A two-stage meta-analysis identifies several new loci for Parkinson's Disease

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10−10, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci

Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Molecular genetic analysis of tau related neurodegeneration

Tau protein is deposited as neurofibrillary tangles in Alzheimer's disease and in a range of other neurodegenerative diseases, designated tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), some forms of frontotemporal dementia (FTD) and the parkinsonism dementia complex of Guam (PDC). The role of the tau gene in these conditions is analysed, using molecular genetic techniques. In a series of British patients PSP is associated with the tau A0 allele and the A0 allele occurs on a segment of genetic variability designated the HI haplotype, spanning 100 kb of DNA. PSP is not associated with genetic markers flanking tau and is not associated with variability in ApoE or α-synuclein. Clinically diagnosed FTD, and pathologically diagnosed PiD and Parkinson's disease are not associated with tau. Neither ApoE nor tau has any effect on the age at onset of PSP. Cases of pathologically diagnosed PSP with atypical clinical presentations and atypical tau protein deposition patterns have a lower frequency of the tau PSP susceptibility haplotype. Tau was sequenced in 22 families with FTD of whom 11 had mutations in tau: exon 10 +14, exon 10 +16 and the P301S mutation. Pathologically the FTD cases were split into FTD with tau inclusions, FTD with ubiquitin inclusions and FTD lacking distinctive histopathology. The presence of tau mutations correlated with the presence of tau pathology. In general, pathologically defined PiD cases did not have tau mutations, however two individuals with the G398R mutation were identified. Both of these cases had atypical immunohistochemical characteristics. In general, PSP cases did not have tau mutations although one young onset individual clinically diagnosed to have PSP was identified to have a tau exon 10+16 mutation. The clinical and pathological features of amyotrophic lateral sclerosis (ALS) and PDC on Guam were analysed. PDC shares clinical similarities with PSP and other tauopathies. PDC and ALS usually appear as separate clinical and pathological entities. A genome wide association study of PDC was carried out which provided evidence for the association of PDC with chromosome 14 and chromosome 20. These regions will need to be investigated in a second data set and evaluated in a family based study before their significance can be determined

Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: a systematic review

Dentatorubral-pallidoluysian atrophy (DRPLA) is an inherited neurodegenerative disorder regarded as found almost exclusively among the Japanese. We have performed as systematic review of published literature to investigate the clinical and genetic characteristics of non-Asian DRPLA. We identified 183 non-Asian patients in 27 families reported with DRPLA with a variable level of clinical information. Mean age at onset was 31 (range 1–67) with epilepsy, ataxia, and chorea common presenting features. A highly significant relationship was identified between repeat length and age at onset with repeat length accounting for 62% of the observed variation in age at onset (P < 0.0001). In addition, a highly significant relationship between repeat length and main presenting complaint was identified (P < 0.001). There was evidence of marked anticipation with a median intergenerational reduction in age at onset of 19 years with a corresponding increase of five repeats per generation. DRPLA is not exclusively found among the Japanese but has been reported worldwide. As such, DRPLA should be considered in the differential diagnosis of a wide spectrum of neurological disease, particularly if there is a dominant family history. Non-Asian DRPLA clinico-genetic phenomenology are similar to Asian series and our study confirms marked genetic anticipation together with a clear association between repeat length and clinical phenotype and disease severity

Client and therapist views on exercise programmes for early-mid stage Parkinson's disease and Huntington's disease

Purpose. Physiotherapists frequently prescribe home exercise programmes for individuals with Parkinson’s disease (PD) and Huntington’s disease (HD); however, little is known about clients’ perceptions of such programmes and any barriers that may affect participation and compliance. Method. A qualitative design was used to capture the attitudes and experiences of people with early-mid stage HD and PD, and with physiotherapists who have experience in neurodegenerative diseases. Two focus groups were conducted for physiotherapists (n¼8); individual interviews were conducted for clients with HD and PD (n¼10). Conversations were digitally recorded and transcribed, and transcriptions were analysed using grounded theory and validated through researcher triangulation. Concepts were categorised according to emerging themes and findings were verified by participants. Results. Both groups cited several barriers to engagement in exercise programmes, which included disease-specific impairments, individual safety and the location at which exercising takes place. Therapists felt that a client’s cognition could affect their ability to participate in an exercise programme. Therapists and clients offered a number of strategies to overcome barriers to exercise. Conclusions. Therapists should work in collaboration with clients to evaluate their individual considerations, identify barriers to exercise and design a client-specific programme that is acceptable and feasible for the client

Psychiatric disorders, myoclonus dystonia, and the epsilon-sarcoglycan gene: a systematic review

Background: Mutations in the maternally imprinted epsilon-sarcoglycan gene occur in 30%–50% of myoclonus-dystonia cases. Psychiatric symptoms, particularly obsessive-compulsive disorder, have been described in some patients. Methods: We systematically reviewed 22 reports of psychiatric symptoms in myoclonus-dystonia, dividing individuals according to clinical and mutation status. Results: Clinically manifesting mutation carriers demonstrated an excess of psychiatric disorders compared with nonmutation carriers (P < .001). No differences were seen between non-motor-manifesting carriers and nonmutation carriers with the exception of alcohol excess/dependence, higher in non-motor-manifesting carriers. Conclusions: The results confirm the association of epsilon-sarcoglycan gene mutations with psychiatric disease and suggest a possible separation of the motor and psychiatric effects

A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease

We report a novel presenilin-1 (PSEN1) mutation, I202F occurring in a Welsh kindred with familial Alzheimer's disease. The average age at onset was 53 years. The I202F mutation occurs in alignment with previously reported PSEN1 mutations in the fourth transmembrane domain and confirms that PSEN1 mutations line up along transmembrane alpha-helices

The genetic aetiology of late-onset chronic progressive cerebellar ataxia

Background An increasing number of dominant and recessive disorders have been associated with late onset chronic progressive ataxia (LOCA) complicating the formulation of a rational diagnostic strategy. Furthermore, there is marked geographic and ethnic variation in the relative importance of these individual disorders and the cause of such observed variation remains unexplained. Methods We have systematically investigated a populationbased cohort of patients with chronic progressive LOCA for SCA 1,2,3,6,7,8,10,12,17, FXTAS and FRDA. In addition we have examined repeat length polymorphism in chromosomes from a genetically homogeneous and representative control population to investigate the association of high-normal repeats and disease prevalence. Results A total of 178 patients including 55 familial cases segregating in 38 kindreds and 123 sporadic were investigated. Pathological expansions were identified in 11/38 (28.9 %) of families and in 5/123 (4.1 %) of sporadic patients. The most frequent diagnoses were SCA6 (6 families and 1 sporadic patient), DRPLA (4 families) and SCA8 (1 family). In addition, one elderly female patient was identified with “possible FXTAS”. Six (2 %) control patients were noted to have expanded SCA8 alleles. Conclusions SCA6 and DRPLA were the most frequent genetic diagnoses identified. Patterns of highnormal allele frequency in this UK population were distinct compared to other ethnic groups but this was poorly predictive of the distribution of disease in this region. The relative contribution of new mutation formation and founder effects to the prevalence of familial ataxia is uncertain, and further exploration of these factors will require detailed analysis of disease allele haplotypes and meiotic instability of intermediate length alleles