scholarly journals Longitudinal Alterations of Alpha-Synuclein, Amyloid Beta, Total, and Phosphorylated Tau in Cerebrospinal Fluid and Correlations Between Their Changes in Parkinson's Disease

2018 ◽  
Vol 9 ◽  
Author(s):  
Mahsa Dolatshahi ◽  
Shayan Pourmirbabaei ◽  
Aida Kamalian ◽  
Amir Ashraf-Ganjouei ◽  
Mehdi Yaseri ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Beta ◽  
Alpha Synuclein ◽  
Phosphorylated Tau

scholarly journals Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Laura Ibanez ◽  
Jorge A. Bahena ◽  
Chengran Yang ◽  
Umber Dube ◽  
Fabiana H. G. Farias ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Beta ◽  
Alpha Synuclein ◽  
Phosphorylated Tau ◽  
Polygenic Risk ◽  
Total Tau ◽  
Genomic Architecture ◽  
Genome Wide ◽  
Csf Biomarker

AbstractAlpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 plays a role in Parkinson’s disease (p = 1.4 × 10−05) and age at onset (p = 7.6 × 10−06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1–42 (p = 3.8 × 10−06), higher mean cortical binding potentials (p = 5.8 × 10−08), and higher Braak amyloid beta score (p = 4.4 × 10−04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta1–42, and APOE.

scholarly journals Clearing Extracellular Alpha-Synuclein from Cerebrospinal Fluid: A New Therapeutic Strategy in Parkinson’s Disease

2018 ◽  
Vol 8 (4) ◽  
pp. 52 ◽  
Author(s):  
Manuel Menéndez-González ◽  
Huber Padilla-Zambrano ◽  
Cristina Tomás-Zapico ◽  
Benjamin García
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Therapeutic Strategy ◽  
Alpha Synuclein

scholarly journals Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Yui Nakayama ◽  
Satoru Morimoto ◽  
Misao Yoneda ◽  
Shigeki Kuzuhara ◽  
Yasumasa Kokubo
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phosphorylated Tau ◽  
Total Tau ◽  
Lateral Sclerosis

Objective. Amyotrophic lateral sclerosis/parkinsonism-dementia complex is classified as one of the tauopathies. Methods. The total tau, phosphorylated tau, and amyloid β42 levels were assayed in cerebrospinal fluid from patients with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (), Alzheimer’s disease (), Parkinson’s disease (), amyotrophic lateral sclerosis (), and controls () using specific enzyme-linked immunosorbent assay methods. Results. Total tau and phosphorylated tau did not increase and amyloid β42 was relatively reduced in Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. Relatively reduced amyloid β42 might discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from amyotrophic lateral sclerosis and Parkinson’s disease, and the ratios of phosphorylated-tau to amyloid β42 could discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease. Conclusions. Cerebrospinal fluid analysis may be useful to differentiate amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease.

scholarly journals Alpha-Synuclein Protofibrils in Cerebrospinal Fluid: A Potential Biomarker for Parkinson's Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1429-1442
Author(s):  
Marianne von Euler Chelpin ◽  
Linda Söderberg ◽  
Johanna Fälting ◽  
Christer Möller ◽  
Marco Giorgetti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Area Under The Curve ◽  
Corticobasal Degeneration ◽  
Alpha Synuclein ◽  
Cross Reactivity ◽  
Potential Biomarker ◽  
Csf Levels

Background: Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective: To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α-synuclein protofibrils (α-syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods: A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer’s disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ42)>530 pg/mL, and phosphorylated tau (p-tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α-synuclein (α-syn) levels were analyzed with a commercial ELISA-kit. Results: The assay is specific to α-syn PF, with no cross-reactivity to monomeric α-syn, or the β- and γ-synuclein variants. CSF α-syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p = 0.02). The accuracy of predicting PD using α-syn PF is significantly different from controls (area under the curve 0.68, p = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α-syn were significantly different between the PD and CBD groups (p = 0.04). Conclusion: The developed method specifically quantifies α-syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls.

scholarly journals Targeting alpha synuclein and amyloid beta by a multifunctional, brain-penetrant dopamine D2/D3 agonist D-520: Potential therapeutic application in Parkinson’s disease with dementia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Deepthi Yedlapudi ◽  
Liping Xu ◽  
Dan Luo ◽  
Gregory B. Marsh ◽  
Sokol V. Todi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Beta ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Dopamine D2 ◽  
Potential Therapeutic Application ◽  
Aβ Aggregation

AbstractA significant number of people with Parkinson’s disease (PD) develop dementia in addition to cognitive dysfunction and are diagnosed as PD with dementia (PDD). This is characterized by cortical and limbic alpha synuclein (α-syn) accumulation, and high levels of diffuse amyloid beta (Aβ) plaques in the striatum and neocortical areas. In this regard, we evaluated the effect of a brain-penetrant, novel multifunctional dopamine D2/D3 agonist, D-520 on the inhibition of Aβ aggregation and disintegration of α-syn and Aβ aggregates in vitro using purified proteins and in a cell culture model that produces intracellular Aβ-induced toxicity. We further evaluated the effect of D-520 in a Drosophila model of Aβ1-42 toxicity. We report that D-520 inhibits the formation of Aβ aggregates in vitro and promotes the disaggregation of both α-syn and Aβ aggregates. Finally, in an in vivo Drosophila model of Aβ1-42 dependent toxicity, D-520 exhibited efficacy by rescuing fly eyes from retinal degeneration caused by Aβ toxicity. Our data indicate the potential therapeutic applicability of D-520 in addressing motor dysfunction and neuroprotection in PD and PDD, as well as attenuating dementia in people with PDD.

scholarly journals Different structures and pathologies of alpha-synuclein fibrils derived from preclinical and postmortem patients of Parkinson's disease

2021 ◽  
Author(s):  
Yun Fan ◽  
Yunpeng Sun ◽  
Wenbo Yu ◽  
Youqi Tao ◽  
Wencheng Xia ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Electron Microscopic ◽  
Lewy Neurites ◽  
The Difference ◽  
A Minor

alpha-Synuclein (alpha-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson's disease (PD). Studies have shown that alpha-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of alpha-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified alpha-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro alpha-syn aggregation, and the amplified fibrils are more potent in inducing endogenous alpha-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of alpha-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD alpha-syn aggregation and suggests potential alteration of alpha-syn fibrils during the progression of PD clinical phases.

scholarly journals A/T/(N) Profile in Cerebrospinal Fluid of Parkinson’s Disease with/without Cognitive Impairment and Dementia with Lewy Bodies

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1015
Author(s):  
Giovanni Bellomo ◽  
Federico Paolini Paoletti ◽  
Elena Chipi ◽  
Maya Petricciuolo ◽  
Simone Simoni ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Amyloid Plaques ◽  
Phosphorylated Tau ◽  
Total Tau ◽  
One Year

Neuropathological investigations report that in synucleinopathies with dementia, namely Parkinson’s disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB), the histopathological hallmarks of Alzheimer’s Disease (AD), in particular amyloid plaques, are frequently observed. In this study, we investigated the cerebrospinal fluid (CSF) AD biomarkers in different clinical phenotypes of synucleinopathies. CSF Aβ42/Aβ40 ratio, phosphorylated tau and total tau were measured as markers of amyloidosis (A), tauopathy (T) and neurodegeneration (N) respectively, in 98 PD (48 with mild cognitive impairment, PD-MCI; 50 cognitively unimpaired, PD-nMCI), 14 PDD and 15 DLB patients, and 48 neurological controls (CTRL). In our study, CSF AD biomarkers did not significantly differ between CTRL, PD-MCI and PD-nMCI patients. In PD-nMCI and PD-MCI groups, A-/T-/N- profile was the most represented. Prevalence of A+ was similar in PD-nMCI and PD-MCI (10% and 13%, respectively), being higher in PDD (64%) and in DLB (73%). DLB showed the lowest values of Aβ42/Aβ40 ratio. Higher total tau at baseline predicted a worse neuropsychological outcome after one year in PD-MCI. A+/T+, i.e., AD-like CSF profile, was most frequent in the DLB group (40% vs. 29% in PDD).

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