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

Abstract

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

Methods: In-depth neuropathological analysis of 27 patients with non-demented ALS who had undergone cognitive testing (Edinburgh Cognitive and Behaviour ALS Screen (ECAS)) during life. Analysis involved assessing 43 kDa Tar-DNA binding protein (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 extramotor 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.

Keywords: ALS; ECAS; Neuropathology; TDP-43; cognition.

Figure 1

Subdomain cognitive dysfunction detected by the ECAS relates to specific regional distribution of TDP-43 pathology. (A) Pathological TDP-43 staining, demonstrating characteristic cytoplasmic aggregation and nuclear clearance of TDP-43. Images are taken at 20× magnification, illustrating mild, moderate and severe scoring of pathology. (B) Sensitivity and specificity analysis assessing the utility of ECAS subdomains in predicting TDP-43 pathology in corresponding brain regions, demonstrating high positive predictive value. Values are percentage with 95% CIs. ECAS, Edinburgh Cognitive and Behavioural Amytrophic lateral sclerosis Screen.

Figure 2

Cell-type specific TDP-43 pathology differs between individuals. Pathological TDP-43 staining, demonstrating (A) predominantly glial inclusions; (B) mixed glial and neuronal inclusions and (C) predominantly neuronal inclusions. Images are taken at 20× magnification; red arrows indicate neurons and blue arrows indicate glial cells. (D) Frequency distribution demonstrating the number of cases with each of these characteristic cell-type specific inclusions. Each column is subdivided into red (evidence of cognitive dysfunction) and blue (no evidence of cognitive dysfunction) showing that there is no apparent link between cell-type specific TDP-43 accumulation and cognitive dysfunction in the cases that we analysed. ALS, amyotrophic lateral sclerosis; TDP-43, 43 kDa Tar-DNA binding protein.