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  • How common and what are the determinants of sub-optimal care for Parkinson's disease patients: the Milton Keynes community study.

    24 October 2018

    OBJECTIVES: Limited data currently exists within the UK addressing the level of Parkinson's disease (PD) healthcare provision. We investigated whether care for PD patients in a UK community met national guidelines, and the determinants of sub-optimal care for this patient group. METHODS: 340 PD patients were identified from a population of 242,606 (crude prevalence 140 per 100,000 (95% CI 126-156 per 100,000), age-adjusted prevalence 199 per 100,000 (95% CI 178-221 per 100,000)). 248 out of 340 (73%) PD patients identified took part, completing rating scales assessing cognitive, non-motor and sociodemographic variables. RESULTS AND CONCLUSIONS: 9% of patients had never seen a neurologist for their PD and 18.5% were sub-optimally managed; defined as (a) delay between initial diagnosis and first consultation by a specialist >1 year and (b) patients who had not had specialist PD review for >1 year. Older age, poor cognition and worse mobility were major factors in determining sub-optimal care whilst lower education level and tremor as initial symptom were more modest predictors. 20% of patients had been started on dopaminergic therapies including ergot-derived agonists by their GP prior to referral and less than a third had seen allied health professionals throughout their illness. Further work is required to test whether these findings are generalizable across the country and identify what can be done to ensure equal access to specialist care so that all PD patients have access to best practice.

  • Nigral degeneration and striatal dopaminergic dysfunction in idiopathic and Parkin-linked Parkinson's disease.

    24 October 2018

    We have used MR segmented inversion recovery ratio imaging (SIRRIM) of the substantia nigra pars compacta to detect and correlate nigral signal change in idiopathic Parkinson's disease (PD) and parkin patients with striatal (18)F-dopa uptake. Nine PD patients, nine parkin patients, and eight control subjects were studied with a combination of MR inversion recovery sequences sensitive to nigral cell loss. Blinded independent observer rating and quantified nigral signal analysis were performed on all subjects. Striatal regions of interest were defined on T(1)-weighted MRI co-registered to (18)F-dopa positron emission tomography. On blinded observer rating of the SIRRIM dorsal and ventral nigral images, 25% (2/8) of control subjects, 44% (4/9) of PD patients, and 67% (6/9) of parkin patients were classified as abnormal. Quantified total nigral signal intensities were reduced to a greater extent in the parkin compared to PD patients. There was a greater predilection for signal reduction in the ventral nigral slice of the PD compared to the parkin patient group, who showed a more uniform involvement. All PD and parkin patients were discriminated from controls on the basis of caudate and putamen (18)F-dopa Ki reductions. Our results suggest that MR segmented inversion recovery ratio imaging shows poor sensitivity for discriminating parkin and idiopathic PD patients from normal controls. Where nigral signal abnormalities were seen, parkin patients manifested generalized nigral cell loss with widespread striatal dopamine terminal dysfunction compared with the lateral nigral targeting seen in PD and selective loss of putamen (18)F-dopa uptake.

  • Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.

    5 November 2018

    BACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. FINDINGS: The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7-69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23-2·83) compared with 1·00 in the lowest quintile of disease risk. INTERPRETATION: These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. FUNDING: Wellcome Trust, National Institute on Aging, and US Department of Defense.

  • A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.

    24 October 2018

    Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.

  • Genetic loading in familial migraine with aura.

    24 October 2018

    Migraine with aura (MA) arises from a combination of genetic and environmental factors. The sibling risk, age at onset, and aura type were compared in 54 MA probands categorised by family history of MA. Three family types were ascertained each having an MA proband and: (1) an MA parent and MA offspring (three generation; n=15), (2) either an MA parent or an MA offspring (two generation; n=20), and (3) neither an MA parent nor an MA offspring (one generation; n=19). The crude recurrence risk to siblings of probands was 2.7-fold higher in three generation compared with two generation MA families (chi(2)=6.24, p=0.0125) and 4.8-fold higher in three generation compared with one generation MA families (chi(2)=9.95, p<0.002). The mean age at onset decreased with an increase in genetic load. The MA probands from three generation families were significantly younger than probands from the one generation families (F=5.14, p=0.030). MA probands from three generation families were more likely to report more than one type of aura than MA probands from two generation families (chi(2)=4.44, p=0.035). The significant difference in genetic loading and the earlier age at onset in the three generation families add further evidence for a genetic basis for MA and the difference in sibling risks demonstrates that the MA population is heterogeneous.

  • Follow-up investigation of 12 proposed linkage regions in multiple sclerosis.

    24 October 2018

    Multiple sclerosis (MS) is an autoimmune disease with overwhelming evidence for genetic determination, and for which a maternal parent-of-origin effect has been reported. As with many complex diseases, multiple suggestive linkage signals have been observed. However, the only unambiguous association and linkage identified to date is with alleles of the human lymphocyte antigen (HLA) class II region. We have now carried out high-density microsatellite genotyping for 12 of the most promising regions (1p, 1q, 2q, 4q, 5p, 9q, 10p, 11p, 12q, 17q, 18p, 19p) from a whole-genome scan in 552 affected sibling pairs. This has been carried out in 194 families containing avuncular pairs. These permit examination of parent-of-origin effects in non-colineal pairs when divided into likely maternal and paternal trait transmission. The results do not confirm any non-major histocompatibility complex linkage in the overall subset nor in the maternal, paternal or HLA-DRB1*1501 subsets. We were able to establish exclusion for a locus with lambda(AV) > or = 1.3 for all the previously suggested regions. These results again raise the possibility that the paradigm of multiple genes of small individual effect used to justify genome searches in MS is incorrect.

  • A multigenerational family with multiple sclerosis.

    24 October 2018

    We report a family with 15 individuals affected with multiple sclerosis present in three and possibly four generations. The segregation of multiple sclerosis within this pedigree is consistent with an autosomal dominant mode of inheritance with reduced penetrance. The clinical characteristics of the affected individuals are indistinguishable from those seen in sporadic multiple sclerosis with respect to sex ratio, age at onset, onset symptom, MRI and clinical course. Eleven of 14 cases (78.6%) were positive for the known multiple sclerosis-associated major histocompatibility complex (MHC) Class II HLA DRB1*15 allele. Parametric linkage analysis gave a non-significant LOD score of 0.31 (theta; = 0.33) for the DRB1 gene. However, among 11 affected children with at least one DRB1*15 bearing parent, all 11 out of 11 received at least one copy of this known susceptibility allele. A transmission disequilibrium test analysis was significant for the DRB1*15 allele within this single family; P = 0.0054. The inheritance pattern in this family suggests the presence of a single major locus responsible for multiple sclerosis susceptibility, with DRB1 acting as an important modifier. This family could be an important resource for the identification of a multiple sclerosis susceptibility gene.