Original research: initial development of a pragmatic tool to estimate cognitive decline risk focusing on potentially modifiable factors in Parkinson's disease.

Introduction: Cognitive decline is common in Parkinson's disease (PD). Calculating personalized risk of cognitive decline in PD would allow for appropriate counseling, early intervention with available treatments, and inclusion in disease-modifying trials. Methods: Data were from the Parkinson's Progression Markers Initiative de novo cohort. Baseline scores were calculated for Lifestyle for Brain Health (LIBRA) and the Montreal Parkinson Risk of Dementia Scale (MoPaRDS) per prior literature and preliminary Parkinson's disease Risk Estimator for Decline In Cognition Tool (pPREDICT) by attributing a point for fourteen posited risk factors. Baseline and 5-year follow-up composite cognitive scores (CCSs) were calculated from a neuropsychological battery and used to define cognitive decliners (PD-decline) versus maintainers (PD-maintain). Results: The PD-decline group (n = 44) had higher LIBRA (6.76 ± 0.57, p < 0.05), MoPaRDS (2.45 ± 1.41, p < 0.05) and pPREDICT (4.52 ± 1.66, p < 0.05) scores compared to the PD-maintain group (n = 263; LIBRA 4.98 ± 0.20, MoPaRDS 1.68 ± 1.16, pPREDICT 3.38 ± 1.69). Area-under-the-curve (AUC) for LIBRA was 0.64 (95% confidence interval [CI], 0.55-0.73), MoPaRDS was 0.66 (95% CI, 0.58-0.75) and for pPREDICT was 0.68 (95% CI, 0.61-0.76). In linear regression analyses, LIBRA (p < 0.05), MoPaRDS (p < 0.05) and pPREDICT (p < 0.05) predicted change in CCS. Only age stratified by sex (p < 0.05) contributed significantly to the model for LIBRA. Age and presence of hallucinations (p < 0.05) contributed significantly to the model for MoPaRDS. Male sex, older age, excessive daytime sleepiness, and moderate-severe motor symptoms (all p < 0.05) contributed significantly to the model for pPREDICT. Conclusion: Although MoPaRDS is a PD-specific tool for predicting cognitive decline relying on only clinical features, it does not focus on potentially modifiable risk factors. LIBRA does focus on potentially modifiable risk factors and is associated with prediction of all-cause dementia in some populations, but pPREDICT potentially demonstrates improved performance in cognitive decline risk calculation in individuals with PD and may identify actionable risk factors. As pPREDICT incorporates multiple potentially modifiable risk factors that can be obtained easily in the clinical setting, it is a first step in developing an easily assessable tool for a personalized approach to reduce dementia risk in people with PD.

Original research: longitudinal evaluation of cognitively demanding daily function using performance-based functional assessment highlights heterogeneous trajectories in cognitive and functional abilities in people with Parkinson's disease.

Background: Longitudinal assessment of functional abilities in Parkinson's disease (PD) is needed to determine the efficacy of cognitive interventions in providing meaningful improvements in daily life. Additionally, subtle changes in instrumental activities of daily living may precede a clinical diagnosis of dementia and could aid earlier detection of and intervention for cognitive decline. Objective: The primary goal was to validate the longitudinal application of the University of California San Diego Performance-Based Skills Assessment (UPSA). An exploratory secondary goal was to determine whether UPSA may identify individuals at higher risk of cognitive decline in PD. Methods: Seventy participants with PD completed the UPSA with at least one follow-up visit. Linear mixed effects modeling was used to identify associations between baseline UPSA score and cognitive composite score (CCS) over time. Descriptive analysis of four heterogeneous cognitive and functional trajectory groups and individual case examples was performed. Results: Baseline UPSA score predicted CCS at each timepoint for functionally impaired and unimpaired groups (p < 0.01) but did not predict the rate change in CCS over time (p = 0.83). Participants displayed heterogenous trajectories in both UPSA and CCS during the follow-up period. Most participants maintained both cognitive and functional performance (n = 54), though some displayed cognitive and functional decline (n = 4), cognitive decline with functional maintenance (n = 4), and functional decline with cognitive maintenance (n = 8). Conclusion: The UPSA is a valid measure of cognitive functional abilities over time in PD. Given the heterogeneity of functional and cognitive trajectories, this performance-based assessment did not predict cognitive decline with this relatively short follow-up. Further work is needed to understand longitudinal functional assessments in PD-associated cognitive impairment.

Prognosis in substance abuse-related acute toxic leukoencephalopathy: A scoping review.

OBJECTIVES: Abuse of opiates, cocaine, and lipophilic inhalants (e.g., toluene) can damage brain myelin and cause acute toxic leukoencephalopathy (TL), but little is known about recovery or prognosis in this condition. In light of the ongoing opiate epidemic in the United States, it is important to understand the natural history of patients who have acute neurological complications from illicit drug exposure. Our aim was to conduct a scoping review of the literature regarding prognosis in described cases of substance abuse-related TL. METHODS: A strategic search of PubMed, Ovid, Cumulative Index to Nursing, and Allied Health Literature (CINAHL) databases yielded adult cases of acute TL from opiates, cocaine, or inhalants. Cases and case series were eligible for inclusion if they described acute leukoencephalopathy with a clear temporal association with opiate, cocaine, or inhalant abuse. Inclusion was contingent on availability of clinical descriptions until death or ≥ 4 weeks follow-up with neuroimaging consistent with TL. RESULTS: Among 52 cases from 14 articles, 21 (40.4%) individuals died with mean time to death of 28.2 days; with mean follow-up of 12.8 months, 10 (19.2%) survived with no recovery, 17 (32.7%) had partial recovery, and 4 (7.7%) individuals had full recovery. CONCLUSION: Substance abuse-related acute TL often has a poor prognosis, but partial or even full recovery is possible in a subgroup of individuals over months to years.

Connexin 35b expression in the spinal cord of Danio rerio embryos and larvae.

Electrical synapses are expressed prominently in the developing and mature nervous systems. Unlike chemical synapses, little is known about the developmental role of electrical synapses, reflecting the limitations imposed by the lack of selective pharmacological blockers. At a molecular level, the building blocks of electrical synapses are connexin proteins. In this study, we report the expression pattern for neuronally expressed connexin 35b (cx35b), the zebrafish orthologue of mammalian connexin (Cx) 36. We find that cx35b is expressed at the time of neural induction, indicating a possible early role in neural progenitor cells. Additionally, cx35b localizes to the ventral spinal cord during embryonic and early larval stages. We detect cx35b mRNA in secondary motor neurons (SMNs) and interneurons. We identified the premotor circumferential descending (CiD) interneuron as one interneuron subtype expressing cx35b. In addition, cx35b is present in other ventral interneurons of unknown subtype(s). This early expression of cx35b in SMNs and CiDs suggests a possible role in motor network function during embryonic and larval stages.