Janna van Wetering, Natasja A. C. Deshayes, Joëlle Boone, Inês Rodrigues Fernandes, Dagmar H. Hepp, Henk W. Berendse, Laura E. Jonkman, Annemieke J. M. Rozemuller, Wilma D. J. van de Berg
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引用次数: 0
Abstract
The clinical heterogeneity of multiple system atrophy (MSA) may, along with the primary aggregation of alpha-synuclein (α-syn), partly be shaped by co-pathologies, such as amyloid-beta (Aβ), phosphorylated (p)-tau, and pTDP-43, though their relevance remains unclear. Here, we aimed to characterize the prevalence, morphology, regional patterns, and clinical relevance of co-pathologies in a well-characterized MSA autopsy cohort. Regional load (%area) and morphological characterization of α-syn (KM51), Aβ (6F/3D), p-tau (AT8), and pTDP-43 (pSer409) pathology were assessed in limbic regions of MSA (n = 70) donors from the Netherlands Brain Bank. APOE-ε4 genotyping and clinical parameters of the cohort were collected. Associations with clinical features were analyzed using ANCOVA and mixed linear models, adjusted for age and sex. Aβ, p-tau, and pTDP-43 pathology were detected in 31%, 91%, and 11% of all MSA cases, respectively, with the highest burdens in the entorhinal cortex and amygdala. Mixed MSA + AD cases had a higher age at death (75 ± 7 vs. 64 ± 7, p < 0.001), and more frequently APOE-ε4 alleles (p < 0.001) than pure MSA. Cognitive impairment (CDR scores) was associated with diffuse and compact Aβ plaques across all regions (r ≥ 0.24, p ≤ 0.015), p-tau pathology in CA1 and CA3 + 4 (r ≥ 0.32, p ≤ 0.020), and neuronal α-syn inclusions in the amygdala (r = 0.54, p < 0.001). No robust correlations were found between total α-syn burden and Aβ or p-tau. Misdiagnoses increased with co-pathology burden (Aβ: p = 0.040; p-tau: p = 0.020) and age at onset (80% in those with onset > 75 years). Our results demonstrate that limbic Aβ, p-tau, and neuronal α-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset. By providing a systematic quantitative and morphological assessment of co-pathologies in limbic regions of MSA, our study advances beyond prior prevalence reports and highlights their direct clinical relevance. These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.