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1.  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.
PMCID: PMC4083477  PMID: 22733217
2.  Patent Foramen Ovale, Subclinical Cerebrovascular Disease and Ischemic Stroke in a Population-Based Cohort 
To evaluate the relationship between patent foramen ovale (PFO), ischemic stroke and subclinical cerebrovascular disease in the general population.
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.
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.
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).
In this community-based cohort, PFO was not associated with an increased risk of clinical stroke or subclinical cerebrovascular disease.
PMCID: PMC3696432  PMID: 23644084
Echocardiography; Cerebrovascular Disorders; Atrium; Stroke; Epidemiology
3.  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.
PMCID: PMC3562426  PMID: 23023095
4.  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.
PMCID: PMC3891834  PMID: 23110865
5.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
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).
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.
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.
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.
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.
PMCID: PMC3771392  PMID: 23400560
6.  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.
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.
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.
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).
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).
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.
PMCID: PMC3600634  PMID: 23473112
Left atrial volume; Silent brain infarct; White matter hyperintensity volume; Magnetic resonance imaging; Three-dimensional echocardiography
7.  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.
PMCID: PMC3751169  PMID: 23527743
ADNI; vascular; cognitive decline; biomarkers; cluster
8.  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.
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.
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.
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.
PMCID: PMC3752976  PMID: 23362080
stroke; cognitive function; brain MRI
9.  Apolipoprotein Epsilon 4 Allele Modifies Waist-to-Hip Ratio Effects on Cognition and Brain Structure 
This study aimed to determine whether relationships between obesity, as measured by waist-to-hip ratio (WHR), and cognition and brain structure were modified by the apolipoprotein epsilon 4 allele (apoE4). The sample included 1,969 stroke and dementia-free participants from the Framingham Offspring Cohort who underwent neuropsychological (NP) testing and structural Magnetic Resonance Imaging (MRI) between 1999–2002. WHR was categorized into sex-specific quartiles with those in Q4 representing central obesity. Multivariate linear regression estimated the relationships between Q4-WHR, cognitive and MRI measures; interaction terms examined modification of these relationships by the presence of apoE4. All analyses were cross sectional.
ApoE4 status significantly modified a number of associations. Specifically, we observed a significant negative relationship between Q4-WHR and a measure of executive function in the apoE4+ group but not in the apoE4− group. Similarly, we observed a stronger negative relationship between Q4-WHR and a measure of memory function for those in the apoE4+ group compared to those in the apoE4− group. Additionally, apoE4 status modified the relationship between Q4-WHR and two measures of structural brain integrity. First, a paradoxical finding of a negative association between WHR and frontal brain volume that was significant only for those in the apoE4- group, and a second finding that WHR was significantly associated with greater white matter hyperintensity volume only in the apoE4+ group.
These findings suggest that associations between central adiposity and both neuropsychological performance and underlying brain structure are highly complex and must be considered in the context of possible modifying genetic influences.
PMCID: PMC3613758  PMID: 21835633
waist-to-hip ratio; apoE4; metabolic syndrome; obesity; Alzheimer’s disease
10.  Combining Boundary-Based Methods With Tensor-Based Morphometry in the Measurement of Longitudinal Brain Change 
Tensor-based morphometry is a powerful tool for automatically computing longitudinal change in brain structure. Because of bias in images and in the algorithm itself, however, a penalty term and inverse consistency are needed to control the over-reporting of nonbiological change. These may force a tradeoff between the intrinsic sensitivity and specificity, potentially leading to an under-reporting of authentic biological change with time. We propose a new method incorporating prior information about tissue boundaries (where biological change is likely to exist) that aims to keep the robustness and specificity contributed by the penalty term and inverse consistency while maintaining localization and sensitivity. Results indicate that this method has improved sensitivity without increased noise. Thus it will have enhanced power to detect differences within normal aging and along the spectrum of cognitive impairment.
PMCID: PMC3775845  PMID: 23014714
Biomedical imaging; brain boundary shift; image matching; image registration; Kullback–Liebler; tensor-based morphometry (TBM)
11.  Imaging markers for Alzheimer disease 
Neurology  2013;81(5):487-500.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
PMCID: PMC3776529  PMID: 23897875
Journal of Alzheimer's disease : JAD  2013;33(0 1):S417-S426.
Cerebrovascular risk factors and stroke are highly prevalent with advancing age and stroke may be more common than Alzheimer’s disease, particularly amongst older men. While stroke mortality continues to decline, the prevalence of individuals with various vascular risk factors continues to rise and many are undiagnosed or undertreated. Asymptomatic cerebrovascular brain injury that includes asymptomatic brain infarction, white matter hyperintensities and even accelerated brain atrophy is even more frequent than clinical stroke. Moreover, the impact of cerebrovascular risk factors on brain injury appears to begin in middle life and additively increases the likelihood of later life dementia. This review focuses on the use of neuroimaging and genetics to understand the impact of asymptomatic vascular risk factors on the trajectories of cognitive aging as well as incident cognitive impairment, stroke and mortality. Results of this review emphasize the need for early detection and treatment of vascular risk factors to improve the cognitive health of our rapidly aging population.
PMCID: PMC3786369  PMID: 23034523
Magnetic Resonanace Imaging; white matter hyperintensities; cerebrovascular disease; pathophysiology
13.  Early Brain Loss in Circuits Affected by Alzheimer’s Disease is Predicted by Fornix Microstructure but may be Independent of Gray Matter 
In a cohort of community-recruited elderly subjects with normal cognition at initial evaluation, we found that baseline fornix white matter (WM) microstructure was significantly correlated with early volumetric longitudinal tissue change across a region of interest (called fornix significant ROI, fSROI), which overlaps circuits known to be selectively vulnerable to Alzheimer’s dementia pathology. Other WM and gray matter regions had much weaker or non-existent associations with longitudinal tissue change. Tissue loss in fSROI was in turn a significant factor in a survival model of cognitive decline, as was baseline fornix microstructure. These findings suggest that WM deterioration in the fornix and tissue loss in fSROI may be the early beginnings of posterior limbic circuit and default mode network degeneration. We also found that gray matter baseline volumes in the entorhinal cortex and hippocampus predicted cognitive decline in survival models. But since GM regions did not also significantly predict brain-tissue loss, our results may imply a view in which early, prodromal deterioration appears as two quasi independent processes in white and gray matter regions of the limbic circuit crucial to memory.
PMCID: PMC4035735  PMID: 24904414
fornix diffusivity; longitudinal brain change; limbic circuit; default mode network; normal cognition
14.  Effects of T2-Weighted MRI Based Cranial Volume Measurements on Studies of the Aging Brain 
Many brain aging studies use total intracranial volume (TIV) as a proxy measure of premorbid brain size that is unaffected by neurodegeneration. T1-weighted Magnetic Resonance Imaging (MRI) sequences are commonly used to measure TIV, but T2-weighted MRI sequences provide superior contrast between the cerebrospinal fluid (CSF) bounding the premorbid brain space and surrounding dura mater. In this study, we compared T1-based and T2-based TIV measurements to assess the practical impact of this superior contrast on studies of brain aging. 810 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, including healthy elders and those with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD), received T1-weighted and T2-weighted MRI at their baseline evaluation. TIV was automatically estimated from T1-weighted images using FreeSurfer version 4.3 (T1TIV), and an automated active contour method was used to estimate TIV from T2-weighted images (T2TIV). The correlation between T1TIV and T2TIV was high (.93), and disagreement was greater on larger heads. However, correcting a FreeSurfer-based measure of total parenchymal volume by dividing it by T2TIV led to stronger expected associations with a standardized measure of cognitive dysfunction (MMSE) in Poisson regression models among individuals with AD (z=1.73 vs. 1.09) and MCI (z=3.15 vs. 2.79) than a corresponding parenchymal volume measure divided by T1TIV. This effect was enhanced when the analysis was restricted to the cases where T1TIV and T2TIV disagreed the most. These findings suggest that T2-based TIV measurements may be higher fidelity than T1-based TIV measurements, thus leading to greater sensitivity to detect biologically plausible brain-behavior associations.
PMCID: PMC3864960  PMID: 24353391
total intracranial volume; segmentation; FreeSurfer; MRI; image processing
15.  Voxel and Surface-Based Topography of Memory and Executive Deficits in Mild Cognitive Impairment and Alzheimer’s Disease 
Brain imaging and behavior  2012;6(4):551-567.
Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are associated with a progressive loss of cognitive abilities. In the present report, we assessed the relationship of memory and executive function with brain structure in a sample of 810 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, including 188 AD, 396 MCI, and 226 healthy older adults (HC). Composite scores of memory (ADNI-Mem) and executive function (ADNI-Exec) were generated by applying modern psychometric theory to item-level data from ADNI’s neuropsychological battery. We used voxel-based morphometry (VBM) and surface-based association (SurfStat) analyses to evaluate relationships of ADNI-Mem and ADNI-Exec with grey matter (GM) density and cortical thickness across the whole brain in the combined sample and within diagnostic groups. We observed strong associations between ADNI-Mem and medial and lateral temporal lobe atrophy. Lower ADNI-Exec scores were associated with advanced GM and cortical atrophy across broadly distributed regions, most impressively in the bilateral parietal and temporal lobes. We also evaluated ADNI-Exec adjusted for ADNI-Mem, and found associations with GM density and cortical thickness primarily in the bilateral parietal, temporal, and frontal lobes. Within-group analyses suggest these associations are strongest in patients with MCI and AD. The present study provides insight into the spatially unbiased associations between brain atrophy and memory and executive function, and underscores the importance of structural brain changes in early cognitive decline.
PMCID: PMC3532574  PMID: 23070747
Voxel-based morphometry (VBM); Surface-based Analysis; Memory; Executive Function; Alzheimer’s disease; Mild Cognitive Impairment
16.  Relationship between baseline brain metabolism measured using [18F]FDG PET and memory and executive function in prodromal and early Alzheimer's disease 
Brain imaging and behavior  2012;6(4):568-583.
Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer's disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.
PMCID: PMC3532575  PMID: 23179062
mild cognitive impairment (MCI); Alzheimer's disease (AD); FDG PET; memory; executive function
17.  Genetic architecture of resilience of executive functioning* 
Brain imaging and behavior  2012;6(4):621-633.
The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H2=0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value=4.31×10−7). rs3748348 is in strong linkage disequilibrium (D′ of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the α-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value=7×10−7). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience.
PMCID: PMC3607298  PMID: 22711244
Memory; Executive functioning; Alzheimer’s disease; Psychometrics; Resilience; GWAS
18.  Next frontiers in the genetic epidemiology of Alzheimer’s disease 
European journal of epidemiology  2012;27(11):831-836.
PMCID: PMC3774602  PMID: 23132737
19.  Anatomical Mapping of White Matter Hyperintensities (WMH) 
Stroke; a journal of cerebral circulation  2004;36(1):10.1161/01.STR.0000150668.58689.f2.
Background and Purpose
MRI segmentation and mapping techniques were used to assess evidence in support of categorical distinctions between periventricular white matter hyperintensities (PVWMH) and deep WMH (DWMH). Qualitative MRI studies generally identify 2 categories of WMH on the basis of anatomical localization. Separate pathophysiologies and behavioral consequences are often attributed to these 2 classes of WMH. However, evidence to support these empirical distinctions has not been rigorously sought.
MRI analysis of 55 subjects included quantification of WMH volume, mapping onto a common anatomical image, and spatial localization of each WMH voxel. WMH locations were then divided into PVWMH and DWMH on the basis of distance from the lateral ventricles and correlations, with total WMH volume determined. Periventricular distance histograms of WMH voxels were also calculated.
PVWMH and DWMH were highly correlated with total WMH (R2>0.95) and with each other (R2>0.87). Mapping of all WMH revealed smooth expansion from around central cerebrospinal fluid spaces into more distal cerebral white matter with increasing WMH volume.
PVWMH, DWMH, and total WMH are highly correlated with each other. Moreover, spatial analysis failed to identify distinct subpopulations for PVWMH and DWMH. These results suggest that categorical distinctions between PVWMH and DWMH may be arbitrary, and conclusions regarding individual relationships between causal factors or behavior for PVWMH and DWMH may more accurately reflect total WMH volume relationships.
PMCID: PMC3816357  PMID: 15576652
cerebrovascular disorders; magnetic resonanace imaging; white matter
20.  Influence of Functional Connectivity and Structural MRI Measures on Episodic Memory 
Neurobiology of aging  2012;33(11):2612-2620.
Age related memory decline is the consequence of multiple biological factors that lead to brain structural and functional change, including gray matter atrophy, white matter injury, and loss of functional coordination between regions. However, the independent roles that each of these brain changes play in mediating memory decline is not clear. Therefore, we used magnetic resonance imaging (MRI) to measure gray matter volume (GM), white matter hyperintensities (WMH) volumes, and BOLD fMRI based functional connectivity among default mode network nodes in 76 cognitive normal older adults. We found that GM, WMH and connectivity between left inferior parietal and medial prefrontal cortex (MPF_LIP) were independently associated with episodic memory performance. Within the group with GM volumes below the median, greater MPF_LIP connectivity was associated with better memory performance, whereas this association was not present for individuals with GM volume above the median. These findings confirm the heterogeneous nature of brain-behavior relationships in cognitive aging. In addition, the relationship between resting state functional connectivity and memory performance, particularly amongst those individuals with more brain atrophy, strongly suggests compensation against the effects of neuronal injury.
PMCID: PMC3353006  PMID: 22285758
MRI measures; Gray matter; white matter hyperintensity; resting-state MRI; Functional connectivity; Episodic memory performance
21.  Lipoprotein phospholipase A2 (Lp-PLA2) and cerebral microbleeds (CMBs) in the Framingham Heart Study 
Background and Purpose
Cerebral microbleeds (CMBs) due to cerebral amyloid angiopathy generally occur in lobar regions, while those due to hypertensive vasculopathy are deep. Inflammation may be an underlying mechanism for CMB, with varying associations according to CMB location. Lipoprotein phospholipase-A2 (Lp-PLA2) is a circulating enzyme marker of vascular inflammation associated with risk of ischemic stroke and dementia. We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMBs, with possible regional specificity.
Framingham Offspring participants aged ≥65 years with available Lp-PLA2 measures and brain MRI were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMBs, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure, APOE, current smoking, and diabetes.
819 participants (mean age 73 years; 53% women) were included; 106 (13%) had CMBs; 82 (10%) lobar and 27 (3%) deep. We did not observe significant associations of CMB and LpPLA2 measures in multivariable adjusted analyses. However, there was a significant interaction between APOE genotype and Lp-PLA2 activity in their relation to presence of deep CMBs (p-interaction=0.01). Among persons with APOE ε3/ε3, the OR for deep CMB was 0.95 [0.59–1.53; p=0.83], while among those with at least one ε2 or ε4 allele, OR=3.46 [1.43–8.36; p=0.006].
In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMBs. The association of higher levels of Lp-PLA2 activity with deep CMBs among those with at least one APOE ε2 or ε4 allele merits replication.
PMCID: PMC3544291  PMID: 22961963
22.  Associations between vascular risk factors, carotid atherosclerosis and cortical volume and thickness in older adults 
Background and Purpose
To investigate whether the Framingham Cardiovascular Risk Profile (FCRP) and carotid artery intima-media thickness (CIMT) are associated with cortical volume and thickness.
Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3T and 4T MRI at three sites. Freesurfer (v5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of FCRP and CIMT with cortical volume and thickness
152 subjects (82 men) were aged 78 (±7) years old, 94 had a CDR of 0, 58 had a clinical dementia rating (CDR) of 0.5 and the mean mini-mental status examination (MMSE) was 28 ± 2. FCRP score was inversely associated with total gray matter (GM) volume, parietal and temporal GM volume (adjusted p<0.04). FCRP was inversely associated with parietal and total cerebral GM thickness (adjusted p<0.03). CIMT was inversely associated with thickness of parietal GM only (adjusted p=0.04). Including history of myocardial infarction or stroke and radiologic evidence of brain infarction, or apoE genotype did not alter relationships with FCRP or CIMT.
Increased cardiovascular risk was associated with reduced GM volume and thickness in regions also affected by Alzheimer’s disease (AD), independent of infarcts and apoE genotype. These results suggest a “double hit” toward developing dementia when someone with incipient AD also has high cardiovascular risk.
PMCID: PMC3732460  PMID: 22984010
Framingham cardiovascular risk profile; carotid intima media thickness; gray matter; cortical volume; cortical thickness; atrophy
23.  Impact of Markov Random Field Optimizer on MRI-based Tissue Segmentation in the Aging Brain 
Automatically segmenting brain magnetic resonance images into grey matter, white matter, and cerebrospinal fluid compartments is a fundamentally important neuroimaging problem whose difficulty is heightened in the presence of aging and neurodegenerative disease. Current methods overlap greatly in terms of identifiable algorithmic components, and the impact of specific components on performance is generally unclear in important real-world scenarios involving serial scanning, multiple scanners, and neurodegenerative disease. Therefore we evaluated the impact that one such component, the Markov Random Field (MRF) optimizer that encourages spatially-smooth tissue labelings, has on brain tissue segmentation performance. Two challenging elderly sets were used to test segmentation consistency across scanners and biological plausibility of tissue change estimates; and a simulated young brain data set was used to test accuracy against ground truth. Comparisons among Graph Cuts (GC), Belief Propagation (BP), and Iterative Conditional Modes (ICM) suggested that in the elderly brain, BP and GC provide the highest segmentation performance, with a slight advantage to BP, and that performance is often superior to that provided by popular methods SPM and FAST. Conversely, SPM and FAST excelled in the young brain, thus emphasizing the unique challenges involved in imaging the aging brain.
PMCID: PMC3806072  PMID: 22256150
24.  Changes in Brain Volume and Cognition in a Randomized Trial of Exercise and Social Interaction in a Community-Based Sample of Non-Demented Chinese Elders 
Physical exercise has been shown to increase brain volume and improve cognition in randomized trials of non-demented elderly. Although greater social engagement was found to reduce dementia risk in observational studies, randomized trials of social interventions have not been reported. A representative sample of 120 elderly from Shanghai, China was randomized to four groups (Tai Chi, Walking, Social Interaction, No Intervention) for 40 weeks. Two MRIs were obtained, one before the intervention period, the other after. A neuropsychological battery was administered at baseline, 20 weeks, and 40 weeks. Comparison of changes in brain volumes in intervention groups with the No Intervention group were assessed by t-tests. Time-intervention group interactions for neuropsychological measures were evaluated with repeated-measures mixed models. Compared to the No Intervention group, significant increases in brain volume were seen in the Tai Chi and Social Intervention groups (p < 0.05). Improvements also were observed in several neuropsychological measures in the Tai Chi group, including the Mattis Dementia Rating Scale score (p = 0.004), the Trailmaking Test A (p = 0.002) and B (p = 0.0002), the Auditory Verbal Learning Test (p = 0.009), and verbal fluency for animals (p = 0.01). The Social Interaction group showed improvement on some, but fewer neuropsychological indices. No differences were observed between the Walking and No Intervention groups. The findings differ from previous clinical trials in showing increases in brain volume and improvements in cognition with a largely non-aerobic exercise (Tai Chi). In addition, intellectual stimulation through social interaction was associated with increases in brain volume as well as with some cognitive improvements.
PMCID: PMC3788823  PMID: 22451320
Cognition; exercise; intervention studies; magnetic resonance imaging; pilot study; Tai Chi
25.  Vascular Contributions to Cognitive Impairment and Dementia 
Background and Purpose
This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.
The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.
PMCID: PMC3778669  PMID: 21778438
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment

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