Diagnostic utility of cerebrospinal fluid α‐synuclein in Parkinson's disease: A systematic review and meta‐analysis

Eusebi, Paolo; Giannandrea, David; Biscetti, Leonardo; Abraha, Iosief; Chiasserini, Davide; Orso, Massimiliano; Calabresi, Paolo; Parnetti, Lucilla

doi:10.1002/mds.27110

Cited by 169 publications

(137 citation statements)

References 56 publications

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“…Measurement of CSF alpha‐synuclein with other PD‐related biomarkers like TREM2 and DA metabolism may validate the utility of CSF and/or plasma alpha‐synuclein as a biomarker, not for the diagnosis or progression of PD, but for specific drug effects like Nilotinib. We observed some variability in oligomeric CSF alpha‐synuclein but the combination with TREM2 and DA metabolism as well as plasma alpha‐synuclein suggest that with longer drug exposure oligomeric alpha‐synuclein that longitudinally increases in the CSF of PD patients may be a reliable measure of Nilotinib effects on changes of PD‐related biomarkers …”

Section: Discussionmentioning

confidence: 87%

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

104

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Nilotinib is a broad‐based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c‐Abl) and discoidin domain receptors ( DDR 1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha‐synuclein and attenuates inflammation in models of Parkinson's disease ( PD ). We previously showed that Nilotinib penetrates the blood‐brain barrier ( BBB ) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies ( DLB ). We performed a physiologically based population pharmacokinetic/pharmacodynamic (pop PK / PD ) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open‐label random single dose ( RSD ) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid ( CSF ) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose‐independent manner and 200 mg Nilotinib increases the level of 3,4‐Dihydroxyphenylacetic acid ( DOPAC ) and homovanillic acid ( HVA ), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha‐synuclein and appears to reduce CSF oligomeric: total alpha‐synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells ( TREM )‐2, suggesting an anti‐inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha‐synuclein.

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Section: Discussionmentioning

confidence: 87%

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pagán

Hebron

Wilmarth

et al. 2019

Pharmacology Res & Perspec

104

View full text Add to dashboard Cite

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“…Developing a reliable assay for CSF SYN assay has proven difficult, in part because CSF SYN is present in relatively low amounts and leakage of peripheral blood into CSF during lumbar puncture can contaminate measurements . Most, but not all, studies have found CSF total SYN to be lower in PD compared to healthy controls . Higher levels of CSF total SYN were associated with faster cognitive decline in the DATATOP study .…”

Section: In Vivo Biomarker Associations With Patient Subtypesmentioning

confidence: 99%

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

2019

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PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha‐synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta‐amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease‐modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society

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“…However, clinical manifestation of PD is heterogeneous and overlaps with other related neurodegenerative disorders, which can hinder accurate diagnosis . Although many studies have reported biochemical differences in biofluids from PD and healthy control (HC) patients, these differences are often at the population level, with significant overlap between groups, and are not useful diagnostic tests for individual patients . Currently, dopaminergic imaging methods provide the highest accuracy for diagnosing parkinsonism, although they neither distinguish PD from parkinsonism with dopaminergic deficit nor report on the pathogenesis of decreased dopamine levels .…”

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confidence: 99%

Comparative study of cerebrospinal fluid α‐synuclein seeding aggregation assays for diagnosis of Parkinson's disease

et al. 2019

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Background PD diagnosis is based primarily on clinical criteria and can be inaccurate. Biological markers, such as α‐synuclein aggregation, that reflect ongoing pathogenic processes may increase diagnosis accuracy and allow disease progression monitoring. Though α‐synuclein aggregation assays have been published, reproducibility, standardization, and validation are key challenges for their development as clinical biomarkers. Objective To cross‐validate two α‐synuclein seeding aggregation assays developed to detect pathogenic oligomeric α‐synuclein species in CSF using samples from the same PD patients and healthy controls from the BioFIND cohort. Methods CSF samples were tested by two independent laboratories in a blinded fashion. BioFIND features standardized biospecimen collection of clinically typical moderate PD patients and nondisease controls. α‐synuclein aggregation was measured by protein misfolding cyclic amplification (Soto lab) and real‐time quaking‐induced conversion (Green lab). Results were analyzed by an independent statistician. Results Measuring 105 PD and 79 healthy control CSF samples, these assays showed 92% concordance. The areas under the curve from receiver operating characteristic curve analysis for the diagnosis of PD versus healthy controls were 0.93 for protein misfolding cyclic amplification, 0.89 for real‐time quaking‐induced conversion, and 0.95 when considering only concordant assay results. Clinical characteristics of false‐positive and ‐negative subjects were not different from true‐negative and ‐positive subjects, respectively. Conclusions These α‐synuclein seeding aggregation assays are reliable and reproducible for PD diagnosis. Assay parameters did not correlate with clinical parameters, including disease severity or duration. This assay is highly accurate for PD diagnosis and may impact clinical practice and clinical trials. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Diagnostic utility of cerebrospinal fluid α‐synuclein in Parkinson's disease: A systematic review and meta‐analysis

Cited by 169 publications

References 56 publications

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

Comparative study of cerebrospinal fluid α‐synuclein seeding aggregation assays for diagnosis of Parkinson's disease

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