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1.  Predicting missing biomarker data in a longitudinal study of Alzheimer disease 
Lo, Raymond Y. | Jagust, William J. | Aisen, Paul | Jack, Clifford R. | Toga, Arthur W. | Beckett, Laurel | Gamst, Anthony | Soares, Holly | C. Green, Robert | Montine, Tom | Thomas, Ronald G. | Donohue, Michael | Walter, Sarah | Dale, Anders | Bernstein, Matthew | Felmlee, Joel | Fox, Nick | Thompson, Paul | Schuff, Norbert | Alexander, Gene | DeCarli, Charles | Bandy, Dan | Chen, Kewei | Morris, John | Lee, Virginia M.-Y. | Korecka, Magdalena | Crawford, Karen | Neu, Scott | Harvey, Danielle | Kornak, John | Saykin, Andrew J. | Foroud, Tatiana M. | Potkin, Steven | Shen, Li | Buckholtz, Neil | Kaye, Jeffrey | Dolen, Sara | Quinn, Joseph | Schneider, Lon | Pawluczyk, Sonia | Spann, Bryan M. | Brewer, James | Vanderswag, Helen | Heidebrink, Judith L. | Lord, Joanne L. | Petersen, Ronald | Johnson, Kris | Doody, Rachelle S. | Villanueva-Meyer, Javier | Chowdhury, Munir | Stern, Yaakov | Honig, Lawrence S. | Bell, Karen L. | Morris, John C. | Mintun, Mark A. | Schneider, Stacy | Marson, Daniel | Griffith, Randall | Clark, David | Grossman, Hillel | Tang, Cheuk | Marzloff, George | Toledo-Morrell, Leylade | Shah, Raj C. | Duara, Ranjan | Varon, Daniel | Roberts, Peggy | Albert, Marilyn S. | Pedroso, Julia | Toroney, Jaimie | Rusinek, Henry | de Leon, Mony J | De Santi, Susan M | Doraiswamy, P. Murali | Petrella, Jeffrey R. | Aiello, Marilyn | Clark, Christopher M. | Pham, Cassie | Nunez, Jessica | Smith, Charles D. | Given, Curtis A. | Hardy, Peter | Lopez, Oscar L. | Oakley, MaryAnn | Simpson, Donna M. | Ismail, M. Saleem | Brand, Connie | Richard, Jennifer | Mulnard, Ruth A. | Thai, Gaby | Mc-Adams-Ortiz, Catherine | Diaz-Arrastia, Ramon | Martin-Cook, Kristen | DeVous, Michael | Levey, Allan I. | Lah, James J. | Cellar, Janet S. | Burns, Jeffrey M. | Anderson, Heather S. | Laubinger, Mary M. | Bartzokis, George | Silverman, Daniel H.S. | Lu, Po H. | Graff-Radford MBBCH, Neill R | Parfitt, Francine | Johnson, Heather | Farlow, Martin | Herring, Scott | Hake, Ann M. | van Dyck, Christopher H. | MacAvoy, Martha G. | Benincasa, Amanda L. | Chertkow, Howard | Bergman, Howard | Hosein, Chris | Black, Sandra | Graham, Simon | Caldwell, Curtis | Hsiung, Ging-Yuek Robin | Feldman, Howard | Assaly, Michele | Kertesz, Andrew | Rogers, John | Trost, Dick | Bernick, Charles | Munic, Donna | Wu, Chuang-Kuo | Johnson, Nancy | Mesulam, Marsel | Sadowsky, Carl | Martinez, Walter | Villena, Teresa | Turner, Scott | Johnson, Kathleen B. | Behan, Kelly E. | Sperling, Reisa A. | Rentz, Dorene M. | Johnson, Keith A. | Rosen, Allyson | Tinklenberg, Jared | Ashford, Wes | Sabbagh, Marwan | Connor, Donald | Jacobson, Sandra | Killiany, Ronald | Norbash, Alexander | Nair, Anil | Obisesan, Thomas O. | Jayam-Trouth, Annapurni | Wang, Paul | Lerner, Alan | Hudson, Leon | Ogrocki, Paula | DeCarli, Charles | Fletcher, Evan | Carmichael, Owen | Kittur, Smita | Mirje, Seema | Borrie, Michael | Lee, T-Y | Bartha, Dr Rob | Johnson, Sterling | Asthana, Sanjay | Carlsson, Cynthia M. | Potkin, Steven G. | Preda, Adrian | Nguyen, Dana | Tariot, Pierre | Fleisher, Adam | Reeder, Stephanie | Bates, Vernice | Capote, Horacio | Rainka, Michelle | Hendin, Barry A. | Scharre, Douglas W. | Kataki, Maria | Zimmerman, Earl A. | Celmins, Dzintra | Brown, Alice D. | Gandy, Sam | Marenberg, Marjorie E. | Rovner, Barry W. | Pearlson, Godfrey | Anderson, Karen | Saykin, Andrew J. | Santulli, Robert B. | Englert, Jessica | Williamson, Jeff D. | Sink, Kaycee M. | Watkins, Franklin | Ott, Brian R. | Wu, Chuang-Kuo | Cohen, Ronald | Salloway, Stephen | Malloy, Paul | Correia, Stephen | Rosen, Howard J. | Miller, Bruce L. | Mintzer, Jacobo
Neurology  2012;78(18):1376-1382.
Objective:
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
Methods:
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
Results:
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
Conclusion:
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
doi:10.1212/WNL.0b013e318253d5b3
PMCID: PMC3345787  PMID: 22491869
2.  Perceived Stress Is Associated With Subclinical Cerebrovascular Disease in Older Adults 
Objective
To examine the association of perceived stress with magnetic resonance imaging (MRI) markers of subclinical cerebrovascular disease in an elderly cohort.
Design
Cross -sectional study
Setting
Community based cohort in Chicago, IL
Participants
571 adults (57% female; 58.1% African American; 41.9% non-Hispanic white; mean [SD] age=79.8 [5.9] years) from the Chicago Health and Aging Project (CHAP), an epidemiologic study of aging, completed questionnaires on perceived stress, medical history, and demographics as part of an in-home assessment, and 5 years later underwent a clinical neurological examination and magnetic resonance imaging (MRI) of the brain.
Outcome Measures
Volumetric MRI assessments of white matter hyperintensity volume (WMHV), total brain volume (TBV), and cerebral infarction.
Results
Stress was measured with 6 items from the Perceived Stress Scale (PSS); item responses, ranging from never (0) to often (3), were summed to create an overall stress score, (mean (SD) = 4.9 (3.3), range 0–18). Most participants had some evidence of vascular disease on MRI, with 153 (26.8%) having infarctions. In separate linear and logistic regression models adjusted for age, sex, education, race and time between stress assessment and MRI, each 1-point increase in PSS score was associated with significantly lower TBV (coefficient= −0.111; SE=0.049; t[563]=−2.28; P=0.023) and 7% greater odds of infarction (odds ratio=1.07; 95% CI=1.01, 1.13; Wald χ2[1]=4.90; P=0.027). PSS scores were unrelated to WMHV. Results were unchanged with further adjustment for smoking, body mass index, physical activity, history of heart disease, stroke, diabetes, and hypertension, depressive symptoms and dementia.
Conclusions
Greater perceived stress was significantly and independently associated with cerebral infarction and lower brain volume assessed 5 years later in this elderly cohort.
doi:10.1016/j.jagp.2012.06.001
PMCID: PMC3707931  PMID: 23567443
MR measures; perceived stress; biracial population sample
3.  White matter hyperintensities are associated with visual search behavior independent of generalized slowing in aging 
Neuropsychologia  2013;52:93-101.
A fundamental controversy is whether cognitive decline with advancing age can be entirely explained by decreased processing speed, or whether specific neural changes can elicit cognitive decline, independent of slowing. These hypotheses are anchored by studies of healthy older individuals where age is presumed the sole influence. Unfortunately, advancing age is also associated with asymptomatic brain white matter injury. We hypothesized that differences in white matter injury extent, manifest by MRI white matter hyperintensities (WMH), mediate differences in visual attentional control in healthy aging, beyond processing speed differences. We tested young and cognitively healthy older adults on search tasks indexing speed and attentional control. Increasing age was associated with generally slowed performance. WMH was also associated with slowed search times independent of processing speed differences. Consistent with evidence attributing reduced network connectivity to WMH, these results conclusively demonstrate that clinically silent white matter injury contributes to slower search performance indicative of compromised cognitive control, independent of generalized slowing of processing speed.
doi:10.1016/j.neuropsychologia.2013.10.011
PMCID: PMC3924853  PMID: 24183716
Cognitive control; Visual attention; Aging; Cerebrovascular disease; Cognitive neuroscience; Neuroimaging
4.  Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions 
Neurology  2014;83(1):40-47.
Objective:
The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).
Methods:
Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [11C]Pittsburgh compound B–PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index.
Results:
Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk.
Conclusion:
Aβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.
doi:10.1212/WNL.0000000000000550
PMCID: PMC4114172  PMID: 24907234
5.  Longitudinal Trajectories of Everyday Function by Diagnostic Status 
Psychology and aging  2013;28(4):1070-1075.
Generalized linear mixed models were used to examine longitudinal trajectories of everyday functional limitations by diagnostic stability/progression. Older adults (N=384) were followed an average 3.6 years; participants were grouped by diagnosis at study baseline and last follow-up (normal cognition, Mild Cognitive Impairment (MCI) or dementia at each time point). At study baseline there were clear group differences; most notably, among participants initially characterized as cognitively normal, those who developed MCI or dementia over follow-up already demonstrated greater functional impairment compared to those who remained cognitively normal. Change in functional impairment progressed slowly in the early disease groups, but showed an accelerated worsening in those converting to dementia.
doi:10.1037/a0034069
PMCID: PMC4021720  PMID: 24364409
Everyday Function; Activities of daily living; Mild Cognitive Impairment; Dementia; Cognition; Aging
6.  Course and etiology of dysexecutive MCI in a community sample 
Background
Amnestic MCI (aMCI) is associated with an elevated risk of progressing to Alzheimer’s disease. Much less is known about the course of dysexecutive MCI (dMCI). The goals of this study were to determine: How the profile of cognitive deficits differs over time between patients with dMCI, aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with strokes and white matter hyperintensities on MRI than aMCI.
Methods
A prospective evaluation of an inception cohort of 1167 ethnically-diverse elders recruited from an urban community-based sample and followed with clinical and neuropsychological testing over an average of 4.5 years (SD=0.8). A subset of the subjects had MRI scans. We compared four groups of MCI patients: single domain amnestic and dysexecutive MCI and multiple domain MCI with and without executive dysfunction.
Results
Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple domain MCI did not increase risk of progression to dementia. Patients with multiple domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer’s type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to have strokes, but not white matter hyperintensities, detected on MRI than patients with aMCI.
Conclusions
DMCI appears to follow a different course, and be less associated with AD and more associated with stroke, than aMCI.
doi:10.1016/j.jalz.2012.10.014
PMCID: PMC3933297  PMID: 23452959
7.  Loss of Fornix White Matter Volume as a Predictor of Cognitive Impairment in Cognitively Normal Elderly Individuals 
JAMA neurology  2013;70(11):1389-1395.
IMPORTANCE
Magnetic resonance imaging markers of incipient cognitive decline among healthy elderly individuals have become important for both clarifying the biological underpinnings of dementia and clinically identifying healthy individuals at high risk of cognitive decline. Even though the role of hippocampal atrophy is well known in the later stages of decline, the ability of fornix-hippocampal markers to predict the earliest clinical deterioration is less clear.
OBJECTIVES
To examine the involvement of the hippocampus-fornix circuit in the very earliest stages of cognitive impairment and to determine whether the volumes of fornix white matter and hippocampal gray matter would be useful markers for understanding the onset of dementia and for clinical intervention.
DESIGN
A longitudinal cohort of cognitively normal elderly participants received clinical evaluations with T1-weighted magnetic resonance imaging and diffusivity scans during repeated visits over an average of 4 years. Regression and Cox proportional hazards models were used to analyze the relationships between fornix and hippocampal measures and their predictive power for incidence and time of conversion from normal to impaired cognition.
SETTING
A cohort of community-recruited elderly individuals at the Alzheimer Disease Center of the University of California, Davis.
PARTICIPANTS
A total of 102 cognitively normal elderly participants, with an average age of 73 years, recruited through community outreach using methods designed to enhance ethnic diversity.
MAIN OUTCOMES AND MEASURES
Our preliminary hypothesis was that fornix white matter volume should be a significant predictor of cognitive decline among normal elderly individuals and that fornix measures would be associated with gray matter changes in the hippocampus.
RESULTS
Fornix body volume and axial diffusivity were highly significant predictors (P = .02 and .005, respectively) of cognitive decline from normal cognition. Hippocampal volume was not significant as a predictor of decline but was significantly associated with fornix volume and diffusivity (P = .004).
CONCLUSIONS AND RELEVANCE
This could be among the first studies establishing fornix degeneration as a predictor of incipient cognitive decline among healthy elderly individuals. Predictive fornix volume reductions might be explained at least in part by clinically silent hippocampus degeneration. The importance of this finding is that white matter tract measures may become promising candidate biomarkers for identifying incipient cognitive decline in a clinical setting, possibly more so than traditional gray matter measures.
doi:10.1001/jamaneurol.2013.3263
PMCID: PMC4059679  PMID: 24018960
8.  Amylin deposition in the brain: a second amyloid in Alzheimer’s disease ? 
Annals of neurology  2013;74(4):10.1002/ana.23956.
Objectives
Hyperamylinemia, a common pancreatic disorder in obese and insulin resistant patients, is known to cause amylin oligmerization and cytotoxicity in pancreatic islets leading to β-cell mass depletion and development of type-2 diabetes. Recent data revealed that hyperamylinemia also affects the vascular system, heart and kidneys. We, therefore, hypothesized that oligomerized amylin might accumulate in cerebrovascular system and brain parenchyma of diabetic patients.
Methods
Amylin accumulation in the brain of diabetic patients with vascular dementia or Alzheimer’s disease (AD), non-diabetic patients with AD, and age-matched healthy controls was assessed by quantitative real-time PCR, immunohistochemistry, western blot and ELISA.
Results
Amylin oligomers and plaques were identified in the temporal lobe gray matter from diabetic patients, but not controls. In addition, extensive amylin deposition was found in blood vessels and perivascular spaces. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late-onset AD without clinically apparent diabetes. Mixed amylin and Aβ deposits were occasionally observed. However, amylin accumulation leads to amyloid formation independent of Aβ deposition. Tissues infiltrated by amylin show increased interstitial space, vacuolation, spongiform change, and capillaries bended at amylin accumulation sites. Unlike the pancreas, there was no evidence of amylin synthesis in the brain.
Interpretations
Metabolic disorders and aging promote accumulation of amylin amyloid in cerebrovascular system and gray matter altering microvasculature and tissue structure. Amylin amyloid formation in the wall of cerebral blood vessels may also induce failure of elimination of Aβ from the brain, thus contributing to the etiology of AD.
doi:10.1002/ana.23956
PMCID: PMC3818462  PMID: 23794448
9.  Amylin: what might be its role in Alzheimer’s disease and how could this affect therapy? 
Expert review of proteomics  2013;10(5):403-405.
doi:10.1586/14789450.2013.841549
PMCID: PMC4068803  PMID: 24117198
Alzheimer’s disease; amylin; amyloid; cerebrovascular disease; dementia; hyperamylinemia; hyperinsulinemia; insulin resistance; obesity; type 2 diabetes
10.  Serum BDNF and VEGF levels are associated with Risk of Stroke and Vascular Brain Injury: Framingham Study 
Stroke; a journal of cerebral circulation  2013;44(10):10.1161/STROKEAHA.113.001447.
Background and Purpose
BDNF, a major neurotrophin and VEGF, an endothelial growth factor have a documented role in neurogenesis, angiogenesis and neuronal survival. In animal experiments they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample.
Methods
In 3440 stroke/TIA-free FHS participants (mean age 65±11yrs, 56%W), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological (NP) tests available (N=1863 and 2104, respectively; mean age 61±9yrs, 55%W, in each) we related baseline BDNF and logVEGF to log-white matter hyperintensity volume (lWMHV) on brain MRI, and to visuospatial memory and executive function tests.
Results
During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age-, sex- and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (HR comparing BDNF Q1 versus Q2–4:1.47, 95%CI:1.09–2.00, p=0.012; and HR/SD increase in logVEGF:1.21, 95%CI:1.04–1.40, p=0.012). Persons with higher BDNF levels had less lWMHV (β±SE=−0.05±0.02; p=0.025), and better visual memory (β±SE=0.18±0.07; p=0.005).
Conclusions
Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.
doi:10.1161/STROKEAHA.113.001447
PMCID: PMC3873715  PMID: 23929745
BDNF; VEGF; Risk; Stroke; Brain MRI; Subclinical
11.  Brain Imaging and Cognitive Predictors of Stroke and Alzheimer Disease in the Framingham Heart Study 
Background and purpose
Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer’s disease (AD) risk.
Methods
A cognitive battery was administered to 1,679 dementia and stroke-free Framingham Offspring (age>55; mean=65.7±7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD during up to 10 years of follow-up. As a secondary analysis, we explored these associations in the FHS Original cohort (mean age 67.5±7.3 and 84.8±3.3 at the cognitive assessment and MRI examination, respectively).
Results
A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored <1.5 standard-deviations below predicted mean scores, for age and education, on an executive function test, had a higher risk of future stroke (HR=2.27;95%CI:1.06–4.85) and AD (3.60;95%CI:1.52–8.52); additional cognitive tests also predicted AD. Participants with low (<20%ile) total brain volume and high (>20%ile) white matter hyperintensity volume had a higher risk of stroke (HR=1.97;95%CI:1.03–3.77 and HR=2.74;95%CI:1.51–5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the Offspring and Original cohorts (HR=4.41;95%CI:2.00–9.72 and HR=2.37;95%CI:1.12–5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imagingmarkers.
Conclusions
Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction.
doi:10.1161/STROKEAHA.113.000947
PMCID: PMC3974341  PMID: 23920020
stroke; Alzheimer’s disease; cognitive function; brain MRI
12.  Relations of arterial stiffness and endothelial function to brain aging in the community 
Neurology  2013;81(11):984-991.
Objective:
To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.
Methods:
Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998–2001) and brain MRI and cognition (1999–2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).
Results:
Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05).
Conclusions:
Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.
doi:10.1212/WNL.0b013e3182a43e1c
PMCID: PMC3888200  PMID: 23935179
13.  Cortical thickness mediates the effect of β-amyloid on episodic memory 
Neurology  2014;82(9):761-767.
Objective:
To investigate the associations among β-amyloid (Aβ), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease.
Methods:
In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aβ deposition using [11C] Pittsburgh compound B–PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index.
Results:
Increased Aβ was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aβ deposition. Increased Aβ was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aβ and memory performance. While age had a marginal effect on these associations, the relationship between Aβ and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B–positive subjects, in whom Aβ remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aβ and memory after controlling for vascular risk.
Conclusion:
These results suggest strong links among Aβ, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aβ, cortical thickness, and memory.
doi:10.1212/WNL.0000000000000170
PMCID: PMC3945649  PMID: 24489134
14.  Quantifying Cognitive Reserve in Older Adults by Decomposing Episodic Memory Variance: Replication and Extension 
The theory of cognitive reserve attempts to explain why some individuals are more resilient to age-related brain pathology. Efforts to explore reserve have been hindered by measurement difficulties. Reed et al. (2010) proposed quantifying reserve as residual variance in episodic memory performance that remains after accounting for demographic factors and brain pathology (whole brain, hippocampal, and white matter hyperintensity volumes). This residual variance represents the discrepancy between an individual’s predicted and actual memory performance. The goals of the present study were to extend these methods to a larger, community-based sample and to investigate whether the residual reserve variable is explained by age, predicts longitudinal changes in language, and predicts dementia conversion independent of age. Results support this operational measure of reserve. The residual reserve variable was associated with higher reading ability, lower likelihood of meeting criteria for mild cognitive impairment, lower odds of dementia conversion independent of age, and less decline in language abilities over 3 years. Finally, the residual reserve variable moderated the negative impact of memory variance explained by brain pathology on language decline. This method has the potential to facilitate research on the mechanisms of cognitive reserve and the efficacy of interventions designed to impart reserve.
doi:10.1017/S1355617713000738
PMCID: PMC3777696  PMID: 23866160
Cognition; Aging; Mild cognitive impairment; Dementia; Statistical models; Magnetic resonance imaging
15.  Demographic Predictors of Cognitive Change in Ethnically Diverse Older Persons 
Psychology and aging  2013;28(3):633-645.
The purpose of this study was to evaluate how demographic variables relate to cognitive change and address whether cross-sectional demographic effects on cognitive tests are mirrored in differences in longitudinal trajectories of cognitive decline. We hypothesized that race and ethnicity, education, and language of test administration would relate to cross-sectional status and that the rate of cognitive decline would differ among African Americans, Hispanics, and Caucasians, across levels of educational attainment, and according to linguistic background. Participants were 404 educationally, ethnically, and cognitively diverse older adults enrolled in an ongoing longitudinal study of cognition. Mixed-effects regression analysis was used to measure baseline status and longitudinal change in episodic memory, executive functioning, and semantic memory. Results showed that ethnicity and education were strongly associated with baseline scores, but were, at most, weakly associated with change in cognition over time after accounting for confounding variables. There was evidence that the episodic-memory scores of Spanish-speaking Hispanic participants with limited education underestimated their true abilities in the initial evaluation, which may reflect lack of familiarity with the testing environment. These results—consistent with other reports in the literature—suggest that cross-sectional effects of demographic variables on cognitive-test scores result from differences in life experiences that directly influence test performance and do not indicate greater disease effects on cognition in minorities and those with limited education.
doi:10.1037/a0031645
PMCID: PMC3778107  PMID: 23437898
cognitive change; African Americans; Hispanics; ethnic differences; dementia
16.  Dissociable Effects of Alzheimer Disease and White Matter Hyperintensities on Brain Metabolism 
JAMA neurology  2013;70(8):1039-1045.
Importance
Cerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia.
Objective
To examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment.
Design and Setting
Cohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada.
Participants
Two hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period.
Main Outcomes and Measures
Quantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid β-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18.
Results
In converters, greater WMHs were associated with decreased frontal metabolism (−0.048; 95% CI, −0.067 to −0.029) but not temporoparietal metabolism (0.010; 95% CI, −0.010 to 0.030). Greater cerebrospinal fluid β-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000–0.010) but not frontal metabolism (0.002; 95% CI, −0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027–0.076).
Conclusions and Relevance
The dissociation of WMHs and cerebrospinal fluid β-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters.
doi:10.1001/jamaneurol.2013.1878
PMCID: PMC3779687  PMID: 23779022
17.  APOE genotype and MRI markers of cerebrovascular disease 
Neurology  2013;81(3):292-300.
Objective:
We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.
Methods:
We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n = 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis.
Results:
APOE ε4 carrier status and APOE ε44 genotype were associated with increasing white matter hyperintensity burden (sample size–weighted z score meta-analysis [meta]-p = 0.0034 and 0.0030) and presence of cerebral microbleeds (meta odds ratio [OR] = 1.24, 95% confidence interval [CI] [1.07, 1.43], p = 0.004, and 1.87 [1.26, 2.78], p = 0.002), especially lobar. APOE ε2 carrier status was associated with increasing white matter hyperintensity load (z score meta-p = 0.00053) and risk of brain infarct (meta OR = 1.41[1.09, 1.81], p = 0.008).
Conclusions:
APOE ε4 and APOE ε2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE ε4 with an increased burden of CVD could be partly contributing to the relationship between APOE ε4 and AD, APOE ε2 was associated with MRI markers of CVD in the opposite direction compared to AD.
doi:10.1212/WNL.0b013e31829bfda4
PMCID: PMC3770168  PMID: 23858411
18.  Assessing the brain as an end-organ of vascular disease 
Nature reviews. Cardiology  2012;9(8):435-436.
A spectrum of common illnesses that constitute risk factors for cardiovascular diseases is associated with both cognitive impairment and high population mortality. Many clinical trials are focused on the prevention of cardiovascular mortality, but cognitive impairment should now be regarded as a similarly important outcome.
doi:10.1038/nrcardio.2012.92
PMCID: PMC4083477  PMID: 22733217
19.  Patent Foramen Ovale, Subclinical Cerebrovascular Disease and Ischemic Stroke in a Population-Based Cohort 
Objectives
To evaluate the relationship between patent foramen ovale (PFO), ischemic stroke and subclinical cerebrovascular disease in the general population.
Background
PFO is more frequently found in stroke patients than in stroke-free controls. However, the PFO-related stroke risk in the general population is not well established, and the relationship between PFO and silent brain infarcts (SBI) is not known.
Methods
PFO presence was assessed by transthoracic echocardiography with saline contrast injection in 1,100 stroke-free individuals over age 39 of a community-based sample followed for a mean of 11 years. In addition, 360 participants underwent brain magnetic resonance imaging (MRI) for SBI detection. We evaluated the risk of stroke associated with PFO after adjusting for established stroke risk factors, and examined the odds of having SBI among those with and without PFO.
Results
A PFO was present in 164 participants (14.9%). Over a mean follow up of 11.0 ± 4.5 years, 111 ischemic strokes occurred (10.1%), 15 (9.2%) in the PFO + and 96 (10.3%) in the PFO− groups. The 12.5 year cumulative risk of stroke was 10.1% (standard error 2.5%) in the PFO+ and 10.4% (standard error 1.1%) in the PFO− group (p=0.46). The adjusted hazard ratio for PFO and stroke was 1.10 (95% confidence interval 0.64–1.91). In the MRI subcohort, PFO was not associated with SBI (adjusted odds ratio 1.15, 95% CI 0.50–2.62).
Conclusions
In this community-based cohort, PFO was not associated with an increased risk of clinical stroke or subclinical cerebrovascular disease.
doi:10.1016/j.jacc.2013.03.064
PMCID: PMC3696432  PMID: 23644084
Echocardiography; Cerebrovascular Disorders; Atrium; Stroke; Epidemiology
20.  Extrapyramidal signs by dementia severity in Alzheimer’s disease and dementia with Lewy bodies 
Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are common etiologies of dementia with overlapping clinical features. Our objective was to determine which extrapyramidal signs (EPS) are most helpful in identifying DLB. We analyzed data from the National Alzheimer’s Coordinating Center, including demographics, Unified Parkinson’s Disease Rating Scale (UPDRS) scores, Mini Mental State Exam (MMSE) scores, and clinical diagnosis. The subjects were divided into three groups: AD, DLB or LBV (Lewy body variant). The UPDRS motor scores were totaled and analyzed within and across MMSE strata using regression techniques. Next, we divided UPDRS subscores into 9 EPS, dichotomized as either present or absent. Logistic regression analysis was used to compare each of the EPS in the AD and LB (DLB+LBV) groups. DLB subjects (n=130) were more likely to be male, younger, and have higher MMSE scores (p<0.001) than AD (n=1,826) or LBV (n=105) subjects. Differences were found for total UPDRS score and number of EPS (p<0.001), after controlling for age, gender and MMSE. Logistic regression models demonstrated that masked facies best differentiated AD from LB (OR=6.5, p<0.001, 95% CI: 3.8–11.1). If these findings are neuropathologically validated, then the presence of specific EPS may help clinicians better differentiate AD and DLB.
doi:10.1097/WAD.0b013e31826f040d
PMCID: PMC3562426  PMID: 23023095
21.  Standardization of Analysis Sets for Reporting Results from ADNI MRI Data 
The ADNI 3D T1-weighted MRI acquisitions provide a rich dataset for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising: screening visits, 1 year completers (subjects who all have screening, 6 and 12 month scans), two year annual completers (screening, 1, and 2 year scans), two year completers (screening, 6 months, 1 year, 18 months (MCI only) and 2 years) and complete visits (screening, 6 months, 1 year, 18 months (MCI only), 2, and 3 year (normal and MCI only) scans). As the ADNI-GO/ADNI-2 data becomes available, updated standard analysis sets will be posted regularly.
doi:10.1016/j.jalz.2012.06.004
PMCID: PMC3891834  PMID: 23110865
22.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
Importance
β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).
Objective
To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.
Design and Setting
A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.
Participants
Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants.
Interventions
Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing.
Main Outcome Measures
Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.
Results
Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.
Conclusions and Relevance
In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
doi:10.1001/2013.jamaneurol.405
PMCID: PMC3771392  PMID: 23400560
23.  Left Atrial Volumes and Reservoir Function Are Associated With Subclinical Cerebrovascular Disease: The Cardiovascular Abnormalities and Brain Lesions (CABL) Study 
JACC. Cardiovascular imaging  2013;6(3):313-323.
Objectives
To assess the relationship of left atrial (LA) phasic volumes and LA reservoir function with subclinical cerebrovascular disease in a stroke-free community-based cohort.
Background
An increase in LA size is associated with cardiovascular events including stroke. However, it is not known whether LA phasic volumes and reservoir function are associated with subclinical cerebrovascular disease.
Methods
LA minimum (LAVmin) and maximum (LAVmax) volumes, and LA reservoir function, measured as total emptying volume (LAEV) and total emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography in 455 stroke-free participants from the community-based Cardiovascular Abnormalities and Brain Lesions (CABL) study. Subclinical cerebrovascular disease was assessed as silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV) by brain magnetic resonance imaging (MRI).
Results
SBI prevalence was 15.4%; mean WMHV was 0.66±0.92%. Participants with SBI showed greater LAVmin (17.1±9.3 vs. 12.5±5.6 ml/m2, p<0.01) and LAVmax (26.6±8.8 vs. 23.3±7.0 ml/m2, p<0.01) compared to those without SBI. LAEV (9.5±3.4 vs. 10.8±3.9 ml/m2, p<0.01) and LAEF (38.7±14.7% vs. 47.0±11.9%, p<0.01) were also reduced in participants with SBI. In univariate analyses, greater LA volumes and smaller reservoir function were significantly associated with greater WMHV. In multivariate analyses, LAVmin remained significantly associated with SBI [adjusted odds ratio (OR) per SD increase: 1.37, 95% confidence intervals (CI) 1.04–1.80, p<0.05] and with WMHV (β=0.12, p<0.01), whereas LAVmax was not independently associated with either. Smaller LAEF was independently associated with SBI (adjusted OR=0.67, 95% CI 0.50–0.90, p<0.01) and WMHV (β=−0.09, p<0.05).
Conclusions
Greater LA volumes and reduced LA reservoir function are associated with subclinical cerebrovascular disease detected by brain MRI in subjects without history of stroke. LAVmin and LAEF, in particular, are more strongly associated with SBI and WMHV than the more commonly measured LAVmax, and their relationship with subclinical brain lesions is independent of other cardiovascular risk factors.
doi:10.1016/j.jcmg.2012.10.019
PMCID: PMC3600634  PMID: 23473112
Left atrial volume; Silent brain infarct; White matter hyperintensity volume; Magnetic resonance imaging; Three-dimensional echocardiography
24.  Subgroup of ADNI Normal Controls Characterized by Atrophy and Cognitive Decline Associated With Vascular Damage 
Psychology and aging  2013;28(1):191-201.
Previous work examining Alzheimer’s Disease Neuroimaging Initiative (ADNI) normal controls using cluster analysis identified a subgroup characterized by substantial brain atrophy and white matter hyperintensities (WMH). We hypothesized that these effects could be related to vascular damage. Fifty-three individuals in the suspected vascular cluster (Normal 2) were compared with 31 individuals from the cluster characterized as healthy/typical (Normal 1) on a variety of outcomes, including magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers, vascular risk factors and outcomes, cognitive trajectory, and medications for vascular conditions. Normal 2 was significantly older but did not differ on ApoE4+ prevalence. Normal 2 differed significantly from Normal 1 on all MRI measures but not on Amyloid-Beta1-42 or total tau protein. Normal 2 had significantly higher body mass index (BMI), Hachinksi score, and creatinine levels, and took significantly more medications for vascular conditions. Normal 2 had marginally significantly higher triglycerides and blood glucose. Normal 2 had a worse cognitive trajectory on the Rey’s Auditory Verbal Learning Test (RAVLT) 30-min delay test and the Functional Activity Questionnaire (FAQ). Cerebral atrophy associated with multiple vascular risks is common among cognitively normal individuals, forming a distinct subgroup with significantly increased cognitive decline. Further studies are needed to determine the clinical impact of these findings.
doi:10.1037/a0031063
PMCID: PMC3751169  PMID: 23527743
ADNI; vascular; cognitive decline; biomarkers; cluster
25.  Association of Parental Stroke with Brain Injury and Cognitive Measures in Offspring – The Framingham Heart Study 
Background and purpose
Parental stroke has been related to an increased risk of stroke in the offspring. This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke.
Methods
Multivariable regression analyses were used to relate parental stroke to cross-sectional and change in brain magnetic resonance imaging measures and cognitive function among the offspring, with and without adjustment for vascular risk factors.
Results
Stroke- and dementia-free Framingham Offspring (n=1,297, age:61±9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (WMHV;β=0.17±0.08; p=0.027), and with lower visual memory performance (β =−0.80±0.34; p=0.017). During a 6 year follow-up, parental stroke was also associated with increase in WMHV (odds ratio [OR] = 1.87;95%CI:1.03–3.38) and decline in executive function (Trails B–A; OR=1.81;95%CI:1.06–3.09). The associations with WMHV and visual memory attenuated after additional adjustment for concomitant vascular risk factors.
Conclusions
Parental stroke by age 65 years is associated with increased vascular brain injury and lower memory in offspring equivalent to 3 and 7 years of brain aging, respectively. This may be partly attributed to inheritance of vascular risk factors.
doi:10.1161/STROKEAHA.112.680520
PMCID: PMC3752976  PMID: 23362080
stroke; cognitive function; brain MRI

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