#AANAM – C9orf72 Mutations Linked to Early, Worse Cognitive Deficits

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People with amyotrophic lateral sclerosis (ALS) associated with mutations in the C9orf72 gene have early and more severe cognitive impairment than patients without such mutations, according to a study in Italy.

In addition, patients carrying these mutations and considered cognitively normal showed “subclinical” cognitive impairment, particularly in memory and executive function tasks, when motor symptoms were already present.

More studies are needed to better understand this subclinical or presymptomatic impairment and its evolution over time to assess its clinical relevance, the researchers noted.

The study, “A different cognitive and behavioral profile in ALS patients with or without C9orf72 expansion,” was presented by Cristina Moglia, MD, PhD, of University of Turin’s ALS Center, in Italy, at the 2021 virtual American Academy of Neurology Annual Meeting, running April 17–22.

More than one-third of ALS patients experience cognitive or behavioral problems, such as impaired executive function, deficits in social and emotional cognition, and apathy.

Executive function is a set of mental skills that include working memory, planning, attention, flexible thinking, and self-control. Social and emotional cognition refers to how a person processes, understands, and uses information from others to interact with them.

In addition, at diagnosis, about 15% of ALS patients show cognitive impairment that may be classified as frontotemporal dementia (FTD), while 35% have intermediate cognitive deficits.

ALS patients with an expansion of a specific sequence of the C9orf72 gene — the most common genetic cause of ALS and FTD — “are more likely to present cognitive and behavioral impairment,” Moglia said.

However, whether these mutations are associated with impairment in specific cognitive domains remains largely unclear.

To shed light on this subject, Moglia and her colleagues retrospectively analyzed cognitive and behavioral data of 741 ALS patients, consecutively seen at the Turin ALS center between 2010 and 2018.

A total of 68 patients carried C9orf72 expansions (ALSC9-positive), while 673 patients did not (ALSC9-negative).

Cognitive and behavior symptoms were assessed with a battery of validated tests, and patient data were compared with those of 129 healthy individuals who also underwent the same neuropsychological assessments.

Patients were divided into three groups according to their cognitive function: normal cognitive function, intermediate cognitive impairment, and FTD.

Patients’ motor impairment was assessed with King’s clinical staging system, which evaluates the anatomical spread of ALS, based on the number of affected regions, as well as late-stage nutritional and respiratory failure.

King’s stages range from 1 for early disease with one region involved, to 4 for late disease, with stage 5 being death. Included patients comprised stages 1 to 3.

Results showed that ALSC9-positive patients were significantly younger than those without C9orf72 expansions at all levels of cognitive impairment.

Among cognitively normal patients, those carrying C9orf72 mutations had significantly lower scores in executive function and verbal memory tests than those without such mutations. These ALSC9-positive patients also showed worse performance than healthy individuals in nearly all cognitive domains evaluated.

“This could imply in [ALSC9-positive] patients a ‘cognitive’ presymptomatic/subclinical condition characterized by lower performances at specific cognitive tasks when motor symptoms are already present,” the researchers wrote.

Among patients classified as having intermediate cognitive impairment, ALSC9-positive patients had poorer executive function, attention, working memory, and verbal memory than those without such mutations.

No cognitive differences were observed between patients classified as having FTD with and without C9orf72 expansions.

“Overall, across different degrees of cognitive/behavioral impairment, [ALSC9-positive] patients showed worse performance at verbal memory tasks, more severe impairment in tests exploring the executive function and visual memory,” Moglia said.

The researcher added that while her team previously showed that “age is a strong determinant of the onset of cognitive dysfunction in ALS,” these new data highlighted that the presence of C9orf72 expansions “influences cognition independently of patients’ age.”

In addition, across King’s stages 1 to 3, ALSC9-positive patients showed significantly worse performance in tests of executive function and verbal and visual memory, while ALSC9-negative patients appeared to have more anxiety and depression.

In turn, “behavioral impairment was identified with similar frequency at each stage in both [groups] of patients,” Moglia said, with apathy, the most affected behavioral domain in both groups, increasing with King’s stage scores.

These findings suggest that ALS patients with C9orf72 expansions have a distinct neuropsychological profile, and that verbal memory impairment is “a key cognitive feature” in these patients, Moglia said.

This is likely explained “by executive function deficits, as poor performances in both memory and executive tasks are frequently found associated in patients,” she added.

Additional studies in which patients are followed over time are needed to “clarify whether the subclinical cognitive impairment seen in ALSC9-positive patients tend to progress over time to clinical overt cognitive impairment,” Moglia said.