# Contribution of comorbid pathologies to amyotrophic lateral sclerosis with cognitive or behavioral abnormalities

## TL;DR

This study explores how comorbid brain diseases affect cognitive and behavioral issues in people with ALS, finding that conditions like Alzheimer's and others can contribute to these problems.

## Contribution

The study identifies the role of comorbid pathologies in cognitive/behavioral abnormalities in ALS, even when TDP-43 pathology is absent.

## Key findings

- Comorbid pathologies like AD, AGD, and PART are common in elderly ALS patients with cognitive or behavioral issues.
- Hippocampal sclerosis contributes to memory impairment in ALS cases without comorbid pathologies.
- Cortical TDP-43 pathology is not always present in ALS patients with cognitive or behavioral abnormalities.

## Abstract

Amyotrophic lateral sclerosis (ALS) often presents with cognitive or behavioral abnormalities. The cortical involvement of TAR DNA-binding protein-43 (TDP-43) pathology is considered a major cause of these abnormalities. However, the contribution of underlying comorbid pathologies remains unclear.

We investigated the clinicopathological characteristics of 29 autopsy cases of ALS with cognitive or behavioral abnormalities and evaluated the association between clinical symptoms and comorbid pathologies such as Alzheimer’s disease (AD), argyrophilic grain disease (AGD), dementia with Lewy bodies (DLB), and primary age-related tauopathy (PART), as well as the presence of cortical TDP-43 pathology.

Of the 29 patients, 17 exhibited comorbid pathologies (AD, AGD, or PART), which may contribute to cognitive or behavioral abnormalities. None of the cases met the pathological criteria for DLB. The group with comorbid pathologies was significantly older, but clinical symptoms did not differ between the groups. Behavioral abnormalities and memory impairment were frequently observed in both groups. All six subjects without cortical TDP-43 pathology had comorbid pathologies, which had a notable effect on cognitive or behavioral abnormalities. Hippocampal sclerosis and memory impairment were observed in ALS cases without comorbid pathologies.

A high frequency of comorbid pathologies is observed in elderly patients with ALS presenting with cognitive or behavioral abnormalities. There are cases of ALS in which comorbid pathologies such as AD, AGD, and PART may contribute to cognitive or behavioral abnormalities, even in the absence of cortical TDP-43 pathology. Hippocampal sclerosis of ALS may contribute to memory impairment independently of comorbid pathologies.