Cerebrospinal Fluid Biomarkers in Parkinson's Disease with Dementia and Dementia with Lewy Bodies

Parnetti, Lucilla; Tiraboschi, Pietro; Lanari, Alessia; Peducci, Maria; Padiglioni, Chiara; D’Amore, Cataldo; Pierguidi, Laura; Tambasco, Nicola; Rossi, Aroldo; Calabresi, Paolo

doi:10.1016/j.biopsych.2008.02.016

Cited by 158 publications

(140 citation statements)

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“…These data were confirmed by personal studies [9], corroborating the opinion that CSF levels of tau may be a biomarker for the presence and severity of neurodegeneration [784,785], while others did not see such biomarker changes [786][787][788]. Other recent studies showed that CSF AS is currently unsuitable to differentiate between PD and atypical parkinsonism [789].…”

Section: α-Synuclein As a Biomarker For Synucleinopathiesmentioning

confidence: 55%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Section: α-Synuclein As a Biomarker For Synucleinopathiesmentioning

confidence: 55%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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“…There was no difference in A‐Beta levels between PD and HC subjects. Prior studies have shown similar changes in α‐syn and tau in PD subjects,29, 49, 50, 51, 52 but the PPMI cohort is unique as a large, prospectively enrolled, previously untreated PD cohort with well‐characterized clinical, imaging, biospecimen, and genetic biomarkers.…”

Section: Discussionmentioning

confidence: 99%

The Parkinson's progression markers initiative (PPMI) – establishing a PD biomarker cohort

Marek

Chowdhury

Siderowf

et al. 2018

Ann Clin Transl Neurol

428

339

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ObjectiveThe Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker‐defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease‐modifying therapeutic trials.MethodsA total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.ResultsApproximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS‐UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α‐synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t‐tau (45/53) and p‐tau (16/18) were reduced in PD versus HC (P < 0.01),Interpretation PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

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“…However, the CSF biomarkers of sCJD and dementia with Lew body sometime concomitant an overlap, with reduced levels of amyloid beta 42 and induced levels of tau [60,[63][64][65]. Therefore, supplementation of alpha synuclein levels may be helpful for the perspective of differential diagnostics.…”

Section: Alpha-synuclein and Beta-amyloidmentioning

confidence: 99%