Distinct characteristics of limbic-predominant age-related TDP-43 encephalopathy in Lewy body disease

Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer's disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (n = 313), AD (n = 282), LBD + AD (n = 355), and aging (n = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of TMEM106B rs1990622 and GRN rs5848. These data highlight clinicopathological and genetic features of LATE-LBD.

Peripheral Pathways to Neurovascular Unit Dysfunction, Cognitive Impairment, and Alzheimer’s Disease

“…TDP-43 proteinopathy was first identified in ALS and frontotemporal lobar degeneration ( Neumann et al, 2006 ). However, TDP-43 neuropathology was also identified in post-mortem AD brain ( Amador-Ortiz et al, 2007 ; Uryu et al, 2008 ; Josephs et al, 2014 , 2016 ), and is often observed in older adults with LATE ( Nelson et al, 2019 ; Katsumata et al, 2020 ; Robinson et al, 2020 ; Uemura et al, 2022 ). TDP-43 frequently coexists with tau and α-synuclein in brain tissue of subjects with AD and dementia with Lewy bodies ( Higashi et al, 2007 ).…”

Neurovascular Dysfunction in Diverse Communities With Health Disparities—Contributions to Dementia and Alzheimer’s Disease

“…The neuropathologies found in the post-mortem brains of ADRD patients are complex and multifactorial. A number of amyloid isotypes accumulate in the brains of these patients including amyloid-β (Aβ) plaques, neurofibrillary tau tangles (NFTs), Lewy body α-synuclein pathologies, and transactive response DNA and RNA binding protein 43 kDa aggregates ( Nelson et al, 2019 ; Robinson et al, 2021 ; Uemura et al, 2022 ). These neuropathologies are often associated with neurovascular abnormalities including large macroscopic, lacunar and microscopic infarcts, hemorrhages, and vessel pathologies including cerebral amyloid angiopathy, intracranial atherosclerosis and arteriolosclerosis.…”

Distinct neurotoxic TDP-43 fibril polymorphs can be generated by heterotypic interactions with α-synuclein

“…In LBD, the severity of αS pathology in the temporal cortex was observed to be significantly more among TDP-43 positive patients, which correlated with the severity of TDP-43 pathology in the amygdala (26). Perhaps the most compelling evidence for selective influence of αS on TDP-43 proteinopathy comes from LATE patient brains in which distinct neuropathological changes are observed in PrLD/αS aggregates containing LATE-LBD and LATE-AD co-pathologies compared to pure LATE (27).…”

“…Similarly, incubation of exogenous αS fibrils in SH-SY5Y cells enhances TDP-43 phosphorylation and aggregation (43). More compelling pathological evidence of the interaction between the two proteins comes from a recent study which showed that TDP-43 aggregates co-exist with αS aggregates in LATE-LBD and LATE-AD co-pathologies, exhibiting histopathological differences between pure LATE, LATE-LBD and LATE-AD (27). These observations also suggest that the polymorphic fibrils of TDP-43 observed in these patients could be consequential of the influence by αS.…”