Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau<sub>181</sub>, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease

Kang, Ju‐Hee

doi:10.1001/jamaneurol.2013.3861

Cited by 310 publications

(480 citation statements)

References 52 publications

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“…Measurements of Aβ1–42, T ‐tau, and P ‐tau 181 were obtained for CSF samples at the University of Pennsylvania using the multiplex Luminex xMAP platform (Luminex Corp: Austin, Texas, USA) with research‐use‐only Fujirebio‐Innogenetics INNO‐BIA AlzBio3 immunoassay kit‐based reagents (Innogenetics Inc: Harvard, MA, USA) from a single lot as described previously 27, 28. All standards, aqueous controls, and CSF samples (including 2 CSF pools for quality control, 75 μ L each) were analyzed in duplicate in each run 27, 28.…”

Section: Methodsmentioning

confidence: 99%

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

Marek

Chowdhury

Siderowf

et al. 2018

Ann Clin Transl Neurol

433

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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Section: Methodsmentioning

confidence: 99%

“…All standards, aqueous controls, and CSF samples (including 2 CSF pools for quality control, 75 μ L each) were analyzed in duplicate in each run 27, 28. The reported values were calculated as the arithmetic mean of the concentration of the duplicates.…”

Section: Methodsmentioning

confidence: 99%

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

Marek

Chowdhury

Siderowf

et al. 2018

Ann Clin Transl Neurol

433

339

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“…High levels of p-Tau have also been observed in vivo in several toxin [16][17][18] and transgenic α-Syn models of PD, 19,20 suggesting that p-Tau may be an important common factor in the neurodegeneration of not only tauopathies but also of synucleinopathies, such as PD. [21][22][23][24] Most studies to date have focused on the formation and accumulation of Tau and p-Tau in idiopathic PD. Yet several studies have provided evidence that leucine-rich repeat kinase-2 (LRRK2), a kinase, that when mutated is involved in familial forms of PD, can directly interact with, and activate GSK-3β, resulting in increased p-TAU formation.…”

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confidence: 99%

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

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Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson's disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.

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“…Whether this model can identify individuals with prodromal or preclinical PD has not been tested. CSF biochemical markers were also analyzed using multivariate logistic regression for PD diagnosis, with only relatively low AUCs achieved 13. As far as we know, there have been no attempts to combine body fluid biomarkers with clinical measures in a multivariate diagnosis model for PD diagnosis or prediction.…”

Section: Discussionmentioning

confidence: 99%

Combining clinical and biofluid markers for early Parkinson's disease detection

Stewart

Aasly

et al. 2017

Ann Clin Transl Neurol

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Accurate early diagnosis of Parkinson's disease is essential. Using data available from the Parkinson's Progression Markers Initiative study, we identified a multivariate logistic regression model including cerebrospinal fluid α‐synuclein, olfactory function, age, and gender that achieved a high degree of discrimination between patients with Parkinson's disease and healthy control or scan without evidence of dopaminergic deficit participants. Additionally, the model could predict the conversion of scan without evidence of dopaminergic deficit to Parkinson's disease, as well as discriminate between normal and impaired subjects with leucine‐rich repeat kinase 2 mutations. Although further validation is needed, this model may serve as an alternative method to neuroimaging screening in Parkinson's disease studies.

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Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau₁₈₁, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease

Cited by 310 publications

References 52 publications

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

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

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

Combining clinical and biofluid markers for early Parkinson's disease detection

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Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau181, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease

Cited by 310 publications

References 52 publications

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

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

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

Combining clinical and biofluid markers for early Parkinson's disease detection

Contact Info

Product

Resources

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Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau₁₈₁, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease