A nationwide study of the incidence, prevalence and mortality of Parkinson’s disease in the Norwegian population

Epidemiological studies of Parkinson’s disease (PD) show variable and partially conflicting findings with regard to incidence, prevalence, and mortality. These differences are commonly attributed to technical and methodological factors, including small sample sizes, differences in diagnostic practices, and population heterogeneity. We leveraged the Norwegian Prescription Database, a population-based registry of drug prescriptions dispensed from Norwegian pharmacies to assess the incidence, prevalence, and mortality of PD in Norway. The diagnosis of PD was defined based on the prescription of dopaminergic drugs for the indication of PD over a continuous time. During 2004–2017, 12,229 males and 9831 females met our definition for PD diagnosis. PD prevalence increased over the observation period, with larger changes observed in the older age groups. Incidence and prevalence of PD increased with age, peaking at 85 years. The male/female prevalence ratio was 1.5 across all ages, whereas the incidence ratio increased with age, from 1.4 in those 60 years, to 2.03 among those >90 years. While PD mortality was generally higher than that of the general population, mortality odds ratios decreased with age, approaching 1.0 among individuals >90 years old. When adjusted for the sex-specific mortality of the general population, the mortality among females with PD was equal to or higher than the mortality among males with PD. Our findings demonstrate that the epidemiological features of PD, including sex-differences, are age and time-period dependent and indicate that sex differences in PD mortality are unlikely to stem from disease-specific negative impact of survival in males.publishedVersio

EEGIFT: Group Independent Component Analysis for Event-Related EEG Data

Independent component analysis (ICA) is a powerful method for source separation and has been used for decomposition of EEG, MRI, and concurrent EEG-fMRI data. ICA is not naturally suited to draw group inferences since it is a non-trivial problem to identify and order components across individuals. One solution to this problem is to create aggregate data containing observations from all subjects, estimate a single set of components and then back-reconstruct this in the individual data. Here, we describe such a group-level temporal ICA model for event related EEG. When used for EEG time series analysis, the accuracy of component detection and back-reconstruction with a group model is dependent on the degree of intra- and interindividual time and phase-locking of event related EEG processes. We illustrate this dependency in a group analysis of hybrid data consisting of three simulated event-related sources with varying degrees of latency jitter and variable topographies. Reconstruction accuracy was tested for temporal jitter 1, 2 and 3 times the FWHM of the sources for a number of algorithms. The results indicate that group ICA is adequate for decomposition of single trials with physiological jitter, and reconstructs event related sources with high accuracy

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease

We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson’s disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels—measured by 31phosphorous magnetic resonance spectroscopy—and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.publishedVersio

Neuronal complex I deficiency occurs throughout the Parkinson's disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage.

Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process

NSAID use is not associated with Parkinson's disease incidence: A Norwegian Prescription Database study

Objective: Whether use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of incident Parkinson’s disease (PD) remains unresolved. Here, we employed the Norwegian Prescription Database to examine whether NSAID use is associated with a lower incidence of PD. Methods: We compared the incidence of PD among users of NSAIDs in a population-based retrospective study using the Norwegian Prescription Database from 2004 to 2017. In total 7580 PD patients were identified using dopaminergic therapy over time as proxy for PD diagnosis. Analyses were performed with minimum 90 and 365 defined daily dose (DDD) NSAID exposure, respectively. Time-dependent Cox regression model and a binary logistic regression analysis with a 5-year lag until PD diagnosis were performed for all NSAIDs. Results: There was overall no decrease in incidence of PD among NSAID users compared to controls. Using a minimum of 90 or 365 DDD threshold of exposure produced similar results. Analysis of individual NSAIDs did not show difference in PD incidence compared to controls Age-specific incidence rates of PD were comparable to reported age-specific incidence rates in previous studies. Interpretation: Our findings provide no evidence that cumulative high exposure to NSAIDs affects the risk of developing PD.publishedVersio

A nationwide study of the incidence, prevalence and mortality of Parkinson’s disease in the Norwegian population

Epidemiological studies of Parkinson’s disease (PD) show variable and partially conflicting findings with regard to incidence, prevalence, and mortality. These differences are commonly attributed to technical and methodological factors, including small sample sizes, differences in diagnostic practices, and population heterogeneity. We leveraged the Norwegian Prescription Database, a population-based registry of drug prescriptions dispensed from Norwegian pharmacies to assess the incidence, prevalence, and mortality of PD in Norway. The diagnosis of PD was defined based on the prescription of dopaminergic drugs for the indication of PD over a continuous time. During 2004–2017, 12,229 males and 9831 females met our definition for PD diagnosis. PD prevalence increased over the observation period, with larger changes observed in the older age groups. Incidence and prevalence of PD increased with age, peaking at 85 years. The male/female prevalence ratio was 1.5 across all ages, whereas the incidence ratio increased with age, from 1.4 in those 60 years, to 2.03 among those >90 years. While PD mortality was generally higher than that of the general population, mortality odds ratios decreased with age, approaching 1.0 among individuals >90 years old. When adjusted for the sex-specific mortality of the general population, the mortality among females with PD was equal to or higher than the mortality among males with PD. Our findings demonstrate that the epidemiological features of PD, including sex-differences, are age and time-period dependent and indicate that sex differences in PD mortality are unlikely to stem from disease-specific negative impact of survival in males

NSAID use is not associated with Parkinson's disease incidence: A Norwegian Prescription Database study

Objective: Whether use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of incident Parkinson’s disease (PD) remains unresolved. Here, we employed the Norwegian Prescription Database to examine whether NSAID use is associated with a lower incidence of PD. Methods: We compared the incidence of PD among users of NSAIDs in a population-based retrospective study using the Norwegian Prescription Database from 2004 to 2017. In total 7580 PD patients were identified using dopaminergic therapy over time as proxy for PD diagnosis. Analyses were performed with minimum 90 and 365 defined daily dose (DDD) NSAID exposure, respectively. Time-dependent Cox regression model and a binary logistic regression analysis with a 5-year lag until PD diagnosis were performed for all NSAIDs. Results: There was overall no decrease in incidence of PD among NSAID users compared to controls. Using a minimum of 90 or 365 DDD threshold of exposure produced similar results. Analysis of individual NSAIDs did not show difference in PD incidence compared to controls Age-specific incidence rates of PD were comparable to reported age-specific incidence rates in previous studies. Interpretation: Our findings provide no evidence that cumulative high exposure to NSAIDs affects the risk of developing PD

Nicotinamide riboside supplementation is not associated with altered methylation homeostasis in Parkinson’s disease

Summary: Replenishing nicotinamide adenine dinucleotide (NAD) via supplementation of nicotinamide riboside (NR) has been shown to confer neuroprotective effects in models of aging and neurodegenerative diseases, including Parkinson’s disease (PD). Although generally considered safe, concerns have been raised that NR supplementation could impact methylation dependent reactions, including DNA methylation, because of increased production and methylation dependent breakdown of nicotinamide (NAM). We investigated the effect of NR supplementation on DNA methylation in a double blinded, placebo-controlled trial of 29 human subjects with PD, in blood cells and muscle tissue. Our results show that NR had no impact on DNA methylation homeostasis, including individuals with common pathogenic mutations in the MTHFR gene known to affect one-carbon metabolism. Pathway and methylation variance analyses indicate that there might be minor regulatory responses to NR. We conclude that short-term therapy with high-dose NR for up to 30 days has no deleterious impact on methylation homeostasis

Neuronal complex I deficiency occurs throughout the Parkinson's disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage.

Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease

We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson’s disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels—measured by 31phosphorous magnetic resonance spectroscopy—and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials