Tau pathology associates with in vivo cortical thinning in Lewy body disorders

Abstract

Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Ab 1-42 > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBDÀAD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBDÀAD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Ab, and alpha-synuclein using digital histopathology in five representative neocortical regions. Results: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBDÀAD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Ab or alpha-synuclein pathology. Interpretation: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.

Functional connectivity in mild cognitive impairment with Lewy bodies

“…It is possible that this difference is influenced by the fact that PD-MCI patients already have a longer disease duration compared to MCI-LB patients with comparable levels of cognitive impairment. One could also argue that PD-MCI may represent a more pure alpha-synucleinopathy whereas in MCI-LB there may be more Alzheimer's disease co-pathology which could influence the phenotype [53,54]. Sliding-window methods have been criticised for requiring the choice of a window size which affects their temporal resolution and statistical validity [55,56].…”

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

“…473 Amyloid-b and Tau interconnections were recently reviewed by Ciccone et al 474 Furthermore, the co-occurrence of Tau and a-synuclein in neuropathological inclusions has been observed in other neurodegenerative diseases since the early 1990s, including AD with Lewy bodies 475 and dementia with Lewy bodies (DLB). [476][477][478] Only recently, however, the direct relationship between these proteins and Tau fibrillization has been investigated. Heterotypic induction of Tau fibrillization has been demonstrated upon co-incubation with pre-aggregated amyloid-b fragments 469 or monomeric a-synuclein, which bound Tau through its C-terminus.…”

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

“…In clinically defined DLB, unpublished data suggest that DLB-AD appears to exhibit a distinct CSF immunophenotypic pattern, raising the importance of exploratory biomarker discovery work to further refine biological subgroups in DLB. Moreover, in autopsy-defined DLB, there is lower overall tau compared to AD and higher temporal lobe enrichment of tau that is associated with both cortical thinning and cognitive impairment (37,83). Although the longitudinal assessment of AD biomarker progression in DLB is understudied, there are conflicting results in PD (32,84) that appear to be explained by variable disease stages and methods of measurement in individual studies, but also intrinsic biological variability between patients.…”