Neuropathologic Role of Inositol (1,4,5)-Trisphosphate Receptor Proteolysis

Ischemic brain injury represents a major cause of death and disability. Developing targeted therapies for neuroprotection requires increased understanding of the molecular mechanisms of neuronal injury following ischemia. Both disruption of Ca2+ homeostasis and pathological activation of proteases are believed to play causal roles in delayed neuronal death after ischemia-reperfusion. Presented here are data supporting a novel role for proteolysis of an intracellular Ca2+ release channel, inositol 1,4,5-trisphosphate receptor (InsP3R), in ischemic brain injury. We identified a unique calpain cleavage site in the type 1 InsP3R (InsP3R1) and utilized a recombinant truncated form of the channel (capn-InsP3R1) to investigate the functional consequences of InsP3R1 proteolysis. Using a combination of single-channel electrophysiology and single-cell Ca2+ imaging, we determined that capn-InsP3R1 has InsP3-independent gating and constitutive channel activity. This constitutive channel activity decreased Ca2+ content of intracellular stores in Neuro-2A cells by increasing endoplasmic reticulum (ER) Ca2+ leak. Additionally, capn-InsP3R1 compromised ER Ca2+ buffering capacity in primary cortical cultures, leading to decreased neuronal viability and enhanced sensitivity to excitotoxic injury. Using stereotaxic intracerebral injection of viral vectors, we transduced neurons in vivo with capn-InsP3R1 and observed spontaneous degeneration of subpopulations of neurons in the hippocampus. Together, these results reveal a previously unknown role of calpain-cleaved InsP3R1 in disruption of intracellular Ca2+ homeostasis and neuronal death. Importantly, we also provide evidence of calpain-mediated proteolysis of InsP3R1 in neurons in the cerebellum after ischemic brain injury. The findings presented here provide the first functional studies of calpain-cleaved InsP3R1, and advance our understanding of the pathological role of the cleaved channel in neurodegeneration. Inhibiting Ca2+ release through calpain-cleaved InsP3R1 may emerge as a novel therapeutic strategy for intervention in ischemic brain injury and other neurodegenerative diseases associated with disruption of Ca2+ homeostasis

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The Experience of OFF Periods in Parkinson’s Disease: Descriptions, Triggers, and Alleviating Factors

Purpose: Wearing off of Parkinson’s disease medication is common, but triggers and coping strategies for this transient phenomenon are poorly understood. We aimed to assess the lived experience of OFF periods for people with Parkinson’s disease. Methods: Participants in the longitudinal Fox Insight study who endorsed OFF periods were invited to complete a survey consisting of both multiple-choice and free-text responses. Descriptive statistics were used to summarize multiple-choice responses, and free-text responses were classified into themes through iterative discussion by 3 movement disorders specialists. Results: A total of 2110 participants (52.4% male) completed the survey. Tremor was the most common description of OFF periods (n = 1038, 49.2%), followed by gait changes (n = 535, 25.4%) and rigidity (n = 430, 20.4%). Of 1498 specific triggers for OFF symptoms, the most common was stress (n = 920, 61.4%), followed by anxiety/depression (n = 476, 31.8%) and tiredness/fatigue (n = 351, 23.4%). Common coping strategies (n = 1416 responses) included exercise (n = 678, 47.9%), taking a break (n = 504, 35.6%), and meditation (n = 276, 19.5%). Conclusions: Although OFF periods are common, the individual experiences of OFF vary. This knowledge could be used to develop new counseling strategies for OFF periods in people with Parkinson’s disease

Triggers and alleviating factors for fatigue in Parkinson's disease.

BackgroundFatigue is common in Parkinson's Disease, but few effective treatments are available for it. Exploring triggers and alleviating factors, including effects of exercise, could inform development of management strategies for Parkinson's Disease fatigue.ObjectivesTo examine triggers and alleviating factors for fatigue reported by individuals with Parkinson's Disease, including perceived effect of exercise.MethodsA sample of individuals with self-reported Parkinson's Disease participating in the study Fox Insight were administered an online survey. The survey included the Parkinson's Fatigue Scale, the Physical Activity Scale for the Elderly, and multiple-choice questions about triggers and alleviating factors for fatigue.ResultsAmong the sample of 1,029 individuals with Parkinson's disease, mean (standard deviation (SD)) age was 67.4 (9.3) years, 44.0% were female. Parkinson's Fatigue Scale score ranged from 16-80, mean (SD) 48.8 (16.2). Poor sleep (62.1%) and physical exertion (45.1%) were frequently reported triggers for fatigue. Coping strategies including sitting quietly (58.1%), laying down with or without napping, and exercise (20%). Physical Activity Scale for the Elderly scores were higher in those who reported that exercise alleviated their fatigue (49.7%) compared to those who reported it worsened their fatigue (18.9%) (mean (SD) score 158.5 (88.8) vs 119.8 (66.6) respectively; pConclusionsSeveral behavioral and environmental triggers and alleviating strategies for fatigue are reported by individuals with Parkinson's disease. Many feel that exercise alleviates fatigue, though the relationship between exercise and fatigue in Parkinson's Disease appears complex. This exploratory study may inform future development of treatments or coping strategies for Parkinson's disease fatigue

The experience of care partners of patients with Parkinson's disease psychosis.

BackgroundParkinson's disease psychosis (PDP) has a major impact on quality of life and care partner burden; however, little is known about the lived experiences of care partners in managing PDP.ObjectiveTo understand how care partners of individuals with PDP experience their role and articulate their needs related to psychosis.MethodsThis was a qualitative study of semi-structured telephone interviews. Recruitment was conducted online via the clinical study matching tool, Fox Trial Finder; study activities took place remotely via telephone interviews. Transcripts of the phone interviews were analyzed by grounded theory methods, and a codebook of key themes that emerged from the analysis was developed.ResultsNine care partners (all female) were interviewed. Discussion topics in the codebook included (1) care partner burden and guilt; (2) communication with medical professionals; (3) coping strategies; (4) emotional reactions of the care partner to psychosis; (5) sources of knowledge about PD psychosis; (6) attitudes towards medications for PDP; (7) strategies to care for loved ones with psychosis; (8) psychosis triggers.ConclusionsThis qualitative analysis uncovers important aspects of the care partner experience, including challenges in navigating the medical system and communicating with professionals. Providers treating patients with PDP should be aware of these constraints and provide added support for strained care partners

Fox Insight collects online, longitudinal patient-reported outcomes and genetic data on Parkinson's disease.

Fox Insight is an online, longitudinal health study of people with and without Parkinson's disease with targeted enrollment set to at least 125,000 individuals. Fox Insight data is a rich data set facilitating discovery, validation, and reproducibility in Parkinson's disease research. The dataset is generated through routine longitudinal assessments (health and medical questionnaires evaluated at regular cycles), one-time questionnaires about environmental exposure and healthcare preferences, and genetic data collection. Qualified Researchers can explore, analyze, and download patient-reported outcomes (PROs) data and Parkinson's disease- related genetic variants at https://foxden.michaeljfox.org. The full Fox Insight genetic data set, including approximately 600,000 single nucleotide polymorphisms (SNPs), can be requested separately with institutional review and are described outside of this data descriptor

Current and projected future economic burden of Parkinson's disease in the U.S.

Parkinson's disease (PD) is one of the world's fastest growing neurological disorders. Much is unknown about PD-associated economic burdens in the United States (U.S.) and other high-income nations. This study provides a comprehensive analysis of the economic burdens of PD in the U.S. (2017) and projections for the next two decades. Multiple data sources were used to estimate the costs of PD, including public and private administrative claims data, Medicare Current Beneficiary Survey, Medical Expenditure Panel Survey, and a primary survey (n = 4,548) designed for this study. We estimated a U.S. prevalence of approximately one million individuals with diagnosed Parkinson's disease in 2017 and a total economic burden of $51.9 billion. The total burden of PD includes direct medical costs of$25.4 billion and $26.5 billion in indirect and non-medical costs, including an indirect cost of$14.2 billion (PWP and caregiver burden combined), non-medical costs of $7.5 billion, and$4.8 billion due to disability income received by PWPs. The Medicare program bears the largest share of excess medical costs, as most PD patients are over age 65. Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037. The economic burden of PD was previously underestimated. Our findings underscore the substantial burden of PD to society, payers, patients, and caregivers. Interventions to reduce PD incidence, delay disease progression, and alleviate symptom burden may reduce the future economic burden of PD

Using Technology to Assess, Understand and Treat Gait Impairments in Parkinson's Disease -- a Review of Recent Studies

The researchers conducted a comprehensive review of recent studies (from Jan 2022 to May 2023) related to the use of technology to assess, understand, and treat gait impairments in Parkinson's disease (PD). The review underscores the significant role of technology in advancing the understanding and treatment of gait issues in Parkinson's disease