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01-10-2019 | Alzheimer's Disease | Original Paper

Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation

Authors: Cathrine Petersen, Amber L. Nolan, Elisa de Paula França Resende, Zachary Miller, Alexander J. Ehrenberg, Maria Luisa Gorno-Tempini, Howard J. Rosen, Joel H. Kramer, Salvatore Spina, Gil D. Rabinovici, Bruce L. Miller, William W. Seeley, Helmut Heinsen, Lea Tenenholz Grinberg

Published in: Acta Neuropathologica | Issue 4/2019

Abstract

The clinical spectrum of Alzheimer’s disease (AD) extends well beyond the classic amnestic–predominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (p = 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (p = 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with worsening visuospatial dysfunction. In addition, unbiased hierarchical clustering based on regional NFT densities identified three groups characterized by a low overall NFT burden, high overall burden, and cortical-predominant burden, respectively, which were found to differ in sex ratio, age, disease duration, and clinical presentation. In comparison, the typical, hippocampal sparing, and limbic-predominant subtypes derived from a previously proposed algorithm did not reproduce the same degree of clinical relevance in this sample. Overall, our results suggest domain-specific functional consequences of regional NFT accumulation. Mapping these consequences presents an opportunity to increase understanding of the neuropathological framework underlying atypical clinical manifestations.

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Title: Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation
Authors: Cathrine Petersen
Amber L. Nolan
Elisa de Paula França Resende
Zachary Miller
Alexander J. Ehrenberg
Maria Luisa Gorno-Tempini
Howard J. Rosen
Joel H. Kramer
Salvatore Spina
Gil D. Rabinovici
Bruce L. Miller
William W. Seeley
Helmut Heinsen
Lea Tenenholz Grinberg
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Alzheimer's Disease
Pathology
Published in: Acta Neuropathologica / Issue 4/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02036-6

At a glance: The STEP trials

Springer Medicine

Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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