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

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

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

Association of CSF Glucocerebrosidase Activity With the Risk of Incident Dementia in Patients With Parkinson Disease

Background and Objectives Variations in the glucocerebrosidase gene (GBA) are common risk factors for Parkinson disease (PD) and dementia in PD (PDD) and cause a reduction in the activity of the lysosomal enzyme glucocerebrosidase (GCase). It is anticipated that GCase dysfunction might contribute to a more malignant disease course and predict cognitive impairment in PD, although evidence is lacking. We aimed to discover whether CSF GCase activity is altered in newly diagnosed patients with PD and associated with future development of dementia. Methods Patients with PD were participants of the ongoing population-based longitudinal ParkWest study in Southwestern Norway and were followed prospectively for up to 10 years. CSF was collected at diagnosis, and GBA carrier status was obtained. Control samples were from persons without neurodegenerative disorders. GCase activity was measured using a validated assay. PD dementia diagnosis was set according to the Movement Disorder Society criteria, and parametric accelerated failure time models were applied to analyze the association of GCase activity with dementia-free survival. Results This study enrolled 117 patients with PD (mean age 67.2 years, including 12 GBA non‐synonymous variant carriers) and 50 control participants (mean age 64 years). At the time of diagnosis, GCase activity was reduced in patients with PD with (mean ± SD, 0.92 ± 0.40 mU/mg, n = 12) or without GBA variations (1.00 ± 0.37 mU/mg, n = 105) compared with controls (1.20 ± 0.35, n = 50). GCase activity at the time of diagnosis was lower in patients with PD who developed dementia within 10 years (0.85 ± 0.27 mU/mg, n = 41) than in those who did not (1.07 ± 0.40 mU/mg, n = 76, p = 0.001). A 0.1-unit reduction in baseline GCase activity was associated with a faster development of PDD (hazard ratio 1.15, 95% CI 1.03–1.28, p = 0.014). Discussion The association of early CSF GCase activity with long-term progression to PD dementia will have important implications for the design of clinical trials for GCase targeting therapies and patient management. Classification of Evidence This study provides Class III evidence that reduced CSF GCase activity at the time of PD diagnosis is associated with an increased risk for later development of PDD.publishedVersio

Inflammatory biomarkers in newly diagnosed patients with Parkinson’s disease and related neurodegenerative disorders

Background and Objectives Neuroinflammation contributes to Parkinson disease (PD) pathology, and inflammatory biomarkers may aid in PD diagnosis. Proximity extension assay (PEA) technology is a promising method for multiplex analysis of inflammatory markers. Neuroinflammation also plays a role in related neurodegenerative diseases, such as dementia with Lewy bodies (DLB) and Alzheimer disease (AD). The aim of this work was to assess the value of inflammatory biomarkers in newly diagnosed patients with PD and in patients with DLB and AD. Methods Patients from the Norwegian ParkWest and Dementia Study of Western Norway longitudinal cohorts (PD, n = 120; DLB, n = 15; AD, n = 27) and 44 normal controls were included in this study. A PEA inflammation panel of 92 biomarkers was measured in the CSF. Disease-associated biomarkers were identified using elastic net (EN) analysis. We assessed the discriminatory power of disease-associated biomarkers using receiver operating characteristic (ROC) curve analysis and estimated the optimism-adjusted area under the curve (AUC) using the bootstrapping method. Results EN analysis identified 9 PEA inflammatory biomarkers (ADA, CCL23, CD5, CD8A, CDCP1, FGF-19, IL-18R1, IL-6, and MCP-2) associated with PD. Seven of the 9 biomarkers were included in a diagnostic panel, which was able to discriminate between those with PD and controls (optimism-adjusted AUC 0.82). Our 7-biomarker PD panel was also able to distinguish PD from DLB and from AD. In addition, 4 inflammatory biomarkers were associated with AD and included in a panel, which could distinguish those with AD from controls (optimism-adjusted AUC 0.87). Our 4-biomarker AD panel was also able to distinguish AD from DLB and from PD. Discussion In our exploratory study, we identified a 7-biomarker panel for PD and a 4-biomarker panel for AD. Our findings indicate potential inflammation-related biomarker candidates that could contribute toward PD-specific and AD-specific diagnostic panels, which should be further explored in other larger cohorts.publishedVersio

Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci

Parkinson disease (PD) is a complex neurodegenerative disorder influenced by both environmental and genetic factors. While genome wide association studies have identified several susceptibility loci, many causal variants and genes underlying these associations remain undetermined. Identifying these is essential in order to gain mechanistic insight and identify biological pathways that may be targeted therapeutically. We hypothesized that gene-based enrichment of rare mutations is likely to be found within susceptibility loci for PD and may help identify causal genes. Whole-exome sequencing data from two independent cohorts were analyzed in tandem and by meta-analysis and a third cohort genotyped using the NeuroX-array was used for replication analysis. We employed collapsing methods (burden and the sequence kernel association test) to detect gene-based enrichment of rare, protein-altering variation within established PD susceptibility loci. Our analyses showed trends for three genes (GALC, PARP9 and SEC23IP), but none of these survived multiple testing correction. Our findings provide no evidence of rare mutation enrichment in genes within PD-associated loci, in our datasets. While not excluding that rare mutations in these genes may influence the risk of idiopathic PD, our results suggest that, if such effects exist, much larger sequencing datasets will be required for their detection.publishedVersio