C9orf72 gene expansion results in greater impairment among patients with ALS

Patients with ALS who have an expansion in the C9orf72 gene displayed a different neuropsychological profile, with greater impairment in executive function and verbal memory, than patients with ALS who did not have the expansion.

The findings from this study, which were published in Neurology, demonstrated that verbal memory was “a particularly vulnerable function” in patients with the C9orf72 gene. These patients showed poorer performance even when classified as cognitively normal.

“Six to 10 percent of ALS patients carry a GGGGCC pathological expansion in the first intron of the C9orf72 gene,” the researchers wrote. “Previous papers have indicated that patients carrying C9orf72 pathological expansion are more likely to present a cognitive and behavioral impairment than those who are not mutated.”

The present study aimed to determine whether patients with ALS and the C9orf72 expansion displayed a different impairment in cognitive and behavioral domains compared with patients with ALS who did not have the C9orf72 expansion.

Barbara Iazzolino, PsyD, of the ALS Center in the department of neuroscience at the University of Torino in Turin, Italy, and colleagues enrolled patients with ALS who had been diagnosed at the Turin ALS Center between 2010 and 2018 and who participated in cognitive/behavioral and genetic testing. The researchers compared patients’ neuropsychological patterns at the same degree of cognitive and behavioral deficit according to the revised ALS-FTD Consensus Criteria and at the same level of motor impairment according to King’s staging system, which is based on the spread of motor symptoms in 3 different body regions — bulbar, upper limbs and lower limbs — and on the use of non-invasive ventilation and enteral nutrition, according to the researchers. The five stages of the King’s staging include 1 (one region involved); 2 (two regions involved); 3 (three regions involved); 4A (patient requires gastrotomy); and 4B (patient requires non-invasive ventilation).

The final study cohort comprised 741 patients with ALS, including 68 patients with the C9orf72 expansion and 673 without it, and 129 controls. Patients and controls did not differ in terms of the main demographic variables. Iazzolino and colleagues observed that patients with ALS and the C9orf72 expansion were younger than patients with ALS who did not have the expansion “at all levels of cognitive impairment” but did not demonstrate any other significant difference.

The researchers found that, despite being approximately 7 years younger, patients with the C9orf72 expansion had significantly lower scores on tests that explored executive functions and verbal memory both when categorized as cognitively normal and when diagnosed in the intermediate cognitive categories. Patients with the expansion and intermediate cognitive impairment also had significantly lower scores on tests looking at executive functions, attention, working memory and verbal memory.

Patients with the expansion scored significantly lower than patients without the expansion at King’s stage 1 and 3 “in almost all the examined neuropsychological domains.” Patients with the expansion also experienced cognitive impairment more often than patients without it (P < .001), and, at King’s stage 2, a more severe impact only in the verbal memory domain. Iazzolino and colleagues found comparable impairment in terms of behavioral function between the two cohorts.

Patients with the C9orf72 expansion more often also had at least one test under the normative cut-off in all domains across King’s stages, according to Iazzolino and colleagues. However, the researchers observed that this difference was significant only for the executive functions (P = .004), visual memory (P = .002) and verbal memory (P = .03) at King’s stage 1; for visual memory (P = .003) and verbal memory (P = .02) at King’s stage 2; and for executive functions (P = .04), verbal memory (P = .023), fluid intelligence (P = .035), attention and working memory (P = .031) and cognitive flexibility (P = .04) at King’s stage 3.

“Our data suggest that [patients with the C9orf72 expansion] show a different neuropsychological profile compared to [patients without the expansion],” the researchers wrote. “Longitudinal studies are necessary to clarify whether this subclinical cognitive impairment in [patients with the C9orf72 expansion] tends to progress over time to a clinically overt cognitive impairment.”