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1.  White matter tract covariance patterns predict age-declining cognitive abilities 
NeuroImage  2015;125:53-60.
Previous studies investigating the relationship of white matter (WM) integrity to cognitive abilities and aging and have either focused on a global measure or a few selected WM tracts. Ideally, contribution from all of the WM tracts should be evaluated at the same time. However, the high collinearity among WM tracts precludes systematic examination of WM tracts simultaneously without sacrificing statistical power due to stringent multiple-comparison corrections. Multivariate covariance techniques enable comprehensive simultaneous examination of all WM tracts without being penalized for high collinearity among observations.
Method
In this study, Scaled Subprofile Modeling (SSM) was applied to the mean integrity of 18 major WM tracts to extract covariance patterns that optimally predicted four cognitive abilities (perceptual speed, episodic memory, fluid reasoning, and vocabulary) in 346 participants across ages 20 to 79 years old. Using expression of the covariance patterns, age-independent effects of white matter integrity on cognition and the indirect effect of WM integrity on age-related differences in cognition were tested separately, but inferences from the indirect analyses were cautiously made given cross-sectional data set was used in the analysis.
Results
A separate covariance pattern was identified that significantly predicted each cognitive ability after controlling for age except for vocabulary, but Age by WM covariance pattern interactions were not significant for any of the three abilities. Furthermore, each of the patterns mediated the effect of age on the respective cognitive ability. A distinct set of WM tracts was most influential in each of the three patterns. The WM covariance pattern accounting for fluid reasoning showed the most number of influential WM tracts whereas the episodic memory pattern showed the least number.
Conclusion
Specific patterns of WM tracts make significant contributions to the age-related differences in perceptual speed, episodic memory, and fluid reasoning but not vocabulary. Other measures of brain health will need to be explored to reveal the major influences on the vocabulary ability.
doi:10.1016/j.neuroimage.2015.10.016
PMCID: PMC4691375  PMID: 26477658
Diffusion tensor imaging; multivariate statistics; principal component analysis; mediation; cognition
2.  The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease 
JAMA neurology  2016;73(10):1231-1237.
Importance
The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association.
Objective
To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD.
Design, Setting, and Participants
The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights–Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015.
Main Outcomes and Measures
Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD.
Results
A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0 [9] years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women [68.2%]; 1900 men [31.8%]; mean [SD] age, 76.5 [7.0] years). Hypertension was associated with decreased LOAD risk (odds ratio [OR], 0.63; 95% CI, 0.55-0.72); type 2 diabetes and heart disease were not. History of stroke conferred greater than 2-fold increased risk for LOAD (OR, 2.23; 95% CI, 1.75-2.83). Adjustment for APOE ε4 did not alter results. The genetic risk score was associated with LOAD (OR, 2.85; 95% CI, 2.05-3.97) but did not change the independent association of LOAD with hypertension or stroke. In the WHICAP sample, hypertension was not associated with LOAD (OR, 0.99; 95% CI, 0.88-1.11), whereas history of stroke increased the risk for LOAD (OR, 1.96; 95% CI, 1.56-2.46). The effect of hypertension on LOAD risk was also mediated by stroke in the NIA-LOAD and the WHICAP samples.
Conclusions and Relevance
In familial and sporadic LOAD, a history of stroke was significantly associated with increased disease risk and mediated the association between selected CV risk factors and LOAD, which appears to be independent of the LOAD-related genetic background.
doi:10.1001/jamaneurol.2016.2539
PMCID: PMC5155512  PMID: 27533593
3.  Neuropsychiatric effects of neurodegeneration of the medial vs. lateral ventral prefrontal cortex in humans 
Animal evidence suggests that a brain network involving the medial and rostral ventral prefrontal cortex (PFC) is central for threat response and arousal and a network involving the lateral and caudal PFC plays an important role in reward learning and behavioral control. In this study, we contrasted the neuropsychiatric effects of degeneration of the medial versus lateral PFC in 43 patients with Frontotemporal dementia and 11 patients with Corticobasal Syndrome using MRI, the Neuropsychiatric Inventory (NPI), and the Sorting, Tower, Twenty Questions, and Fluency tests of the Delis-Kaplan Executive Function System (D-KEFS). Deviations in MRI grey matter volume from 86 age-matched healthy control subjects were determined for the patients using FreeSurfer. Multivariate regression was used to determine which brain areas were associated with specific neuropsychiatric and cognitive symptoms. Decreased grey matter volume of the right medial ventral PFC was associated with increased anxiety and apathy, decreased volume of the right lateral ventral PFC with apathy and inappropriate repetitive behaviors, and of the left lateral ventral PFC with poor performance on the sorting and Twenty Questions task in patients with FTD and CBS. Similar to in animal studies, damage to the medial OFC appears to be associated with a disruption of arousal, and damage to the lateral OFC appears to be associated with deficits in trial-and-error learning and behavioral dysregulation. Studies of brain dysfunction in humans are valuable to bridge animal and human neuropsychiatric research.
doi:10.1016/j.cortex.2015.08.002
PMCID: PMC4689656  PMID: 26343341
Neurodegeneration; Prefrontal cortex; Neuropsychiatry; Lesion studies
4.  Mediterranean diet and brain structure in a multiethnic elderly cohort 
Neurology  2015;85(20):1744-1751.
Objective:
To determine whether higher adherence to a Mediterranean-type diet (MeDi) is related with larger MRI-measured brain volume or cortical thickness.
Methods:
In this cross-sectional study, high-resolution structural MRI was collected on 674 elderly (mean age 80.1 years) adults without dementia who participated in a community-based, multiethnic cohort. Dietary information was collected via a food frequency questionnaire. Total brain volume (TBV), total gray matter volume (TGMV), total white matter volume (TWMV), mean cortical thickness (mCT), and regional volume or CT were derived from MRI scans using FreeSurfer program. We examined the association of MeDi (scored as 0–9) and individual food groups with brain volume and thickness using regression models adjusted for age, sex, ethnicity, education, body mass index, diabetes, and cognition.
Results:
Compared to lower MeDi adherence (0–4), higher adherence (5–9) was associated with 13.11 (p = 0.007), 5.00 (p = 0.05), and 6.41 (p = 0.05) milliliter larger TBV, TGMV, and TWMV, respectively. Higher fish (b = 7.06, p = 0.006) and lower meat (b = 8.42, p = 0.002) intakes were associated with larger TGMV. Lower meat intake was also associated with larger TBV (b = 12.20, p = 0.02). Higher fish intake was associated with 0.019 mm (p = 0.03) larger mCT. Volumes of cingulate cortex, parietal lobe, temporal lobe, and hippocampus and CT of the superior-frontal region were associated with the dietary factors.
Conclusions:
Among older adults, MeDi adherence was associated with less brain atrophy, with an effect similar to 5 years of aging. Higher fish and lower meat intake might be the 2 key food elements that contribute to the benefits of MeDi on brain structure.
doi:10.1212/WNL.0000000000002121
PMCID: PMC4653103  PMID: 26491085
5.  Breadth and age-dependency of relations between cortical thickness and cognition 
Neurobiology of aging  2015;36(11):3020-3028.
Recent advances in neuroimaging have identified a large number of neural measures that could be involved in age-related declines in cognitive functioning. A popular method of investigating neural-cognition relations has been to determine the brain regions in which a particular neural measure is associated with the level of specific cognitive measures. Although this procedure has been informative, it ignores the strong interrelations that typically exist among the measures in each modality. An alternative approach involves investigating the number and identity of distinct dimensions within the set of neural measures and within the set of cognitive measures prior to examining relations between the two types of measures. The procedure is illustrated with data from 297 adults between 20 and 79 years of age with cortical thickness in different brain regions as the neural measures, and performance on 12 cognitive tests as the cognitive measures. The results revealed that most of the relations between cortical thickness and cognition occurred at a general level corresponding to variance shared among different brain regions and among different cognitive measures. In addition, the strength of the thickness-cognition relation was substantially reduced after controlling the variation in age, which suggests that at least some of the thickness-cognition relations in age-heterogeneous samples may be attributable to the influence of age on each type of measure.
doi:10.1016/j.neurobiolaging.2015.08.011
PMCID: PMC4609615  PMID: 26356042
6.  Medicare Utilization and Expenditures Around Incident Dementia in a Multiethnic Cohort 
Background.
Few studies have examined patterns of health care utilization and costs during the period around incident dementia.
Methods.
Participants were drawn from the Washington Heights-Inwood Columbia Aging Project, a multiethnic, population-based, prospective study of cognitive aging of Medicare beneficiaries in a geographically defined area of northern Manhattan. Medicare utilization and expenditure were examined in individuals with clinically diagnosed dementia from 2 years before until 2 years after the initial diagnosis. A sample of non-demented individuals who were matched on socio-demographic and clinical characteristics at study enrollment was used as controls. Multivariable regression analysis estimated effects on Medicare utilization and expenditures associated with incident dementia.
Results.
During the 2 years before incident dementia, rates of inpatient admissions and outpatient visits were similar between dementia patients and non-demented controls, but use of home health and skilled nursing care and durable medical equipment were already higher in dementia patients. Results showed a small but significant excess increase associated with incident dementia in inpatient admissions but not in other areas of care. In the 2 years before incident dementia, total Medicare expenditures were already higher in dementia patients than in non-demented controls. But we found no excess increases in Medicare expenditures associated with incident dementia.
Conclusions.
Demand for medical care already is increasing and costs are higher at the time of incident dementia. There was a small but significant excess risk of inpatient admission associated with incident dementia.
doi:10.1093/gerona/glv124
PMCID: PMC4612389  PMID: 26311543
Incident dementia; Medicare; Health care use; Health care expenditures; Longitudinal follow-up
7.  Late-life memory trajectories in relation to incident dementia and regional brain atrophy 
Journal of neurology  2015;262(11):2484-2490.
The trajectory, or slope, of cognitive decline may provide differentiation of older adults with and without incipient neurodegenerative disease. Cognitive aging phenotypes based on memory trajectories could be used as outcome measures for clinical trials or observational studies of risk and protective factors for dementia. This study used growth mixture modeling (GMM) to identify trajectory groups based on age- and education-corrected composite memory scores derived from immediate, delayed and recognition trials of the Selective Reminding Test. Participants included 2593 participants initially without dementia (mean age at entry = 76) in a community-based study of aging and dementia in northern Manhattan. Trajectory groups were compared on consensus diagnoses of dementia and structural MRI measures of hippocampal volume and entorhinal cortical thickness. Heterogeneity in memory trajectories allowed us to identify four groups: Stable-High (43.5 %), Stable-Low (17.1 %), Decliner (26.8 %), and Rapid Decliner (12.5 %). Decliners had more brain atrophy and higher rates of conversion to dementia. This study highlights the heterogeneity in cognitive aging and provides evidence that most elderly maintain memory function as they age. Associations with dementia and imaging measures validate subgroups of older adults identified with GMM based on their memory trajectories. Future research should use these memory trajectory phenotypes to determine whether dementia risk and protective factors differ for individuals following different memory trajectories.
doi:10.1007/s00415-015-7871-8
PMCID: PMC4819990  PMID: 26259562
Cognitive aging; Alzheimer's disease; MRI
8.  Examining the association between Apolipoprotein E (APOE) and self-reported sleep disturbances in non-demented older adults 
Neuroscience letters  2015;606:72-76.
We aimed to examine the association between apolipoprotein E (APOE) and sleep disturbances. This is a cross-sectional study, from the Washington Heights-Inwood Community Aging Project (WHICAP). A total of 1,944 non-demented older adults took part in the study. Sleep dysfunction was measured using sleep categories derived from the RAND Medical Outcomes Study Sleep Scale. Genetic association between APOE-ε4 genotype and sleep disturbances was assessed using unadjusted linear regression models. Secondary analyses were conducted adjusting for age, sex, education, ethnicity and body mass index (BMI). In the unadjusted model, individuals carrying the APOE-ε4 allele showed lower levels of snoring (β=−0.02, SE= 0.01, p =0.010) and sleep apnea (β=−0.01, SE= 0.01, p =0.037) when compared to non-ε4 carriers. After covariates’ adjustment, ε4 carriers demonstrated stronger association with lower levels of both snoring (β=−0.02, SE= 0.01, p=0.006), and sleep apnea (β=−0.01, SE= 0.01, p=0.018). Our results suggest that APOE-ε4 is associated with decreased problems in snoring and sleep apnea, in non-demented older adults.
doi:10.1016/j.neulet.2015.08.037
PMCID: PMC4598304  PMID: 26314507
Apolipoprotein E; aging; older adults; sleep problems
9.  Is residual memory variance a valid method for quantifying cognitive reserve? A longitudinal application 
Neuropsychologia  2015;77:260-266.
Cognitive reserve describes the mismatch between brain integrity and cognitive performance. Older adults with high cognitive reserve are more resilient to age-related brain pathology. Traditionally, cognitive reserve is indexed indirectly via static proxy variables (e.g., years of education). More recently, cross-sectional studies have suggested that reserve can be expressed 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). The present study extends these methods to a longitudinal framework in a community-based cohort of 244 older adults who underwent two comprehensive neuropsychological and structural magnetic resonance imaging sessions over 4.6 years. On average, residual memory variance decreased over time, consistent with the idea that cognitive reserve is depleted over time. Individual differences in change in residual memory variance predicted incident dementia, independent of baseline residual memory variance. Multiple-group latent difference score models revealed tighter coupling between brain and language changes among individuals with decreasing residual memory variance. These results suggest that changes in residual memory variance may capture a dynamic aspect of cognitive reserve and could be a useful way to summarize individual cognitive responses to brain changes. Change in residual memory variance among initially non-demented older adults was a better predictor of incident dementia than residual memory variance measured at one time-point.
doi:10.1016/j.neuropsychologia.2015.09.009
PMCID: PMC4778075  PMID: 26348002
cognitive reserve; cognitive ageing; dementia; structural MR imaging; memory; brain atrophy
10.  Olfactory identification deficits and increased mortality in the community 
Annals of neurology  2015;78(3):401-411.
Objective
To examine the association between odor identification deficits and future mortality in a multiethnic community cohort of older adults.
Methods
Participants were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Follow-up occurred at 2-year intervals with information on death obtained from informant interviews and the National Death Index.
Results
During follow-up (mean 4.1 SD 2.6 years), 349 of 1169 (29.9%) participants died. Participants who died were more likely to be older (p < 0.001), male (p < 0.001), have lower UPSIT scores (p < 0.001), and have a diagnosis of dementia (p < 0.001). In a Cox model, the association between lower UPSIT score and mortality (Hazard Ratio 1.07 per point interval, 95%CI 1.05 to 1.08, p<0.001) persisted after controlling for age, gender, education, ethnicity, language, modified Charlson medical comorbidity index, dementia, depression, alcohol abuse, head injury, smoking, Body Mass Index, vision and hearing impairment (Hazard Ratio=1.05, 95%CI 1.03 to 1.07, p<0.001). Compared to the fourth quartile with the highest UPSIT scores, hazard ratios for mortality for the first, second, and third quartiles of UPSIT scores were 3.81 (95%CI 2.71 to 5.34), 1.75 (95%CI 1.23 to 2.50), and 1.58 (95%CI 1.09 to 2.30), respectively. Participant mortality rate was 45% in the lowest quartile of UPSIT scores (anosmia) and 18% in the highest quartile of UPSIT scores.
Interpretation
Impaired odor identification, particularly in the anosmic range, is associated with increased mortality in older adults even after controlling for dementia and medical comorbidity.
doi:10.1002/ana.24447
PMCID: PMC4546561  PMID: 26031760
11.  β-Amyloid Deposition Is Associated with Decreased Right Prefrontal Activation during Task Switching among Cognitively Normal Elderly 
The Journal of Neuroscience  2016;36(6):1962-1970.
The accumulation of β-amyloid (Aβ) peptides, a pathological hallmark of Alzheimer's disease (AD), has been associated with functional alterations, often in an episodic memory system with a particular emphasis on medial temporal lobe function. The topography of Aβ deposition, however, largely overlaps with frontoparietal control (FPC) regions implicated in cognitive control that has been shown to be impaired in early mild AD. To understand the neural mechanism underlying early changes in cognitive control with AD, we examined the impact of Aβ deposition on task-evoked FPC activation using functional magnetic resonance imaging (fMRI) in humans. Forty-three young and 62 cognitively normal older adults underwent an fMRI session during an executive contextual task in which task difficulty varied: single (either letter case or vowel/consonant judgment task) vs dual (switching between letter case and vowel/consonant decisions) task. Older subjects additionally completed 18F-florbetaben positron emission tomography scans and were classified as either amyloid positive (Aβ+) or negative (Aβ−). Consistent with previous reports, age-related increases in brain activity were found in FPC regions commonly identified across groups. For both task conditions, Aβ-related increases in brain activity were found compared with baseline activity. For higher cognitive control load, however, Aβ+ elderly showed reduced task-switching activation in the right inferior frontal cortex. Our findings suggest that with Aβ deposition, brain activation in the cognitive control region reaches a maximum with lower control demand and decreases with higher control demand, which may underlie early impairment in cognitive control with AD progression.
SIGNIFICANCE STATEMENT The accumulation of β-amyloid (Aβ) peptides, a pathological hallmark of Alzheimer's disease, spatially overlaps with frontoparietal control (FPC) regions implicated in cognitive control, but the impact of Aβ deposition on FPC regions is largely unknown. Using functional magnetic resonance imaging with a task-switching task, we found Aβ-related increases in FPC regions compared with baseline activity. For higher cognitive control load, however, Aβ-related hypoactivity was found in the right inferior frontal cortex, a region highly implicated in cognitive control. The findings suggest that with Aβ deposition, task-related brain activity may reach a plateau early and undergo downstream pathways of neural dysfunction, which may relate to the early impairment of cognitive control seen in the progression of Aβ pathology.
doi:10.1523/JNEUROSCI.3266-15.2016
PMCID: PMC4748078  PMID: 26865619
amyloid PET; β-amyloid; cognitive control; cognitively normal older adults; fMRI; frontoparietal cortex
12.  Cognitive correlates of white matter lesion load and brain atrophy 
Neurology  2015;85(5):441-449.
Objective:
We investigated white matter lesion load and global and regional brain volumes in relation to domain-specific cognitive performance in the stroke-free Northern Manhattan Study (NOMAS) population.
Methods:
We quantified white matter hyperintensity volume (WMHV), total cerebral volume (TCV), and total lateral ventricular (TLV) volume, as well as hippocampal and cortical gray matter (GM) lobar volumes in a subgroup. We used general linear models to examine MRI markers in relation to domain-specific cognitive performance, adjusting for key covariates.
Results:
MRI and cognitive data were available for 1,163 participants (mean age 70 ± 9 years; 60% women; 66% Hispanic, 17% black, 15% white). Across the entire sample, those with greater WMHV had worse processing speed. Those with larger TLV volume did worse on episodic memory, processing speed, and semantic memory tasks, and TCV did not explain domain-specific variability in cognitive performance independent of other measures. Age was an effect modifier, and stratified analysis showed that TCV and WMHV explained variability in some domains above age 70. Smaller hippocampal volume was associated with worse performance across domains, even after adjusting for APOE ε4 and vascular risk factors, whereas smaller frontal lobe volumes were only associated with worse executive function.
Conclusions:
In this racially/ethnically diverse, community-based sample, white matter lesion load was inversely associated with cognitive performance, independent of brain atrophy. Lateral ventricular, hippocampal, and lobar GM volumes explained domain-specific variability in cognitive performance.
doi:10.1212/WNL.0000000000001716
PMCID: PMC4534076  PMID: 26156514
13.  The right insula contributes to memory awareness in cognitively diverse older adults 
Neuropsychologia  2015;75:163-169.
Unawareness of memory loss is a challenging characteristic of Alzheimer’s disease (AD) and other age-related neurodegenerative conditions at their earliest stages, adversely affecting important outcomes such as patient decision making and safety. The basis of this metacognitive disturbance has been elusive; however it is almost certainly determined in part by compromise to brain regions critical for self-assessment. The subjectivity of traditional measurements of self-awareness in dementia has likely limited the rigor with which its neuroanatomic correlates can be established. Here we objectively measure memory awareness (metamemory) using a Feeling of Knowing (FOK) task in a group of cognitively diverse older adults, including 14 with mild AD and 20 cognitively healthy older adults. Performance on the metamemory task was examined in relation to the structural integrity of 14 bilateral neuroanatomic regions hypothesized to support self-awareness. Less accurate metamemory was associated only with reduced right insular volume (r = .41, p = .019). Implications of the current findings for models of metacognitive aging are discussed, with attention to the role of the insula in the conscious detection of errors.
doi:10.1016/j.neuropsychologia.2015.05.032
PMCID: PMC4546518  PMID: 26049091
Awareness; Anosognosia; Metacognition; Alzheimer’s disease; Insula
14.  Infectious Burden and Cognitive Decline in the Northern Manhattan Study 
Objectives
To determine whether infectious burden (IB) is associated with worse performance and decline on a battery of neuropsychological tests.
Design
Prospective cohort study (Northern Manhattan Study (NOMAS)).
Setting
Community.
Participants
A subsample of 588 stroke-free NOMAS participants with IB and cognitive data (mean age 71±8, 62% female, 14% white, 16% black, 70% Hispanic) and 419 with repeat cognitive testing.
Measurements
Samples used for IB data were collected at baseline. Two waves of neurocognitive assessments occurred during follow-up. Participants underwent a neuropsychological battery and had repeated testing (mean time span 6±2 years). Using factor analysis–derived domain-specific Z scores for language, memory, executive function, and processing speed, associations between a quantitative stroke risk-weighted IB index (IBI), based on five common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex viruses 1 and 2), and cognitive performance and decline in each domain was examined.
Results
Adjusting for demographic characteristics, socioeconomic status, crystallized cognitive abilities, and vascular risk factors, the IBI was inversely associated with executive function at baseline (beta=−0.10, p=.01) but not with baseline language, memory, or processing speed performance in adjusted analyses. The IBI was associated with cognitive decline in the memory domain, adjusting for demographic and vascular risk factors (p=.02).
Conclusion
A quantitative measure of IB explained variability in baseline executive function performance and associated with decline in memory. Past exposure to common infections may contribute to vascular cognitive impairment and warrants further study.
doi:10.1111/jgs.13557
PMCID: PMC4878014  PMID: 26289683
infections; bacterial infections; viral infections; cognitive decline; epidemiology
15.  Differing effects of education on cognitive decline in diverse elders with low versus high educational attainment 
Neuropsychology  2014;29(4):649-657.
Objective
In light of growing debate over whether and how early-life educational experiences alter late-life cognitive trajectories, this study sought to more thoroughly investigate the relationship between educational attainment and rates of late-life cognitive decline in a racially, ethnically, and educationally diverse population.
Method
3,435 older adults in the community-based Washington Heights-Inwood Columbia Aging Project were administered neuropsychological tests of memory, language, visuospatial function, and processing speed at approximate 24-month intervals for up to 18 years. Second-order latent growth curves estimated direct and indirect (through income) effects of educational attainment on rates of global cognitive decline separately in individuals with low (0-8 years) and high (9-20 years) educational attainment.
Results
More years of education was associated with higher cognitive level and slower cognitive decline in individuals with low or high educational attainment. The association between having more than 9 years of education and exhibiting slower cognitive decline was fully mediated by income. While additional years of education up to 8 years was also associated with higher income, this did not explain associations between education and cognitive change in the low-education group.
Conclusions
Early education (i.e., up to 8 years) may promote aspects of development during a sensitive period of childhood that protect against late-life cognitive decline independent of income. In contrast, later education (i.e., beyond 9 years) is associated with higher income, which may influence late-life cognitive health through multiple, non-mutually exclusive pathways.
doi:10.1037/neu0000141
PMCID: PMC4362867  PMID: 25222199
Cognitive aging; socioeconomic status; income; statistical modeling
16.  Subclinical cerebrovascular disease inversely associates with learning ability 
Neurology  2015;84(23):2362-2367.
Objective:
Memory has been examined in subjects with imaging markers of cerebrovascular disease, but learning has been less well studied. We examined the relationship among subclinical cerebrovascular disease, cerebral volumes, and verbal learning in an ethnically and racially diverse community sample.
Methods:
A clinically stroke-free subset of Northern Manhattan Study participants underwent cognitive testing and brain MRI with quantification of white matter hyperintensity volume (WMHV) and total cerebral volume (TCV) using semiautomated segmentation. We used generalized linear regression and mixed models to examine the association between imaging findings and verbal learning.
Results:
There were 1,272 participants (61% women, mean age 70 ± 9 years). Participants with greater WMHV and smaller TCV remembered fewer total words on a list-learning task (β = −0.83 per SD change in WMHV, 95% confidence interval [CI] = −1.22 to −0.45, p < 0.0001; and β = 0.48 per SD change in TCV, 95% CI = 0.05 to 0.90, p = 0.03, respectively). Subclinical brain infarction (SBI) was not associated with total words learned (β = −0.04, 95% CI = −1.08 to 1.00, p = 0.94). Those with greater WMHV had increased odds of a flatter learning slope. After excluding participants with SBI, the association between total words learned and WMHV remained significant. All measurements were adjusted for age, education, race/ethnicity, medical insurance status, and the presence of SBI.
Conclusions:
White matter hyperintensities, a marker of cerebral small vessel disease, may have an impact on learning slope. This suggests that verbal learning performance can be incorporated into neuropsychological measures for vascular cognitive impairment and that cerebrovascular disease discovered on imaging affects the ability to learn new information.
doi:10.1212/WNL.0000000000001657
PMCID: PMC4464740  PMID: 26002489
17.  Cerebral autoregulation, beta amyloid, and white matter hyperintensities are interrelated 
Neuroscience letters  2015;592:54-58.
Emerging studies link vascular risk factors and cerebrovascular health to the prevalence and rates of progression in Alzheimer’s disease (AD). The brain’s ability to maintain constant blood flow across a range of cerebral perfusion pressures, or autoregulation, may both promote and result from small vessel cerebrovascular disease and AD-related amyloid pathology. Here, we examined the relationship among cerebral autoregulation, small vessel cerebrovascular disease, and amyloid deposition in 14 non-demented older adults. Reduced cerebral autoregulation, was associated with increased amyloid deposition and increased white matter hyperintensity volume, which, in turn were positively associated with each other. For the first time in humans, we demonstrate an interrelationship among AD pathology, small vessel cerebrovascular disease, and cerebral autoregulation. Vascular factors and AD pathology are not independent but rather appear to interact.
doi:10.1016/j.neulet.2015.03.005
PMCID: PMC4430835  PMID: 25748319
Cerebral autoregulation; White matter hyperintensities; Amyloid; Alzheimer’s disease
18.  Healthcare use and cost in dementia caregivers: Longitudinal results from the Predictors Caregiver Study 
OBJECTIVE:
To examine the effects of caregiver and patient characteristics on caregivers’ medical care use and cost.
METHODS:
147 caregiver/patient dyads were followed annually for 6 years in 3 academic AD centers in the US. Logistic, negative binomial, and generalized linear mixed models were used to examine overall effects of caregiver/patient characteristics on caregivers’ hospitalizations, doctor visits, outpatient tests and procedures, and prescription and over-the-counter medications.
RESULTS:
Patients’ comorbid conditions and dependence were associated with increased healthcare use and costs of caregivers. Increases in caregiver depressive symptoms are associated with increases in multiple domains of caregivers’ healthcare use and costs.
DISCUSSION:
Findings suggest that we should expand our focus on dementia patients to include family caregivers to obtain a fuller picture of effects of caregiving. Primary care providers should integrate caregivers’ needs in healthcare planning and delivery. Clinical interventions that treat patients and caregivers as a whole will likely achieve the greatest beneficial effects.
doi:10.1016/j.jalz.2013.12.018
PMCID: PMC4164583  PMID: 24637299
caregiving; medical care; cost; dementia; Alzheimer’s disease; longitudinal study
19.  Mediterranean diet and leukocyte telomere length in a multi-ethnic elderly population 
Age  2015;37(2):24.
Leukocyte telomere length (LTL) is considered as the marker of biological aging and may be related to environmental factors. The current study aimed to examine the relation between Mediterranean-type diet and LTL. We used a cross-sectional study of 1743 multi-ethnic community residents of New York aged 65 years or older. Mediterranean-type diet (MeDi) was calculated from dietary information collected using a food frequency questionnaire. LTL was measured from leukocyte DNA using a real-time PCR method to measure T/S ratio, the ratio of telomere (T) to single-copy gene (S) sequence. Regression analysis showed that the MeDi score was not associated with LTL in the overall study population (β = 12.5; p = 0.32) after adjusting for age, sex, education, ethnicity, caloric intake, smoking, and physical and leisure activities. However, we found a significant association between MeDi and LTL among non-Hispanic whites (β = 48.3; p = 0.05), and the results held after excluding dementia subjects (β = 49.6; p = 0.05). We further found that, in the whole population, vegetable and cereal consumption above the sex-specific population median was associated with longer LTL (β = 89.1, p = 0.04) and shorter LTL (β = −93.5; p = 0.03), respectively. Among non-Hispanic whites, intake of meat or dairy below sex-specific population medians was associated with longer LTL (β = 154.7, p = 0.05; β = 240.5, p < 0.001, respectively). We found that higher adherence to a MeDi was associated with longer LTL among whites but not among African Americans and Hispanics. Additionally, a diet high in vegetables but low in cereal, meat, and dairy might be associated with longer LTL among healthy elderly.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-015-9758-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-015-9758-0
PMCID: PMC4352412  PMID: 25750063
Telomere; Diet; Aging
20.  Aβ-related hyperactivation in fronto-parietal control regions in cognitively normal elderly 
Neurobiology of aging  2015;36(12):3247-3254.
The accumulation of beta amyloid (Aβ) peptides, a pathological hallmark of Alzheimers disease, has been associated with functional alterations in cognitively normal elderly, most often in the context of episodic memory (EM) with a particular emphasis on the medial temporal lobes. The topography of Aβ deposition, however, highly overlaps with fronto-parietal control (FPC) regions implicated in cognitive control/working memory (WM). To examine Aβ-related functional alternations in the FPC regions during a WM task, we imaged 42 young and 57 cognitively normal elderly using functional magnetic resonance imaging during a letter Sternberg task with varying load. Based on 18F-Florbetaben positron emission tomography (PET) scan, we determined older subjects amyloid positivity (Aβ+) status. Within brain regions commonly recruited by all subject groups during the delay period, age and Aβ deposition were independently associated with load-dependent frontoparietal hyperactivation, while additional compensatory Aβ-related hyperactivity was found beyond the FPC regions. The present results suggest that Aβ-related hyperactivation is not specific to the EM system but occurs in the frontoparietal control regions as well.
doi:10.1016/j.neurobiolaging.2015.08.016
PMCID: PMC4788982  PMID: 26382734
Aging; Beta-amyloid deposition; Frontoparietal control regions; Working Memory; fMRI; Amyloid PET
21.  Assessing Fluctuating Cognition in Dementia Diagnosis: Interrater Reliability of the Clinician Assessment of Fluctuation 
Fluctuating cognition (FC) is a core feature of dementia with Lewy bodies (DLB) but is challenging to assess. This study assessed the reliability and validity of the Clinician Assessment of Fluctuation (CAF), which assesses FC in patients with dementia. Interrater agreement of CAF outcomes (FC present and FC severe) was evaluated between physicians and nonphysicians in 141 patients with Alzheimer’s disease (AD) or DLB. Frequency of CAF outcomes by clinical and neuropathological diagnosis was examined. We found that interrater reliability was fair on FC present and almost perfect on FC severe, and both outcomes were higher in patients with clinical DLB than with clinical AD and were qualitatively more often endorsed in cases with neuropathological evidence of Lewy bodies. We conclude that the CAF is a reliable measure of FC and can be valuable in differential dementia diagnosis.
doi:10.1177/1533317515603359
PMCID: PMC4758876  PMID: 26340964
fluctuating cognition; dementia; dementia with Lewy Bodies; Alzheimer’s Disease
22.  Ideal Cardiovascular Health and Cognitive Aging in the Northern Manhattan Study 
Background
The American Heart Association defined target levels for 7 cardiovascular health (CVH) factors: smoking, body mass index, physical activity, diet, blood pressure, cholesterol, and glucose. We hypothesized that a greater number of American Heart Association ideal CVH metrics would be associated with less decline in cognitive performance in our multiethnic population.
Methods and Results
A subsample from the population‐based Northern Manhattan Study underwent repeated neuropsychological testing (mean interval 6±2 years). Domain‐specific Z scores were derived by using factor analysis for the domains of Episodic Memory, Semantic Memory, Executive Function, and Processing Speed, based on initial performance and decline over time. Linear regression models were constructed to examine the relationship between the number of ideal CVH metrics at enrollment with later cognitive performance and decline, adjusting for sociodemographics and magnetic resonance imaging brain markers. Among 1033 participants (mean age at initial cognitive assessment 72±8 years, 39% male, 19% black, 16% white, 65% Hispanic; n=722 with repeat testing), 3% had 0 ideal factors, 15% had 1 factor, 33% had 2 factors, 30% had 3 factors, 14% had 4 factors, 4% had 5 factors, 1% had 6 factors, and 0% had 7 factors. An increasing number of ideal CVH factors was associated with better processing speed at initial assessment and less decline. The association was driven by nonsmoking and glucose. Among those with better cognitive performance at initial assessment, positive associations were observed between the number of ideal CVH factors and less decline in the domains of Executive Function and Episodic Memory.
Conclusions
The number of ideal CVH metrics was associated with less decline in the domains of Processing Speed and, to a lesser extent, of Executive Function and Episodic Memory. Ideal CVH promotion benefits brain health and cognitive aging.
doi:10.1161/JAHA.115.002731
PMCID: PMC4943249  PMID: 26984255
blood pressure; epidemiology; glucose; risk factors; smoking; Cardiovascular Disease; Epidemiology; Race and Ethnicity; Risk Factors
23.  Longitudinal relationships between Alzheimer’s disease progression and psychosis, depressed mood and agitation/aggression 
Objectives
Behavioral and psychological symptoms of dementia (BPSD) are prevalent in Alzheimer’s disease (AD) and are related to poor outcomes such as nursing home placement. No study has examined the impact of individual BPSD on dependence, a clinically important feature that reflects changing patient needs and their impact on caregivers. The current study characterized independent cross-sectional and longitudinal relationships between three BPSD (i.e., psychosis, depressed mood, and agitation/aggression), cognition, and dependence to better understand the interplay between these symptoms over time.
Design
The Predictors Study measured changes in BPSD, cognition, and dependence in AD patients every six months. Cross-sectional and longitudinal relationships between individual BPSD, cognition, and dependence over six years were characterized using multivariate latent growth curve modeling. This approach characterizes independent changes in multiple outcome measures over time.
Setting
Four memory clinics in the United States and Europe.
Participants
517 patients with probable Alzheimer’s disease.
Measurements
Columbia University Scale for Psychopathology, modified Mini-Mental State Exam, Dependence Scale.
Results
Both psychosis and depressed mood at study entry were associated with worse subsequent cognitive decline. Independent of cognitive decline, initial psychosis was associated with worse subsequent increases in dependence. Rates of increase in agitation/aggression separately correlated with rates of declines in both cognition and independence.
Conclusions
Although purely observational, findings support the poor prognosis associated with psychosis and depression in AD. Results also show that agitation/aggression tracks declines in cognition and independence independently over time. Targeted intervention for individual BPSD, particularly psychosis, could have broad impacts on not only patient well-being, but also care costs and family burden.
doi:10.1016/j.jagp.2013.03.014
PMCID: PMC3858495  PMID: 23871118
dementia; statistical modeling; depression
24.  Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community 
Neurology  2015;84(2):182-189.
Objective:
To determine the predictive utility of baseline odor identification deficits for future cognitive decline and the diagnosis of Alzheimer disease (AD) dementia.
Methods:
In a multiethnic community cohort in North Manhattan, NY, 1,037 participants without dementia were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). In 757 participants, follow-up occurred at 2 years and 4 years.
Results:
In logistic regression analyses, lower baseline UPSIT scores were associated with cognitive decline (relative risk 1.067 per point interval; 95% confidence interval [CI] 1.040, 1.095; p < 0.0001), and remained significant (relative risk 1.065 per point interval; 95% CI 1.034, 1.095; p < 0.0001) after including covariates. UPSIT, but not Selective Reminding Test–total immediate recall, predicted cognitive decline in participants without baseline cognitive impairment. During follow-up, 101 participants transitioned to AD dementia. In discrete time survival analyses, lower baseline UPSIT scores were associated with transition to AD dementia (hazard ratio 1.099 per point interval; 95% CI 1.067, 1.131; p < 0.0001), and remained highly significant (hazard ratio 1.072 per point interval; 95% CI 1.036, 1.109; p < 0.0001) after including demographic, cognitive, and functional covariates.
Conclusions:
Impairment in odor identification was superior to deficits in verbal episodic memory in predicting cognitive decline in cognitively intact participants. The findings support the cross-cultural use of a relatively inexpensive odor identification test as an early biomarker of cognitive decline and AD dementia. Such testing may have the potential to select/stratify patients in treatment trials of cognitively impaired patients or prevention trials in cognitively intact individuals.
doi:10.1212/WNL.0000000000001132
PMCID: PMC4336090  PMID: 25471394
25.  Reconsidering harbingers of dementia: Progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence 
Neurobiology of aging  2014;36(1):27-32.
Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted MRI, in the pathogenesis and diagnosis of Alzheimer's disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the current study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy, cortical thickness). Three hundred three non-demented older adults (mean age = 79.24±5.29) received high-resolution MRI at baseline and then again 4.6 years (SD=1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling (SEM), we calculated latent difference scores of parietal/non-parietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the SEM framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH, in addition to degenerative changes in the medial temporal lobe, predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD.
doi:10.1016/j.neurobiolaging.2014.07.019
PMCID: PMC4268124  PMID: 25155654

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