Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Autor:	Kouri N; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Frankenhauser I; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Paracelsus Medical Private University, Salzburg, Austria., Peng Z; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida., Labuzan SA; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Boon BDC; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Moloney CM; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Pottier C; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Wickland DP; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida., Caetano-Anolles K; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Corriveau-Lecavalier N; Department of Radiology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Tranovich JF; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Wood AC; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Hinkle KM; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Lincoln SJ; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Spychalla AJ; Department of Radiology, Mayo Clinic, Rochester, Minnesota., Senjem ML; Department of Radiology, Mayo Clinic, Rochester, Minnesota., Przybelski SA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota., Engelberg-Cook E; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Schwarz CG; Department of Radiology, Mayo Clinic, Rochester, Minnesota., Kwan RS; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida., Lesser ER; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida., Crook JE; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida., Carter RE; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida., Ross OA; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Lachner C; Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, Florida., Ertekin-Taner N; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Department of Neurology, Mayo Clinic, Jacksonville, Florida., Ferman TJ; Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, Florida., Fields JA; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota., Machulda MM; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota., Ramanan VK; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Nguyen AT; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Reichard RR; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Jones DT; Department of Radiology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Graff-Radford J; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Boeve BF; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Knopman DS; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Petersen RC; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Jack CR Jr; Department of Radiology, Mayo Clinic, Rochester, Minnesota., Kantarci K; Department of Radiology, Mayo Clinic, Rochester, Minnesota., Day GS; Department of Neurology, Mayo Clinic, Jacksonville, Florida., Duara R; Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida., Graff-Radford NR; Department of Neurology, Mayo Clinic, Jacksonville, Florida., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Lowe VJ; Department of Radiology, Mayo Clinic, Rochester, Minnesota., Vemuri P; Department of Radiology, Mayo Clinic, Rochester, Minnesota., Murray ME; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
Jazyk:	angličtina
Zdroj:	JAMA neurology [JAMA Neurol] 2024 Jun 01; Vol. 81 (6), pp. 619-629.
DOI:	10.1001/jamaneurol.2024.0784
Abstrakt:	Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.
Databáze:	MEDLINE
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