Summary Background 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. Methods A prediction algorithm for global cognitive impairment (defined as Mini Mental State Exam (MMSE) ≤25) was built using data from 1,350 patients with 5,165 longitudinal visits over 12.8 (median, 2.8) years. Age at onset, MMSE, education, motor exam score, gender, depression and GBA mutations, machine selected through stepwise Cox’ hazards analysis and Akaike’s information criterion, were used to compute the multivariable predictor. Independent validation was achieved in another 1,132 patients with 19,127 visits over 8.6 (median, 6.5) years. Findings The cognitive risk score accurately predicted cognitive impairment within ten years of disease onset with an area under the curve (AUC) of >0.85 in both the discovery (95% CI, 0.821–0.902) and validation populations (95% CI, 0.779 – 0.913). 72.6% of patients scoring in the highest quartile were cognitively impaired by ten years vs. 3.7% 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 0.877 (95% CI 0.788–0.943) and high negative predictive value (0.920, 95% 0.877–0.954) at the predefined cutoff (0.196). Performance was stable in 10,000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson’s. It could improve trials of cognitive interventions and inform on prognosis.

Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

Corticostriatal projection neurons (CStrPN) project from the neocortex to ipsilateral and contralateral striata to control and coordinate motor programs and movement. They are clinically important as the predominant cortical population that degenerates in Huntington's disease and corticobasal ganglionic degeneration, and their injury contributes to multiple forms of cerebral palsy. Together with their well-studied functions in motor control, these clinical connections make them a functionally, behaviorally, and clinically important population of neocortical neurons. Little is known about their development. "Intratelencephalic" CStrPN (CStrPNi), projecting to the contralateral striatum, with their axons fully within the telencephalon (intratelencephalic), are a major population of CStrPN. CStrPNi are of particular interest developmentally because they share hodological and axon guidance characteristics of both callosal projection neurons (CPN) and corticofugal projection neurons (CFuPN); CStrPNi send axons contralaterally before descending into the contralateral striatum. The relationship of CStrPNi development to that of broader CPN and CFuPN populations remains unclear; evidence suggests that CStrPNi might be evolutionary "hybrids" between CFuPN and deep layer CPN-in a sense "chimeric" with both callosal and corticofugal features. Here, we investigated the development of CStrPNi in mice-their birth, maturation, projections, and expression of molecular developmental controls over projection neuron subtype identity.

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.