Mitochondrial haplogroups and cognitive progression in Parkinson's disease.
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ABSTRACT:
SUBMITTER: Liu G
PROVIDER: S-EPMC10202390 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Publications
Mitochondrial haplogroups and cognitive progression in Parkinson's disease.
Liu Ganqiang G Ni Chunming C Zhan Jiamin J Li Weimin W Luo Junfeng J Liao Zhixiang Z Locascio Joseph J JJ Xian Wenbiao W Chen Ling L Pei Zhong Z Corvol Jean-Christophe JC Maple-Grødem Jodi J Campbell Meghan C MC Elbaz Alexis A Lesage Suzanne S Brice Alexis A Hung Albert Y AY Schwarzschild Michael A MA Hayes Michael T MT Wills Anne-Marie AM Ravina Bernard B Shoulson Ira I Taba Pille P Kõks Sulev S Beach Thomas G TG Cormier-Dequaire Florence F Alves Guido G Tysnes Ole-Bjørn OB Perlmutter Joel S JS Heutink Peter P van Hilten Jacobus J JJ Barker Roger A RA Williams-Gray Caroline H CH Scherzer Clemens R CR
Brain : a journal of neurology 20230101 1
Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients ...[more]
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Project description:Aims and objectivesA new pathomechanism of Parkinson's disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability.Methods104 early-onset PD patients (EOPD, age at onset ≤ 50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay.ResultsPARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C > A, P333P). In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p = 0.040; p = 0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04-4.04; p = 0.038).ConclusionsOur results indicate that co-occurrence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients.
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Project description:Parkinson's disease is a complex neurodegenerative disorder that is about 1.5 times more prevalent in males than females. Extensive work has been done to identify the genetic risk factors behind Parkinson's disease on autosomes and more recently on Chromosome X, but work remains to be done on the male-specific Y chromosome. In an effort to explore the role of the Y chromosome in Parkinson's disease, we analysed whole-genome sequencing data from the Accelerating Medicines Partnership-Parkinson's disease initiative (1466 cases and 1664 controls), genotype data from NeuroX (3491 cases and 3232 controls) and genotype data from UKBiobank (182 517 controls, 1892 cases and 3783 proxy cases), all consisting of male European ancestry samples. We classified sample Y chromosomes by haplogroup using three different tools for comparison (Snappy, Yhaplo and Y-LineageTracker) and meta-analysed this data to identify haplogroups associated with Parkinson's disease. This was followed up with a Y-chromosome association study to identify specific variants associated with disease. We also analysed blood-based RNASeq data obtained from the Accelerating Medicines Partnership-Parkinson's disease initiative (1020 samples) and RNASeq data obtained from the North American Brain Expression Consortium (171 samples) to identify Y-chromosome genes differentially expressed in cases, controls, specific haplogroups and specific tissues. RNASeq analyses suggest Y-chromosome gene expression differs between brain and blood tissues but does not differ significantly in cases, controls or specific haplogroups. Overall, we did not find any strong associations between Y-chromosome genetics and Parkinson's disease, suggesting the explanation for the increased prevalence in males may lie elsewhere.
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Project description:IntroductionCognitive impairment is a common complication of Parkinson's disease (PD) and identifying risk factors for progression to Parkinson's disease dementia (PDD) is important. However, little research has been done comparing the utility of commonly used cognitive screening tests in predicting cognitive progression in PD.MethodsWe retrospectively reviewed data from patients with PD enrolled in the Pacific Udall Center who had baseline and longitudinal neuropsychological and global cognitive screening tests. The diagnostic accuracies of 3 common screening tests were compared: Montreal Cognitive Assessment (MoCA), Mattis Dementia Rating Scale (DRS-2), and Mini Mental Status Examination (MMSE). Cognitive diagnoses of PD with mild cognitive impairment (PD-MCI) and PDD were based on full neuropsychological testing and established Movement Disorder Society criteria. Logistic regression and Cox proportional hazards regression models were used to examine predictors of cognitive decline.ResultsFour hundred seventy patients for whom scores on all 3 screening tests were available from the same assessment were included in a cross-sectional analysis. The MoCA demonstrated the best overall diagnostic accuracy for PD-MCI (AUC= 0.79, sensitivity= 76.4%) and for PDD (AUC= 0.89, sensitivity= 81.0%) compared to the DRS-2 and MMSE. A longitudinal analysis was performed on the subset of patients (316/470; 67.2%) who were nondemented at baseline and had undergone two or more assessments. After controlling for covariates, the MoCA was the only test associated with progression to PDD (OR= 1.27 95% CI 1.1 - 1.5, p=0.001) and faster time to dementia (HR = 1.3, 95% CI 1.1 - 1.4, p<0.0001).ConclusionsThis study provides additional support for the use of the MoCA as a primary screening tool for cognitive impairment in PD and is the first to show that the MoCA is a predictor of conversion to PDD.
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Project description:BackgroundCognitive decline is well recognized in Parkinson's disease (PD) and a major concern for patients and caregivers. Apolipoprotein E (APOE), catechol-O-methyl transferase (COMT), and microtubule-associated protein tau (MAPT) are of interest related to their contributions to cognitive decline or dementia in PD.ObjectiveHere, we investigate whether APOE, COMT, or MAPT influence the rate of cognitive decline in PD patients.MethodsWe relied on 634 PD patients and 879 controls to examine gene-PD susceptibility associations, and nested longitudinal cohort of 246 patients from the case-control study, which followed patients on average 5 years and 7.5 years into disease. We repeatedly assessed cognitive symptom progression with the MMSE and conducted a full neuropsychological battery on a subset of 183 cognitively normal patients. We used repeated-measures regression analyses to assess longitudinal associations between genotypes and cognitive progression scores.ResultsThe MAPT H1 haplotype was associated with PD susceptibility. APOE 4 carriers (ɛ4+) (p = 0.03) and possibly COMT Met/Met (p = 0.06) carriers exhibited faster annual decline on the MMSE. Additionally, APOEɛ4+ carriers showed faster decline in many of the neuropsychological test scores. No such differences in neuropsychological outcomes were seen for the COMT genotypes.ConclusionThis work supports a growing set of research identifying overlapping etiology and pathology between synucleinopathies, such as PD, Alzheimer's disease, and tauopathies, especially in the context of cognitive dysfunction in PD. We provide support for the argument that APOE ɛ4+ and COMT Met/Met genotypes can be used as predictors of faster cognitive decline in PD.
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