Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.

Cognitive Profile in Parkinson's Disease Dementia Patients with Low versus Normal Cerebrospinal Fluid Amyloid Beta.

Introduction: In patients with Parkinson's disease (PD), low cerebrospinal fluid (CSF) amyloid beta 1-42 (Ab42) at baseline is the most consistent CSF biomarker as a risk factor for developing dementia. Low CSF Ab42 is, however, a typical hallmark of Alzheimer's disease (AD). Hence, low CSF Ab42 in patients with PD may indicate presence of comorbid AD pathology and may predict a more AD-like cognitive profile when they develop dementia. Our study aimed to investigate if low CSF Ab42 at baseline is associated with a more AD-like cognitive profile in PD patients with dementia. Methods: In a prospectively followed-up, population-based cohort of newly diagnosed PD patients, we compared the cognitive profile of dementia in those with a low CSF Ab42 level at baseline with that of patients who had normal levels at the time when they developed dementia. Four different cognitive domain z-scores (memory, attention, executive, visuospatial) were calculated. Patients were subdivided into three tertiles or categorized dichotomously based on the baseline CSF Ab42 levels as measured by electrochemiluminescence and ELISA. Results: During 10-year follow-up, 37 patients met the inclusion criteria. Memory domain composite z-scores, memory subtest z-scores, and the difference between long-delay free recall versus recognition scores were not significantly different between the groups. Composite z-scores of visuospatial functions significantly differed between the tertiles, which was not significant after Bonferroni correction. In the dichotomous group analysis, z-scores of visuospatial functions significantly differed between the two groups. The other cognitive domain z-scores were not significantly different. Conclusions: In patients with PD dementia, low CSF Ab42 level at baseline is not associated with a specific cognitive profile.

Corrigendum to "The ePark study protocol: A decentralized trial of individual video-assisted cognitive behavioural therapy for depressive disorder in Parkinson's disease" [Contemp. Clinic. Trials Commun. 32 (2023) 101080].

[This corrects the article DOI: 10.1016/j.conctc.2023.101080.].

Identification of diagnostic and prognostic biomarkers of PD using a multiplex proteomics approach.

Given the complexity of Parkinson's disease (PD), achieving acceptable diagnostic and prognostic accuracy will require the support of a panel of diverse biomarkers. We used Proximity extension assays to measure a panel of 92 proteins in CSF of 120 newly diagnosed PD patients and 45 control subjects without neurological disease. From 75 proteins detectable in the CSF of >90% of the subjects, regularized regression analysis identified four proteins (ß-NGF, CD38, tau and NCAN) as downregulated in newly diagnosed PD patients (age at diagnosis 67.2 ± 9.4 years) compared to controls (age 65.4 ± 10.9 years). Higher tau (ß -0.82 transformed MMSE points/year, 95% CI -1.37 to -0.27, P = 0.005) was also linked to faster cognitive decline over the first ten years after PD diagnosis. These findings provide insights into multiple aspects of PD pathophysiology and may serve as the foundation for identifying new biomarkers and therapeutic targets.

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.

Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia.

Background: There is a need to better understand the rate of cognitive and motor decline of Dementia with Lewy bodies (DLB) and Parkinson's disease Dementia (PDD). Objectives: To compare the rate of cognitive and motor decline in patients with DLB and PDD from the E-DLB Consortium and the Parkinson's Incidence Cohorts Collaboration (PICC) Cohorts. Methods: The annual change in MMSE and MDS-UPDRS part III was estimated using linear mixed regression models in patients with at least one follow-up (DLB n = 837 and PDD n = 157). Results: When adjusting for confounders, we found no difference in the annual change in MMSE between DLB and PDD (-1.8 [95% CI -2.3, -1.3] vs. -1.9 [95% CI -2.6, -1.2] [P = 0.74]). MDS-UPDRS part III showed nearly identical annual changes (DLB 4.8 [95% CI 2.1, 7.5]) (PDD 4.8 [95% CI 2.7, 6.9], [P = 0.98]). Conclusions: DLB and PDD showed similar rates of cognitive and motor decline. This is relevant for future clinical trial designs.

Treatment of motor symptoms in Parkinson's disease. / Behandling av motoriske symptomer ved Parkinsons sykdom.

In recent years, the development of new therapies and improvements in our understanding of older therapies have led to changes in the management of Parkinson's disease. However, current Norwegian and international therapy recommendations present a range of different options as being equally viable. In this clinical review, we propose an updated algorithm for the medical treatment of motor symptoms in Parkinson's disease, based on evidence-based recommendations and our own personal experience and opinions.

Inflammatory Biomarkers in Newly Diagnosed Patients With Parkinson 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.

Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson's disease.

Aberrant proteostasis is thought to be implicated in Parkinson's disease (PD), but patient-derived evidence is scant. We hypothesized that impaired proteostasis is reflected as altered transcriptome-proteome correlation in the PD brain. We integrated transcriptomic and proteomic data from prefrontal cortex of PD patients and young and aged controls to assess RNA-protein correlations across samples. The aged brain showed a genome-wide decrease in mRNA-protein correlation. Genes encoding synaptic vesicle proteins showed negative correlations, likely reflecting spatial separation of mRNA and protein into soma and synapses. PD showed a broader transcriptome-proteome decoupling, consistent with a proteome-wide decline in proteostasis. Genes showing negative correlation in PD were enriched for proteasome subunits, indicating accentuated spatial separation of transcript and protein in PD neurons. In addition, PD showed positive correlations for mitochondrial respiratory chain genes, suggesting a tighter regulation in the face of mitochondrial dysfunction. Our results support the hypothesis that aberrant proteasomal function is implicated in PD pathogenesis.

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.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

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.

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.

Frailty in Parkinson's disease and its association with early dementia: A longitudinal study.

INTRODUCTION: Frailty is recognized as a clinical condition associated with increased vulnerability for developing negative health outcomes but has been little studied in patients with Parkinson's disease (PD). Here, we investigated the risk of frailty in de novo PD patients and its association with subsequent development of dementia. METHODS: We conducted a three-year longitudinal population-based study of 192 drug-naive newly diagnosed PD patients and 172 controls (No-PD) matched for age, sex, and education. Frailty was measured using the frailty index (FI). Logistic regression models, adjusting for potential confounders, were conducted to assess the association between frailty at the time of PD diagnosis and the subsequent odds for developing PD dementia during follow-up. RESULTS: The mean baseline FI score was higher in the PD (0.21 ± 0.10) than in the No-PD group (0.11 ± 0.07, p < 0.001). One-third of PD patients had high-FI (>0,25), compared to 5% in the no-PD group. Participants with PD had an increased risk to present frailty with an odds ratio (OR) of 6.68 (SE 2.70 IC 95% [3.15; 15.62], p-value <0.001) compared to the No-PD group. PD Participants with greater FI measured at baseline had increased odds of having dementia within three years of follow-up, after adjustment for age and sex (OR 2.91 SE 1.00 IC 95% [1.54; 5.99] p-value = 0.002). CONCLUSION: Frailty is common in people with newly diagnosed PD and associated with increased odds for subsequent development of dementia in a three-year follow-up. This study emphasizes the prognostic importance of frailty in PD from the earliest clinical stages.