Cognitive and Antipsychotic Medication Use in Monoallelic GBA-Related Parkinson Disease

Abstract

Mutations in glucosidase, beta, acid (GBA) are associated with cognitive impairment in Parkinson disease (PD) as well as dementia with Lewy bodies. For both of these diseases, dementia and hallucinations are typically treated with cholinesterase inhibitors and antipsychotics. However, in some lysosomal storage disorders certain antipsychotic medications are poorly tolerated. This study examined cholinesterase inhibitor and antipsychotic use in monoallelic GBA-related PD to explore potential pharmacogenetic relationships. Monoallelic GBA mutation carriers with PD (GBA-PD) with at least two clinic visits (n ¼ 34) were matched for age-of-onset and gender to GBA and leucine-rich repeat kinase 2 (LRRK2) mutation negative idiopathic PD subjects (IPD) (n ¼ 60). Information regarding cholinesterase inhibitor and antipsychotic use as well as impaired cognition (UPDRS Mentation >1) and hallucinations (UPDRS Thought Disorder >1) were obtained. GBA-PD more frequently reported hallucinations (HR ¼ 5.0; p ¼ 0.01) and they were more likely to have cognitive impairment but this was not statistically significant (HR 2.2, p ¼ 0.07). Antipsychotic use was not significantly different between GBA-PD and IPD (HR ¼ 1.9; p ¼ 0.28), but GBA-PD were more likely to have sustained cholinesterase inhibitor use (HR ¼ 3.1; p ¼ 0.008), even after adjustment for cognition and hallucinations. Consistent with reports of worse cognition, GBA-PD patients are more likely to use cholinesterase inhibitors compared to IPD. While there was no difference in antipsychotic use between IPD and GBA-PD, persistent use of quetiapine in GBA-PD suggests that it is tolerated and that a significant interaction is unlikely. Further prospective study in larger samples with more extensive cognitive assessment is warranted to better understand pharmacogenetic relationships in GBA-PD.

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

“…Patients who carry GBA1 mutations present a higher prevalence and severity of bradykinesia, motor complications, hyposmia, autonomic impairment, sexual dysfunction, hallucinations, cognitive decline, depression and anxiety (Alcalay et al, 2012;Beavan and Schapira, 2013;Brockmann et al, 2011;Lesage et al, 2010;Li et al, 2014;McNeill et al, 2012;Wang et al, 2014;Winder-Rhodes et al, 2013;Zokaei et al, 2014). Because of the increased rate of clinical decline, patients with GBA1 mutations often initiate therapies earlier compared with non-mutation carriers (Angeli et al, 2013;Barrett et al, 2014).…”

Cognitive and motor functioning in elderly glucocerebrosidase mutation carriers

“…This includes worse performance on broad screening measures of cognitive functioning (e.g., the Montreal Cognitive Assessment; Brockmann et al, 2011), and more specifically, deficits in visual short-term memory (Zokaei et al, 2014), memory and visuospatial functioning (Alcalay et al, 2012; Mata et al, 2016), and executive functioning and working memory (Mata et al, 2016). In addition, GBA -PD is related to neuropsychiatric symptoms such as depression and anxiety (Brockmann et al, 2011; Swan et al, 2016), and those with GBA -PD are more likely to have hallucinations and sustained cholinesterase inhibitor use (Barrett et al, 2014). …”

Glucocerebrosidase Mutations in Parkinson Disease

“…GBA-mutation PD patients appeared to have a higher risk of reporting hallucinations when compared to idiopathic PD patients, but no differences between mild and severe mutations were found [73]. A statistically significant higher frequency of hallucinations in PD patients with GBA mutation was not confirmed in all studies [62,72].…”

“…However, significant differences in cognitive function between PD patients with and without GBA mutations were not confirmed in some studies [13,62,71,72]. It has been reported that there is significantly higher frequency of usage of acetylcholine esterase inhibitors for dementia in GBA PD compared with idiopathic PD [73], and one study found significant differences in selfreported cognitive impairment [74]. PD patients with GBA mutation also showed a more rapid cognitive decline [51,52,54], although this evidence was not supported by all studies [69].…”