Pathological drivers of neurodegeneration in suspected non-Alzheimer\u2019s disease pathophysiology

L E M Wisse,S R Das,L Xie,R De Flores,M Grossman,D A Wolk,C T Mcmillan,J Q Trojanowski,E B Lee,P A Yushkevich,D Irwin

doi:10.1186/s13195-021-00835-2

Abstract

BackgroundLittle is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects.MethodsSubjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume.ResultsSNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume.ConclusionSNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported.

Highlights

Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid
The primary goal of Alzheimer’s Disease Neuroimaging Initiative (ADNI) has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)
As the present study focused on the medial temporal lobe (MTL), a composite score was calculated by averaging the scores of CA1, entorhinal cortex (ERC), and amygdala for each lesion of interest

Summary

Introduction

Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. In 2011, a framework for the preclinical stage of Alzheimer’s disease (AD) was proposed in which it was argued that β-amyloid deposition is followed by neurodegeneration and subtle cognitive impairments [1]. Adding to the clinical significance of this category, SNAP has been reported to show clinical and cognitive decline [8,9,10] and ongoing neurodegeneration [10, 11] compared to their biomarkernegative counterparts, though not in all studies [12,13,14]. Evidence for clinical progression has more frequently been reported in MCI-SNAP than cognitively normal SNAP individuals (CN-SNAP). The selection of the study population in extant studies likely affects the findings regarding the clinical course, demographics, and etiology of SNAP

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Results

Discussion

Conclusion