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Purpose Parkinson's disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinson's Genetics Study seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic and environmental basis of PD susceptibility, symptoms and progression. Participants In the pilot phase reported here, 1819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme records. The average age at the time of the questionnaire was 64±6 years. We collected patient-reported information and sociodemographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred and thirty-two participants (84.2%) met all inclusion criteria, and 1499 provided a DNA sample via traditional post. Findings to date 65% of participants were men, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions. Future plans We plan to recruit sex-matched and age-matched unaffected controls, genotype all participants and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.National Institutes of Health, US Department of Defense.

Lysosomal storage disorders (LSDs) comprise a class of inherited diseases characterized by disruption of normal lysosomal function. Incompletely degraded substrates accumulate, accompanied by cellular dysfunction and death. Neuroinflammation occurs as a reaction to substrate accumulation within microglia and astrocytes or as a response to primary neuronal or oligodendroglial damage.1 Neuroinflammation is of particular relevance in mediating the neuropathology associated with LSDs. Metachromatic leukodystrophy (MLD; Online Mendelian Inheritance in Man database #250100), a demyelinating LSD caused by mutations in the arylsulfatase A (ARSA) gene,2 is a prototypical example of LSD with progressive accumulation of undegraded sulfatides in the nervous system as well as neuroinflammation and neurodegeneration. MLD is an autosomal recessive disease with an estimated incidence of 1:40,000 to 1:100,000.3 The disease is classified into late infantile, juvenile, and adult forms according to the age at onset of symptoms. Clinical manifestations, which consist of unrelenting motor and cognitive impairment, progress rapidly and are more severe in the early onset variants, frequently leading to death within the first decade of life. A correlation between MLD phenotype and ARSA mutations has recently been suggested.4,5 Considerable research activity is currently focused on developing strategies to target brain disease in MLD and other LSDs with central nervous system (CNS) involvement. Gene therapy,6–8 enzyme replacement therapy,9 and small molecular weight compounds are advancing from preclinical to early clinical studies and may enable disease-modifying treatments for these thus far incurable, devastating diseases. Clinical phenotypes and disease progression are highly variable, thus complicating the study of new therapies. Tracking aspects of the complex CNS pathology and their response to novel treatments is particularly challenging. To facilitate therapeutics development, biomarkers of brain disease that can be monitored in support of clinical endpoints would be helpful. Molecular changes have been increasingly appreciated in various neurological diseases in cells outside the nervous system, including in circulating blood cells.10–13 We hypothesized that deciphering the molecular networks progressively perturbed in patients with MLD, and possibly in other LSDs, could highlight novel markers potentially useful for accelerating therapeutics development.