GBA Variants Impact Cognitive Status in Amyotrophic Lateral Sclerosis

DNA genetics
DNA genetics
Researchers sought to determine the effect GBA variants have on cognitive status in patients with amyotrophic lateral sclerosis.

Expectancy effects on dopamine signaling are largely responsible for anxiety reduction through selective serotonin reuptake inhibitors (SSRIs) in patients with social anxiety disorder (SAD), researchers found in a study published in Translational Psychiatry.

Researchers randomly assigned sex- and age-matched patients (17 men and 10 women aged 31.1±10.3 years) with SAD to either overt (n=14) or covert (n=13) treatment with escitalopram 20 mg daily for 9 weeks (following 1 week of 10 mg) after assessing them with positron emission tomography (PET). Patients who had recently ended or were undergoing psychiatric treatment were excluded from the study.

Patients received different descriptions of the efficacy of the drug. Researchers told the patients in the overt group that they would receive escitalopram, which was demonstrated to be effective for SAD. They told the individuals in the covert group that they would receive a non-effective neurokinin-1-receptor antagonist, an active placebo with side effects that mimicked those of escitalopram but without any expectation of improvement in symptoms.

They found that patients in the overt group experienced reduced availability of dopamine (DAT) nondisplaceable binding potentials (BPND) while the covert group experienced increases in BPND.

Serotonin (SERT) occupancy levels were inversely associated with DAT BPND in the overt group and increased DAT BPND in the group that received covert treatment.

Logistic regression analysis of transporter changes and group indicated that including SERTxDAT interaction to the models with main effects of SERT and DAT significantly raised R2 variance (interaction/main effects: putamen = 0.28/0.02; left pallidum = 0.19/0.03, right thalamus = 0.41/0.11), apart from in the right pallidum (0.27/0.27).

Clinical analysis after 9 weeks found that the overt group experienced more improvement (Mdiff ± SD = 47.07±19.23, Cohen’s d = 2.33) compared with the covert (Mdiff = 21.46±17.25, Cohen’s d = 0.93) group, as determined through self-report of symptoms on the Liebowitz Social Anxiety Scale (LSAS-SR). More individuals in the overt group (57%) than in the covert group (15%) responded to treatment (Fisher’s exact test: OR = 0.15, P =.046).

Limitations of the study included only 2 of the 4 arms in the balanced placebo design being used and no measurement of subjective expectancies during treatment.

“[T]he anti-anxiety properties of SSRIs appear to be largely dependent on expectancy effects on dopamine signaling while SERT blockade is not sufficient for symptom remission,” the investigators said. “This provides new insights on the key therapeutic mechanisms of SSRIs, incorporating psychological effects on dopamine neurotransmission.”


Hjorth OR, Frick A, Gingnell M, et al. Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial. Translational Psychiatry. Published online November 3, 2021. doi: 10.1038/s41398-021-01682-3

Variants in the glucocerebrosidase (GBA) gene are associated with an increased risk for cognitive impairment in patients with amyotrophic lateral sclerosis (ALS), according to study findings presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, held from April 2 to April 7 in Seattle, Washington, and virtually from April 24-26, 2022.

GBA polymorphisms represent “known risk factors for Lewy Body Dementia [LBD] and cognitive impairment Parkinson disease [PD],” the researchers explained. The objective of the current study was to assess the impacts of GBA variants on the cognitive status of patients with ALS.

The study population consisted of 751 patients with ALS and full genetic and neuropsychological data who were diagnosed in Piemonte and Valle d’Aosta, Italy, between 2007 and 2015. Additionally, the researchers included 677 healthy control individuals in the analysis set.

Patients with ALS were classified as having ALS with normal cognition (ALS-CN), ALS with intermediate cognitive deficits, or ALS with frontotemporal dementia (ALS-FTD). The researchers performed a single-variant association test to compare the frequency of GBA variants between patients with ALS and healthy control individuals. Additionally, the researchers performed a binomial test to assess the prevalence of GBA mutations across cognitive status groups. To investigate the associations between GBA genotype and cognitive functioning, the researchers used a linear mixed-effects models and gene-based rare-variants association test.

They identified 3 common GBA polymorphisms: p.E365K; p.T408M; and p.N409S. According to the researchers, these GBA polymorphisms are known risk factors for LBD as well as cognitive impairment in PD. The identified variants were observed in 18 patients with ALS (2.3%) and 15 healthy control individuals (2.2%).

In the single-variant analysis, the researchers confirmed that the GBA variants were not a risk factor for ALS. They also subsequently identified 7 other GBA variants. In patients with ALS who carried GBA variants, approximately 72.2% had cognitive impairment vs 47.1% in patients who didn’t carry these variants (P =.03).

The association between GBA variants and cognitive impairment in ALS was confirmed in a linear mixed-effects model that controlled for sex, age, site of onset, bulbar signs at diagnosis, decline in the revised ALS Functional Rating Scale, and C9orf72 status (P =.02). According to collapsing tests, enrichment of rare disruptive GBA variants were found in cognitively impaired patients with ALS (P =.02).

The researchers stated that the findings of an association between GBA variants and an increased risk of cognitive impairment in patients with ALS support “the role of lysosomal impairment in the underlying neurodegenerative process.”


Chio A, Grassano M, Moglia C, et al. GBA variants influence cognitive status of ALS patients. Presented at: the 2022 AAN Annual Meeting; April 2-7, 2022; Seattle, Washington; April 24-26, 2022; Virtual Meeting. Abstract S11.004.

This article originally appeared on Neurology Advisor