MRI) 5.7±1.4 years (range=2.9-8.9) after their baseline cognitive assessment... [read more]

  • Regional white matter hyperintensities: aging, Alzheimer's disease risk, and cognitive function

    Alex C. Birdsill, Rebecca L. Koscik, Erin M. Jonaitis, Sterling C. Johnson, Ozioma C. Okonkwo, Bruce P. Hermann, Asenath LaRue, Mark A. Sager, Barbara B. Bendlin

    Neurobiology of Aging. 2014 Apr;35(4):769-76.


    White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood... [read more]

  • Cerebral blood flow is diminished in asymptomatic middle-aged adults with maternal history of Alzheimer’s disease

    Ozioma C. Okonkwo, Guofan Xu, Jennifer M. Oh, N. Maritza Dowling, Cynthia M. Carlsson, Catherine L. Gallagher, Alex C. Birdsill, Matthew Palotti, Whitney Wharton, Bruce P. Hermann, Asenath LaRue, Barbara B. Bendlin, Howard A. Rowley, Sanjay Asthana, Mark A. Sager, Sterling C. Johnson

    Cereb Cortex. 2014 Apr;24(4):978-88. Epub 2012 Dec 12.


    Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in understanding preclinical brain changes in persons at risk for Alzheimer’s disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n=28), patients with amnestic mild cognitive impairment (aMCI, n=23), older cognitively-normal adults (OCN, n=24), and asymptomatic middle-aged adults (n=252) with and without family history (FH) of AD... [read more]

  • Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

    Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM

    Nature Communications. 2014 Apr 1;5:3557.


    Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats. The value of CR as a tool to understand human ageing relies on translatability of CR's effects in primates... [read more]

  • Amyloid burden and neural function in people at risk for AD

    Johnson SC, Christian BT, Okonkwo OC, Oh J, Harding S, Xu G, Hillmer AT, Wooten DW, Murali D, Barnhart T, Hall LT, Racine AM, Klunk WE, Mathis CA, Bendlin BB, Gallagher CL, Carlsson CM, Rowley HA, Hermann BP, Dowling NM, Asthana S, Sager MA

    Neurobiol Aging. 2014 Mar;35(3):576-84.


    To determine the relationship between amyloid burden and neural function in healthy adults at risk for Alzheimer’s Disease (AD), we used multi-modal imaging with [C-11]Pittsburgh Compound B positron emission tomography (PET), [F-18]Fluorodeoxyglucose (FDG) PET and MRI, together with cognitive measurement in 201 subjects (mean age 60.1, range 46 to 73) from the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Using a qualitative rating, 18% of the sample were strongly amyloid positive (Aβ+), 41% indeterminate (Aβi) and 41% negative (Aβ-)... [read more]

  • Emergence of Mild Cognitive Impairment in Late-Middle-Aged Adults in the Wisconsin Registry for Alzheimer’s Prevention Study

    Koscik RL, LaRue A, Jonaitis EM, Okonkwo OC, Johnson SC, Bendlin BB, Hermann BP, Sager MA.

    Dementia and Geriatric Cognitive Disorders. 2014;38(1-2):16-30. Epub 2014 Feb 20.


    AIM: It is difficult to reliably detect the earliest signs of Alzheimer's disease (AD)-associated cognitive impairment. Our aim was to compare 3 psychometric methods of identifying amnestic mild cognitive impairment (aMCI) in a middle-aged longitudinal cohort enriched for AD risk. METHODS: Wisconsin Registry for Alzheimer's Prevention (WRAP) participants with 3 waves of cognitive assessment over approximately 6 years were coded as meeting each of 3 psychometric aMCI definitions: (a) 'aMCI standard-baseline' used published norms to establish cutoffs for baseline performance; (b) 'aMCI robust-baseline' applied WRAP-specific robust norms to baseline, and (c) 'aMCI robust-multiwave' applied these robust norms across 3 waves of assessment... [read more]

  • Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation

    Annie M. Racine, Nagesh Adluru, Andrew L. Alexander, Bradley T. Christian, Ozioma C. Okonkwo, Jennifer Oh, Caitlin A. Cleary, Alex Birdsill, Ansel T. Hillmer, Dhanabalan Murali, Todd E. Barnhart, Catherine L. Gallagher, Cynthia M. Carlsson, Howard A. Rowley, N. Maritza Dowling, Sanjay Asthana, Mark A. Sager, Barbara B. Bendlin, Sterling C. Johnson

    NeuroImage Clinical. 2014 Feb 19;4:604-14.


    Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer’s disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET)... [read more]

  • Randomized Denoising Autoencoders for Smaller and Efficient Imaging Based AD Clinical Trials

    Vamsi K. Ithapu, Vikas Singh, Ozioma Okonkwo, Sterling C. Johnson

    Proceedings of Medical Image Computing and Computer-Assisted Intervention (MICCAI) 2014, LNCS Vol 8674, 2014, pp 470-478.


    There is growing body of research devoted to designing imaging-based biomarkers that identify Alzheimer’s disease (AD) in its prodromal stage using statistical machine learning methods. Recently several authors investigated how clinical trials for AD can be made more efficient (i.e., smaller sample size) using predictive measures from such classification methods... [read more]


  • Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques

    Willette AA, Coe CL, Birdsill AC, Bendlin BB, Colman RJ, Alexander, AL, Allison DB, Weindruch RH, Johnson SC.

    Age (Dordr). 2013 Dec;35(6):2215-27. Epub 2013 Mar 6.


    Higher systemic levels of the proinflammatory cytokine interleukin-6 (IL-6) were found to be associated with lower gray matter volume and tissue density in old rhesus macaques. This association between IL-6, and these brain indices were attenuated by long-term 30 % calorie restriction (CR)... [read more]

  • Speeding up Permutation Testing in Neuroimaging

    Hinrichs, Chris, Ithapu, Vamsi K., Sun, Qinyuan, Johnson, Sterling C., and Singh, Vikas

    Advances in Neural Information Processing Systems (NIPS). 2013 Dec; 2013:890-898.


    Multiple hypothesis testing is a significant problem in nearly all neuroimaging studies. In order to correct for this phenomena, we require a reliable estimate of the Family-Wise Error Rate (FWER)... [read more]

  • Low cerebral blood flow is associated with lower memory function in metabolic syndrome.

    Alex C Birdsill, Cynthia M Carlsson, Auriel A Willette, Ozioma C Okonkwo, Sterling C Johnson, Guofan Xu, Jennifer M Oh, Catherine L Gallagher, Rebecca L Koscik, Erin M Jonaitis, Bruce P Hermann, Asenath LaRue, Howard A Rowley, Sanjay Asthana, Mark A Sager, Barbara B Bendlin

    Obesity (Silver Spring). 2013 Jul;21(7):1313-20. Epub 2013 May 19.


    Background: Metabolic syndrome (MetS)—a cluster of cardiovascular risk factors—is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown... [read more]

  • Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: a preliminary quantitative imaging study

    Sridharan A, Pehar M, Salamat MS, Pugh TD, Bendlin BB, Willette AA, Anderson RM, Kemnitz JW, Colman RJ, Weindruch RH, Puglielli L, Johnson SC

    Brain Res. 2013 May 1;1508:1-8.


    While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods... [read more]

  • Characterizing the relationship between functional MRI-derived measures and clinical outcomes in patients with vascular lesions

    Gallagher TA, Nair VA, Regner MF, Young BM, Radtke A, Pankratz J, Holdsworth RL, Baniulis D, Kornder NK, Voss J, Austin BP, Moritz C, Meyerand ME, Prabhakaran V

    Neurosurgical Focus 2013 Apr;34(4):E8.


    Background and Purpose—Functional magnetic resonance imaging (fMRI) has proven to be an effective component of pretreatment planning in patients harboring a variety of different brain lesions. Our group has recently reported significant relationships concerning distances between brain tumor border and area of functional activation (Lesion-to-Activation-Distance; LAD) with regard to patient morbidity and mortality... [read more]

  • White matter microstructural integrity and executive function in Parkinson’s disease

    Gallagher C, Bell B, Bendlin B, Palotti M, Okonkwo O, Sodhi A, Wong R, Buyan-Dent L, Johnson S, Willette A, Harding S, Ninman N, Kastman E, Alexander A

    J Int Neuropsychol Soc. 2013 Mar;19(3):349-54.


    Recent studies suggest that white matter abnormalities contribute to both motor and non-motor symptoms of Parkinson’s disease. The present study was designed to investigate the degree to which diffusion tensor magnetic resonance imaging (DTI) indices are related to executive function in Parkinson’s patients... [read more]

  • Neural correlates of behavioral variation in healthy adults’ antisaccade performance

    Schaeffer DJ, Amlung MT, Li Q, Krafft CE, Austin BP, Dyckman KA, McDowell JE.

    Psychophysiology. 2013 Apr;50(4):325-33.


    Cognitive control is required for correct antisaccade performance. High antisaccade error rates characterize certain psychiatric disorders, but can be highly variable, even among healthy groups... [read more]

  • Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults

    Auriel A. Willette, Guofan Xu, Sterling C. Johnson, Alex C. Birdsill, Erin M. Jonaitis, Mark A. Sager, Bruce P. Hermann, Asenath La Rue, Sanjay Asthana, Barbara B. Bendlin

    Diabetes Care. 2013 Feb;36(2):443-9.


    Objective: Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer’s disease. Insulin resistance may play a role in Alzheimer’s disease etiopathogenesis... [read more]


  • Q-MKL: Matrix-induced Regularization in Multi-Kernel Learning with Applications to Neuroimaging

    Chris Hinrichs, Vikas Singh, Jiming Peng, Sterling C. Johnson

    In Advances in Neural Information Processing Systems (NIPS) 25, pp. 1430-1438. 2012.


    Multiple Kernel Learning (MKL) generalizes SVMs to the setting where one simultaneously trains a linear classifier and chooses an optimal combination of given base kernels. Model complexity is typ- ically controlled using various norm regularizations on the base kernel mixing coefficients... [read more]

  • Wavelet based multi-scale shape features on arbitrary surfaces for cortical thickness discrimination

    Won Hwa Kim, Deepti Pachauri, Charles Hatt, Moo K. Chung, Sterling C. Johnson, Vikas Singh

    In Advances in Neural Information Processing Systems (NIPS) 25, pp. 1250-1258. 2012.


    Hypothesis testing on signals defined on surfaces (such as the cortical surface) is a fundamental component of a variety of studies in Neuroscience. The goal here is to identify regions that exhibit changes as a function of the clinical condition under study... [read more]

  • Brain volumetric and microstructural correlates of executive and motor performance in aged rhesus monkeys

    Aadhavi Sridharan, Auriel A Willette, Barbara B Bendlin, Andrew L Alexander, Christopher L Coe, Mary Lou Voytko, Ricki J Colman, Joseph W Kemnitz, Richard H Weindruch, Sterling C Johnson

    Front Aging Neurosci. 2012;4:31.


    The aged rhesus macaque exhibits brain atrophy and behavioral deficits similar to normal aging in humans. Here we studied the association between cognitive and motor performance and anatomic and microstructural brain integrity measured with 3T magnetic resonance imaging in aged monkeys... [read more]

  • Longitudinal volumetric changes following traumatic brain injury: A tensor based morphometry study

    Kimberly D. M. Farbota, Aparna Sodhi, Barbara B. Bendlin, Donald G. McLaren, Guofan Xu, Howard A. Rowley, Sterling C. Johnson

    J Int Neuropsychol Soc. 2012 Nov;18(6):1006-18.


    After traumatic injury the brain undergoes a prolonged period of degenerative change that is paradoxically accompanied by cognitive recovery. The spatiotemporal pattern of atrophy and the specific relationships of atrophy to cognitive changes are ill understood... [read more]

  • Effects of Atorvastatin on Cerebral Blood Flow in Middle-Aged Adults at Risk for Alzheimer's Disease: A Pilot Study

    Carlsson, C. M., Xu, G., Wen, Z., Barnet, J. H., Blazel, H. M., Chappell, R. J., Stein, J. H., Asthana, S., Sager, M. A., Alsop, D. C., Rowley, H. A., Fain, S. B., & Johnson, S. C.

    Curr Alzheimer Res. 2012 Oct;9(8):990-7.


    Background/Aims: Hypercholesterolemia in midlife increases risk for Alzheimer's disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD... [read more]

  • Longitudinal diffusion tensor imaging and neuropsychological correlates in traumatic brain injury patients

    Kimberly D Farbota, Barbara B Bendlin, Andrew L Alexander, Howard A Rowley, Robert J Dempsey and Sterling C Johnson

    Frontiers in Humans Neuroscience. 2012 Jun 19; 6:160. eCollection 2012.


    Traumatic brain injury often involves focal cortical injury and white matter (WM) damage that can be measured shortly after injury. Additionally, slowly evolving WM change can be observed but there is a paucity of research on the duration and spatial pattern of long-term changes several years post-injury... [read more]

  • CSF T-Tau/Ab42 Predicts White Matter Microstructure in Healthy Adults at Risk for Alzheimer’s Disease

    Bendlin BB, Carlsson CM, Johnson SC, Zetterberg H, Blennow K, Willette AA, Okonkwo OC, Sodhi A, Ries ML, Birdsill AC, Alexander AL, Rowley HA, Puglielli L, Asthana S, Sager MA

    PLoS One. 2012;7(6):e37720. doi: 10.1371/journal.pone.0037720. Epub 2012 Jun 6.


    Cerebrospinal fluid (CSF) biomarkers T-Tau and Ab42 are linked with Alzheimer’s disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging... [read more]

  • Calorie restriction reduces the influence of glucoregulatory dysfunction on regional brain volume in aged rhesus monkeys

    Willette AA Bendlin BB Colman RJ Kastman EK Field AS Alexander AL Sridharan A Allison DB Anderson R Voytko ML Kemnitz JW Weindruch RH Jonhson SC

    Diabetes, 2012 May;61(5):1036-42


    Insulin signaling dysregulation is related to neural atrophy in hippocampus and other areas affected by neurovascular and neurodegenerative disorders. It is not known if long-term calorie restriction (CR) can ameliorate this relationship through improved insulin signaling, or if such an effect might influence task learning and performance... [read more]

  • Head size may modify the impact of white matter lesions on dementia

    Skoog I, Olesen PJ, Blennow K, Palmertz B, Johnson SC, Bigler ED

    Neurobiology of Aging 2012 Jul;33(7):1186-93


    We aimed to examine whether total intracranial volume (TICV), a marker of premorbid brain size, modified the impact of the apolipoprotein E (apoE) e4 phenotype and ischemic white matter lesions (WMLs) on odds for dementia. The study comprised a population-based sample of 104 demented and 135 nondemented 85-year-olds, and included physical and neuropsychiatric examinations, and head computerized tomography (CT)... [read more]

  • Current status and future perspectives of magnetic resonance high-field imaging: a summary

    Prabhakaran V, Nair VA, Austin BP, La C, Gallagher TA, Wu Y, McLaren DG, Xu G, Turski P, Rowley H.

    Neuroimaging Clinics of North America 2012;22(2):373-397.


    There are several magnetic resonance (MR) imaging techniques that benefit from high-field MR imaging. This article describes a range of novel techniques that are currently being used clinically or will be used in the future for clinical purposes as they gain popularity... [read more]

  • Practice-related changes in neural activation patterns investigated via wavelet-based clustering analysis

    Lee J, Park C, Dyckman KA, Lazar NA, Austin BP, Li Q, McDowell JE.

    Hum Brain Mapp. 2013 Sep;34(9):2276-91.


    Objectives: To evaluate brain activation using functional magnetic resonance imaging (fMRI) and specifically, activation changes across time associated with practice-related cognitive control during eye movement tasks. Experimental design: Participants were engaged in antisaccade performance (generating a glance away from a cue) while fMR images were acquired during two separate test sessions: (1) at pre-test before any exposure to the task and (2) at post-test, after 1 week of daily practice on antisaccades, prosaccades (glancing toward a target), or fixation (maintaining gaze on a target)... [read more]

  • Evidence from cluster analysis for differentiation of antisaccade performance groups based on speed/accuracy trade-offs

    Li Q, Amlung MT, Valtcheva M, Camchong J, Austin BP, Dyckman KA, Unsworth N, Clementz BA, McDowell JE.

    International Journal of Psychophysiology 2012;85(2):274-277.


    Anti and pro-saccade performance in single or mixed contexts was explored in a large sample of young adults (n=281). ANOVAs were first conducted to evaluate trial type, context and gender effects... [read more]

  • A generalized form of context-dependent psychophysiological interactions (gPPI): A comparison to standard approaches

    McLaren, DG Ries, ML Xu, G Johnson, SC

    NeuroImage, 2012 Jul 16;61(4):1277-1286


    Functional MRI (fMRI) allows one to study task-related regional responses and task-dependent connectivity analysis using psychophysiological interaction (PPI) methods. The latter affords the additional opportunity to understand how brain regions interact in a task-dependent manner... [read more]

  • Family history of Alzheimer disease predicts hippocampal atrophy in healthy middle-aged adults

    Okonkwo OC, Xu G, Dowling NM, Bendlin BB, LaRue A, Hermann BP, Koscik R, Jonaitis EM, Rowley HA, Carlsson CM, Asthana S, Sager MA, Johnson SC

    Neurology, 2012 May 29;78(22):1769-76


    Objective: To evaluate the longitudinal influence of family history (FH) of Alzheimer disease (AD) and apolipoprotein E4 (APOE4) on brain atrophy and cognitive decline over 4 years among asymptomatic middle-aged individuals. Methods: Participants were cognitively-healthy adults with (FH+,n=60) and without (FH-,n=48) FH of AD (mean age at baseline=54 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention... [read more]

  • Medial Prefrontal Functional Connectivity - Relation to Memory Self-appraisal Accuracy in Older Adults with and without Memory Disorders

    Ries ML, McLaren DG, Bendlin BB, Xu G, Rowley HA, Birn R, Kastman EK, Sager MA, Asthana S, Johnson SC

    Neuropsychologia, 2012 Apr;50(5):603-11


    It is tentatively estimated that 25% of people with early Alzheimer's disease (AD) show impaired awareness of disease-related changes in their own cognition. Research examining both normative self-awareness and altered awareness resulting from brain disease or injury points to the central role of the medial prefrontal cortex (MPFC) in generating accurate self-appraisals... [read more]

  • MKL-Based Sample Enrichment and Customized Outcomes Enable Smaller AD Clinical Trials

    Chris Hinrichs, N. Maritza Dowling, Sterling C. Johnson, Vikas Singh

    Machine Learning and Interpretation in Neuroimaging (MLINI) 2011, Lecture Notes in Artificial Intelligence (LNAI) 7263, pp. 124-131, 2012.


    Recently, the field of neuroimaging analysis has seen a large number of studies which use machine learning methods to make predictions about the progression of Alzheimer's Disease (AD) in mildly demented subjects. Among these, Multi-Kernel Learning (MKL) has emerged as a powerful tool for systematically aggregating diverse data views, and several groups have shown that MKL is uniquely suited to combining different imaging modalities into a single learned model... [read more]

  • The Effects of Ramipril in Individuals at Risk for Alzheimer's Disease: Results of a Pilot Clinical Trial

    Wharton W, Stein JH, Korcarz C, Sachs J, Olson SR, Zetterberg H, Dowling M, Ye S, Gleason CE, Underbakke G, Jacobson LE, Johnson SC, Sager MA, Asthana S, Carlsson CM.

    J Alzheimers Dis. 2012;32(1):147-56.


    Research shows that certain antihypertensives taken during midlife confer Alzheimer's disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-β (Aβ) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD... [read more]


  • Capacity-speed relationships in prefrontal cortex

    Prabhakaran V, Rypma B, Narayanan NS, Meier TB, Austin BP, Nair VA, Naing L, Thomas LE, Gabrieli JD

    PLoS ONE 2011;6(11):e27504.


    Working memory (WM) capacity and WM processing speed are simple cognitive measures that underlie human performance in complex processes such as reasoning and language comprehension. These cognitive measures have shown to be interrelated in behavioral studies, yet the neural mechanism behind this interdependence has not been elucidated... [read more]

  • Effects of Hypoperfusion in Alzheimer's Disease

    Austin BP, Nair VA, Meier TB, Xu G, Rowley HA, Carlsson CM, Johnson SC, Prabhakaran V.

    Journal of Alzheimer's Disease. 2011;26 Suppl 3:123-33


    The role of hypoperfusion in Alzheimer's disease (AD) is a vital component to understanding the pathogenesis of this disease. Disrupted perfusion is not only evident throughout disease manifestation, it is also demonstrated during the pre-clinical phase of AD (i.e., mild cognitive impairment) as well as in cognitively healthy persons at high-risk for developing AD due to family history or genetic factors... [read more]

  • Topology based Kernels with Application to Inference Problems in Alzheimer’s disease

    Pachauri D, Hinrichs C, Chung MK, Johnson SC, Singh V

    IEEE Transaction on Medical Imaging. 2011 Oct;30(10):1760-70


    Alzheimer’s disease (AD) research has recently witnessed a great deal of activity focused on developing new statistical learning tools for automated inference using imaging data. The workhorse for many of these techniques is the Support Vector Machine (SVM) framework (or more generally kernel based methods)... [read more]

  • A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson's disease

    Gallagher CL, Johnson SC, Bendlin BB, Chung MK, Holden JE, Oakes TR, Brooks BR, Konapacki RA, Dogan S, Abbs J, Xu G, Nickles RJ, Pyzalski RW, DeJesus OT, Brown WD.

    Brain Imaging Behav. 2011 Sep;5(3):203-11.


    Although [18F]fluoro-L-dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson’s disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson’s disease (PD) patients and 11 healthy controls... [read more]

  • A within-subject comparison of 6-[18F]fluoro-m-tyrosine and 6-[18F]fluoro-L-dopa in Parkinson's disease

    Gallagher CL, Christian BT, Holden JE, Dejesus OT, Nickles RJ, Buyan-Dent L, Bendlin BB, Harding SJ, Stone CK, Mueller B, Johnson SC.

    Mov Disord. 2011 Sep;26(11):2032-8.


    Progression of Parkinson's disease symptoms is imperfectly correlated with positron emission tomography biomarkers for dopamine biosynthetic pathways. The radiopharmaceutical 6-[(18) F]fluoro-m-tyrosine is not a substrate for catechol-O-methyltransferase and therefore has a more favorable uptake-to-background ratio than 6-[(18) F]fluoro-L-dopa... [read more]

  • Calorie restriction reduces psychological stress reactivity and its association with brain volume and microstructure in aged rhesus monkeys

    Willette AA, Coe CL, Colman RJ, Bendlin BB, Kastman EK, Field AS, Alexander AL, Allison DB, Weindruch RH, Johnson SC.

    Psychoneuroendocrinology. 2012 Jul;37(7):903-16.


    BACKGROUND: Heightened stress reactivity is associated with hippocampal atrophy, age-related cognitive deficits, and increased risk for Alzheimer's disease. This temperament predisposition may aggravate age-associated brain pathology or be reflective of it... [read more]

  • Rate of 6-[18F]fluoro-L-dopa uptake decline in striatal subregions in Parkinson’s disease

    Gallagher CL, Oakes TR, Johnson SC, Chung MK, Holden JE, Bendlin BB, Xu G, McLaren DG, Nickles RJ, Pyzalski R, Dejesus O, Brown WD.

    Movement Disorders; March, 2011, 26(4): 614-20.


    Using both a volume of interest (VOI) and whole brain voxel-wise approach, we compared rates of decline of 6-L-[18F]-fluorodopa (FDOPA) positron emission tomography (PET) uptake ipsilateral (IL) and contralateral (CL) to the initially symptomatic limbs over 4.5 years in 26 subjects with Parkinson’s disease (PD) and 11 controls. The VOI approach used six subregions: Head/body of caudate nucleus, whole putamen, and posterior putamen... [read more]

  • Predictive Markers for AD in a Multi-Modality Framework: An Analysis of MCI Progression in the ADNI Population

    Hinrichs C, Singh V, Xu G, Johnson S.C.

    NeuroImage 2011 Mar 15;55(2):574-89. Epub 2010 Dec 10


    Alzheimer's Disease (AD) and other neurodegenerative diseases affect over 20 million people worldwide, and this number is projected to significantly increase in the coming decades. Proposed imaging-based markers have shown steadily improving levels of sensitivity/specificity in classifying individual subjects as AD or normal... [read more]

  • Anti-inflammatory drugs reduce age-related decreases in brain volume in cognitively normal older adults

    Walther K, Bendlin BB, Glisky EL, Trouard TP, Lisse JR, Posever JO, Ryan L.

    Neurobiol Aging. 2011 Mar;32(3):497-505. Epub 2009 Apr 22.


    Previous studies have indicated a decreased risk for developing Alzheimer's disease in anti-inflammatory (AI) drug users. Yet few studies have determined whether AI drug use provides a protective effect against normal age-related changes in the brains of older adults... [read more]

  • The Effect of TOMM40 Poly-T length on Gray Matter Volume and Cognition in Middle-Aged Persons with APOE ε3/ε3 Genotype

    Johnson SC, La Rue, A, Hermann BP, Xu G, Koscik R, Jonaitis EM, Bendlin BB, Hogan KJ, Roses AD, Saunders AM, Lutz MW, Asthana S, Green RC, Sager MA

    Alzheimers and Dementia 7, 456-465


    Objective: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE ε4 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has been shown to influence age of onset in LOAD, with very long poly-T length associated with earlier disease onset, and short poly-T length associated with later onset... [read more]

  • Functional Magnetic Resonance Imaging of Swallowing: From Neurophysiology to Neuroplasticity

    Georgia Malandraki, Sterling Johnson, JoAnne Robbins

    Head Neck. 2011 Oct;33 Suppl 1:S14-20.


    Swallowing is a complex neurogenic sensorimotor process involving all levels of the neuraxis and a vast number of muscles and anatomic structures. Disruption of any of these anatomic or functional components can lead to swallowing disorders (also known as dysphagia)... [read more]

  • Effects of Hypoperfusion in Alzheimer's Disease (Book Chapter)

    Austin BP, Nair VA, Meier TB, Xu G, Rowley HA, Carlsson CM, Johnson SC, Prabhakaran V.

    Advances in Alzheimer's Disease, Handbook of Imaging the Alzheimer Brain. 2011;2:253-63.


    The role of hypoperfusion in Alzheimer's disease (AD) is a vital component to understanding the pathogenesis of this disease. Disrupted perfusion is not only evident throughout disease manifestation, it is also demonstrated during the pre-clinical phase of AD (i.e., mild cognitive impairment) as well as in cognitively healthy persons at high-risk for developing AD due to family history or genetic factors... [read more]

  • Swallowing Intentional off-state in aging and Alzheimer’s Disease: A preliminary study

    Humbert IA, McLaren DG, Malandraki G, Johnson SC, Robbins JA

    J Alzheimers Dis. 2011;26(2):347-54.


    Frontal cortical activation is elicited when subjects have been instructed not to initiate a sensorimotor task. The goal of this preliminary fMRI study was to examine BOLD response to a "Do Not Swallow" instruction (an intentional "off-state") in the context of other swallowing tasks in 3 groups of participants (healthy young, healthy old, and early Alzheimer's disease (AD))... [read more]

  • Mapping the structural brain changes in Alzheimer's disease: the independent contribution of two imaging modalities

    Canu E, McLaren DG, Fitzgerald ME, Bendlin BB, Zoccatelli G, Alessandrini F, Pizzini FB, Ricciardi GK, Beltramello A, Johnson SC, Frisoni GB.

    J Alzheimers Dis. 2011;26 Suppl 3:263-74.


    The macrostructural atrophy of Alzheimer's disease (AD) has been fully described. Current literature reports that also microstructural alterations occur in AD since the early stages... [read more]

  • Exercise improves executive function and achievement and alters brain activation in overweight children: a randomized, controlled trial

    Davis CL, Tomporowski PD, McDowell JE, Austin BP, Miller PH, Yanasak NE, Allison JD, Naglieri JA

    Health Pscyhology 2011 Jan;30(1):91-8.


    OBJECTIVE: This experiment tested the hypothesis that exercise would improve executive function. DESIGN: Sedentary, overweight 7- to 11-year-old children (N = 171, 56% girls, 61% Black, M ± SD age = 9.3 ± 1.0 years, body mass index [BMI] = 26 ± 4.6 kg/m², BMI z-score = 2.1 ± 0.4) were randomized to 13 ± 1.6 weeks of an exercise program (20 or 40 min/day), or a control condition. MAIN OUTCOME MEASURES: Blinded, standardized psychological evaluations (Cognitive Assessment System and Woodcock-Johnson Tests of Achievement III) assessed cognition and academic achievement. Functional MRI measured brain activity during executive function tasks. RESULTS: Intent to treat analysis revealed dose-response benefits of exercise on executive function and mathematics achievement... [read more]


  • NSAIDs may protect against age-related brain atrophy

    Bendlin Barbara B, Newman Lisa M , Ries Michele L , Puglielli Luigi , Carlsson Cynthia M , Sager Mark A , Rowley Howard A , Gallagher Catherine L ,Willette Auriel A , Alexander Andrew L , Asthana Sanjay , Johnson Sterling C

    Front Aging Neurosci. 2010 Sep 3;2. pii: 35.


    The use of non-steroidal anti-inflammatory drugs (NSAIDs) in humans is associated with brain differences including decreased number of activated microglia. In animals, NSAIDs are associated with reduced microglia, decreased amyloid burden, and neuronal preservation... [read more]

  • White matter is altered with parental family history of Alzheimer’s disease

    Bendlin BB, Ries ML, Canu E, Sodhi A, Lazar M, Alexander AL, Carlsson CM, Sager MA, Asthana S, Johnson SC

    Alzheimers Dement. 2010 Sep;6(5):394-403. Epub 2010 Aug 14.


    Background: Brain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer’s disease (AD), suggesting that alterations can be detected decades before AD diagnosis. While the effect of Apolipoprotein E (ApoE) ε4 on the brain is well studied, less is known about the effect of family history of AD... [read more]

  • Homocysteine, neural atrophy, and the effect of caloric restriction in rhesus monkeys

    Willette AA, Gallagher C, Bendlin BB, McLaren DG, Kastman EK, Canu E, Kosmatka KJ, Field AS, Alexander AL, Colman RJ, Voytko ML, Weindruch RH, Coe CL, Johnson SC

    Neurobiol Aging. epub August 2010. In Press.


    Higher serum homocysteine (Hcy) levels in humans are associated with vascular pathology and greater risk for dementia, as well as lower global and regional volumes in frontal lobe and hippocampus. Calorie restriction (CR) in rhesus monkeys (Macaca mulatta) may confer neural protection against age- or Hcy-related vascular pathology... [read more]

  • Low HDL cholesterol is associated with lower gray matter volume in cognitively healthy adults

    Ward MA, Bendlin BB, McLaren DG, Hess TM, Gallagher CL, Kastman EK, Rowley HA, Asthana S, Carlsson CM, Sager MA, Johnson SC

    Frontiers in Aging Neuroscience (2010). July 15, 2


    Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer's disease (FHAD) alters this effect... [read more]

  • Age-related changes in neural volume and microstructure associated with interleukin-6 are ameliorated by a calorie-restricted diet in old rhesus monkeys

    Willette AA, Bendlin BB, McLaren DG, Canu E, Kastman EK, Kosmatka KJ, Xu G, Field AS, Alexander AL, Colman RJ, Weindruch RH, Coe CL, Johnson SC.

    Neuroimage. 2010 Jul 1;51(3):987-94. Epub 2010 Mar 15.


    Systemic levels of proinflammatory cytokines such as interleukin-6 (IL-6) increase in old age and may contribute to neural atrophy in humans. We investigated IL-6 associations with age in T1-weighted segments and microstructural diffusion indices using MRI in aged rhesus monkeys (Macaca mulatta)... [read more]

  • Effects of aging and calorie restriction on white matter in rhesus macaques.

    Bendlin BB, Canu E, Willette A, Kastman EK, McLaren DG, Kosmatka KJ, Xu G, Field AS, Colman RJ, Coe CL, Weindruch RH, Alexander AL, Johnson SC.

    Neurobiol Aging. 2011 Dec;32(12):2319.e1-11. Epub 2010 Jun 11.


    Rhesus macaques on a calorie restricted diet (CR) develop less age-related disease, have virtually no indication of diabetes, are protected against sarcopenia, and potentially live longer. Beneficial effects of caloric restriction likely include reductions in age-related inflammation and oxidative damage... [read more]

  • A Calorie-Restricted Diet Decreases Brain Iron Accumulation and Preserves Motor Performance in Old Rhesus Monkeys

    Erik Kastman, Auriel Willette, Christopher L. Coe, Barbara Bendlin, Kris Kosmatka, Donald McLaren, Guofan Xu, Elisa Canu, Aaron Field, Andrew L. Alexander, Mary Lou Voytko, T. Mark Beasley, Ricki Colman, Richard Weindruch, and Sterling Johnson

    Journal of Neuroscience. 2010, 30(23):7940-7947


    Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using MRI, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n = 24; 13 males, 11 females) and standard diets (n = 17; 8 males, 9 females)... [read more]

  • White Matter in Aging and Cognition: A Cross-sectional Study of Microstructure in Adults Aged Eighteen to Eighty-Three

    Bendlin, B.B., Fitzgerald, M., Ries, M., Xu, Guofan, Kastman, K., Thiel, B., Rowley, H., Lazar, M., Alexander, A., & Johnson, SC

    Dev Neuropsychol. 2010 May;35(3):257-77.


    Structural brain change and concomitant cognitive decline are the seemingly unavoidable escorts of aging. Despite accumulating studies detailing the effects of age on the brain and cognition, the relationship between white matter features and cognitive function in aging have only recently received attention and remain incompletely understood... [read more]

  • Reliability and Precision of Pseudo-continuous Arterial Spin Labeling Perfusion MRI on 3.0 T and Comparison with 15O-water PET in Elderly Subjects at Risk for Alzheimer’s Disease

    Guofan Xu; Howard A Rowley; Gaohong Wu; David C. Alsop; Ajit Shankaranarayanan; Maritza Dowling; Bradley T. Christian, Terrence R. Oakes, Sterling C Johnson

    NMR in Biomedicine. 2010 Apr;23(3):286-93.


    Arterial spin labeling (ASL) offers MRI measurement of cerebral blood flow (CBF) in vivo, and may offer clinical diagnostic utility in populations such as those with early Alzheimer’s Disease (AD). In the current study, we investigated the reliability and precision of a pseudo-continuous ASL (pcASL) sequence that was performed two or three times within one hour on eight young normal control subjects, and 14 elderly subjects including 11 with normal cognition, 1 with AD and 2 with Mild Cognitive Impairment (MCI)... [read more]

  • Rhesus Macaque Brain Morphometry: A Methodological Comparison of Voxel-Wise Approaches

    McLaren DG,Kosmatka KJ, Kastman EK, Bendlin BB, Johnson SC

    Methods. 2010 Mar;50(3):157-65


    Voxel-based morphometry studies have become increasingly common in human neuroimaging over the past several years; however, few studies have utilized this method to study morphometry changes in non-human primates. Here we describe the application of voxel-wise morphometry methods to the rhesus macaque (Macaca mulatta) using the 112RM-SL template and priors (McLaren et al... [read more]

  • Developing a national strategy to prevent dementia: Leon Thal Symposium 2009

    Khachaturian ZS, Barnes D, Einstein R, Johnson SC, Lee V, Roses A, Sager MA, Shankle WR, Snyder PJ, Petersen RC, Schellenberg G, Trojanowski J, Aisen P, Albert MS, Breitner JC, Buckholtz N, Carrillo M, Ferris S, Greenberg BD, Grundman M, Khachaturian AS,

    Alzheimers Dement, Mar;6(2):89-97


    Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27-28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia... [read more]

  • Microstructural diffusion changes are independent of macrostructural volume loss in moderate to severe Alzheimer’s disease

    Canu E, McLaren DG, Fitzgerald ME, Bendlin BB, Zoccatelli G, Alessandrini F, Pizzini FB, Ricciardi GK, Beltramello A, Johnson SC, Frisoni GB

    J Alzheimers Dis. 2010;19(3):963-76.


    Although it is established that Alzheimer’s disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD... [read more]

  • Awareness of memory abilities in community-dwelling older adults with suspected dementia and mild cognitive impairment

    Lin F, Wharton W, Dowling NM, Ries ML, Johnson SC, Carlsson CM, Asthana S, Gleason CE

    Dement Geriatr Cogn Disord. 2010;30(1):83-92


    AIMS: To examine awareness of memory abilities by groups (healthy control, suspected dementia/mild cognitive impairment, MCI, and diagnosed dementia/MCI), and to describe group differences in the relationship between awareness and cognitive performance in a community sample. METHODS: In a cross-sectional design, 183 subjects were evaluated in a community setting and categorized into 3 groups based on their cognitive performance and reported medical history. Awareness of memory abilities was quantified using a published anosognosia ratio (AR) comparing the estimated to the objective memory performance by subjects... [read more]


  • Midlife predictors of Alzheimer's disease

    Bendlin BB, Carlsson CM, Gleason CE, Johnson SC, Sodhi A, Gallagher CL, Puglielli L, Engelman CD, Ries ML, Xu G, Wharton W, Asthana S.

    Maturitas. 2010 Feb;65(2):131-7.


    Factors contributing to increased risk for Alzheimer's disease (AD) include age, sex, genes, and family history of AD. Several risk factors for AD are endogenous; however, accumulating evidence implicates modifiable risk factors in the pathogenesis of AD... [read more]

  • Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys

    Ricki J. Colman, Rozalyn M. Anderson, Sterling C. Johnson, Erik K. Kastman, Kristopher J. Kosmatka, T. Mark Beasley, David B. Allison, Christina Cruzen, Heather A. Simmons, Joseph W. Kemnitz, Richard Weindruch

    Science. 2009 Jul 10;325(5937):201-4.


    Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research... [read more]

  • Spatially augmented LPboosting for AD classification with evaluations on the ADNI dataset

    Hinrichs C, Singh V, Mukherjee L, Xu G, Chung MK, Johnson SC

    Neuroimage. 2009 May 27.


    Structural and functional brain images are playing an important role in helping us understand the changes associated with neurological disorders such as Alzheimer's disease (AD). Recent efforts have now started investigating their utility for diagnosis purposes... [read more]

  • Posterior Cingulate and Lateral Parietal Gray Matter Volume in Older Adults with Depressive Symptoms

    Michele L. Ries, Allison Wichmann, Barbara B. Bendlin, Sterling C. Johnson

    Brain Imaging Behav. 2009 Sep;3(3):233-239. Epub 2009 Apr 15.


    Depressive symptoms occurring late in life are an important risk factor for Alzheimer’s disease. The latest research finds that onset of depressive symptoms in late life may herald the development of AD, not only for aMCI patients, but also for cognitively-normal older adults... [read more]

  • A population-average MRI-based atlas collection of the rhesus macaque

    McLaren DG, Kosmatka KJ, Oakes TR, Kroenke CD, Kohama SG, Matochik JA, Ingram DK, Johnson SC

    Neuroimage. 2009 Mar 1;45(1):52-9.


    Magnetic resonance imaging (MRI) studies of non-human primates are becoming increasingly common; however, the well-developed voxel-based methodologies used in human studies are not readily applied to non-human primates. In the present study, we create a population-average MRI-based atlas collection for the rhesus macaque (Macaca mulatta) that can be used with common brain mapping packages such as SPM or FSL... [read more]

  • Neurophysiology of swallowing: effects of age and bolus type

    Humbert IA, Fitzgerald ME, McLaren DG, Johnson S, Porcaro E, Kosmatka K, Hind J, Robbins J

    Neuroimage. 2009 Feb 1;44(3):982-91. Epub 2008 Oct 28.


    This study examined age-related changes in swallowing from an integrated biomechanical and functional imaging perspective in order to more comprehensively characterize changes in swallowing associated with age. We examined swallowing-related fMRI brain activity and videoflouroscopic biomechanics of three bolus types (saliva, water and barium) in 12 young and 11 older adults... [read more]

  • The influence of parental history of Alzheimer's disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory

    Xu G, McLaren DG, Ries ML, Fitzgerald ME, Bendlin BB, Rowley HA, Sager MA, Atwood C, Asthana S, Johnson SC

    Brain. 2009 Feb;132(Pt 2):383-91. Epub 2008 Oct 1.


    First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals... [read more]

  • A preliminary study of the safety, feasibility and cognitive efficacy of soy isoflavone supplements in older men and women

    Gleason CE, Carlsson CM, Barnet JH, Meade SA, Setchell KD, Atwood CS, Johnson SC, Ries ML, Asthana S

    Age Ageing. 2009 Jan;38(1):86-93. Epub 2008 Dec 2.


    BACKGROUND: a small number of reports exist on the cognitive effects of soy isoflavones, the findings from which are mixed. Isoflavone efficacy is dependent upon conversion of glycosides contained in soy foods and supplements to the biologically active aglycons... [read more]


  • Neurophysiology and neuroanatomy of reflexive and volitional saccades: evidence from studies of humans

    McDowell JE, Dyckman KA, Austin BP, Clementz BA

    Brain and Cognition 2008 Dec;68(3):255-70.


    This review provides a summary of the contributions made by human functional neuroimaging studies to the understanding of neural correlates of saccadic control. The generation of simple visually guided saccades (redirections of gaze to a visual stimulus or pro-saccades) and more complex volitional saccades require similar basic neural circuitry with additional neural regions supporting requisite higher level processes... [read more]

  • Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging

    Bendlin BB, Ries ML, Lazar M, Alexander AL, Dempsey RJ, Rowley HA, Sherman JE, Johnson SC

    Neuroimage. 2008 Aug 15;42(2):503-14. Epub 2008 May 7.


    Traumatic brain injury (TBI) is associated with brain volume loss, but there is little information on the regional gray matter (GM) and white matter (WM) changes that contribute to overall loss. Since axonal injury is a common occurrence in TBI, imaging methods that are sensitive to WM damage such as diffusion-tensor imaging (DTI) may be useful for characterizing microstructural brain injury contributing to regional WM loss in TBI... [read more]

  • Common neural circuitry supporting volitional saccades and its disruption in schizophrenia patients and relatives

    Camchong J, Dyckman KA, Austin BP, Clementz BA, McDowell JE

    Biological Psychiatry 2008 Dec 15;64(12):1042-50.


    BACKGROUND: People with schizophrenia and their biological relatives have deficits in executive control processes such as inhibition and working memory as evidenced by performance abnormalities on antisaccade (AS) and ocular motor delayed response (ODR) tasks. METHODS: The present functional magnetic resonance imaging (fMRI) study was conducted to investigate brain activity associated with these putative indices of schizophrenia risk by: 1) directly comparing neural functioning in 15 schizophrenia patients, 13 of their first-degree biological relatives (primarily siblings), and 14 healthy participants; and 2) assessing executive function associated with volitional saccades by using a combination of AS and ODR tasks. RESULTS: Behavioral data showed that patients and relatives both made more volitional saccade errors. Imaging data demonstrated that within the context of preserved activity in some neural regions in patients and relatives, there were two distinct patterns of disruptions in other regions... [read more]

  • Effect of parental family history of Alzheimer's disease on serial position profiles

    La Rue A, Hermann B, Jones JE, Johnson S, Asthana S, Sager MA

    Alzheimers Dement. 2008 Jul;4(4):285-90.


    BACKGROUND: An exaggerated recency effect (ie, disproportionate recall of last-presented items) has been consistently observed in the word list learning of patients with Alzheimer's disease (AD). Our study sought to determine whether there were similar alterations in serial position learning among asymptomatic persons at risk for AD as a result of parental family history... [read more]

  • Atorvastatin Therapy is Associated with Greater and Faster Cerebral Hemodynamic Response

    Guofan Xu, Michele E. Fitzgerald, Zhifei Wen, Sean B. Fain, David C. Alsop, Timothy Carroll, Michele L. Ries, Howard A. Rowley, Mark A. Sager, Sanjay Asthana, Sterling C. Johnson, Cynthia M. Carlsson

    Brain Imaging and Behavior. vol. 2, no. 2, pp. 94-104. June, 2008.


    Hypercholesterolemia in midlife increases the risk of subsequent cognitive decline, neurovascular disease, and Alzheimer’s disease (AD), and statin use is associated with reduced prevalence of these outcomes. While statins improve vasoreactivity in peripheral arteries and large cerebral arteries, little is known about the effects of statins on cerebral hemodynamic responses and cognition in healthy asymptomatic adults... [read more]

  • Magnetic resonance imaging characterization of brain structure and function in mild cognitive impairment: a review

    Ries ML, Carlsson CM, Rowley HA, Sager MA, Gleason CE, Asthana S, Johnson SC

    J Am Geriatr Soc. 2008 May;56(5):920-34. Epub 2008 Apr 9.


    Given the predicted increase in prevalence of Alzheimer's disease (AD) in the coming decades, early detection and intervention in persons with the predementia condition known as mild cognitive impairment (MCI) is of paramount importance. Recent years have seen remarkable advances in the application of neuroimaging and other biomarkers to the study of MCI... [read more]

  • Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial

    Sparks DL, Lemieux SK, Haut MW, Baxter LC, Johnson SC, Sparks LM, Sampath H, Lopez JE, Sabbagh MH, Connor DJ

    Cleve Clin J Med. 2008 Mar;75 Suppl 2:S87-93.


    Numerous clinical studies suggest a link between elevated cholesterol and increased risk of Alzheimer disease (AD), and the preponderance of data suggests that statin therapy may reduce the risk of AD later in life. The first clinical investigation of statin therapy in patients with AD, the AD Cholesterol-Lowering Treatment (ADCLT) trial, found that atorvastatin 80 mg/day was associated with improvements relative to placebo on some, but not all, cognitive measures after 6 months and 1 year of therapy... [read more]

  • Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimer's disease

    Carlsson CM, Gleason CE, Hess TM, Moreland KA, Blazel HM, Koscik RL, Schreiber NT, Johnson SC, Atwood CS, Puglielli L, Hermann BP, McBride PE, Stein JH, Sager MA, Asthana S

    J Alzheimers Dis. 2008 Mar;13(2):187-97.


    BACKGROUND: Statins reduce amyloid-beta (Abeta) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Abeta metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD... [read more]

  • Associative learning over trials activates the hippocampus in healthy elderly but not mild cognitive impairment

    Johnson SC, Schmitz TW, Asthana S, Gluck MA, Myers C

    Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2008 Mar;15(2):129-45.


    The ability to form associations between choice alternatives and their contingent outcomes is an important aspect of learning that may be sensitive to hippocampal dysfunction in memory disorders of aging such as amnestic mild cognitive impairment (MCIa), or early Alzheimer disease. In this preliminary study we examined brain activation using functional magnetic resonance imaging (fMRI) in 12 healthy elderly participants and nine patients with MCIa during an associative learning task... [read more]



  • Hormone effects on fMRI and cognitive measures of encoding: importance of hormone preparation

    Gleason CE, Schmitz TW, Hess T, Koscik RL, Trivedi MA, Ries ML, Carlsson CM, Sager MA, Asthana S, Johnson SC

    Neurology. 2006 Dec 12;67(11):2039-41.


    We compared fMRI and cognitive data from nine hormone therapy (HT)-naive women with data from women exposed to either opposed conjugated equine estrogens (CEE) (n = 10) or opposed estradiol (n = 4). Exposure to either form of HT was associated with healthier fMRI response; however, CEE-exposed women exhibited poorer memory performance than either HT-naive or estradiol-exposed subjects... [read more]

  • Neural correlates of self-evaluative accuracy after traumatic brain injury

    Schmitz TW, Rowley HA, Kawahara TN, Johnson SC

    Neuropsychologia. 2006;44(5):762-73. Epub 2005 Sep 8.


    Individuals who have sustained a traumatic brain injury (TBI) often exhibit an array of cognitive deficits, yet perhaps most maladaptive of these sequelae is the frequent occurrence of reduced insight into one's own condition. In such cases, TBI individuals may overestimate their post-injury level of socio-cognitive functioning, leading to disparities between how they perceive themselves and what others observe... [read more]

  • Network analysis of single-subject fMRI during a finger opposition task

    Smith JF, Chen K, Johnson S, Morrone-Strupinsky J, Reiman EM, Nelson A, Moeller JR, Alexander GE

    Neuroimage. 2006 Aug 1;32(1):325-32. Epub 2006 Jun 2.


    The analysis of functional magnetic resonance imaging (fMRI) data has typically relied on univariate methods to identify areas of brain activity related to cognitive and behavioral task performance. We investigated the ability of multivariate network analysis using a modified form of principal component analysis, the Scaled Subprofile Model (SSM), applied to single-subject fMRI data to identify patterns of interactions among brain regions over time during an anatomically well-characterized simple motor task... [read more]

  • Relationship of cognitive measures and gray and white matter in Alzheimer's disease

    Baxter LC, Sparks DL, Johnson SC, Lenoski B, Lopez JE, Connor DJ, Sabbagh MN

    J Alzheimers Dis. 2006 Aug;9(3):253-60.


    OBJECTIVE: To examine the relationship between commonly used screening cognitive measures with gray and white matter integrity in patients with mild to moderate AD. BACKGROUND: New neuroimaging techniques, such as voxel-based morphometry (VBM), make it possible to study the relationship between structural brain integrity and cognitive functioning in AD... [read more]

  • Computational models of the hippocampal region: implications for prediction of risk for Alzheimer's disease in non-demented elderly

    Gluck MA, Myers CE, Nicolle MM, Johnson S

    Curr Alzheimer Res. 2006 Jul;3(3):247-57.


    We have pursued an interdisciplinary research program to develop novel behavioral assessment tools for evaluating specific memory impairments following damage to the medial temporal lobe, including the hippocampus and associated structures that show pathology early in the course of Alzheimer's disease (AD). Our approach uses computational models to identify the functional consequences of hippocampal-region damage, leading to testable predictions in both rodents and humans... [read more]

  • The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation

    Johnson SC, Schmitz TW, Trivedi MA, Ries ML, Torgerson BM, Carlsson CM, Asthana S, Hermann BP, Sager MA

    J Neurosci. 2006 May 31;26(22):6069-76.


    First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E epsilon4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor... [read more]

  • Self-appraisal decisions evoke dissociated dorsal-ventral aMPFC networks

    Schmitz TW, Johnson SC

    Neuroimage. 2006 Apr 15;30(3):1050-8. Epub 2005 Dec 2.


    The anterior medial prefrontal cortex (aMPFC) is consistently active during personally salient decisions, yet the differential contributory processes of this region along the dorsal-ventral axis are less understood. Using a self-appraisal decision-making task and functional magnetic resonance imaging, we demonstrated task-dependent connectivity of ventral aMPFC with amygdala, insula, and nucleus accumbens, and dorsal aMPFC connectivity with dorsolateral PFC and bilateral hippocampus... [read more]

  • Application of Brodmann's area templates for ROI selection in white matter tractography studies

    Thottakara P, Lazar M, Johnson SC, Alexander AL

    Neuroimage. 2006 Feb 1;29(3):868-78. Epub 2005 Oct 21.


    Brodmann's areas are part of the common vernacular used by neuroscientists to indicate specific location of brain activity in functional brain imaging studies. Here, we have employed a template based on the Brodmann's areas as a means of compartmentalizing underlying white matter pathways... [read more]

  • Task-dependent posterior cingulate activation in mild cognitive impairment

    Ries ML, Schmitz TW, Kawahara TN, Torgerson BM, Trivedi MA, Johnson SC

    Neuroimage. 2006 Jan 15;29(2):485-92. Epub 2005 Aug 15.


    Neuroimaging research has demonstrated that the posterior cingulate cortex (PCC) is functionally compromised in individuals diagnosed with amnestic mild cognitive impairment (MCI), a major risk factor for the development of Alzheimer's disease (AD). In functional MRI studies with healthy participants, this same region is active during self-appraisal (requiring retrieval of semantic knowledge about the self) as well as episodic recognition of previously learned information... [read more]

  • Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's disease: a cross-sectional study

    Trivedi MA, Schmitz TW, Ries ML, Torgerson BM, Sager MA, Hermann BP, Asthana S, Johnson SC

    BMC Med. 2006 Jan 13;4:1.


    BACKGROUND: The presence of the apolipoprotein E (APOE) epsilon4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the epsilon4 allele on hippocampal activation has not been firmly established... [read more]

  • Structural MRI discriminates individuals with Mild Cognitive Impairment from age-matched controls: A combined neuropsychological and voxel based morphometry study.

    Trivedi MA, Wichmann AK, Torgerson BM, Ward MA, Schmitz TW, Ries ML, Koscik RL, Asthana S, Johnson SC

    Alzheimers Dement. 2006;2(4):296-302.


    BACKGROUND: Several previous studies have reported that amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer's disease (AD), is associated with greater atrophy in the medial temporal lobe (MTL) and posterior cingulate gyrus (PCG). METHOD: In the present study, we examined the cross-sectional accuracy (i.e., the sensitivity and specificity) of voxel-based morphometry (VBM) in discriminating individuals with MCI (n =15) from healthy age-matched controls (n =15)... [read more]


  • The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study

    Ward MA, Carlsson CM, Trivedi MA, Sager MA, Johnson SC

    BMC Neurol. 2005 Dec 2;5:23.


    BACKGROUND: Obesity causes or exacerbates a host of medical conditions, including cardiovascular, pulmonary, and endocrine diseases. Recently obesity in elderly women was associated with greater risk of dementia, white matter ischemic changes, and greater brain atrophy... [read more]

  • The cerebral response during subjective choice with and without self-reference

    Johnson SC, Schmitz TW, Kawahara-Baccus TN, Rowley HA, Alexander AL, Lee J, Davidson RJ

    J Cogn Neurosci. 2005 Dec;17(12):1897-906.


    The anterior medial prefrontal (AMPFC) and retrosplenial (RSC) cortices are active during self-referential decision-making tasks such as when participants appraise traits and abilities, or current affect. Other appraisal tasks requiring an evaluative decision or mental representation, such as theory of mind and perspective-taking tasks, also involve these regions... [read more]


  • Functional MRI neuroanatomic correlates of the Hooper Visual Organization Test

    Moritz CH, Johnson SC, McMillan KM, Haughton VM, Meyerand ME

    J Int Neuropsychol Soc. 2004 Nov;10(7):939-47.


    The Hooper Visual Organization Test (VOT), a commonly applied neuropsychological test of visual spatial ability, is used for assessing patients with suspected right hemisphere, or parietal lobe involvement. A controversy has developed over whether the inferences of this test metric can be assumed to involve global, lateralized, or regional functionality... [read more]

  • Voxel-based morphometry of unilateral temporal lobe epilepsy reveals abnormalities in cerebral white matter

    McMillan AB, Hermann BP, Johnson SC, Hansen RR, Seidenberg M, Meyerand ME

    Neuroimage. 2004 Sep;23(1):167-74.


    Voxel-based morphometric (VBM) investigations of temporal lobe epilepsy have focused on the presence and distribution of gray matter abnormalities. VBM studies to date have identified the expected abnormalities in hippocampus and extrahippocampal temporal lobe, as well as more diffuse abnormalities in the thalamus, cerebellum, and extratemporal neocortical areas... [read more]

  • Metacognitive evaluation, self-relevance, and the right prefrontal cortex

    Schmitz TW, Kawahara-Baccus TN, Johnson SC

    Neuroimage. 2004 Jun;22(2):941-7.


    The capability to foster metacognitive evaluations (MEs) of oneself and others represents a major component of conscious awareness. Separate emerging lines of brain activation research examining ME have converged on the medial prefrontal cortex as a common finding... [read more]

  • Hippocampal adaptation to face repetition in healthy elderly and mild cognitive impairment

    Johnson SC, Baxter LC, Susskind-Wilder L, Connor DJ, Sabbagh MN, Caselli RJ

    Neuropsychologia. 2004;42(7):980-9.


    We examined the dynamic process of encoding novel repeating faces using functional MRI (fMRI) in non-demented elderly volunteers with and without diagnosed memory problems. We hypothesized that adaptation (repetition dependent reduction in activity) would occur in the mesial temporal lobe (MTL), and that this would be associated with cognitive status... [read more]

  • Functional MRI and Wada determination of language lateralization: a case of crossed dominance

    Ries ML, Boop FA, Griebel ML, Zou P, Phillips NS, Johnson SC, Williams JP, Helton KJ, Ogg RJ

    Epilepsia. 2004 Jan;45(1):85-9.


    The Wada test has historically been the conventional procedure for determining language lateralization before neurosurgery. However, functional magnetic resonance imaging (fMRI) offers a less invasive alternative to the Wada procedure... [read more]



  • Neural correlates of self-reflection

    Sterling C. Johnson, Leslie C. Baxter, Lana S. Wilder, James G. Pipe, Joseph E. Heiserman, George P. Prigatano

    Brain, Vol. 125, No. 8, 1808-1814, August 2002


    The capacity to reflect on one’s sense of self is an important component of self-awareness. In this paper, we investigate some of the neurocognitive processes underlying reflection on the self using functional MRI... [read more]