Biomarkers of neurodegeneration and glial activation validated in Alzheimer’s disease assessed in longitudinal cerebrospinal fluid samples of Parkinson’s disease

Aim: Several pathophysiological processes are involved in Parkinson's disease (PD) and could inform in vivo biomarkers. We assessed an established biomarker panel, validated in Alzheimer's Disease, in a PD cohort. Methods: Longitudinal cerebrospinal fluid (CSF) samples from PPMI (252 PD, 115 healthy controls, HC) were analyzed at six timepoints (baseline, 6, 12, 24, 36, and 48 months follow-up) using Elecsys® electrochemiluminescence immunoassays to quantify neurofilament light chain (NfL), soluble TREM2 receptor (sTREM2), chitinase-3-like protein 1 (YKL40), glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), S100, and total α-synuclein (αSyn). Results: αSyn was significantly lower in PD (mean 103 pg/ml vs. HC: 127 pg/ml, p0.05) and none showed a significant difference longitudinally. We found significantly higher levels of all these markers between PD patients who developed cognitive decline during follow-up, except for αSyn and IL-6. Conclusion: Except for αSyn, the additional biomarkers did not differentiate PD and HC, and none showed longitudinal differences, but most markers predict cognitive decline in PD during follow-up

Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts.

OBJECTIVE: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. METHODS: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. RESULTS: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04-20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21-1.03]). CONCLUSIONS: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.The Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Researc

Differences in the Presentation and Progression of Parkinson's Disease by Sex.

BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.This study was supported by the Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Research

Elevated In Vitro Kinase Activity in Peripheral Blood Mononuclear Cells ofLeucine-RichRepeat Kinase 2G2019SCarriers: A NovelEnzyme-LinkedImmunosorbent Assay-Based Method

Background Leucine-rich repeat kinase 2 kinase inhibitors are being vigorously pursued as potential therapeutic options; however, there is a critical need for sensitive and quantitative assays of leucine-rich repeat kinase 2 function and target engagement. Objectives Our objective was to compare collection and storage protocols for peripheral blood mononuclear cells, and to determine the optimal conditions for downstream analyses of leucine-rich repeat kinase 2 in PD cohorts. Methods Here, we describe enzyme-linked immunosorbent assay-based assays capable of detecting multiple aspects of leucine-rich repeat kinase 2 function at endogenous levels in human tissues. Results In peripheral blood mononuclear cells from both healthy and affected carriers of the G2019S mutation in leucine-rich repeat kinase 2, we report, for the first time, significantly elevated in vitro kinase activity, while detecting a significant increase in pS935/leucine-rich repeat kinase 2 in idiopathic PD patients. Conclusions Quantitative assays such as these described here could potentially uncover specific markers of leucine-rich repeat kinase 2 function that are predictive of disease progression, aid in patient stratification, and be a critical component of upcoming clinical trials. (c) 2020 International Parkinson and Movement Disorder Societ

Joint status of patients with nonsevere hemophilia A

Background: Joint bleeding in hemophilia may eventually lead to joint damage. In nonsevere hemophilia, joint bleeds occur infrequently. Currently, knowledge on the joint status of patients with nonsevere hemophilia using objective imaging is limited. Objective: To investigate the joint status in patients with nonsevere hemophilia A. Methods: This cross-sectional study included patients with nonsevere hemophilia A aged 24–55 years. Joint status was assessed by magnetic resonance imaging (MRI) of the elbows, knees, and ankles and International Prophylaxis Study Group (IPSG) scores were calculated. Lifetime joint bleeding history was collected from medical files. The contribution of factors to joint outcome was explored using multivariable linear regression analysis. Results: In total, 51 patients were included, of whom 19 (37%) had moderate and 32 (63%) had mild hemophilia. Patients had a median age of 43 years (interquartile range [IQR] 32–50), a median factor VIII activity of 10 IU/dl (IQR 4–16) and a median annual joint bleeding rate (AJBR) of 0.0 (IQR 0.0–0.2). Soft-tissue changes (IPSG subscore > 0) in the elbows, knees, and ankles were present in 19%, 71%, and 71% of patients, respectively. Osteochondral changes (IPSG subscore > 0) in the elbows, knees, and ankles were present in 0%, 20%, and 35% of patients, respectively. In 14% of bleed-free joints, hemosiderin depositions were observed. Age and AJBRs were most strongly associated with the IPSG score. Conclusion: This study demonstrates that a substantial proportion of adults with nonsevere hemophilia has joint changes on MRI despite low joint bleeding rates

Longitudinal Measurements of Glucocerebrosidase activity in Parkinson's patients.

ObjectiveReduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsWe measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.ResultsFifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.InterpretationGCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation

Longitudinal Measurements of Glucocerebrosidase activity in Parkinson's patients.

ObjectiveReduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsWe measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.ResultsFifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.InterpretationGCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation

Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease.

BackgroundCerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).ObjectiveThe aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.MethodsAbsolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.ResultsBaseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug-naive individuals, but some changed on starting levodopa treatment.ConclusionsHVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease

Background: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).Objective: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.Methods: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.Results: Baseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug-naive individuals, but some changed on starting levodopa treatment.Conclusions: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Keywords: CSF; Parkinson's disease; biomarker; catecholamine; homovanillic acid; monoamine metabolites; neurotransmitter