Study Links Cognitive Impairment with Toxic Protein Clumps in ALS

Cognitive impairment in amyotrophic lateral sclerosis (ALS) may be linked to the buildup of the protein TDP-43 in the brain, a new study suggests. However, TDP-43 alone likely isn’t the cause of such impairment, and due to the study’s small sample size, more research is needed to clarify the findings.

The study, “Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS,” was published in the Journal of Neurology, Neurosurgery, and Psychiatry. 

More than a third of people with ALS experience behavioral or cognitive symptoms, such as difficulty with language, deficits in social cognition (how a person processes and uses information about other people), and in executive function (a set of mental skills that include working memory, flexible thinking, and self-control). An additional 15% of people with ALS experience frontotemporal dementia (FTD).

Previous studies have linked cognitive impairment and/or FTD in ALS with a buildup of TDP-43. In the brains of people with ALS, this protein is not folded properly and forms clumps that are toxic to neurons.

However, those studies “are limited as cohorts have been assessed by different cognitive tests not designed for ALS or physical disability,” the researchers who authored the new study wrote.

“The introduction of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) enables a more cohesive approach,” they stated, explaining that “this standardised tool assesses ALS-related cognitive deficits (verbal fluency, executive and language functions) and is sensitive to milder cognitive impairments.”

ECAS is a fast and easy screening tool that assesses five cognitive domains. Three of the domains — executive function, language, and verbal fluency —  allow doctors to examine ALS-specific functions, whereas memory and visuospatial functions are combined to examine ALS-nonspecific functions. This enables the distinction from other diseases with cognitive and behavioral deficits.

In the new study, researchers assessed TDP-43 in the brains of 27 people (15 female, 12 male) with ALS who had taken the ECAS test for neuropsychological assessments before they died.

Of these, seven met ECAS criteria for ALS with cognitive impairment (ALSci). All seven of these individuals had evidence of TDP-43 pathology in their brains.

“There were no cases where cognitive impairment was present in the absence of TDP-43 pathology,” the researchers wrote, “however, there was a small subgroup (n=6) of patients who had TDP-43 pathology with no cognitive impairment (false negatives).”

Put another way, an assessment of ALSci by ECAS scores had a specificity of 100% predicting TDP-43 buildup (meaning there were no false positives), and a sensitivity of 43.75%, which is the proportion of true positives that are correctly identified as such. The overall accuracy of ECAS at predicting TDP-43 deficiency was 66.67%.

Furthermore, 11 study participants had impairment on at least one specific domain of the ECAS (language, executive function, etc.). These specific impairments seemed to correlate with the observed distribution of TDP-43 in the brain.

For example, eight people had at least mild language impairment on the ECAS. All eight of these had TDP-43 pathology in regions of the brain that are known to be involved in language processing and speech, such as Broca’s area. Similarly, the three individuals with executive function impairment all had TDP-43 pathology in related regions of the brain.

However, there was TDP-43 pathology observed in other regions without associated symptoms. For example, four people had TDP-43 pathology in the hippocampus, a region of the brain with critical roles in learning and memory, but none of them exhibited memory defects.

Collectively, these data suggest that TDP-43 pathology is likely involved in ALSci, with possible associations between the precise symptoms experienced and the exact brain regions affected. But, because TDP-43 pathology was observed in unaffected brains, too, it’s highly unlikely this protein is the root cause of the cognitive impairment.

Nonetheless, the results indicate that ECAS scores could be used to predict whether a person has TDP-43 pathology in their brain while the person is alive, rather than having to wait to autopsy the brain. This could be useful in determining who to enroll in certain clinical trials, for instance, including only people with such protein pathology in studies of compounds that target it.

“Given that no false positives would be identified, the use of the ECAS as a stratification tool would not result in anyone being incorrectly included in such a clinical trial,” the researchers wrote.

The researchers also noticed that TDP-43 wasn’t present in the same type of cell in every brain. In some brains, the protein was almost exclusively present in neurons, the brain cells that send electrical signals. In others, TDP-43 was almost exclusively in glia, a population of brain cells with a number of important functions other than sending electrical signals. Other brains had a mix in both glia and neurons.

No clear differences were identified between these brains. “This is likely due to the small sample size evaluated and clearly warrants further investigation … to evaluate conclusively whether these phenotypes impact on clinical characteristics of ALS and or FTD,” the researchers wrote.