Kathryn V. Papp

Immediate and delayed effects of cognitive interventions in healthy elderly: a review of current literature and future directions.

Research on the potential effects of cognitive intervention in healthy elderly has been motivated by (1) the apparent effectiveness of cognitive rehabilitation in Alzheimers disease (AD) patients; (2) the face validity of bolstering skills eventually burdened by disease; (3) interest in low‐cost/noninvasive methods of preventing or delaying onset of disease; (4) the epidemiologic research suggesting protective effects of educational attainment and lifelong participation in cognitively stimulating activities; (5) the burgeoning industry of brain training products and requisite media attention; and (6) the aging world population.

Effect of Tai Chi on Cognitive Performance in Older Adults: Systematic Review and Meta‐Analysis

To summarize and critically evaluate research on the effects of Tai Chi on cognitive function in older adults.

Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

Importance A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear. Objective To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline). Design, Setting, and Participants This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ-/ND-), 1 (Aβ+/ND-), and 2 (Aβ+/ND+) and SNAP (Aβ-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016. Main Outcomes and Measures Evidence of amyloid-independent tau deposition and/or cognitive decline. Results Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = -0.005 [SE, 0.036]; parahippocampal gyrus, β = -0.001 [SE, 0.027]; and inferior temporal lobe, β = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = -0.125 [SE, 0.041]; parahippocampal gyrus, β = -0.074 [SE, 0.030]; and inferior temporal lobe, β = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = -0.239 [SE, 0.042]; stage 1, β = -0.242 [SE, 0.051]; and SNAP, β = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = -0.082 [SE, 0.037]; P = .03). Conclusions and Relevance In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ- CN individuals.

Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline: Tau, Amyloid, FDG, and Memory in Normal Aging

The aim of this article was to evaluate in normal older adults and preclinical Alzheimers disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline.

Biological Markers of Cognition in Prodromal Huntington's Disease: A Review.

Huntingtons disease (HD), an autosomal-dominant genetic disorder, has historically been viewed as a degenerative movement disorder but it also includes psychiatric symptoms and progressive cognitive decline. There has been a lack of consensus in the literature about whether or not cognitive signs can be detected in carriers before clinical (motor) onset of the disease, i.e., prodromal HD. However, recently validated mathematical formulas to estimate age of clinical onset, refined over the past 5-7 years, have allowed researchers to overcome the methodological limitation of treating all prodromal carriers as a homogenous high-risk group (i.e., whether they may be 2 or 15 years from diagnosis). Here we review 23 articles on the HD prodrome, all of which related cognition to a biological marker of disease burden (i.e., genetic load, neuroimaging). All studies found at least one cognitive domain was associated with disease burden in prodromal HD participants. There was greater variability in both the detection and cognitive domain affected in those farther from onset (or those with less pathology) while most studies reliably found declines in visuomotor performance and working memory in those closer to onset. These findings indicate that cognitive signs can be reliably detected in the HD prodrome when comparing cognition to additional disease markers, however, there continues to be significant variability on cognitive findings among large and methodologically rigorous studies. This may reflect true heterogeneity in the prodromal HD phenotype which must be further explored by analyzing intra-individual variance, determining demographic risk factors associated with decline/protection, and examining if particular HD families exhibit distinct cognitive profiles. These and additional future directions are discussed.

Harvard Aging Brain Study: Dataset and accessibility

ABSTRACT The Harvard Aging Brain Study is sharing its data with the global research community. The longitudinal dataset consists of a 284‐subject cohort with the following modalities acquired: demographics, clinical assessment, comprehensive neuropsychological testing, clinical biomarkers, and neuroimaging. To promote more extensive analyses, imaging data was designed to be compatible with other publicly available datasets. A cloud‐based system enables access to interested researchers with blinded data available contingent upon completion of a data usage agreement and administrative approval. Data collection is ongoing and currently in its fifth year. HIGHLIGHTSThe Harvard Aging Brain Study (HABS) is releasing its dataset for public access.HABS is a longitudinal study of aging and preclinical Alzheimers dementia.Imaging data is compatible with related datasets.Data collection is ongoing and in its fifth year.

Free and cued memory in relation to biomarker-defined abnormalities in clinically normal older adults and those at risk for Alzheimer's disease.

OBJECTIVES Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimers disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD. METHODS A total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Aβ-/ND-), Stage 1 (Aβ+/ND-), Stage 2 (Aβ+/ND+), and suspected non-Alzheimers associated pathology (SNAP; Aβ-/ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT). RESULTS Global memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed. CONCLUSIONS Clinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design.

Processing speed in normal aging: Effects of white matter hyperintensities and hippocampal volume loss

ABSTRACT Changes in cognitive functioning are said to be part of normal aging. Quantitative MRI has made it possible to measure structural brain changes during aging which may underlie these decrements which include slowed information processing and memory loss. Much has been written on white matter hyperintensities (WMH), which are associated with cognitive deficits on tasks requiring processing speed and executive functioning, and hippocampal volume loss, which is associated with memory decline. Here we examine volumetric MRI measures of WMH and hippocampal volume loss together in relation to neuropsychological tests considered to be measures of executive functioning and processing speed in 81 non-demented elderly individuals, aged 75–90. Correlational analysis showed that when controlling for age, both greater WMH volume and smaller hippocampal volume were correlated with slower performances on most tests with the exception of a battery of continuous performance tests in which only WMH was correlated with slower reaction time (RT). We then performed a series of hierarchical multiple regression analyses to examine the independent contributions of greater WMH volume and reduced hippocampal volume to executive functioning and processing speed. The results showed that for the four measures requiring executive functioning and speed of processing, WMH volume and hippocampal volume combined predicted between 21.4% and 37% of the explained variance. These results suggest that WM integrity and hippocampal volume influence cognitive decline independently on tasks involving processing speed and executive function independent of age.

Biomarker validation of a decline in semantic processing in preclinical Alzheimer's disease.

OBJECTIVE Differentially worse performance on category versus letter fluency suggests greater semantic versus retrieval difficulties. This discrepancy, combined with reduced episodic memory, has widespread clinical utility in diagnosing Alzheimers disease (AD). Our objective was to investigate whether changes in semantic processing, as measured by the discrepancy between category and letter fluency, was detectable in preclinical AD: in clinically normal older adults with abnormal β-amyloid (Aβ) deposition on positron emission tomography (PET) neuroimaging. METHOD Clinically normal older adults (mean Mini Mental State Exam (MMSE) score = 29) were classified as Aβ+ (n = 70) or Aβ- (n = 205) using Pittsburgh Compound B-(PET) imaging. Participants completed letter fluency (FAS; word generation to letters F-A-S) and category fluency (CAT; word generation to animals, vegetables, fruits) annually (mean follow-up = 2.42 years). The effect of Aβ status on fluency over time was examined using linear mixed models controlling for age, sex, and education. To dissociate effects related to semantic (CAT) versus retrieval processes (CAT and FAS), we repeated models predicting CAT over time, controlling for FAS and likewise for CAT controlling for FAS. RESULTS At baseline, the Aβ+ group performed better on FAS compared with the Aβ- group but comparably on CAT. Longitudinally, the Aβ+ group demonstrated greater decline on CAT compared with the Aβ- group (p = .0011). This finding remained significant even when covarying for FAS (p = .0107). Aβ+ participants similarly declined compared with Aβ- participants on FAS (p = .0112), but this effect became insignificant when covarying for CAT (p = .1607). CONCLUSION These findings provide biomarker validation for the greater specificity of declines in category versus letter fluency to underlying AD pathology. Our results also suggest that changes in semantic processing occur earlier in the AD trajectory than previously hypothesized. (PsycINFO Database Record

Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals

Animal models of Alzheimer’s disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid’s crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer’s disease.Using longitudinal multimodal imaging data collected in healthy older individuals, Jacobs et al. provide in vivo evidence in humans that amyloid deposition facilitates tau spread along connected pathways and memory decline.