Pathological hyperphosphorylated tau is a key feature of Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Using transgenic mice overexpressing human non-mutated tau (htau mice), we assessed the contribution of tau to peripheral and central neurodegeneration. Indices of peripheral small and large fiber neuropathy and learning and memory performances were assessed at 3 and 6 months of age. Overexpression of human tau is associated with peripheral neuropathy at 6 months of age. Our study also provides evidence that non-mutated tau hyperphosphorylation plays a critical role in memory deficits. In addition, htau mice had reduced stromal corneal nerve length with preservation of sub-basal corneal nerves, consistent with a somatofugal degeneration. Corneal nerve degeneration occurred prior to any cognitive deficits and peripheral neuropathy. Stromal corneal nerve loss was observed in patients with FTD but not AD. Corneal confocal microscopy may be used to identify early neurodegeneration and differentiate FTD from AD.

Introduction

Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype.

Methods

Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments.

Results

Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations.

Discussion

This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients.

Highlights

This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.