Lesion‐network mapping of tau accumulation is predictive of domain‐specific cognitive deficits in Alzheimer’s disease

Abstract

AbstractBackgroundClinical heterogeneity is present in a substantial portion of patients with Alzheimer’s disease (AD). Understanding the underlying pathological differences is an unmet goal towards patient‐tailored medicine in AD. We hypothesized that the brain localization of tau deposition, a key driver of neurodegeneration, is predictive of which cognitive domain predominantly affected. We adopted a symptom‐network mapping approach applied to tau PET, reasoning that the functional connectivity of local tau PET to a cognitive‐domain specific network is predictive of which cognitive ability is impaired.MethodWe included 448 participants consisting of 234 amyloid‐PET‐negative cognitively normal subjects (CN‐Aβ‐), 95 amyloid‐PET‐positive mild cognitive impairment (MCI‐Aβ+) and 119 amyloid‐PET‐positive cognitively normal (CN‐Aβ+) patients. AV1451 tau‐PET was parcellated using the 400 ROI Schaefer atlas. Adopting a lesion‐network mapping approach (Darby et al. Brain 2018), we computed in the Aβ+ participants, subject‐level W‐scores, i.e. the standardized deviation of tau‐PET ROI values from those in CN‐Aβ‐. We computed for each subject and tau‐PET lesion (ROI W‐score > 2) the seed‐based connectivity based on resting‐state fMRI data from Human Connectome Project (n = 1000), rendering patient‐level lesion network maps. In order to identify symptom‐specific lesion‐networks, we regressed composite scores of episodic memory (ADNI‐MEM), executive function (ADNI‐EF), and language (ADNI‐LAN) onto the subject‐level lesion‐network maps, using partial least squares.ResultSubstantial variability in the tau‐PET lesions locations between subjects were observed (Figure 1A), with highest overlaps observed in the lateral and medial temporal cortex and posterior cingulate (Figure 1B). We found for each cognitive domain, a specific tau‐lesion network map: stronger connectivity of tau‐PET lesions to lateral temporal, posterior parietal and lateral prefrontal cortex were associated with lower episodic memory (ADNI‐MEM). In contrast, stronger connectivity to pre‐ and post‐central gyri and superior parietal cortex was associated with lower executive function (ADNI‐EF), and stronger connectivity to inferior frontal and auditory cortex was associated with language function, suggesting the presence of cognitive‐domain specific networks of tau lesions.ConclusionWe identified functional network patterns of local tau PET accumulation that map onto impairment in specific cognitive domains. This approach thus contributes to precision medicine guided prediction of specific cognitive impairments in AD.