Genomic Association Study for Cognitive Impairment in Parkinson's Disease

Background: Cognitive impairment is very common in Parkinson's disease (PD) and constitutes the most debilitating complication of this disease. However, to date, few studies have investigated a genome-wide association in the development of cognitive impairment of PD. We aimed to identify the genetic loci associated with cognitive impairment in patients with sporadic PD by ethnicity-specific genotyping.Materials and methods: We recruited 1,070 patients with PD and performed a genome-wide association study using the Korean Chip, a microarray chip containing 827,400 single-nucleotide polymorphisms (SNPs) optimized for the Korean population. Multiple logistic regression models adjusting for age, sex, years of education, and disease duration were used to compare between patients with and without cognitive impairment, which was defined using the Mini-Mental Status Examination (MMSE) score (MMSE score ≥ 26 vs. < 26) or the Montreal Cognitive Assessment (MoCA) score (MoCA score ≥24 vs. < 24).Results:RYR2 SNP rs10495397 was most significantly associated with cognitive impairment based on the MMSE scores (OR = 3.21; 95% CI = 1.96–5.25, P = 3.36 × 10−6) and CASC17 showed the strongest association with cognitive impairment based on the MoCA scores. However, none of the SNPs were statistically significant after Bonferroni correction.Conclusion:RYR2 may play a role in cognitive impairment in PD by the pathogenic mechanism of neuroinflammation. However, more studies are needed to replicate and validate the results of our functional study.

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Linking a genome-wide association study signal to aLRRK2coding variant in Parkinson's disease

Movement Disorders ◽

10.1002/mds.26495 ◽

2015 ◽

Vol 31 (4) ◽

pp. 484-487 ◽

Cited By ~ 4

Author(s):

Jia Nee Foo ◽

Sun Ju Chung ◽

Louis C. Tan ◽

Herty Liany ◽

Ho-Sung Ryu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Genetic Modifiers of Age at Onset for Parkinson's Disease in Asians: A Genome‐Wide Association Study

Movement Disorders ◽

10.1002/mds.28621 ◽

2021 ◽

Author(s):

Chunyu Li ◽

Ruwei Ou ◽

Yongping Chen ◽

Xiaojing Gu ◽

Qianqian Wei ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Age At Onset ◽

Genome Wide Association ◽

Genetic Modifiers ◽

Genome Wide ◽

A Genome

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α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model

Brain ◽

10.1093/brain/awz380 ◽

2019 ◽

Vol 143 (1) ◽

pp. 249-265 ◽

Cited By ~ 8

Author(s):

Tomoyuki Taguchi ◽

Masashi Ikuno ◽

Mari Hondo ◽

Laxmi Kumar Parajuli ◽

Katsutoshi Taguchi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transgenic Mice ◽

Rem Sleep ◽

Genome Wide Association Study ◽

Artificial Chromosome ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome ◽

Familial Parkinson’S Disease

Abstract Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

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Improving Diversity in Parkinson's Disease Genetics: Findings from the First‐Ever Genome‐Wide Association Study in Latinos

Movement Disorders ◽

10.1002/mds.28782 ◽

2021 ◽

Author(s):

Inas Elsayed ◽

Isabelle Francesca Foote

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide

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122 Use of Pimavanserin in Patients With Parkinson’s Disease Psychosis: Subgroup Analysis of Efficacy and Safety in Patients With and Without Cognitive Impairment

CNS Spectrums ◽

10.1017/s1092852918000202 ◽

2018 ◽

Vol 23 (1) ◽

pp. 77-77 ◽

Cited By ~ 1

Author(s):

Daniel Weintraub ◽

James Norton ◽

Bruce Coate ◽

Candace Andersson ◽

Doral Fredericks ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Subgroup Analysis ◽

Serotonin Receptor ◽

Mmse Score ◽

Cognitively Impaired ◽

Efficacy And Safety ◽

Impaired Group ◽

Moca Score

AbstractObjectiveA planned subgroup analysis of a phase 3 study was performed to evaluate the efficacy and safety of pimavanserin (PIM) in Parkinson’s disease psychosis (PDP) patients withglobal cognitive impairment.BackgroundPDP is frequent, distressing, a leading cause of institutionalization, complicates PD management and is linked to increased morbidity, incident dementia and mortality. PIM, a selective serotonin receptor (5-HT2A) inverse agonist/antagonist, is newly FDA-approved for the treatment of hallucinations and delusions associated with PDP.MethodsIn Study 020, a 6-week FDA registration study, 199 patients with baseline Mini-Mental State Examination (MMSE) score ≥21, moderate-severe psychosis, and on stable PD meds, were randomized to PIM (34 mg/day) or placebo (PBO) for 6 weeks. This subgroup analysis evaluates efficacy and safety between two groups: those with MMSE total score ≥21 but <25 (cognitively impaired; equivalent to Montreal Cognitive Assessment [MoCA] score 15-19) and those with score ≥25 (cognitively normal; equivalent to MoCA score 20-30). Safety assessments were performed on the full safety dataset (i.e., three 6-week placebo-controlled studies) including 614 subjects (PIM=382, PBO=231).ResultsOverall, patients in the PIM group experienced a statistically significant improvement in SAPS-PD scores from baseline to Day 43 compared with PBO (-5.79 vs. -2.73; p=0.001). In the subgroup analysis stratifying by baseline MMSE score, the change from baseline to Day 43 compared with PBO in the cognitively-impaired group (N=50) was numerically larger (-7.11 vs. -0.47; p=0.002). In the full safety dataset examining cognitively impaired patients, there were no between-group (PIM vs. PBO) differences in any treatment-emergent adverse event (TEAE) (57.6% vs. 56.1%) or serious TEAE (6.8% vs. 5.3%). The most common TEAEs occurring at ≥5% in either group were fall (7.4% vs.10.5%), confusional state (6.5% vs.1.8%), and orthostatic hypotension (0.0% vs. 8.8%).ConclusionsIn this subgroup analysis of PDP patients, the treatment effect of PIM on SAPS-PD was larger in the cognitively-impaired group, with similar TEAE and serious TEAE rates. These results hold promise for cognitively-impaired patients that will be further elucidated in future studies.Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.

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