Cognitive Impairment in Genetic Parkinson’s Disease

Cognitive impairment is common in idiopathic Parkinson’s disease (PD). Knowledge of the contribution of genetics to cognition in PD is increasing in the last decades. Monogenic forms of genetic PD show distinct cognitive profiles and rate of cognitive decline progression. Cognitive impairment is higher in GBA- and SNCA-associated PD, lower in Parkin- and PINK1-PD, and possibly milder in LRRK2-PD. In this review, we summarize data regarding cognitive function on clinical studies, neuroimaging, and biological markers of cognitive decline in autosomal dominant PD linked to mutations in LRRK2 and SNCA, autosomal recessive PD linked to Parkin and PINK1, and also PD linked to GBA mutations.

Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson’s Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial

Background: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson’s disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor. Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD). Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18–80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics. Results: Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants. Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.

Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson’s Disease

Parkinson’s Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD/PD in animal models may provide an opportunity for treating neurological manifestations of GD/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1ΔTT/ΔTT). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 μM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1ΔTT/ΔTT mutant flies, compared to GBA1+/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins.

Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease

Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson’s disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. PD carriers of severe mutation L444P in the GBA gene is characterized by the earlier age at onset compared to N370S. Not every carrier of GBA mutations develop PD during one’s lifetime. In the current study we aimed to find common gene expression signatures in PD associated with mutation in the GBA gene (GBA-PD) using RNA-seq. We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.

Glucocerebrosidase Mutations and Motor Reserve in Parkinson’s Disease

Background: The concept of motor reserve explains the individual differences in motor deficits despite similar degrees of nigrostriatal dopamine depletion in Parkinson’s disease (PD). Objective: To investigate glucocerebrosidase (GBA) variants as potential determinants of motor reserve for exploratory purposes. Methods: A total of 408 patients with drug-naïve PD were enrolled from the Parkinson’s Progression Markers Initiative cohort database. All patients underwent SPECT dopamine transporter (DAT) scans and had results for Sanger sequencing of GBA. Parkinsonian motor deficits were assessed using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III). We compared MDS-UPDRS-III scores while adjusting for DAT availability in the putamen (i.e., motor reserve) between the PD groups according to the presence of GBA mutations. Results: Fifty-four (13.2%) patients carried GBA mutations. PD patients with GBA mutations were younger than those without mutations. There were no significant differences in sex, disease duration, years of education, and striatal DAT availability between the PD groups. PD patients with GBA mutations had higher MDS-UPDRS-III scores for the less affected side than those without mutations, despite similar levels of DAT availability in the contralateral putamen. The MDS-UPDRS-III sub-scores of the more affected side did not differ between the two PD groups. Conclusion: The results of this study demonstrated the detrimental effect of GBA variants on individual capacity to cope with PD-related pathologies, with different impacts depending on the motor laterality.