Longitudinal Measurements of Cerebrospinal Fluid Biomarkers in Parkinson's Disease.

The purpose of this study was to investigate whether cerebrospinal fluid (CSF) levels of tau, phosphorylated tau, β-amyloid42 , α-synuclein, neurofilament light, and YKL-40 change over time and if changes correlate with motor progression and/or cognitive decline in patients with PD and controls. We included 63 patients with PD (nondemented) and 21 neurologically healthy controls from the prospective and longitudinal Swedish BioFINDER study, all of whom had clinical assessments and lumbar punctures at baseline and after 2 years. CSF tau levels correlated strongly with α-synuclein. The levels of CSF α-synuclein, tau, phosphorylated tau, neurofilament light, and YKL-40, but not β-amyloid42 , increased in CSF over 2 years in PD. No changes were seen in the control group. Studying patients with a short disease duration ( ≤ 5 years) and patients with a long disease duration ( > 5 years) separately, α-synuclein and tau only increased in the PD group with long disease duration. In the PD group, an increase in phosphorylated tau over 2 years correlated with faster motor progression and faster cognitive decline. An increase in YKL-40 over 2 years correlated with faster cognitive decline. CSF biomarkers reflecting Lewy body pathology and neurodegeneration (α-synuclein), neuronal degeneration (tau, phosphorylated tau, and neurofilament light), and inflammation (YKL-40) increase significantly over 2 years in PD. CSF levels of α-synuclein and tau correlate and remain stable in the early symptomatic phase of PD but increase in the later phase. We hypothesize that CSF α-synuclein levels might increase as a result of more intense neurodegeneration in PD with long disease duration. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Hall S ，Surova Y ，Öhrfelt A ，Swedish BioFINDER Study ，Blennow K ，Zetterberg H ，Hansson O ... -  《-》

CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.

Kang JH ，Mollenhauer B ，Coffey CS ，Toledo JB ，Weintraub D ，Galasko DR ，Irwin DJ ，Van Deerlin V ，Chen-Plotkin AS ，Caspell-Garcia C ，Waligórska T ，Taylor P ，Shah N ，Pan S ，Zero P ，Frasier M ，Marek K ，Kieburtz K ，Jennings D ，Tanner CM ，Simuni T ，Singleton A ，Toga AW ，Chowdhury S ，Trojanowski JQ ，Shaw LM ，Parkinson’s Progression Marker Initiative ... -  《-》

Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40.

Deming Y ，Black K ，Carrell D ，Cai Y ，Del-Aguila JL ，Fernandez MV ，Budde J ，Ma S ，Saef B ，Howells B ，Bertelsen S ，Huang KL ，Sutphen CL ，Tarawneh R ，Fagan AM ，Holtzman DM ，Morris JC ，Goate AM ，Dougherty JD ，Cruchaga C ... -  《BMC Neurology》

Cerebrospinal fluid tau and disease progression in early Parkinson's disease: an 8-year longitudinal study.

To explore whether CSF phosphorylated tau-181 (P-tau181) and total tau (T-tau) are associated with disease progression in early PD patients. We analyzed 8-year longitudinal clinical data from 368 early, drug-naive PD patients and 185 matched controls from the Parkinson's Progression Markers Initiative cohort. CSF P-tau181 and T-tau were measured over 5 years, while CSF α-synuclein was measured over 3 years. Dopamine transporter (DAT) imaging was performed at baseline and at 1, 2, and 4 years. PD patients exhibited significantly lower CSF P-tau181, T-tau and P-tau181/T-tau ratio than controls at each visit. Higher baseline CSF P-tau181 predicted greater increases in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III (estimate: 0.067, P < 0.001) and Montreal Cognitive Assessment (MoCA) scores (estimate: -0.010, P = 0.009). Similarly, higher baseline CSF T-tau predicted greater increases in MDS-UPDRS III (estimate: 0.005, P < 0.001) and MoCA scores (estimate: -0.001, P = 0.013). Higher baseline P-tau181/T-tau ratio predicted greater increases in MDS-UPDRS III (estimate: 0.552, P < 0.001) but was not significantly associated with changes in MoCA scores (estimate: -0.052, P = 0.114). CSF P-tau181 (estimate = 84.889, P < 0.001), T-tau (estimate = 8.297, P < 0.001) and P-tau181/T-tau ratio (estimate = 263.425, P < 0.001) were positively correlated with CSF α-synuclein but not correlated with striatal DAT uptake. Elevated baseline CSF P-tau181, T-tau and P-tau181/T-tau ratio in early PD patients predict accelerated motor deterioration, with P-tau181 and T-tau also predicting cognitive decline, potentially through interactions with α-synuclein. However, the direct role of tau on nigrostriatal dopaminergic degeneration remains uncertain.

Xu F ，Huang H ，Feng J ，Shen Q ，Bao Y ，Zhang D ，Xu Y ... -  《-》

Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study.

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease. A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between amyloid and α-syn and their association with disease progression. Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Tosun D ，Hausle Z ，Thropp P ，Concha-Marambio L ，Lamoureux J ，Lebovitz R ，Shaw LM ，Singleton AB ，Weiner MW ，Alzheimer's Disease Neuroimaging Initiative ，Blauwendraat C ... -  《-》