Cannabis use in Parkinson’s disease—A nationwide online survey study

Objectives The aim of this study was to investigate the frequency of use, attitudes toward, and experiences with cannabis and cannabis-related products among people with Parkinson's disease (PwP) living in Norway. Methods Between February and August 2021, PwP and their caregivers were invited to participate in an anonymous online survey study on cannabis use. N = 530 PwP completed the 24-item survey collecting data on the participants’ history of cannabis use, perceived benefits and adverse effects of cannabis use, and expectations toward health care professionals. N = 108 caregivers completed a brief survey detailing their experience with cannabis use. Results A total of 59 (11.3%) of PwP reported previous or current use of cannabis, compared to 7 (6.6%) of caregivers. Cannabis use was associated with increased disease duration, but not age or gender. Improvement in motor function (69.5%), sleep (52.5%), and pain (37.3%) was the most frequently perceived benefits of cannabis use, with benefits more frequently reported by current than previous users. While half (50.8%) of cannabis users had sought advice from a health care professional regarding cannabis use, only 55 (19.9%) of non-users with an interest in cannabis use had discussed the topic with health care professionals. Principal barriers for discussing cannabis use with health care professionals are discussed. Conclusions One in 20 PwP reports cannabis use, and non-users report widespread interest in cannabis. The use of cannabis is often not reported and unknown for health care professionals, arguing for a vigilant approach to non-prescribed cannabis use in clinical follow-up of PwP.publishedVersio

The ePark study protocol: A decentralized trial of individual video-assisted cognitive behavioural therapy for depressive disorder in Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1.2 million Europeans [1]. The prevalence of PD in people over 60 is about 1%, increasing to 4% in people 80 years and older [2]. Although PD is defined as a motor disorder, non-motor symptoms including neuropsychiatric symptoms such as depression and anxiety, are frequent and disabling, with a major impact on quality of life, caregiver burden and healthcare costs [3]. Current pharmacological treatments for PD neuropsychiatric symptoms, including depression, are often unsatisfactory for several reasons, including frequent adverse effects of medication, elevated risk of polypharmacy, and limited availability for non-pharmacological treatment options [4,5]. Previously published RCTs have demonstrated large effect sizes of face-to-face, telephone administered and online CBT for depressive symptoms in PD [[6], [7], [8]]. Despite strong evidence that cognitive behavioural therapy (CBT) is effective and cost-efficient in reducing depressive symptoms in PD, few patients are offered this treatment [3,[6], [7], [8], [9], [10]]. This is likely due in part to a shortage of CBT therapists at neurological outpatient clinics, particularly in rural areas, resulting in geographical differences in the availability of CBT treatment. This calls for the development of novel, evidence based online therapeutic strategies, which may significantly improve the lives of PD patients suffering from depressive symptoms.publishedVersio

Excessive Daytime Sleepiness and REM Sleep Behavior Disorders in Parkinson's Disease: A Narrative Review on Early Intervention With Implications to Neuroprotection

Sleep contributes to the consolidation of our memory and facilitates learning. Short term sleep deprivation temporarily reduces mnestic capacity, whereas long lasting sleep deprivation is associated with structural changes in the hippocampus and cortical areas. However, it is unknown whether early intervention and treatment of sleep disorders could have a neuroprotective effect. In neurodegenerative diseases sleep disorders can occur at preclinical stages and are frequently observed in patients with established Parkinson's disease (PD) and other α-synucleinopathies. REM sleep behavior disorder (RBD) is recognized as a hallmark for the development of α-synucleinopathies and may predict early cognitive decline, while excessive daytime sleepiness (EDS) is present in 12% of patients with PD before treatment initiation and increases continuously over time, causing substantial restrictions for the patients' social life. In more advanced disease, EDS is associated with dementia. Even though well recognized, limited attention has been given to genetics or the treatment of RBD and EDS in early PD. Systematic screening and early intervention can be expected to increase the patients' quality of life, but it remains unclear if this will also impact disease progression. Intervention studies in preclinical and early stages of α-synucleinopathies are needed to increase our understanding of the underlying pathomechanisms and may also provide important inroads to help clarify whether sleep disturbances are secondary to the neurodegenerative process or also contribute to disease exacerbation

Parkinson’s disease clinical milestones and mortality

Identification of factors predicting and driving mortality in PD is important for patient information, disease management, and design of future clinical trials. This study included newly diagnosed PD patients and normal controls (NC) from a population-based study with repeated assessments over a 10-year period. We used the Kaplan–Meier method to estimate survival, Cox proportional hazards regression models to identify baseline risk factors of mortality, and Cox regression models with time-dependent covariates to evaluate the impact of four clinical milestones of advanced PD (visual hallucinations, recurrent falls, dementia, and nursing home placement) on mortality risk. During the 10-year study, 65 (34.2%) of 190 patients and 25 (12.3%) of 203 NC died, with an unadjusted hazard ratio (HR) of 2.85 (95% CI 1.80–4.52) and a HR of 2.48 (95% CI 1.55–3.95) when adjusted for confounders, including comorbidities. Higher age, more severe motor impairment, and postural instability-gait difficulty (PIGD) phenotype were independent baseline predictors of mortality. Each clinical milestone alone more than doubled the risk of death and had a cumulative effect on mortality, with a HR of 10.83 (95% CI 4.39–26.73) in those experiencing all four milestones. PD patients have an increased mortality risk that is disease-related and becomes evident early during the course of the disease. While motor severity and PIGD phenotype were early risk factors of mortality, clinical milestones signaled a substantially increased risk of death later during the disease course, highlighting their potential significance in clinical disease staging and prognosis.publishedVersio

Seed Amplification Assay as a Diagnostic Tool in Newly-Diagnosed Parkinson's Disease

Seed amplification assays (SAA) are the first credible molecular assay for Parkinson’s disease (PD). However, the value of SAA to support the clinicians’ initial diagnosis of PD is not clear. In our study, we analyzed cerebrospinal fluid samples from 121 PD patients recruited through population screening methods and taken within a median delay of 38 days from diagnosis and 51 normal controls without neurodegenerative disease. SAA yielded a sensitivity of 82.6% (95% CI, 74.7% – 88.9%) and specificity of 88.2% (95% CI, 76.1% – 95.6%). These results highlight the potential of SAA to support the initial diagnosis of PD in clinical practice and research.publishedVersio

Does canine inflammatory bowel disease influence gut microbial profile and host metabolism?

Background: Inflammatory bowel disease (IBD) refers to a diverse group of chronic gastrointestinal diseases, and gut microbial dysbiosis has been proposed as a modulating factor in its pathogenesis. Several studies have investigated the gut microbial ecology of dogs with IBD but it is yet unclear if this microbial profile can alter the nutrient metabolism of the host. The aim of the present study was to characterize the faecal bacterial profile and functionality as well as to determine host metabolic changes in IBD dogs. Twenty-three dogs diagnosed with IBD and ten healthy control dogs were included. Dogs with IBD were given a clinical score using the canine chronic enteropathy clinical activity index (CCECAI). Faecal short-chain fatty acids (SCFA) and ammonia concentrations were measured and quantitative PCR was performed. The concentration of plasma amino acids, acylcarnitines, serum folate, cobalamin, and indoxyl sulfate was determined. Results: No significant differences in the abundance of a selection of bacterial groups and fermentation metabolites were observed between the IBD and control groups. However, significant negative correlations were found between CCECAI and the faecal proportion of Lactobacillus as well as between CCECAI and total SCFA concentration. Serum folate and plasma citrulline were decreased and plasma valine was increased in IBD compared to control dogs. Increased plasma free carnitine and total acylcarnitines were observed in IBD compared with control dogs, whereas short-chain acylcarnitines (butyrylcarnitine + isobutyrylcarnitine and, methylmalonylcarnitine) to free carnitine ratios decreased. Dogs with IBD had a higher 3-hydroxyisovalerylcarnitine + isovalerylcarnitine to leucine ratio compared to control dogs. Conclusions: Canine IBD induced a wide range of changes in metabolic profile, especially for the plasma concentrations of short-chain acylcarnitines and amino acids, which could have evolved from tissue damage and alteration in host metabolism. In addition, dogs with more severe IBD were characterised by a decrease in faecal proportion of Lactobacillus

An Agent-Based Model for Simulating Irrigated Agriculture in the Samambaia Basin in Goiás

Agriculture is one of the main economic activities in Brazil. The intensive use of water for irrigated agriculture leads to water rise demand contributing to increase water stress. Agent-based models help assess this problem with promising applications entailing an organizing principle to inform us of how to view a real-world system and effectively build a model. In this work, agent-based modeling is applied to simulate water usage for irrigation in agricultural production in the Samambaia river basin in the municipality of Cristalina in the Goias state of Brazil. The use of real data enables analysis of resource availability in a scenario with high demand irrigation, allowing a greater understanding of the needs of the parties involved

Ultra-deep whole genome bisulfite sequencing reveals a single methylation hotspot in human brain mitochondrial DNA

While DNA methylation is established as a major regulator of gene expression in the nucleus, the existence of mitochondrial DNA (mtDNA) methylation remains controversial. Here, we characterized the mtDNA methylation landscape in the prefrontal cortex of neurological healthy individuals (n=26) and patients with Parkinson’s disease (n=27), using a combination of whole-genome bisulphite sequencing (WGBS) and bisulphite-independent methods. Accurate mtDNA mapping from WGBS data required alignment to an mtDNA reference only, to avoid misalignment to nuclear mitochondrial pseudogenes. Once correctly aligned, WGBS data provided ultra-deep mtDNA coverage (16,723 ± 7,711) and revealed overall very low levels of cytosine methylation. The highest methylation levels (5.49 ± 0.97%) were found on CpG position m.545, located in the heavy-strand promoter 1 region. The m.545 methylation was validated using a combination of methylation-sensitive DNA digestion and quantitative PCR analysis. We detected no association between mtDNA methylation profile and Parkinson’s disease. Interestingly, m.545 methylation correlated with the levels of mtDNA transcripts, suggesting a putative role in regulating mtDNA gene expression. In addition, we propose a robust framework for methylation analysis of mtDNA from WGBS data, which is less prone to false-positive findings due to misalignment of nuclear mitochondrial pseudogene sequences.publishedVersio

Early Forms of α-Synuclein Pathology Are Associated with Neuronal Complex I Deficiency in the Substantia Nigra of Individuals with Parkinson’s Disease

Idiopathic Parkinson’s disease (iPD) is characterized by degeneration of the dopaminergic substantia nigra pars compacta (SNc), typically in the presence of Lewy pathology (LP) and mitochondrial respiratory complex I (CI) deficiency. LP is driven by α-synuclein aggregation, morphologically evolving from early punctate inclusions to Lewy bodies (LBs). The relationship between α-synuclein aggregation and CI deficiency in iPD is poorly understood. While studies in models suggest they are causally linked, observations in human SNc show that LBs preferentially occur in CI intact neurons. Since LBs are end-results of α-synuclein aggregation, we hypothesized that the relationship between LP and CI deficiency may be better reflected in neurons with early-stage α-synuclein pathology. Using quadruple immunofluorescence in SNc tissue from eight iPD subjects, we assessed the relationship between neuronal CI or CIV deficiency and early or late forms of LP. In agreement with previous findings, we did not observe CI-negative neurons with late LP. In contrast, early LP showed a significant predilection for CI-negative neurons (p = 6.3 × 10−5). CIV deficiency was not associated with LP. Our findings indicate that early α-syn aggregation is associated with CI deficiency in iPD, and suggest a double-hit mechanism, where neurons exhibiting both these pathologies are selectively lost.publishedVersio

CSF neurofilament light chain predicts 10-year clinical and radiologic worsening in multiple sclerosis

Background Neurofilament light chain (NfL) is an attractive biomarker of disease activity and progression in MS, but there is a lack in long-term prognostic data. Objective To test the long-term clinical and radiological prognostic value of cerebrospinal fluid (CSF)-NfL among newly diagnosed patients with MS. Methods Newly diagnosed MS patients where followed prospectively with baseline CSF-NfL and repeated MRI and clinical assessments for up to 10 years. Associations between baseline CSF-NfL and longitudinal MRI and clinical assessments were found by Generalized Estimating Equations analysis. Results Forty-two participants were included. CSF-NfL at baseline was significantly associated with the rate of atrophy in globus pallidus (p = 0.009) and hippocampus (p = 0.001) as evaluated by MRI. Baseline volumes of thalamus (β −0.33; 95% CI −0.57 to −0.10, p = 0.006), T1 (β 0.28; 95% CI 0.11 to 0.44, p = 0.001) and T2 (β 0.16; 95% CI 0.04 to 0.27, p = 0.008) lesions and baseline levels of CSF-NfL (β 0.9; 95% CI 0.3 to 1.5, p = 0.002) significantly predicted EDSS worsening over 10 years. Baseline CSF-NfL gave a comparable prediction to the best MRI volumetric predictors. Conclusion CSF-NfL predicted the clinical and radiological course of newly diagnosed patients with MS over a 10-year period, underlining its prognostic role.publishedVersio