This study examined relations among neuritic and diffuse plaques, neurofibrillary tangles, age, and apolipoprotein E (APOE) in 2 large samples of neuropathology cases, the Religious Orders Study and the Memory and Aging Project. Cognitive status ranged from normal to demented and AD neuropathology ranged from none to severe. Confirmatory factor analysis identified a best-fitting 4-factor solution to describe interrelationships among plaques and tangles: a global neuritic plaque factor; a global diffuse plaque factor; a factor defined by medial temporal neurofibrillary tangles; and a neocortical tangle factor. Results supported a hypothesis that neuritic plaques mediate the association of age and APOE with neocortical tangles, and similarly mediate the effect of APOE on medial temporal tangles. However, medial temporal tangles were related to age independent of neuritic plaques. These results support a primary amyloid-based AD process that accounts for neocortical tangles and makes the largest contribution to medial temporal tangles. A second, age-related but non-amyloid process likely contributes to medial temporal lobe tangles.

Traumatic brain injury (TBI) commonly occurs in civilian and military populations. Some epidemiologic studies previously have associated TBI with an increased risk of Alzheimer disease (AD). Recent clinicopathologic and biomarker studies have failed to confirm the relationship of TBI to the development of AD dementia or pathologic changes, and suggest that other neurodegenerative processes might be linked to TBI. Additional studies are required to determine the long-term consequences of TBI.

This article summarizes a special series of articles from The Advanced Psychometric Methods in Cognitive Aging Research conference, held in June, 2011 at Friday Harbor, Washington. This conference used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to address cognitive change associated with Alzheimer's disease (AD) and how it related to neuroimaging, genetic, and cerebrospinal fluid biomarkers. The 13 articles in this series present innovative approaches to measuring cognition and studying determinants of cognitive decline in AD.

Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer's Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.

Background

Mechanisms linking cognitive and physical functioning in older adults are unclear. We sought to determine whether brain pathological changes relate to the level or rate of physical performance decline.

Methods

This study analyzed data from 305 participants in the autopsy subcohort of the prospective Adult Changes in Thought (ACT) study. Participants were aged 65+ and free of dementia at enrollment. Physical performance was measured at baseline and every two years using the Short Physical Performance Battery (SPPB). Data from 3174 ACT participants with ≥2 SPPB measurements were used to estimate two physical function measures: 1) rate of SPPB decline defined by intercept and slope; and 2) estimated SPPB 5 years prior to death. Neuropathology findings at autopsy included neurofibrillary tangles (Braak stage), neuritic plaques (CERAD level), presence of amyloid angiopathy, microinfarcts, cystic infarcts, and Lewy bodies. Associations (adjusted for sex, age, body mass index and education) between dichotomized neuropathologic outcomes and SPPB measures were estimated using modified Poisson regression with inverse probability weights (IPW) estimated via Generalized Estimating Equations (GEE). Relative risks for the 20^th, 40^th, and 60^th percentiles (lowest levels and highest rates of decline) relative to the 80th percentile (highest level and lowest rate of decline) were calculated.

Results

Decedents with the least vs. most SPPB decline (slope > 75^th vs. < 25^th percentiles) had higher SPPB scores, and were more likely to be male, older, have higher education, and exercise regularly at baseline. No significant associations were observed between neuropathology findings and rate of SPPB decline. Lower predicted SPPB scores 5 years prior to death were associated with higher risk of microinfarcts (RR = 3.08, 95% confidence interval (CI) 0.93-1.07 for the 20^th vs. 80^th percentiles of SPPB) and significantly higher risk of cystic infarcts (RR = 2.72, 95% CI 1.45-5.57 for 20^th vs. 80^th percentiles of SPPB).

Conclusion

Cystic infarcts and microinfarcts, but not neuropathology findings of Alzheimer's disease, were related to physical performance levels five years before death. No pathology findings were associated with rates of physical performance decline. Physical function levels in the years prior to death may be affected by vascular brain pathologies.

Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint.

Background

We sought to examine whether frailty is associated with dementia, Alzheimer's disease (AD), and non-AD dementia risk.

Methods

This is a prospective population-based cohort derived from an integrated health maintenance organization. The sample consisted of 2,619 participants aged 65 and older without dementia at baseline followed from 1994 to 2010. Frailty was defined as having at least 3 of the following criteria: weakness (grip strength), slowness (walking speed), weight loss, low physical activity, and self-reported exhaustion. Follow-up occurred every 2 years to identify incident dementia, possible or probable AD, and non-AD dementia using standard research criteria. Covariates came from self-report and study measures. We used adjusted Cox proportional hazards models to examine the association between frailty and each outcome.

Results

Over a mean follow-up of 6.5 years, 521 participants developed dementia (of which 448 developed AD). In the model adjusted for age, sex, education, and race, the hazard ratio for frailty was 1.78 (95% confidence interval [CI] 1.32-2.40). In the fully adjusted models, the hazard ratio for frailty was 1.20 for all-cause dementia (95% CI 0.85-1.69), 1.08 for AD (95% CI 0.74-1.57), and 2.57 for non-AD dementia (95% CI 1.08-6.11). For all-cause dementia, we found an interaction between baseline cognitive score and frailty (p = .02); hazard ratio for frailty was 1.78 for those with higher global cognition (95% CI 1.14-2.78) and 0.79 for those with lower global cognition (95% CI 0.50-1.26).

Conclusion

Frailty was associated with dementia when adjusting only for demographic variables but not in the fully adjusted model. Frailty was associated with higher risk of developing non-AD dementia but not AD. Although frailty was not associated with all-cause dementia in the entire sample, an association did exist in participants with higher cognitive scores. Mechanisms underlying these associations remain to be elucidated.

Background and objectives

The aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults.

Methods

Autopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated.

Results

The 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT <90 (n = 418) (mean age at death = 83.5 years) and ACT 90+ (n = 401) (mean age at death = 94.2 years) participants. The ACT 90+ cohort had significantly higher rates of limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), microvascular brain injury (μVBI), and total neuropathologic burden. Independent associations between individual neuropathologic lesions and odds of dementia were similar between all 3 groups, with the exception of μVBI, which was associated with increased dementia risk in the ACT <90 group only (odds ratio 1.5, 95% CI 1.2-1.8, p < 0.001). Weighted PAF scores indicated that eliminating μVBI, although more prevalent in ACT 90+ participants, would have little effect on dementia. Conversely, eliminating μVBI in ACT <90 could theoretically reduce dementia at a similar rate to that of AD neuropathologic change (weighted PAF = 6.1%, 95% CI 3.8-8.4, p = 0.001). Furthermore, reducing LATE-NC in The 90+ Study could potentially reduce dementia to a greater degree (weighted PAF = 5.1%, 95% CI 3.0-7.3, p = 0.001) than either ACT cohort (weighted PAFs = 1.69, 95% CI 0.4-2.7).

Discussion

Our results suggest that specific neuropathologic features may differ in their effect on dementia among nonagenarians and centenarians from cohorts with different selection criteria and study design. Furthermore, microvascular lesions seem to have a more significant effect on dementia in younger compared with older participants. The results from this study demonstrate that different populations may require distinct dementia interventions, underscoring the need for disease-specific biomarkers.

Background

Few studies characterize older adult physical activity and sitting patterns using accurate accelerometer and concurrent posture measures. In this descriptive paper, we report accelerometer data collection protocols, consent rates, and physical behavior measures from a population-based cohort study (Adult Changes in Thought, ACT).

Methods

The ACT study holds enrollment steady at approximately 2000 members of Kaiser Permanente Washington aged 65+ without dementia undergoing detailed biennial assessments. In 2016 the ACT-Activity Monitor (ACT-AM) sub-study was initiated to obtain data from wearing activPAL and ActiGraph devices for 7 days following regular biennial visits. We describe the methods protocol of ACT-AM and present characteristics of people who did and did not consent to wear devices. We compute inverse probability of response weights and incorporate these weights in linear regression models to estimate means and 95% confidence intervals (CI) of device-based pattern metrics, adjusted for wear time and demographic factors, and weighted to account for potential selection bias due to device-wear consent.

Results

Among 1885 eligible ACT participants, 56% agreed to wear both devices (mean age 77 years, 56% female, 89% non-Hispanic white, 91% with post-secondary education). On average, those who agreed to wear devices were younger and healthier. Estimated mean (95% CI) activPAL-derived sitting, standing, and stepping times were 10.2 h/day (603-618 min/day), 3.9 h/day (226-239 min/day), and 1.4 h/day (79-84 min/day), respectively. Estimated mean ActiGraph derived sedentary (Vector Magnitude [VM] < =18 counts/15 s), light intensity (VM 19-518 counts/15 s), and moderate-to-vigorous intensity (VM > 518 counts/15 s) physical activity durations were 9.5 h/day (565-577 min/day), 4.5 h/day (267-276 min/day), and 1.0 h/day (59-64 min/day). Participants who were older, had chronic conditions, and were unable to walk a half-mile had higher sedentary time and less physical activity.

Conclusions

Our recruitment rate demonstrates the feasibility of cohort participants to wear two devices that measure sedentary time and physical activity. Data indicate high levels of sitting time in older adults but also high levels of physical activity using cut-points developed for older adults. These data will help researchers test hypotheses related to physical behavior and health in older adults in the future.

Low perceived social support (SS) negatively impacts health outcomes. We developed a measure of perceived SS for use in HIV care. We sought and categorized legacy items, selecting strongest items within categories. We elicited SS concepts from patients in English/Spanish, coded transcripts to match item pool content, and developed new items for salient unrepresented content. In focus groups, patients prioritized highly-matched items. We conducted cognitive interviews on high-priority items, and validity testing on final items against two legacy measures. From interviews (n = 32), we matched the following concepts: sense of belonging/inclusion; communication; emotional support; feeling accepted by others as a person; companionship; and practical support. We identified a new concept: support from friends/family in remaining healthy. Focus groups (n = 23) prioritized emotional support, communication, and support to remain healthy. Cognitive interviews (n = 30) found items were well-understood. The final 8-item measure performed well with patients (n = 708), with good construct validity. We used an Item Response Theory program to create a 3-item Short Form version of the measure, which captures 96% of patients indicating low social support. We developed the Multifactoral Assessment of Perceived Social Support (MAPSS) and Short Form (MAPSS-SF); brief, clinically relevant, sufficiently unidimensional measures of SS for use in HIV care.