Inflammatory Blood Biomarkers Are Associated with Long-Term Clinical Disease Severity in Parkinson's Disease.

An altered immune response has been identified as a pathophysiological factor in Parkinson's disease (PD). We aimed to identify blood immunity-associated proteins that discriminate PD from controls and that are associated with long-term disease severity in PD patients. Immune response-derived proteins in blood plasma were measured using Proximity Extension Technology by OLINK in a cohort of PD patients (N = 66) and age-matched healthy controls (N = 52). In a selection of 30 PD patients, we evaluated changes in protein levels 7-10 years after the baseline and assessed correlations with motor and cognitive assessments. Data from the Parkinson's Disease Biomarkers Program (PDBP) cohort and the Parkinson's Progression Markers Initiative (PPMI) cohort were used for independent validation. PD patients showed an altered immune response compared to controls based on a panel of four proteins (IL-12B, OPG, CXCL11, and CSF-1). The expression levels of five inflammation-associated proteins (CCL23, CCL25, TNFRSF9, TGF-alpha, and VEGFA) increased over time in PD and were partially associated with more severe motor and cognitive symptoms at follow-up. Increased CCL23 levels were associated with cognitive decline and the APOE4 genotype. Our findings provide further evidence for an altered immune response in PD that is associated with disease severity in PD over a long period of time.

CSF Biomarkers Reflecting Protein Pathology and Axonal Degeneration Are Associated with Memory, Attentional, and Executive Functioning in Early-Stage Parkinson's Disease.

In early-stage Parkinson's disease (PD), cognitive impairment is common, and a variety of cognitive domains including memory, attention, and executive functioning may be affected. Cerebrospinal fluid (CSF) biomarkers are potential markers of cognitive functioning. We aimed to explore whether CSF α-synuclein species, neurofilament light chain, amyloid-ß42, and tau are associated with cognitive performance in early-stage PD patients. CSF levels of total-α-synuclein and phosphorylated-α-synuclein, neurofilament light chain, amyloid-ß42, and total-tau and phosphorylated-tau were measured in 26 PD patients (disease duration ≤5 years and Hoehn and Yahr stage 1-2.5). Multivariable linear regression models, adjusted for age, gender, and educational level, were used to assess the relationship between CSF biomarker levels and memory, attention, executive and visuospatial function, and language performance scores. In 26 early-stage PD patients, attention and memory were the most commonly affected domains. A higher CSF phosphorylated-α-synuclein/total-α-synuclein ratio was associated with better executive functioning (sß = 0.40). Higher CSF neurofilament light was associated with worse memory (sß = -0.59), attentional (sß = -0.32), and executive functioning (sß = -0.35). Reduced CSF amyloid-ß42 levels were associated with poorer attentional functioning (sß = 0.35). Higher CSF phosphorylated-tau was associated with worse language functioning (sß = -0.33). Thus, CSF biomarker levels, in particular neurofilament light, were related to the most commonly affected cognitive domains in early-stage PD. This indicates that CSF biomarker levels may identify early-stage PD patients who are at an increased risk of developing cognitive impairment.

Contactin-1 Is Reduced in Cerebrospinal Fluid of Parkinson's Disease Patients and Is Present within Lewy Bodies.

Synaptic degeneration is an early phenomenon in Parkinson's disease (PD) pathogenesis. We aimed to investigate whether levels of synaptic proteins contactin-1 and contactin-2 in cerebrospinal fluid (CSF) of PD patients are reduced compared to dementia with Lewy bodies (DLB) patients and controls and to evaluate their relationship with α-synuclein aggregation. Contactin-1 and -2 were measured in CSF from PD patients (n = 58), DLB patients (n = 72) and age-matched controls (n = 90). Contactin concentration differences between diagnostic groups were assessed by general linear models adjusted for age and sex. Contactin immunoreactivity was characterized in postmortem substantia nigra, hippocampus and entorhinal cortex tissue of PD patients (n = 4) and controls (n = 4), and its relation to α-syn aggregation was evaluated using confocal laser scanning microscopy. Contactin-1 levels were lower in PD patients (42 (36-49) pg/mL) compared to controls (52 (44-58) pg/mL, p = 0.003) and DLB patients (56 (46-67) pg/mL, p = 0.001). Contactin-2 levels were similar across all diagnostic groups. Within the PD patient group, contactin-1 correlated with t-α-syn, tTau and pTau (r = 0.30-0.50, p < 0.05), whereas contactin-2 only correlated with t-α-syn (r = 0.34, p = 0.03). Contactin-1 and -2 were observed within nigral and cortical Lewy bodies and clustered within bulgy Lewy neurites in PD brains. A decrease in CSF contactin-1 may reflect synaptic degeneration underlying Lewy body pathology in PD.

CSF or serum neurofilament light added to α-Synuclein panel discriminates Parkinson's from controls.

BACKGROUND: Neurofilament light chain is a marker of axonal damage and is of interest as a biofluid biomarker for PD. The objective of this study was to investigate whether CSF or serum neurofilament contributes to a combination of CSF biomarkers in defining the optimal biomarker panel for discriminating PD patients from healthy controls. In addition, we aimed to assess whether CSF and/or serum neurofilament levels are associated with clinical measures of disease severity. METHODS: We measured neurofilament light chain levels in CSF and/or serum of 139 PD patients and 52 age-matched healthy controls. We used stepwise logistic regression analyses to test whether neurofilament contributes to a biomarker CSF panel including total, oligomeric, and phosphorylated α-synuclein and Alzheimer's disease biomarkers. Measures of disease severity included disease duration, UPDRS-III, Hoehn & Yahr stage, and MMSE. RESULTS: After correcting for age, CSF neurofilament levels were 42% higher in PD patients compared with controls (P < 0.01), whereas serum neurofilament levels were 37% higher (P = 0.08). Combining CSF neurofilament, phosphorylated-/total α-synuclein, and oligomeric-/total α-synuclein yielded the best-fitting model for discriminating PD patients from controls (area under the curve 0.92). The discriminatory potential of serum neurofilament in the CSF biomarker panel was similar (area under the curve 0.90). Higher serum neurofilament was associated with a lower MMSE score. There were no other associations between CSF and/or serum neurofilament levels and clinical disease severity. CONCLUSIONS: CSF neurofilament contributes to a panel of CSF α-synuclein species in differentiating PD patients from healthy controls. Serum neurofilament may have added value to a biofluid biomarker panel for differentiating PD patients from controls. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Greater motor progression in patients with Parkinson disease who carry LRRK2 risk variants.

OBJECTIVES: In a longitudinal follow-up study, we compared the clinical features and motor progression of patients with Parkinson disease (PD) who are carriers of the leucine-rich repeat kinase 2 (LRRK2) gene risk variants with patients who are noncarriers. METHODS: We prospectively evaluated a cohort of patients with PD for their clinical characteristics, disease severity, and LRRK2 genotype. Carriers of risk variants (G2385R, R1628P, S1647T) and noncarriers were classified separately. A longitudinal, linear mixed model analysis of motor score progression was performed to compare motor progression between the 2 groups. Motor score progression was defined as the difference between Unified Parkinson's Disease Rating Scale motor score at baseline and follow-up scores. RESULTS: A total of 184 patients (122 risk variant carriers and 62 noncarriers) were evaluated and followed up for up to 6.5 years. No differences in demographics and baseline disease characteristics were found. In the longitudinal, linear mixed model analysis, risk variant carriers experienced greater rate of motor progression than noncarriers after 4 years from the date of diagnosis (p ≤ 0.018). CONCLUSIONS: PD LRRK2 risk variant carriers showed greater motor progression after 4 years of disease duration compared with noncarrier patients, suggesting that these risk variants may facilitate neurodegeneration with increasing disease duration.

Prognostic factors for early mortality in Parkinson's disease.

INTRODUCTION: There are few large studies that have evaluated prognostic factors for mortality in Parkinson's disease (PD). This large study aimed to identify demographic and clinical features associated with early mortality in PD. METHODS: PD patients at the National Neuroscience Institute were identified from the Movement Disorders Database from which demographic information and prospectively collected baseline disease characteristics were obtained. All study patients were linked to the Singapore Registry of Birth and Death to obtain information on vital status through December 31, 2012. The prognostic variables analyzed include patient demographics, baseline disease characteristics, and type of PD medication used. Multivariate Cox regression analysis was carried out to identify factors associated with the risk of mortality in PD. RESULTS: Of the 1786 PD patients identified, 363 (20.3%) had died during the 11-year study period. Median survival time from diagnosis was 15.8 years (range 0.3-31). Factors associated with higher mortality (HR, 95% CI) were older age at diagnosis (1.06, 1.03-1.08), male gender (2.29, 1.57-3.35), Hoehn & Yahr (HY) stage ≥ 2.5 (1.54, 1.07-2.22), UPDRS motor score ≥ 30 (1.63, 1.13-2.35), higher bradykinesia subscores (1.05, 1.01-1.09) and cognitive impairment (2.30, 1.55-3.41). CONCLUSIONS: In the largest study to date evaluating baseline disease characteristics prognostic of mortality risk in PD, we found that male gender, older age at diagnosis, higher baseline HY stage, higher baseline UPDRS motor scores, higher bradykinesia subscores and baseline cognitive impairment were associated with early mortality in PD.