Objectives

Abnormally high glucose levels (dysglycemia) increase with age. Epidemiological studies suggest that dysglycemia is a risk factor for cognitive impairment but the underlying pathophysiological mechanisms remain unclear. The objective of this study was to examine the relation of dysglycemia clinical categories (normal glucose tolerance (NGT), pre-diabetes, undiagnosed diabetes, known diabetes) with brain structure in older adults. We also assessed the relation between dysglycemia and cognitive performance.

Design

Cross-sectional and longitudinal cohort study.

Setting

Northern Manhattan (Washington Heights, Hamilton Heights, and Inwood).

Participants

Medicare recipients 65 years and older.

Measurements

Dysglycemia categories were based on HBA1c or history of type 2 diabetes (diabetes). Brain structure (brain infarcts, white matter hyperintensities (WMH) volume, total gray matter volume, total white matter volume, total hippocampus volume) was assessed with brain magnetic resonance imaging; cognitive function (memory, language and visuospatial function, speed) was assessed with a validated neuropsychological battery.

Results

Dysglycemia, defined with HbA1c as a continuous variable or categorically as pre-diabetes and diabetes, was associated with a higher number of brain infarcts, WMH volume and decreased total white matter, gray matter and hippocampus volumes cross-sectionally, and a significant decline in gray matter volume longitudinally. Dysglycemia was also associated with lower performance in language, speed and visuospatial function although these associations were attenuated when adjusted for education, APOE-ε4, ethnic group and vascular risk factors.

Conclusion

Our results suggest that dysglycemia affects brain structure and cognition even in elderly survivors, evidenced by higher cerebrovascular disease, lower white and gray matter volume, and worse language and visuospatial function and cognitive speed.

INTRODUCTION: Chronic exposure to stress has been shown to impact a wide range of health-related outcomes in older adults. Despite extensive animal literature revealing deleterious effects of biological markers of stress on the dentate gyrus subfield of the hippocampus, links between hippocampal subfields and psychological stress have not been studied in humans. This study examined the relationship between perceived stress and hippocampal subfield volumes among racially/ethnically diverse older adults. METHODS AND MATERIALS: Between July 2011 and March 2014, 116 nondemented participants were consecutively drawn from the Einstein Aging Study, an ongoing community-based sample of individuals over the age of 70 residing in Bronx, New York. All participants completed the Perceived Stress Scale, Geriatric Depression Scale, and underwent 3.0 T MRI. FreeSurfer was used to derive total hippocampal volume, hippocampal subfield volumes (CA1, CA2/CA3, CA4/Dentate Gyrus (CA4/DG), and subiculum), entorhinal cortex volume, whole brain volume, and total intracranial volume. RESULTS: Linear regression analyses revealed that higher levels of perceived stress were associated with smaller total hippocampal volume (β = -0.20, t = -2.40, p = 0.02), smaller CA2/CA3 volumes (β = -0.18, t = -2.24, p = 0.03) and smaller CA4/DG volumes (β = -0.19, t = -2.28, p = 0.03) after controlling for total intracranial volume, age, gender, and race. These findings remained unchanged after removal of individuals with clinically significant symptoms of depression. DISCUSSION: Our findings provide evidence of a relationship between a direct indicator of psychological stress and specific hippocampal subfield volumes in elderly individuals. These results highlight the importance of clinical screening for chronic stress in otherwise healthy older adults.

Objective

To determine the effect of three psycholinguistic variables-lexical frequency, age of acquisition (AoA), and neighborhood density (ND)-on lexical-semantic processing in individuals with non-fluent (nfvPPA), logopenic (lvPPA), and semantic primary progressive aphasia (svPPA). Identifying the scope and independence of these features can provide valuable information about the organization of words in our mind and brain.

Method

We administered a lexical decision task-with words carefully selected to permit distinguishing lexical frequency, AoA, and orthographic ND effects-to 41 individuals with PPA (13 nfvPPA, 14 lvPPA, 14 svPPA) and 25 controls.

Results

Of the psycholinguistic variables studied, lexical frequency had the largest influence on lexical-semantic processing, but AoA and ND also played an independent role. The results reflect a brain-language relationship with different proportional effects of frequency, AoA, and ND in the PPA variants, in a pattern that is consistent with the organization of the mental lexicon. Individuals with nfvPPA and lvPPA experienced an ND effect consistent with the role of inferior frontal and temporoparietal regions in lexical analysis and word form processing. By contrast, individuals with svPPA experienced an AoA effect consistent with the role of the anterior temporal lobe in semantic processing.

Conclusions

The findings are in line with a hierarchical mental lexicon structure with a conceptual (semantic) and a lexeme (word-form) level, such that a selective deficit at one of these levels of the mental lexicon manifests differently in lexical-semantic processing performance, consistent with the affected language-specific brain region in each PPA variant.

A recently published framework for the diagnosis of Alzheimer's disease (AD) in research studies would allow diagnosis on the sole basis of two biomarkers (β-amyloid and pathologic tau), even in people with no objective or subjective memory or cognitive changes. This revision will have substantial implications for future Alzheimer's research, and the changes should be rigorously evaluated before widespread adoption. We propose three principles for evaluating any revision to diagnostic frameworks for AD: (1) does the revision improve the validity of the diagnosis; (2) does the revision improve the reliability or reduce the expense of the diagnosis; and (3) will the revision foster innovative and rigorous research across populations. The new diagnostic framework is unlikely to achieve any of these goals. Instead, it has the potential to handicap future researchers, and slow progress towards identifying effective strategies to prevent or treat AD.

Verbal fluency tasks are generally thought to be mediated by frontal brain regions for letter fluency and temporal regions for category fluency. This idea, however, is primarily based on lesion studies and adapted versions of the fluency tasks in functional neuroimaging, without fundamental evidence from structural neuroimaging in healthy individuals. We investigated the cortical structural correlates of letter and category fluency, including overlapping and different regions, in 505 individuals who participated in a community-based study of healthy aging. The correlation between cortical thickness and verbal fluency in whole-brain analyses revealed distinct cortical signatures for letter fluency, primarily in frontal regions, and category fluency, in frontal and temporal-parietal regions. There was a dissociation in the left inferior frontal gyrus between letter and category fluency, with increased thickness in the posterior-dorsal versus anterior-ventral parts, respectively. These results distinguish the detailed anatomical correlates for verbal fluency within the coarse frontal-temporal distinction inferred from lesion studies and among the mixture of regions identified in functional neuroimaging. The evidence for the anatomical substrates of letter and category fluency, each recruiting slightly different language and cognitive processes, can serve both clinical applications as well as a deeper theoretical understanding of the organization of the cerebral cortex.

In normal aging, the cognitive domain of semantic memory remains preserved, while the domain of episodic memory declines to some extent. In Alzheimers disease dementia, both semantic and episodic memory become impaired early in the disease process. Given the need to develop sensitive and accessible cognitive markers for early detection of dementia, we investigated among older adults without dementia whether item-level metrics of semantic fluency related to episodic memory decline above and beyond existing neuropsychological measures and total fluency score. Participants were drawn from the community-based Washington Heights-Inwood Columbia Aging Project cohort (N = 583 English speakers, Mage = 76.3 ± 6.8) followed up to five visits across up to 11 years. We examined the association of semantic fluency metrics with subsequent declines in memory performance using latent growth curve models covaried for age and recruitment wave. Results showed that item-level metrics (e.g., lexical frequency, age of acquisition, and semantic neighborhood density) were associated with a decline in episodic memory-even when covarying for other cognitive tests-while the standard total score was not. Moderation analyses showed that the relationship of semantic fluency metrics with memory decline did not differ across race, sex/gender, or education. In conclusion, item-level data hold a wealth of information with potential to reveal subtle semantic memory impairment, which tracks with episodic memory impairment, among older adults without dementia beyond existing neuropsychological measures. Implementation of psycholinguistic metrics may point to cognitive tools that have better prognostic value or are more sensitive to cognitive change in the context of clinical trials or observational studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background/Study Context: Magnetic resonance imaging (MRI) markers of cerebrovascular disease and atrophy are common in older adults and are associated with cognitive and medical burden. However, the extent to which they are related to health care expenditures has not been examined. We studied whether increased Medicare expenditures were associated with brain markers of atrophy and cerebrovascular disease in older adults.

Methods

A subset of participants (n = 592; mean age = 80 years; 66% women) from the Washington Heights Inwood Columbia Aging Project (WHICAP), a community-based observational study of aging in upper Manhattan, received high-resolution MRI and had Medicare expenditure data on file. We examined the relationship of common markers of cerebrovascular disease (i.e., white matter hyperintensities and presence of infarcts) and atrophy (i.e., whole brain and hippocampal volume) with Medicare expenditure data averaged over a 10-year period. Main outcome measures were (a) mean Medicare payment per year across the 10-year interval; (b) mean payment for outpatient care per year; and (c) mean payment for inpatient care per year of visit. In addition, we calculated the ratio of mean inpatient spending to mean outpatient spending as well as the ratio of mean inpatient spending to mean total Medicare spending.

Results

Increased Medicare spending was associated with higher white matter hyperintensity volume, presence of cerebral infarcts, and smaller total brain volume. When examining specific components of Medicare expenditures, we found that inpatient spending was strongly associated with white matter hyperintensity volume and that increased ratios of inpatient to outpatient and inpatient to total spending were associated with infarcts.

Conclusion

Medicare costs are related to common markers of "silent" cerebrovascular disease and atrophy.

Objective

To investigate genetic variants influencing white matter hyperintensities (WMHs) in the understudied Hispanic population.

Methods

Using 6.8 million single nucleotide polymorphisms (SNPs), we conducted a genome-wide association study (GWAS) to identify SNPs associated with WMH volume (WMHV) in 922 Hispanics who underwent brain MRI as a cross-section of 2 community-based cohorts in the Northern Manhattan Study and the Washington Heights-Inwood Columbia Aging Project. Multiple linear modeling with PLINK was performed to examine the additive genetic effects on ln(WMHV) after controlling for age, sex, total intracranial volume, and principal components of ancestry. Gene-based tests of association were performed using VEGAS. Replication was performed in independent samples of Europeans, African Americans, and Asians.

Results

From the SNP analysis, a total of 17 independent SNPs in 7 genes had suggestive evidence of association with WMHV in Hispanics (p < 1 × 10^-5) and 5 genes from the gene-based analysis with p < 1 × 10^-3. One SNP (rs9957475 in GATA6) and 1 gene (UBE2C) demonstrated evidence of association (p < 0.05) in the African American sample. Four SNPs with p < 1 × 10^-5 were shown to affect binding of SPI1 using RegulomeDB.

Conclusions

This GWAS of 2 community-based Hispanic cohorts revealed several novel WMH-associated genetic variants. Further replication is needed in independent Hispanic samples to validate these suggestive associations, and fine mapping is needed to pinpoint causal variants.

The amyloid cascade model of Alzheimer's disease posits the primacy of amyloid beta deposition preceding tau-mediated neurofibrillary tangle formation. The amyloid-tau-neurodegeneration biomarker-only diagnostic framework similarly requires the presence of amyloid beta for a diagnosis on the Alzheimer's continuum. However, medial temporal lobe tau pathology in the absence of amyloid beta is frequently observed at autopsy in cognitively normal individuals, a phenomenon that may reflect a consequence of aging and has been labelled 'primary age-related tauopathy'. Alternatively, others argue that this tauopathy reflects an early stage of the developmental continuum leading to Alzheimer's disease. We used positron emission tomography imaging to investigate amyloid beta and tau positivity and associations with cognition to better inform the conceptualization of biomarker changes in Alzheimer's pathogenesis. Five hundred twenty-three individuals from the Alzheimer's Disease Neuroimaging Initiative who had undergone flortaucipir positron emission tomography imaging were selected to derive positron emission tomography positivity thresholds using conditional inference decision tree regression. A subsample of 301 individuals without dementia (i.e. those with normal cognition or mild cognitive impairment) had also undergone florbetapir positron emission tomography imaging within 12 months and were categorized into one of the four groups based on cortical amyloid and Braak stage I/II tau positivity: A-/T-, A+/T-, A-/T+, or A+/T+. Tau positivity in the absence of amyloid beta positivity (i.e. A-/T+) comprised the largest group, representing 45% of the sample. In contrast, only 6% of the sample was identified as A+/T-, and the remainder of the sample fell into A-/T- (22%) or A+/T+ (27%) categories. A-/T- and A+/T- groups had the best cognitive performances across memory, language and executive function; the A-/T+ group showed small-to-moderate relative decreases in cognition; and the A+/T+ group had the worst cognitive performances. Furthermore, there were negative associations between Braak stage I/II tau values and all cognitive domains only in the A-/T+ and A+/T+ groups, with strongest associations for the A+/T+ group. Among our sample of older adults across the Alzheimer's pathological spectrum, 7-fold fewer individuals have positron emission tomography evidence of amyloid beta pathology in the absence of tau pathology than the converse, challenging prevailing models of amyloid beta's primacy in Alzheimer's pathogenesis. Given that cognitive performance in the A-/T+ group was poorer than in individuals without either pathology, our results suggest that medial temporal lobe tau without cortical amyloid beta may reflect an early stage on the Alzheimer's pathological continuum.

Objective

Accurate identification of the earliest cognitive changes associated with Alzheimer's disease (AD) is critically needed. Item-level information within tests of category fluency, such as lexical frequency, harbors valuable information about the integrity of semantic networks affected early in AD. To determine the potential of lexical frequency as a cognitive marker of AD risk, we investigated whether lexical frequency of animal fluency output differentiated APOE ε4 carriers from noncarriers in a cross-sectional design among older African-American adults without dementia.

Method

We analyzed animal fluency performance using mean number of items and mean lexical frequency among 230 cognitively normal African Americans with and without the APOE ε4 allele.

Results

Lexical frequency was higher in APOE ε4 carriers than noncarriers when analyzed as a mean score and within time bins. In contrast, we found no group difference in the number of items produced. Lexical frequency was particularly sensitive to ε4 status after the first 10 s of the 60-s animal fluency task.

Conclusion

Our results suggest that psycholinguistic features may hold value as a cognitive biomarker for identifying people at high risk of AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).