Longitudinal tau accumulation and atrophy in aging and alzheimer disease

Abstract

Objective: To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy. Methods: Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB] + , age = 77.6 AE 4.6 years, 25 female [F]/17 male [M]) and 19 PiB + patients with AD (age = 63.1 AE 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated. Results: Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status. Interpretation: Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy.

Tau pathology in cognitively normal older adults

“…This interpretation is supported by the finding of a previous longitudinal tau PET study showing that amyloid1 individuals had steeper tau tracer retention increases in basal and midtemporal, retrosplenial, posterior cingulate, and entorhinal cortex [38]. Another study of longitudinal tau accumulation showed increases in 18 F-AV-1451 retention over 1-3 years in temporal and medial parietal areas in healthy older adults [39]. These findings were further expanded on by a recent study reporting that individuals with baseline 18 F-AV-1451 SUVRs in the second quartile exhibited tau tracer retention increases in inferior and lateral temporal cortex and in posterior cingulate over 18 months [15].…”

Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease

“…However, in many neurodegenerative disorders, brain atrophy is preceded and perhaps caused by the aggregation of pathological agents. In Alzheimer’s disease, the presence of tau is closely linked to [7, 8], and likely precedes [8, 11], gray matter atrophy. However, because gray matter degeneration observed in Alzheimer’s dementia may be caused by many sources other than Alzheimer’s pathology, gray matter degeneration itself cannot be used as proxy for tau (e.g.…”

“…Tau tangles are a pathological hallmark of AD, but they are neither specific to AD, nor to neurodegenerative disease in general. The process of aging appears to lead inevitably to the accumulation of tau tangles in the medial temporal lobe and occasionally beyond, a phenomenon known as primary age-related tauopathy (PART) [9], and in vivo evidence for the longitudinal accumulation of tangles in healthy elderly has been observed [11]. While PART may result in subtle insults to cognition and brain health [52], there is still debate as to whether PART and AD are distinct processes [53].…”

“…In contrast, tau neurofibrillary tangles are strongly correlated with local neurodegeneration and, in turn, cognitive impairment [7, 8]. However, tau tangle aggregation in the medial temporal lobes is a common and fairly innocuous feature of normal aging [9, 10, 11]. Frank cognitive impairment often coincides with the spreading of tau tangles out of the medial temporal lobes and into the surrounding isocortex, a process that animal models have suggested may be potentiated or accelerated by the presence of β -amyloid plaques [12, 13].…”

Time between milestone events in the Alzheimer’s disease amyloid cascade

“…Cross-sectional studies showed early tau deposition in cognitively healthy elderly (with or without significant A pathology) in temporal and medial parietal regions, most dominant in entorhinal and parahippocampal cortex, the amygdala and inferior temporal cortex. Longitudinal studies further suggest that cognitively healthy elderly accumulate tau in the medial temporal and medial parietal lobe, while (A positive) AD dementia patients increased in tau primarily in the frontal lobe (Harrison et al, 2018). The spread of tau beyond the MTL to the parietal lobe and other regions may be a critical milestone in the progression of AD.…”