Cognitive Impairment And Genetic Susceptibility In Parkinson’s Disease

Part1The clinical case-control study of cognitiveimpairment in Parkinson’s DiseaseBackground:Parkinson’s disease (PD) is one of the most common neurodegenerative disorder. Except the motor disorder, non-motor symptoms like cognitive impairment which contribute to increased disease burden and decreased quality of life. Cognitive impairment in PD is characterized by involvement of memory, attention, executive function, visuospatial functioning and language. In addition, behavioral and neuropsychiatric symptoms are also very common. Cognitive impairment may be persistent in nature along the disease course。Epidemiological investigation shows that the point prevalence of dementia associated to Dementia in PD,(PD-D) reaches to30%, and Mild cognitive impairment in PD (PD-MCI) reaches27%in non-demented PD patients. In order to allow more accurate cognitive impairment correlative studies and guide clinical practice, the Movement Disorder Society (MDS) recently introduced a standardized set of criteria for PDD and PD-MCI. Unfortunately, in our country, clinicians did not pay much attention to cognitive impairment in PD and the clinical studies is also poor.Objective:Our study is to apply a set of the MDS criteria for PD-D and PD-MCI to our sample of patients with PD. The objective was to provide a more accurate prevalence rate, cognitive profile of cognitive impairments in PD and to explore the risk factors in a Chinese Han PD population.Methods:We conducted a case-control study among330PD patients and163healthy controls matched with age, education, and gender. The demographic and clinical characteristics of PD was obtained on the baseline interview. All PD patients and healthy controls performed a neuropsychological battery tests. All analyses were computed using Statistical Package for Social Sciences (SPSS) version17.0and Excel version2007statistical software.Results:1.A total of29.09%of subjects95%CI (24.19-28.2) were classified as having PD-MCI and a total of32.12%of subjects95%CI (27.07-37.17) were classified as having PD-D.2.There were significant differences among three groups for educational level. After multivariate logistic analysis adjusting the potential confounders, educational Level was still negatively related to PD cognitive impairment (P<0.001).3. Age at onset, disease duration, UPDRS Ⅲ motor score were differed significantly across the three groups (P<0.01). In the logistic regression analyses, all these factors above remained independently associated with PD-D (P<0.01).4. As expected PD-NC patients and PD-MCI patients outperformed PD-D patients in all cognitive domains; PD-NC patients outperformed PD-MCI patients in most cognitive domains (P<0.001), except language and recognition memory. And compared PD-NC and HCs group, semantic fluency test and digit span-forward test show significant difference (P<0.01).5. Apathy was more obviously in both PD-D and PD-MCI patients, as compared to PD-NC patients. In logistic regression analyses, apathy was still positively related to PD-MCI and PD-D patients (P<0.001). In NPI assessment, the neuropsychiatric symptoms in PD-D is more frequently in most domains in contrast to the two groups without dementia, and the latter groups did not observe obviously difference. In the logistic regression analyses, NPI showed a significant effect of PD-D status (P=0.016).6. The distribution of four subtypes in PD-MCI was in the order ofnaMCI-SD (14.5%)> aMCI-SD (5.5%)> aMCI-MD (4.9%)> naMCI-MD (4.2%). Frontal/executive function was the most common domain dysfunction observed in both single-domain and multiple-domain. Language dysfunction was rarely seen. Comparison of PD-MCI subtypes, there were no significant differences regarding demographic features and neuropsychiatric symptoms, although the mean of the disease duration was longer, cognitive impairment and motor severity was greater in multiple-domain than single-domain subtypes. Using multinomial logistic regression models, only axial functioning/gait contributed significantly with significant differences between naMCI-MD and aMCI-SD (P=0.002).7. Comparison of more extensive neuropsychological testing level II, the simple diagnostic rating level I had only55subjects (51.89%of all subjects) met clinical criteria for probable PD-D, the missed cases were largely due to2checklist items that were not endorsed (absence of GDS-15and MMSE score).Conclusion:1. Our findings are consistent with other studies,cognitive impairment in PD is common in Han Chinese PD population.2. Educational level as a protective factor for cognitive impairment in PD, and older disease onset, longer disease duration and more severe motor symptoms were also independent risk factors for PD-MCI conversion to PD-D.3. The cognitive profile of PD is heterogeneous. The degree of cognitive impairment cross the three groups is in the order of PD-NC <PD-MCI<PDD. And the executive impairment is most common, then followed memory, attention, visuo-spatial and language. Even in cognitively preserved PD-NC patients, there is probably a more frequent subthreshold mild cognitive impairment involving attention and executive dysfunction than healthy population.4. Apathy is an independent risk factor of cognitive impairment in PD; and NPI score was also an independent risk factor for PD-MCI conversion to PD-D. The profile of neuropsychiatric symptoms in PD-D worse than both PD-NC group and PD-MCI group, which did not differ much from the two latter groups.5. The distribution of PD-MCI subtypes was as follows:naMCI-SD >aMCI-SD>aMCI-MD>naMCI-MD, with a prevailing impairment in executive/intentional function. PD-MCI subtypes differed in their motor features, with na-MCI-MD subjects showing particularly pronounced problems with postural instability and gait. Differences among PD-MCI subtypes in PD duration, medication use, mood or behavioral disturbances were not significant.6. The simple diagnostic rating level I seems not sensitive enough for detection of PD-D. Revision of the checklist by altering or eliminating the2problematic checklist items may improve sensitivity. Part2Association of the reported candidate gene polymorphisms with susceptibility to cognitive impairment in Parkinson’s DiseaseBackground:The pathogenesis contributions to cognitive impairment are not well known. A model of cognitive impairment in Parkinson’s disease has been proposed that incorporates roles of pathological correlates, neurotransmitter changes, genetic contributions and aging factors. Studies reported that an association of the number of cortical Lewy bodies, Alzheimer’s-type pathological changes and vascular lesions are all important in cognitive impairment in Parkinson’s disease. Occurrence of PD cognitive impairment may also be influenced by genetic factors, but the relationship with specific genetic factors is not fully understood. There have been suggesting that some variants in GBA%COMT、BDNF、 DYRK1A and APOE gene are susceptible factors to PD cognitive impairment.Objective:In order to full understanding of the genetic variants for predicting the risk of cognitive impairment in Parkinson’s disease.Methods:Genotypes analysis of the5reported genes associated with cognitive impairment in Parkinson’s disease in92PD-NC patients,76PD-MCI patients,100PD-D patients and282normal controls using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) assay.Results:BDNF(rs6265), GBA(L444P), DYRK1A(rs8126696), COMT(rs4680) and APOE(ε4), the allele frequency and genotype frequency of four inheritance models did not differ between HCs group and PD-NC group, HCs group and PD-MCI group, HCs group and PD-D group, PD-NC group and PD-MCI group, PD-NC group and PD-D group, PD-MCI group and PD-D group, respectively.Conclusion:1. In this study, we firstly attempt to systematicly investigate genetic predisposition about cognitive impairment in Chinese Han PD patients. 2. The5genes previously reported association with cognitive impairment in PD did not influence the risk of PD and cognitive dysfunction in the Chinese Han PD patients. Part3Analysis of recent novel GWAS-linked loci implicated in late-onset Alzheimer’s Disease risk with susceptibility to cognitive impairment in Parkinson’s DiseaseBackground:Alzheimer’s disease(AD) is the most common progressive neurodegenerative disorder, which is also the most common form of dementia. Despite AD and PD being clinically distinct entities, there is a possibility of a clinic, pathological and cognitive dysfunction overlap suggesting that the2diseases may represent a biological continuum. Recently, genomewide association studies (GWAS) have identified and confirmed10novel AD susceptibility loci:BIN1(rs744373), CLU (rs11136000, rs2279590, rs9331888), ABCA7(rs3764650), CR1(rs3818361, rs6656401), PICALM (rs3851179, rs541458), MS4A6A (rs610932), CD33(rs3865444), MS4A4E (rs670139), CD2AP (rs9296559) andEPHA1(rs11767557).Objective:To assess the genetic overlap of susceptibility factors between AD and cognitive impairment in Parkinson’s disease.Methods:Genotypes analysis of the14top hits of genetic variants indetified by recent AD GWAS in92PD-NC patients,76PD-MCI patients,100PD-D patients and282normal controls using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) assay.Results:1. None of10genes showed a statistical significance on allele frequency and genotype frequency of four inheritance models when compared between HCs group and PD-NC group, HCs group and PD-MCI group, HCs group and PD-D group, PD-NC group and PD-MCI group, PD-NC group and PD-D group, PD-MCI group and PD-D group, respectively.2. There was no statistical difference observed in the haplotype analysis of CLU, CR1and PICALM genes between HCs group and PD-NC group, HCs group and PD-MCI group, HCs group and PD-D group, PD-NC group and PD-MCI group, PD-NC group and PD-D group, PD-MCI group and PD-D group, respectively.Conclusion:1. In this study, we firstly conducted the association of late-onset AD risk loci with cognitive impairment in PD.2. No significant evidence that supported the association for the GWAS top hits in late-onset AD with PD and cognitive impairment in PD in the Chinese Han population.