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The thought-provoking hypothesis has been empirically tested that cognitive deficits may be an indirect measure of cortical pTDP43 neuropathology
There is a lack of in vivo readout measures to track changes in brain pathology during the course of amyotrophic lateral sclerosis (ALS) which might support the measurement of therapeutic effects in clinical trials. For this, biomarkers need to be specific, reproducible and sensitive to changes in the course of the disease. Established clinical markers of motor deficits are the ALS functional rating scale (ALSFRS-R) and survival. Markers such as neurofilament light chain levels and MRI have been shown to be powerful candidates but have not been introduced into routine yet. Phosphorylated TDP43 (pTDP43) accumulations are reliable postmortem biomarkers of disease pathology in the majority of ALS autopsies and are related to cell death.1 Molecular pTDP43 load has limited use as a biomarker for clinical trials as it can be retrieved post mortem only and not in biological fluids.
A completely new approach to cortical function as a quantitative measure of brain pathology is provided from the field of neuropsychology as introduced by Gregory and colleagues.2
Cognitive function may be impaired in up to 50% of ALS patients in various degrees up to full blown (mostly behavioural variant) frontotemporal dementia (5%–15% of cases); in the former patients, about half of them show deficits in one cognitive domain only, for example, in executive, language or fluency function.3 The pattern of neurocognitive changes in ALS has been described consistently in several studies but it is poorly understood how these cognitive changes are associated with brain pathology in ALS. In previous studies, an overall qualitative association of cognitive outcomes (measured by the established Edinburgh Cognitive and Behavioural ALS Screen, (ECAS))4 and indirect measures of TDP43 pathology has been found.5 Thus, it was suggested for the first time that cognitive deficits might be a biomarker of brain pathology itself. Gregory and colleagues2 extend this understanding and for the first time link cognitive phenotypes in vivo directly to cortical pathology postmortem. For this, they studied 27 non-demented ALS patients using specific neuropsychological deficits as measured by ECAS4 which was correlated to the neuropathology of the disease as characterised by the molecular marker of pTDP43 postmortem. All patients displaying cognitive deficits in executive, language and fluency domains also showed pTDP43 pathology in extramotor brain regions with 100% positive predictive value. ALS-specific deficits in executive function, language function and fluency predicted postmortem pTDP43 findings with 100% specificity in brain regions known to be associated with these cognitive deficits. Interestingly, there were mismatch cases, with ALS patients displaying pTDP43 pathology but no clinical neuropsychological changes. This might indicate the presence of cognitive reserve or cortical reorganisation to compensate for molecular pathology. Further studies of these patients might gain interesting insights into cognitive and behavioural deficits in ALS.
These promising results on the relation between ECAS and pTDP43 load could be the basis for longitudinal studies to estimate the power of cognitive profiles measured with instruments like ECAS for its use as a potential secondary outcome measure beyond motor deficits in clinical trials. This is particularly true for patients carrying expansions in the C9ORF72 gene as these display larger quantitative cognitive deficits—like the authors show—and carry a larger burden of pTDP43 pathology.6 Also, the authors correctly suggest to exclude patients carrying super oxide dismutase and fused in sarcoma mutations from clinical trials using these outcome measures, as they lack major pTDP43 neuropathology and also do not show major cognitive deficits.
Overall, cognitive screening might be a highly specific quantitative measure of cerebral pTDP43 load which is easily applicable at bedside and is inexpensive. It is a functional measure beyond the traditional approaches which focus on the motor system. The hypothesis to use neuropsychological measures as biomarkers for clinical classification and stratification in ALS trials is challenging and appealing.
Contributors Both authors fulfil the criteria for authorship.
Funding This is an EU Joint Programme–Neurodegenerative Disease Research (JPND) Project (’NEEDSinALS; www.NEEDSinALS.com; 01ED1405). The project is supported through the following organisations under the aegis of JPND - www.jpnd.eu: Germany, Bundesministerium für Bildung und Forschung (BMBF, FKZ). This work was additionally funded by the Deutsche Forschungsgemeinschaft (DFG, LU 336/13-2) and the Bundesministerium für Bildung und Forschung (MND-Net 01GM1103A; PaCeMed 01DS18031). DZNE.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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