Use of Off-Label Drugs and Nutrition Supplements among Patients with Amyotrophic Lateral Sclerosis in Norway

Background and Objectives. Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, characterized by gradual paralysis and muscle atrophy. Riluzole, the only approved treatment in Norway, increases mean survival by 3–6 months. The use of off-label medications and nutritional supplements is common in other serious conditions, such as Parkinson’s disease and dementia. The aims of this study were to investigate to what extent Norwegian ALS patients use supplements and off-label medications and whether this is related to their health-related quality-of-life (HRQOL). Materials and Methods. A cross-sectional questionnaire study was performed, where 41 ALS patients reported their use of off-label treatments, as well as self-perceived HRQOL using the RAND-12 questionnaire. Results. A majority of respondents used riluzole. Of the 41 respondents, 18 (43.9%) reported use of off-label medications and 18 (43.9%) used nutritional supplements. Low-dose naltrexone was the most commonly used off-label medication, whereas vitamins accounted for most of the nutritional supplements. The respondents’ RAND-12 component scores were significantly lower than those of the general population. Low-dose naltrexone and vitamin B were associated with a better physical component score. Conclusions. Most of the respondents in our study adhere to the recommended treatment protocols, as less than half of them reported using off-label medications or nutritional supplements against ALS. Positive correlations between physical HRQOL and use of low-dose naltrexone or vitamin B were demonstrated. These results warrant further investigations.publishedVersio

Mortality trends of amyotrophic lateral sclerosis in Norway 1951–2014: an age–period–cohort study

Recent studies suggest that the incidence and mortality of amyotrophic lateral sclerosis (ALS) are increasing. Changing environmental factors could influence disease risk differently throughout life span, and also between genders, birth cohorts, and seasons of birth. We aimed at describing long-term ALS mortality trends in Norway between 1951 and 2014 using age–period–cohort analysis. The Norwegian Cause of Death Registry provided ALS mortality data that were age- and sex-adjusted through direct standardization. Poisson regression analyses were used for identification of mortality trends and potential month of birth effects. We identified 5345 ALS cases, of which 54.7 % were men. ALS mortality increased throughout the whole period (p < 0.001), with a mean annual increase of 1.14 %. The increase was confined to those older than 60 years, but rates consistently dropped amongst the absolute oldest. The increase was mainly driven by birth cohort effects that increased from 1860 until 1934 (p < 0.001). No month of birth effect or change in sex ratio was found. The continuous increase in ALS mortality since 1951 is best explained by the long-term changes in exposure to risk factors or in case ascertainment, affecting men and women equally in the generations born since 1860 and at least into 1934.acceptedVersio

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

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

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

Behandling av motoriske symptomer ved Parkinsons sykdom

Gjennom de siste årene har nye terapimuligheter og økt kunnskap om gamle metoder ført til endringer i vår behandling av Parkinsons sykdom. Likevel åpner alle tilgjengelige norske og utenlandske terapianbefalinger for ulike og ofte sidestilte alternativer. Basert på de evidensbaserte terapianbefalingene og på våre egne personlige erfaringer og oppfatninger presenterer vi i denne kliniske oversikten et forslag til fremgangsmåte for medisinsk behandling av motoriske symptomer ved Parkinsons sykdom

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