Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI

AbstractProtein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson’s disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.

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Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202127 ◽

2020 ◽

Vol 10 (4) ◽

pp. 1541-1549

Author(s):

Seok Jong Chung ◽

Sangwon Lee ◽

Han Soo Yoo ◽

Yang Hyun Lee ◽

Hye Sun Lee ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Early Stage ◽

Striatal Dopamine ◽

Motor Deficits ◽

Dopamine Depletion ◽

Severe Motor ◽

Severe Group ◽

Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

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Development of standardized regression-based formulas to assess meaningful cognitive change in early Parkinson’s disease

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acaa104 ◽

2020 ◽

Author(s):

Hannah L Combs ◽

Kate A Wyman-Chick ◽

Lauren O Erickson ◽

Michele K York

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Test Scores ◽

Prediction Models ◽

Early Stage ◽

Cognitive Change ◽

Cognitive Test ◽

Healthy Controls ◽

Change Over Time ◽

Over Time

Abstract Objective Longitudinal assessment of cognitive and emotional functioning in patients with Parkinson’s disease (PD) is helpful in tracking progression of the disease, developing treatment plans, evaluating outcomes, and educating patients and families. Determining whether change over time is meaningful in neurodegenerative conditions, such as PD, can be difficult as repeat assessment of neuropsychological functioning is impacted by factors outside of cognitive change. Regression-based prediction formulas are one method by which clinicians and researchers can determine whether an observed change is meaningful. The purpose of the current study was to develop and validate regression-based prediction models of cognitive and emotional test scores for participants with early-stage idiopathic PD and healthy controls (HC) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). Methods Participants with de novo PD and HC were identified retrospectively from the PPMI archival database. Data from baseline testing and 12-month follow-up were utilized in this study. In total, 688 total participants were included in the present study (NPD = 508; NHC = 185). Subjects from both groups were randomly divided into development (70%) and validation (30%) subsets. Results Early-stage idiopathic PD patients and healthy controls were similar at baseline. Regression-based models were developed for all cognitive and self-report mood measures within both populations. Within the validation subset, the predicted and observed cognitive test scores did not significantly differ, except for semantic fluency. Conclusions The prediction models can serve as useful tools for researchers and clinicians to study clinically meaningful cognitive and mood change over time in PD.

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Striatal DAT and extrastriatal SERT binding in early-stage Parkinson's disease and dementia with Lewy bodies, compared with healthy controls: An 123I-FP-CIT SPECT study

NeuroImage Clinical ◽

10.1016/j.nicl.2019.101755 ◽

2019 ◽

Vol 22 ◽

pp. 101755 ◽

Cited By ~ 8

Author(s):

Merijn Joling ◽

Chris Vriend ◽

Pieter G.H.M. Raijmakers ◽

Jessica J. van der Zande ◽

Afina W. Lemstra ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dementia With Lewy Bodies ◽

Early Stage ◽

Lewy Bodies ◽

Healthy Controls

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miRNA-based signatures in cerebrospinal fluid as potential diagnostic tools for early stage Parkinson’s disease

Oncotarget ◽

10.18632/oncotarget.24736 ◽

2018 ◽

Vol 9 (25) ◽

pp. 17455-17465 ◽

Cited By ~ 28

Author(s):

Marcia Cristina T. dos Santos ◽

Miguel Arturo Barreto-Sanz ◽

Bruna Renata S. Correia ◽

Rosie Bell ◽

Catherine Widnall ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cerebrospinal Fluid ◽

Early Stage ◽

Diagnostic Tools

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Cerebrospinal fluid amyloid- and phenotypic heterogeneity in de novo Parkinson's disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2012-303808 ◽

2012 ◽

Vol 84 (5) ◽

pp. 537-543 ◽

Cited By ~ 43

Author(s):

G. Alves ◽

K. F. Pedersen ◽

B. R. Bloem ◽

K. Blennow ◽

H. Zetterberg ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cerebrospinal Fluid ◽

De Novo ◽

Phenotypic Heterogeneity

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Movement Disorders Associated with COVID-19

Parkinson s Disease ◽

10.1155/2021/3227753 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Mehri Salari ◽

Bahareh Zaker Harofteh ◽

Masoud Etemadifar ◽

Nahad Sedaghat ◽

Hosein Nouri

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cerebrospinal Fluid ◽

Movement Disorders ◽

Viral Infections ◽

De Novo ◽

Complete Recovery ◽

Neurological Complications ◽

Causal Link ◽

Immune Mediated

As neurological complications associated with COVID-19 keep unfolding, the number of cases with COVID-19-associated de novo movement disorders is rising. Although no clear pathomechanistic explanation is provided yet, the growing number of these cases is somewhat alarming. This review gathers information from 64 reports of de novo movement disorders developing after/during infection with SARS-CoV-2. Three new cases with myoclonus occurring shortly after a COVID-19 infection are also presented. Treatment resulted in partial to complete recovery in all three cases. Although the overall percentage of COVID-19 patients who develop movement disorders is marginal, explanations on a probable causal link have been suggested by numerous reports; most commonly involving immune-mediated and postinfectious and less frequently hypoxic-associated and ischemic-related pathways. The current body of evidence points myoclonus and ataxia out as the most frequent movement disorders occurring in COVID-19 patients. Some cases of tremor, chorea, and hypokinetic-rigid syndrome have also been observed in association with COVID-19. In particular, parkinsonism may be of dual concern in the setting of COVID-19; some have linked viral infections with Parkinson’s disease (PD) based on results from cerebrospinal fluid analyses, and PD is speculated to impact the outcome of COVID-19 in patients negatively. In conclusion, the present paper reviewed the demographic, clinical, and treatment-associated information on de novo movement disorders in COVID-19 patients in detail; it also underlined the higher incidence of myoclonus and ataxia associated with COVID-19 than other movement disorders.

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Endocannabinoid levels in patients with Parkinson’s disease with and without levodopa-induced dyskinesias

10.1101/2020.06.28.20142182 ◽

2020 ◽

Author(s):

Camila Marchioni ◽

Bruno Lopes Santos-Lobato ◽

Maria Eugênia Costa Queiroz ◽

José Alexandre S. Crippa ◽

Vitor Tumas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Endocannabinoid System ◽

Column Switching ◽

Healthy Controls ◽

Highly Sensitive ◽

Liquid Chromatography Tandem Mass ◽

Csf Levels ◽

Ultrahigh Performance Liquid Chromatography ◽

Arachidonoyl Glycerol

AbstractBackgroundLevodopa-induced dyskinesias (LID) in Parkinson’s disease (PD) are frequent complications, and the endocannabinoid system has a role on its pathophysiology.ObjectiveTo test the hypothesis that the functioning of the endocannabinoid system would be altered in PD and in LID by measuring plasma and CSF levels of α-N-arachidonoylethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in patients with PD with and without LID and in healthy controls.MethodsBlood and CSF samples were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. The levels of AEA and 2-AG were measured using a highly sensitive column switching ultrahigh-performance liquid chromatography-tandem mass spectrometry method.ResultsWhen pooled together, patients with PD had lower plasma and CSF levels of 2-AG and higher CSF levels of AEA compared to healthy controls (Mann-Whitney statistics = 303.0, p = 0.02). Patients with PD without LID had lower CSF levels of 2-AG (Kruskal-Wallis statistics = 7.76, p = 0.02) and higher CSF levels of AEA levels than healthy controls (Kruskal-Wallis statistics = 8.81, p = 0.01).ConclusionsThe findings suggest that the endocannabinoid system participates in the pathophysiology of PD symptoms, but its role in the pathophysiology of LID is still unclear.

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Evaluation of cerebrospinal fluid proteins as potential biomarkers for early stage Parkinson’s disease diagnosis

PLoS ONE ◽

10.1371/journal.pone.0206536 ◽

2018 ◽

Vol 13 (11) ◽

pp. e0206536 ◽

Cited By ~ 11

Author(s):

Marcia Cristina T. dos Santos ◽

Dieter Scheller ◽

Claudia Schulte ◽

Irene R. Mesa ◽

Peter Colman ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cerebrospinal Fluid ◽

Early Stage ◽

Disease Diagnosis ◽

Cerebrospinal Fluid Proteins ◽

Potential Biomarkers

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P.015 Long-term progression and prognosis in different subtypes of Parkinson’s disease: validation of a new multi-domain subtyping method

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.116 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S17

Author(s):

S Fereshtehnejad ◽

Y Zeighami ◽

A Dagher ◽

RB Postuma

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Early Stage ◽

Real Life ◽

Clinical Manifestations ◽

Personalized Care ◽

Autonomic Disturbance ◽

Progression Markers

Background: Parkinson’s disease (PD) varies in clinical manifestations and course of progression from person to person. Identification of distinct PD subtypes is of great priority to develop personalized care approaches. We aimed to compare long-term progression and prognosis between different PD subtypes. Methods: Data on 421 individuals with de novo early-onset PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI). Using a newly developed multi-domain subtyping method (based on motor phenotype, RBD, autonomic disturbance, early cognitive deficit), we divided PD population into three subtypes at baseline: “mild motor-predominant”, “Diffuse malignant” and “Intermediate”. Rate of global progression (mixed motor and non-motor features) and developing dementia were compared between the subtypes. Results: Patients with “diffuse malignant” PD experienced 0.5 z-score further worsening of global composite outcome (p=0.017) and 2.2 further decline in MOCA score (p=0.001) after 6-years of follow-up. Hazard for MCI/dementia was significantly higher in “diffuse malignant” (HR=3.2, p<0.001) and “intermediate” (HR=1.8, p<0.001) subtypes. Individuals with “diffuse malignant” PD had the lowest level of CSF amyloid-beta (p=0.006) and SPECT striatal binding ratio (p=0.001). Conclusions: This multi-domain subtyping is a valid method to predict subgroups of PD with distinct patterns of long-term progression at drug-naïve early-stage with potential application in real-life clinical practice.

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