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Open Access 01-12-2023 | Pathology | Research

Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration

Authors: Lucia AA Giannini, Merel O Mol, Ana Rajicic, Renee van Buuren, Lana Sarkar, Sanaz Arezoumandan, Daniel T Ohm, David J Irwin, Annemieke JM Rozemuller, John C van Swieten, Harro Seelaar, Netherlands Brain Bank

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Early pathological features of frontotemporal lobar degeneration (FTLD) due to MAPT pathogenic variants (FTLD-MAPT) are understudied, since early-stage tissue is rarely available. Here, we report unique pathological data from three presymptomatic/early-stage MAPT variant carriers (FTLD Clinical Dementia Rating [FTLD-CDR] = 0–1). We examined neuronal degeneration semi-quantitatively and digitally quantified tau burden in 18 grey matter (9 cortical, 9 subcortical) and 13 white matter (9 cortical, 4 subcortical) regions. We compared presymptomatic/early-stage pathology to an intermediate/end-stage cohort (FTLD-CDR = 2–3) with the same variants (2 L315R, 10 P301L, 6 G272V), and developed a clinicopathological staging model for P301L and G272V variants. The 68-year-old presymptomatic L315R carrier (FTLD-CDR = 0) had limited tau burden morphologically similar to L315R end-stage carriers in middle frontal, antero-inferior temporal, amygdala, (para-)hippocampus and striatum, along with age-related Alzheimer’s disease neuropathological change. The 59-year-old prodromal P301L carrier (FTLD-CDR = 0.5) had highest tau burden in anterior cingulate, anterior temporal, middle/superior frontal, and fronto-insular cortex, and amygdala. The 45-year-old early-stage G272V carrier (FTLD-CDR = 1) had highest tau burden in superior frontal and anterior cingulate cortex, subiculum and CA1. The severity and distribution of tau burden showed some regional variability between variants at presymptomatic/early-stage, while neuronal degeneration, mild-to-moderate, was similarly distributed in frontotemporal regions. Early-stage tau burden and neuronal degeneration were both less severe than in intermediate-/end-stage cases. In a subset of regions (10 GM, 8 WM) used for clinicopathological staging, clinical severity correlated strongly with neuronal degeneration (rho = 0.72, p < 0.001), less strongly with GM tau burden (rho = 0.57, p = 0.006), and did not with WM tau burden (p = 0.9). Clinicopathological staging showed variant-specific patterns of early tau pathology and progression across stages. These unique data demonstrate that tau pathology and neuronal degeneration are present already at the presymptomatic/early-stage of FTLD-MAPT, though less severely compared to intermediate/end-stage disease. Moreover, early pathological patterns, especially of tau burden, differ partly between specific MAPT variants.

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Title: Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration
Authors: Lucia AA Giannini
Merel O Mol
Ana Rajicic
Renee van Buuren
Lana Sarkar
Sanaz Arezoumandan
Daniel T Ohm
David J Irwin
Annemieke JM Rozemuller
John C van Swieten
Harro Seelaar
Netherlands Brain Bank
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Pathology
Intense Pulsed Light
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01588-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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