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

Jenna Gregory* (Corresponding Author), Karina McDade, Thomas H Bak, Suvankar Pal, Siddharthan Chandran, Colin Smith, Sharon Abrahams

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)


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.

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.

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.

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.
Original languageEnglish
Pages (from-to)149-157
Number of pages9
JournalJournal of Neurology, Neurosurgery & Psychiatry
Issue number2
Early online date12 Sept 2019
Publication statusPublished - Feb 2020


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