Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS

Objective
~35% of amyotrophic lateral sclerosis (ALS) patients exhibit mild cognitive deficits in, executive functions, language and fluency, without dementia. The precise pathology of these extra-motor symptoms has remained unknown. This study aimed to determine the pathological correlate of cognitive impairment in non-demented ALS patients.

Methods
In-depth neuropathological analysis of 27 non-demented ALS patients who had undergone cognitive testing (ECAS) during life. Analysis involved assessing TDP-43 accumulation in brain regions specifically involved in executive functions, language functions and verbal fluency to ascertain whether functional deficits would relate to a specific regional distribution of pathology.

Results
All patients with cognitive impairment had TDP-43 pathology in extra-motor brain regions (positive predictive value of 100%). The ECAS also predicted TDP-43 pathology with 100% specificity in brain regions associated with executive, language and fluency domains. We also detected a subgroup with no cognitive dysfunction, despite having substantial TDP-43 pathology, so called mismatch cases.

Conclusions
Cognitive impairment as detected by the ECAS is a valid predictor of TDP-43 pathology in non-demented ALS. The profile of mild cognitive deficits specifically predicts regional cerebral involvement. These findings highlight the utility of the ECAS, in accurately assessing the pathological burden of disease.