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Cognitive decline associated with pathological burden in primary age-related tauopathy.

ABSTRACT: INTRODUCTION:Primary age-related tauopathy (PART) is a neuropathological diagnosis characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. Although most individuals over 50 years of age have evidence of NFTs, the clinical and cognitive consequences of PART are not known. METHODS:We evaluated 226 neuropathologically confirmed PART cases from the National Alzheimer's Coordinating Center database who participated in a total of 846 longitudinal neuropsychological assessments from the Alzheimer's Disease Center program's Uniform Data Set. Mixed-effects statistical models tested whether cognitive decline was associated with Braak stage NFT burden. RESULTS:Higher stages of NFT burden in PART, with no evidence or minimal evidence of amyloid pathology, were associated with more rapid decline on tasks involving episodic and semantic memory along with tests of processing speed and attention. DISCUSSION:We conclude that PART has cognitive consequences that should be considered in the context of emerging tau-targeted therapies in age-associated neurodegenerative diseases.

SUBMITTER: Jefferson-George KS

PROVIDER: S-EPMC5585025 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Cognitive decline associated with pathological burden in primary age-related tauopathy.

Jefferson-George Kyra S KS Wolk David A DA Lee Edward B EB McMillan Corey T CT

Alzheimer's & dementia : the journal of the Alzheimer's Association 20170316 9

<h4>Introduction</h4>Primary age-related tauopathy (PART) is a neuropathological diagnosis characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. Although most individuals over 50 years of age have evidence of NFTs, the clinical and cognitive consequences of PART are not known.<h4>Methods</h4>We evaluated 226 neuropathologically confirmed PART cases from the National Alzheimer's Coordinating Center database who participated in a total of 846 longitudinal ...[more]

PMID: 28322204

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Project description:Primary age-related tauopathy is increasingly recognized as a separate neuropathological entity different from Alzheimer's disease. Both share the neuropathological features of tau aggregates and neuronal loss in the temporal lobe, but primary age-related tauopathy lacks the requisite amyloid plaques central to Alzheimer's disease. While both have similar clinical presentations, individuals with symptomatic primary age-related tauopathy are commonly of more advanced ages with milder cognitive dysfunction. Direct comparison of the neuropsychological trajectories of primary age-related tauopathy and Alzheimer's disease has not been thoroughly evaluated and thus, our objective was to determine how cognitive decline differs longitudinally between these two conditions after the onset of clinical symptoms. Data were obtained from the National Alzheimer's Coordinating Center on participants with mild cognitive impairment at baseline and either no neuritic plaques (i.e. primary age-related tauopathy) or moderate to frequent neuritic plaques (i.e. Alzheimer neuropathological change) at subsequent autopsy. For patients with Alzheimer's disease and primary age-related tauopathy, we compared rates of decline in the sum of boxes score from the CDR® Dementia Staging Instrument and in five cognitive domains (episodic memory, attention/working memory, executive function, language/semantic memory, and global composite) using z-scores for neuropsychological tests that were calculated based on scores for participants with normal cognition. The differences in rates of change were tested using linear mixed-effects models accounting for clinical centre clustering and repeated measures by individual. Models were adjusted for sex, age, education, baseline test score, Braak stage, apolipoprotein ε4 (APOE ε4) carrier status, family history of cognitive impairment, and history of stroke, hypertension, or diabetes. We identified 578 participants with a global CDR of 0.5 (i.e. mild cognitive impairment) at baseline, 126 with primary age-related tauopathy and 452 with Alzheimer's disease. Examining the difference in rates of change in CDR sum of boxes and in all domain scores, participants with Alzheimer's disease had a significantly steeper decline after becoming clinically symptomatic than those with primary age-related tauopathy. This remained true after adjusting for covariates. The results of this analysis corroborate previous studies showing that primary age-related tauopathy has slower cognitive decline than Alzheimer's disease across multiple neuropsychological domains, thus adding to the understanding of the neuropsychological burden in primary age-related tauopathy. The study provides further evidence to support the hypothesis that primary age-related tauopathy has distinct neuropathological and clinical features compared to Alzheimer's disease.

Project description:Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Project description:Importance:The ability to explore associations between reports of subjective cognitive decline (SCD) and biomarkers of early Alzheimer disease (AD) pathophysiologic processes (accumulation of neocortical ?-amyloid [A?] and tau) provides an important opportunity to understand the basis of SCD and AD risk. Objective:To examine associations between SCD and global A? and tau burdens in regions of interest in clinically healthy older adults. Design, Setting, and Participants:This imaging substudy of the Harvard Aging Brain Study included 133 clinically healthy older participants (Clinical Dementia Rating Scale global scores of 0) participating in the Harvard Aging Brain Study who underwent cross-sectional flortaucipir F 18 (previously known as AV 1451, T807) positron emission tomography (FTP-PET) imaging for tau and Pittsburgh compound B carbon 11-labeled PET (PiB-PET) imaging for A?. The following 2 regions for tau burden were identified: the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with AD-related pathologic mechanisms. Data were collected from June 11, 2012, through April 7, 2016. Main Outcomes and Measures:Subjective cognitive decline was measured using a previously published method of z-transforming subscales from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire. The A? level was measured according to a summary distribution volume ratio of frontal, lateral temporal and parietal, and retrosplenial PiB-PET tracer uptake. The FTP-PET measures were computed as standardized uptake value ratios. Linear regression models focused on main and interactive effects of A?, entorhinal cortical, and inferior temporal tau on SCD, controlling for age, sex, educational attainment, and Geriatric Depression Scale score. Results:Of the 133 participants, 75 (56.3%) were women and 58 (43.6%) were men; mean (SD) age was 76 (6.9) years (range, 55-90 years). Thirty-nine participants (29.3%) exhibited a high A? burden. Greater SCD was associated with increasing entorhinal cortical tau burden (??=?0.35; 95% CI, 0.19-.52; P?<?.001) and A? burden (??=?0.24; 95% CI, 0.08-.40; P?=?.005), but not inferior temporal tau burden (??=?0.10; 95% CI, -0.08 to 0.28; P?=?.27). This association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for A? burden (??=?0.36; 95% CI, 0.15-.58; P?=?.001), and no interaction influenced SCD (??=?-0.36; 95% CI, -0.34 to 0.09; P?=?.25). An exploratory post hoc whole-brain analysis also indicated that SCD was predominantly associated with greater tau burden in the entorhinal cortex. Conclusions and Relevance:Subjective cognitive decline is indicative of accumulation of early tauopathy in the medial temporal lobe, specifically in the entorhinal cortex, and to a lesser extent, elevated global levels of A?. Our findings suggest multiple underlying pathways that motivate SCD that do not necessarily interact to influence SCD endorsement. As such, multiple biological factors must be considered when assessing SCD in clinically healthy older adults.

Dataset Information

Cognitive decline associated with pathological burden in primary age-related tauopathy.

Publications

Cognitive decline associated with pathological burden in primary age-related tauopathy.

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