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Al-Kuraishy HM, Sulaiman GM, Mohammed HA, Al-Gareeb AI, Albuhadily AK, Ali AA, Abu-Alghayth MH. Beyond amyloid plaque, targeting α-synuclein in Alzheimer disease: The battle continues. Ageing Res Rev 2025; 105:102684. [PMID: 39914501 DOI: 10.1016/j.arr.2025.102684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/03/2025] [Accepted: 02/03/2025] [Indexed: 02/09/2025]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative brain disease and represents the most frequent type of dementia characterized by cognitive impairment and amnesia. AD neuropathology is connected to the development of synaptic dysfunction and loss of synaptic homeostasis due to an imbalance in the production and clearance of β-amyloid (Aβ) and intracellular neurofibrillary tangles (NFTs). However, AD neuropathology is complex and may relate to the deposition of other misfolded proteins, such as alpha-synuclein (α-Syn). Of note, α-Syn, which is involved in the pathogenesis of Parkinson disease (PD) and Lewy body (LB) dementia, is also implicated in AD neuropathology. However, the potential role of α-Syn in AD neuropathology is elusive. Therefore, this review aims to discuss the pathological role of α-Syn in AD and how targeting α-Syn aggregates may be effective in treating AD.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad 14022, Iraq
| | - Ghassan M Sulaiman
- Department of Applied Sciences, University of Technology, Baghdad 10066, Iraq.
| | - Hamdoon A Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Ali I Al-Gareeb
- Department of Clinical pharmacology and Medicine, College of Medicine, Jabir ibn Hayyan Medical University, Kufa, Najaf 54001, Iraq
| | - Ali K Albuhadily
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad 14022, Iraq
| | - Amer Al Ali
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 255, Al Nakhil, Bisha 67714, Saudi Arabia
| | - Mohammed H Abu-Alghayth
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 255, Al Nakhil, Bisha 67714, Saudi Arabia
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Xu F, Huang H, Feng J, Shen Q, Bao Y, Zhang D, Xu Y. Cerebrospinal fluid tau and disease progression in early Parkinson's disease: an 8-year longitudinal study. J Neurol 2024; 272:61. [PMID: 39680223 DOI: 10.1007/s00415-024-12856-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/12/2024] [Accepted: 12/03/2024] [Indexed: 12/17/2024]
Abstract
OBJECTIVE To explore whether CSF phosphorylated tau-181 (P-tau181) and total tau (T-tau) are associated with disease progression in early PD patients. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Fang Xu
- Department of Neurology, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, Sichuan, 610041, China
| | - Hongyan Huang
- Department of Neurology, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, Sichuan, 610041, China
| | - Jiaming Feng
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiuyan Shen
- Department of Neurology, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, Sichuan, 610041, China
| | - Yi Bao
- Department of Neurology, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, Sichuan, 610041, China
| | - Dan Zhang
- Department of Neurology, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, Sichuan, 610041, China
| | - Yanming Xu
- Department of Neurology, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, Sichuan, 610041, China.
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Kapsali I, Brinia ME, Constantinides VC. Cerebrospinal Fluid Total, Phosphorylated and Oligomeric A-Synuclein in Parkinson's Disease: A Systematic Review, Meta-Analysis and Meta-Regression Study. Biomedicines 2024; 12:2266. [PMID: 39457579 PMCID: PMC11504870 DOI: 10.3390/biomedicines12102266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 09/28/2024] [Accepted: 10/04/2024] [Indexed: 10/28/2024] Open
Abstract
Background: The diagnostic accuracy for Parkinson's disease (PD), a synucleinopathy, based on diagnostic criteria is suboptimal. A biomarker for synucleinopathies is pivotal both from a clinical and from a research point of view. CSF a-synuclein has been extensively studied over the past two decades as a candidate biomarker of synucleinopathies. Herein, we present data on studies focusing on total, phosphorylated and oligomeric CSF a-synuclein in PD. Methods: Pubmed, Scopus and Web of Science were searched for studies with >10 PD patients and control subjects, with data (mean, SD) on total, phosphorylated or oligomeric a-synuclein. Cohen's d, as a measure of effect size, was calculated for all a-synuclein forms. Subgroup analysis and meta-regression were performed in an effort to explain between-study heterogeneity. Results: Thirty studies on total, six studies on oligomeric and one study on phosphorylated a-synuclein were included. Total a-synuclein was decreased and oligomeric a-synuclein increased in PD patients vs. controls. The effect size was medium for total and high for oligomeric a-synuclein. A-syn forms provided suboptimal combined sensitivity/specificity for the differentiation of PD from controls. There was significant between-study heterogeneity. The PD cohort characteristics (sex, age, disease duration, UPDRS, H & Y) and study characteristics (study design, healthy vs. neurological controls, control for CSF blood contamination, method of a-syn measurement) could not account for between-study heterogeneity. Publication bias was limited. Conclusions: CSF a-synuclein levels lack sufficient accuracy to be used as biomarkers for PD. The standardization of (pre)analytical variables may improve the discriminatory power of a-synuclein forms in the future.
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Affiliation(s)
- Ioanna Kapsali
- Neurodegenerative Disorders and Epilepsy Ward, First Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.K.); (M.-E.B.)
| | - Maria-Evgenia Brinia
- Neurodegenerative Disorders and Epilepsy Ward, First Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.K.); (M.-E.B.)
| | - Vasilios C. Constantinides
- Neurodegenerative Disorders and Epilepsy Ward, First Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.K.); (M.-E.B.)
- Neurochemistry and Biomarkers Unit, First Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece
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Krawczuk D, Groblewska M, Mroczko J, Winkel I, Mroczko B. The Role of α-Synuclein in Etiology of Neurodegenerative Diseases. Int J Mol Sci 2024; 25:9197. [PMID: 39273146 PMCID: PMC11395629 DOI: 10.3390/ijms25179197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
A presynaptic protein called α-synuclein plays a crucial role in synaptic function and neurotransmitter release. However, its misfolding and aggregation have been implicated in a variety of neurodegenerative diseases, particularly Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Emerging evidence suggests that α-synuclein interacts with various cellular pathways, including mitochondrial dysfunction, oxidative stress, and neuroinflammation, which contributes to neuronal cell death. Moreover, α-synuclein has been involved in the propagation of neurodegenerative processes through prion-like mechanisms, where misfolded proteins induce similar conformational changes in neighboring neurons. Understanding the multifaced roles of α-synuclein in neurodegeneration not only aids in acquiring more knowledge about the pathophysiology of these diseases but also highlights potential biomarkers and therapeutic targets for intervention in alpha-synucleinopathies. In this review, we provide a summary of the mechanisms by which α-synuclein contributes to neurodegenerative processes, focusing on its misfolding, oligomerization, and the formation of insoluble fibrils that form characteristic Lewy bodies. Furthermore, we compare the potential value of α-synuclein species in diagnosing and differentiating selected neurodegenerative diseases.
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Affiliation(s)
- Daria Krawczuk
- Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15-089 Białystok, Poland; (D.K.); (J.M.)
| | - Magdalena Groblewska
- Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Białystok, Poland;
| | - Jan Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15-089 Białystok, Poland; (D.K.); (J.M.)
| | - Izabela Winkel
- Dementia Disorders Centre, Medical University of Wroclaw, 50-425 Ścinawa, Poland;
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15-089 Białystok, Poland; (D.K.); (J.M.)
- Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Białystok, Poland;
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Liu W, Li W, Liu Z, Li Y, Wang X, Guo M, Wang S, Wang S, Li Y, Jia J. Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults. Alzheimers Res Ther 2024; 16:103. [PMID: 38725083 PMCID: PMC11084056 DOI: 10.1186/s13195-024-01463-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND The role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood. METHODS A total of 331 non-demented individuals were included in the study from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition. RESULTS Higher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1. CONCLUSIONS These findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.
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Affiliation(s)
- Wenying Liu
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Wenwen Li
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Zhaojun Liu
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Yan Li
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Xuechu Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Mengmeng Guo
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Shiyuan Wang
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Shuheng Wang
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Yan Li
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jianping Jia
- Innovation Center for Neurological Disorders and Department of Neurology, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, 100053, China.
- Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, 100053, China.
- Center of Alzheimer's Disease, Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, 100053, China.
- Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China.
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Painous C, Fernández M, Pérez J, de Mena L, Cámara A, Compta Y. Fluid and tissue biomarkers in Parkinson's disease: Immunodetection or seed amplification? Central or peripheral? Parkinsonism Relat Disord 2024; 121:105968. [PMID: 38168618 DOI: 10.1016/j.parkreldis.2023.105968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/10/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024]
Abstract
Over the last two decades there have been meaningful developments on biomarkers of neurodegenerative diseases, extensively (but not solely) focusing on their proteinopathic nature. Accordingly, in Alzheimer's disease determination of levels of total and phosphorylated tau (τ and p-τ, usually p-τ181) along with amyloid-beta1-42 (Aβ1-42) by immunodetection in cerebrospinal fluid (CSF) and currently even in peripheral blood, have been widely accepted and introduced to routine diagnosis. In the case of Parkinson's disease, α-synuclein as a potential biomarker (both for diagnosis and progression tracking) has proved more elusive under the immunodetection approach. In recent years, the emergence of the so-called seed amplification assays is proving to be a game-changer, with mounting evidence under different technical approaches and using a variety of biofluids or tissues, yielding promising diagnostic accuracies. Currently the least invasive but at once more reliable source of biosamples and techniques are being sought. Here we overview these advances.
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Affiliation(s)
- Celia Painous
- Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clínic i Universitari de Barcelona, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders - Clinical and Experimental Research, IDIBAPS, Institut de Neurociències UBNeuro, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Manel Fernández
- Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clínic i Universitari de Barcelona, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders - Clinical and Experimental Research, IDIBAPS, Institut de Neurociències UBNeuro, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Jesica Pérez
- Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clínic i Universitari de Barcelona, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders - Clinical and Experimental Research, IDIBAPS, Institut de Neurociències UBNeuro, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Lorena de Mena
- Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clínic i Universitari de Barcelona, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders - Clinical and Experimental Research, IDIBAPS, Institut de Neurociències UBNeuro, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Ana Cámara
- Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clínic i Universitari de Barcelona, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders - Clinical and Experimental Research, IDIBAPS, Institut de Neurociències UBNeuro, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Yaroslau Compta
- Parkinson's Disease & Movement Disorders Unit, Neurology Service, Hospital Clínic i Universitari de Barcelona, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders - Clinical and Experimental Research, IDIBAPS, Institut de Neurociències UBNeuro, Universitat de Barcelona, Barcelona, Catalonia, Spain.
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Faizan M, Sachan N, Verma O, Sarkar A, Rawat N, Pratap Singh M. Cerebrospinal fluid protein biomarkers in Parkinson's disease. Clin Chim Acta 2024; 556:117848. [PMID: 38417781 DOI: 10.1016/j.cca.2024.117848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/24/2024] [Accepted: 02/25/2024] [Indexed: 03/01/2024]
Abstract
Proteomic profiling is an effective way to identify biomarkers for Parkinson's disease (PD). Cerebrospinal fluid (CSF) has direct connectivity with the brain and could be a source of finding biomarkers and their clinical implications. Comparative proteomic profiling has shown that a group of differentially displayed proteins exist. The studies performed using conventional and classical tools also supported the occurrence of these proteins. Many studies have highlighted the potential of CSF proteomic profiling for biomarker identification and their clinical applications. Some of these proteins are useful for disease diagnosis and prediction. Proteomic profiling of CSF also has immense potential to distinguish PD from similar neurodegenerative disorders. A few protein biomarkers help in fundamental knowledge generation and clinical interpretation. However, the specific biomarker of PD is not yet known. The use of proteomic approaches in clinical settings is also rare. A large-scale, multi-centric, multi-population and multi-continental study using multiple proteomic tools is warranted. Such a study can provide valuable, comprehensive and reliable information for a better understanding of PD and the development of specific biomarkers. The current article sheds light on the role of CSF proteomic profiling in identifying biomarkers of PD and their clinical implications. The article also explains the achievements, obstacles and hopes for future directions of this approach.
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Affiliation(s)
- Mohd Faizan
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Nidhi Sachan
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Oyashvi Verma
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Alika Sarkar
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Neeraj Rawat
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Mahendra Pratap Singh
- Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India; Capacity Building and Knowledge Services, ASSIST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.
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Fernandes M, Maio S, Eusebi P, Placidi F, Izzi F, Spanetta M, De Masi C, Lupo C, Calvello C, Nuccetelli M, Bernardini S, Mercuri NB, Liguori C. Cerebrospinal-fluid biomarkers for predicting phenoconversion in patients with isolated rapid-eye movement sleep behavior disorder. Sleep 2024; 47:zsad198. [PMID: 37542734 DOI: 10.1093/sleep/zsad198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/22/2023] [Indexed: 08/07/2023] Open
Abstract
STUDY OBJECTIVES Patients with isolated rapid-eye-movement sleep behavior disorder (iRBD) have an increased risk of developing neurodegenerative diseases. This study assessed cerebrospinal-fluid (CSF) biomarkers of neurodegeneration and blood-brain barrier (BBB) alteration in patients with iRBD compared to controls and ascertain whether these biomarkers may predict phenoconversion to alpha-synucleinopathies (Parkinson's Disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA)). METHODS Patients and controls underwent between 2012 and 2016 a neurological assessment, a lumbar puncture for CSF biomarker analysis (β-amyloid42 - Aβ42; total-tau, and phosphorylated tau), and BBB alteration (CSF/serum albumin ratio). All patients with iRBD were followed until 2021 and then classified into patients who converted to alpha-synucleinopathies (iRBD converters, cRBD) or not (iRBD non-converters, ncRBD). RESULTS Thirty-four patients with iRBD (mean age 67.12 ± 8.14) and 33 controls (mean age 64.97 ± 8.91) were included. At follow-up (7.63 ± 3.40 years), eight patients were ncRBD and 33 patients were cRBD: eleven converted to PD, 10 to DLB, and two to MSA. Patients with iRBD showed lower CSF Aβ42 levels and higher CSF/serum albumin ratio than controls. Cox regression analysis showed that the phenoconversion rate increases with higher motor impairment (hazard ratio [HR] = 1.23, p = 0.032). CSF Aβ42 levels predicted phenoconversion to DLB (HR = 0.67, p = 0.038) and BBB alteration predicted phenoconversion to PD (HR = 1.20, p = 0.038). DISCUSSION This study showed that low CSF Aβ42 levels and high BBB alteration may predict the phenoconversion to DLB and PD in patients with iRBD, respectively. These findings highlight the possibility to discriminate phenoconversion in iRBD patients through CSF biomarkers; however, further studies are needed.
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Affiliation(s)
- Mariana Fernandes
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
| | - Silvia Maio
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
- Sleep Medicine Centre, Neurology Unit, University Hospital "Tor Vergata", Rome, Italy
| | - Paolo Eusebi
- Department of Medicine, Neurology Clinic, University Hospital of Perugia, Italy
| | - Fabio Placidi
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
- Sleep Medicine Centre, Neurology Unit, University Hospital "Tor Vergata", Rome, Italy
| | - Francesca Izzi
- Sleep Medicine Centre, Neurology Unit, University Hospital "Tor Vergata", Rome, Italy
| | - Matteo Spanetta
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
| | - Claudia De Masi
- Sleep Medicine Centre, Neurology Unit, University Hospital "Tor Vergata", Rome, Italy
| | - Clementina Lupo
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
| | - Carmen Calvello
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
| | - Marzia Nuccetelli
- Department of Clinical Biochemistry and Molecular Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Sergio Bernardini
- Department of Clinical Biochemistry and Molecular Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Nicola Biagio Mercuri
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
- Sleep Medicine Centre, Neurology Unit, University Hospital "Tor Vergata", Rome, Italy
| | - Claudio Liguori
- Department of Systems Medicine, University of Rome 'Tor Vergata", Rome, Italy
- Sleep Medicine Centre, Neurology Unit, University Hospital "Tor Vergata", Rome, Italy
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Prymaczok NC, De Francesco PN, Mazzetti S, Humbert-Claude M, Tenenbaum L, Cappelletti G, Masliah E, Perello M, Riek R, Gerez JA. Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson's disease. NPJ Parkinsons Dis 2024; 10:10. [PMID: 38184623 PMCID: PMC10771530 DOI: 10.1038/s41531-023-00618-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/08/2023] [Indexed: 01/08/2024] Open
Abstract
Parkinson's disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission. Expression of the secreted αSyn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted αSyn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released αSyn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted αSyn is cell-to-cell transmitted. The secreted αSyn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson's disease-like phenotype that includes a robust αSyn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson's disease. In summary, a novel animal model of Parkinson's disease based on enhanced cell-to-cell transmission of αSyn was developed. The neuron-produced cell-to-cell transmitted αSyn triggers all phenotypic features of experimental Parkinson's disease in mice.
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Affiliation(s)
- Natalia Cecilia Prymaczok
- Institute of Molecular Physical Science, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Pablo Nicolas De Francesco
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE), dependent of the Argentine Research Council (CONICET), Scientific Research Commission and University of La Plata Buenos Aires, La Plata, Argentina
| | - Samanta Mazzetti
- Department of Biosciences, Università degli Studi di Milano, Milano, Italy
- Fondazione Grigioni per il Morbo di Parkinson, Milano, Italy
| | - Marie Humbert-Claude
- Laboratory of Neurotherapies and NeuroModulation, Clinical Neuroscience Department, Center for Neuroscience Research, Lausanne University Hospital, Lausanne, Switzerland
| | - Liliane Tenenbaum
- Laboratory of Neurotherapies and NeuroModulation, Clinical Neuroscience Department, Center for Neuroscience Research, Lausanne University Hospital, Lausanne, Switzerland
| | - Graziella Cappelletti
- Department of Biosciences, Università degli Studi di Milano, Milano, Italy
- Fondazione Grigioni per il Morbo di Parkinson, Milano, Italy
| | - Eliezer Masliah
- Division of Neurosciences, National Institute on Aging/NIH, 7201, Wisconsin Ave, Bethesda, MD, USA
| | - Mario Perello
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE), dependent of the Argentine Research Council (CONICET), Scientific Research Commission and University of La Plata Buenos Aires, La Plata, Argentina
| | - Roland Riek
- Institute of Molecular Physical Science, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Juan Atilio Gerez
- Institute of Molecular Physical Science, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
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10
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Chopra A, Outeiro TF. Aggregation and beyond: alpha-synuclein-based biomarkers in synucleinopathies. Brain 2024; 147:81-90. [PMID: 37526295 DOI: 10.1093/brain/awad260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/12/2023] [Accepted: 07/15/2023] [Indexed: 08/02/2023] Open
Abstract
Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic inclusions rich in alpha-synuclein called 'Lewy bodies' and 'Lewy neurites'. Together with dementia with Lewy bodies and multiple system atrophy, Parkinson's disease is part of a group of disorders called synucleinopathies. Currently, diagnosis of synucleinopathies is based on the clinical assessment which often takes place in advanced disease stages. While the causal role of alpha-synuclein aggregates in these disorders is still debatable, measuring the levels, types or seeding properties of different alpha-synuclein species hold great promise as biomarkers. Recent studies indicate significant differences in peptide, protein and RNA levels in blood samples from patients with Parkinson's disease. Seed amplification assays using CSF, blood, skin biopsy, olfactory swab samples show great promise for detecting synucleinopathies and even for discriminating between different synucleinopathies. Interestingly, small extracellular vesicles, such as exosomes, display differences in their cargoes in Parkinson's disease patients versus controls. In this update, we focus on alpha-synuclein aggregation and possible sources of disease-related species released in extracellular vesicles, which promise to revolutionize the diagnosis and the monitoring of disease progression.
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Affiliation(s)
- Avika Chopra
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Tiago Fleming Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany
- Max Planck Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
- Scientific Employee with an Honorary Contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 37075 Göttingen, Germany
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11
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Zheng Y, Li S, Yang C, Yu Z, Jiang Y, Feng T. Comparison of biospecimens for α-synuclein seed amplification assays in Parkinson's disease: A systematic review and network meta-analysis. Eur J Neurol 2023; 30:3949-3967. [PMID: 37573472 DOI: 10.1111/ene.16041] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/23/2023] [Accepted: 08/10/2023] [Indexed: 08/14/2023]
Abstract
BACKGROUND AND PURPOSE Alpha-synuclein seed amplification assays (α-syn SAAs) are promising diagnostic methods for Parkinson's disease (PD) and other synucleinopathies. However, there is limited consensus regarding the diagnostic and differential diagnostic performance of α-syn SAAs on biofluids and peripheral tissues. METHODS A comprehensive research was performed in PubMed, Web of Science, Embase and Cochrane Library. Meta-analysis was performed using a random-effects model. A network meta-analysis based on an ANOVA model was conducted to compare the relative accuracy of α-syn SAAs with different specimens. RESULTS The pooled sensitivity and specificity of α-syn SAAs in distinguishing PD from healthy controls or non-neurodegenerative neurological controls were 0.91 (95% confidence interval [CI] 0.89-0.92) and 0.95 (95% CI 0.94-0.96) for cerebrospinal fluid (CSF); 0.91 (95% CI 0.86-0.94) and 0.92 (95% CI 0.87-0.95) for skin; 0.80 (95% CI 0.66-0.89) and 0.87 (95% CI 0.69-0.96) for submandibular gland; 0.44 (95% CI 0.30-0.59) and 0.92 (95% CI 0.79-0.98) for gastrointestinal tract; 0.79 (95% CI 0.70-0.86) and 0.88 (95% CI 0.77-0.95) for saliva; and 0.51 (95% CI 0.39-0.62) and 0.91 (95% CI 0.84-0.96) for olfactory mucosa (OM). The pooled sensitivity and specificity were 0.91 (95% CI 0.89-0.93) and 0.50 (95% CI 0.44-0.55) for CSF, 0.92 (95% CI 0.83-0.97) and 0.22 (95% CI 0.06-0.48) for skin, and 0.55 (95% CI 0.42-0.68) and 0.50 (95% CI 0.35-0.65) for OM in distinguishing PD from multiple system atrophy. The pooled sensitivity and specificity were 0.92 (95% CI 0.89-0.94) and 0.84 (95% CI 0.73-0.91) for CSF, 0.92 (95% CI 0.83-0.97) and 0.88 (95% CI 0.64-0.99) for skin and 0.63 (95% CI 0.52-0.73) and 0.86 (95% CI 0.64-0.97) for OM in distinguishing PD from progressive supranuclear palsy. The pooled sensitivity and specificity were 0.94 (95% CI 0.90-0.97) and 0.95 (95% CI 0.77-1.00) for CSF and 0.94 (95% CI 0.84-0.99) and 0.86 (95% CI 0.42-1.00) for skin in distinguishing PD from corticobasal degeneration. CONCLUSIONS α-Synuclein SAAs of CSF, skin, saliva, submandibular gland, gastrointestinal tract and OM are promising diagnostic assays for PD, with CSF and skin α-syn SAAs demonstrating higher diagnostic performance.
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Affiliation(s)
- Yuanchu Zheng
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Siming Li
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chen Yang
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhenwei Yu
- Department of Pathophysiology, Beijing Neurosurgical Institute, Beijing, China
| | - Ying Jiang
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Tao Feng
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
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12
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Noguchi-Shinohara M, Ono K. The Mechanisms of the Roles of α-Synuclein, Amyloid-β, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics. Int J Mol Sci 2023; 24:10215. [PMID: 37373401 DOI: 10.3390/ijms241210215] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/06/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aβ, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aβ and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.
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Affiliation(s)
- Moeko Noguchi-Shinohara
- Department of Neurology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan
| | - Kenjiro Ono
- Department of Neurology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan
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13
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Paolini Paoletti F, Gaetani L, Bellomo G, Chipi E, Salvadori N, Montanucci C, Mancini A, Filidei M, Nigro P, Simoni S, Tambasco N, Di Filippo M, Parnetti L. CSF neurochemical profile and cognitive changes in Parkinson's disease with mild cognitive impairment. NPJ Parkinsons Dis 2023; 9:68. [PMID: 37095141 PMCID: PMC10126070 DOI: 10.1038/s41531-023-00509-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 04/05/2023] [Indexed: 04/26/2023] Open
Abstract
Pathophysiological substrate(s) and progression of Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) are still matter of debate. Baseline cerebrospinal fluid (CSF) neurochemical profile and cognitive changes after 2 years were investigated in a retrospective series of PD-MCI (n = 48), cognitively normal PD (PD-CN, n = 40), prodromal Alzheimer's disease (MCI-AD, n = 25) and cognitively healthy individuals with other neurological diseases (OND, n = 44). CSF biomarkers reflecting amyloidosis (Aβ42/40 ratio, sAPPα, sAPPβ), tauopathy (p-tau), neurodegeneration (t-tau, NfL, p-NfH), synaptic damage (α-syn, neurogranin) and glial activation (sTREM2, YKL-40) were measured. The great majority (88%) of PD-MCI patients was A-/T-/N-. Among all biomarkers considered, only NfL/p-NfH ratio was significantly higher in PD-MCI vs. PD-CN (p = 0.02). After 2 years, one-third of PD-MCI patients worsened; such worsening was associated with higher baseline levels of NfL, p-tau, and sTREM2. PD-MCI is a heterogeneous entity requiring further investigations on larger, longitudinal cohorts with neuropathological verification.
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Affiliation(s)
- Federico Paolini Paoletti
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Laboratory of Clinical Neurochemistry, Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Lorenzo Gaetani
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Laboratory of Clinical Neurochemistry, Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giovanni Bellomo
- Laboratory of Clinical Neurochemistry, Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elena Chipi
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Nicola Salvadori
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Chiara Montanucci
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Andrea Mancini
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Marta Filidei
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Pasquale Nigro
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Simone Simoni
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Nicola Tambasco
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Massimiliano Di Filippo
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Lucilla Parnetti
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
- Laboratory of Clinical Neurochemistry, Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
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14
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Shim KH, Kang MJ, Youn YC, An SSA, Kim S. Alpha-synuclein: a pathological factor with Aβ and tau and biomarker in Alzheimer's disease. Alzheimers Res Ther 2022; 14:201. [PMID: 36587215 PMCID: PMC9805257 DOI: 10.1186/s13195-022-01150-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 12/20/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND Alpha-synuclein (α-syn) is considered the main pathophysiological protein component of Lewy bodies in synucleinopathies. α-Syn is an intrinsically disordered protein (IDP), and several types of structural conformations have been reported, depending on environmental factors. Since IDPs may have distinctive functions depending on their structures, α-syn can play different roles and interact with several proteins, including amyloid-beta (Aβ) and tau, in Alzheimer's disease (AD) and other neurodegenerative disorders. MAIN BODY In previous studies, α-syn aggregates in AD brains suggested a close relationship between AD and α-syn. In addition, α-syn directly interacts with Aβ and tau, promoting mutual aggregation and exacerbating the cognitive decline. The interaction of α-syn with Aβ and tau presented different consequences depending on the structural forms of the proteins. In AD, α-syn and tau levels in CSF were both elevated and revealed a high positive correlation. Especially, the CSF α-syn concentration was significantly elevated in the early stages of AD. Therefore, it could be a diagnostic marker of AD and help distinguish AD from other neurodegenerative disorders by incorporating other biomarkers. CONCLUSION The overall physiological and pathophysiological functions, structures, and genetics of α-syn in AD are reviewed and summarized. The numerous associations of α-syn with Aβ and tau suggested the significance of α-syn, as a partner of the pathophysiological roles in AD. Understanding the involvements of α-syn in the pathology of Aβ and tau could help address the unresolved issues of AD. In particular, the current status of the CSF α-syn in AD recommends it as an additional biomarker in the panel for AD diagnosis.
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Affiliation(s)
- Kyu Hwan Shim
- grid.256155.00000 0004 0647 2973Department of Bionano Technology, Gachon University, Seongnam-Si, Gyeonggi-Do Republic of Korea
| | - Min Ju Kang
- Department of Neurology, Veterans Health Service Medical Center, Veterans Medical Research Institute, Seoul, Republic of Korea
| | - Young Chul Youn
- grid.411651.60000 0004 0647 4960Department of Neurology, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Seong Soo A. An
- grid.256155.00000 0004 0647 2973Department of Bionano Technology, Gachon University, Seongnam-Si, Gyeonggi-Do Republic of Korea
| | - SangYun Kim
- grid.412480.b0000 0004 0647 3378Department of Neurology, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam-Si, Gyeonggi-Do Republic of Korea
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15
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Cerebrospinal Fluid Alpha-Synuclein Improves the Differentiation between Dementia with Lewy Bodies and Alzheimer's Disease in Clinical Practice. Int J Mol Sci 2022; 23:ijms232113488. [PMID: 36362275 PMCID: PMC9654229 DOI: 10.3390/ijms232113488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Background: Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer’s disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. Methods: In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. Results: We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p < 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p < 0.01) but not with hippocampal atrophy or white matter lesions. Conclusion: CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers.
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16
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Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson's disease and other synucleinopathies. NPJ Parkinsons Dis 2022; 8:93. [PMID: 35869066 PMCID: PMC9307631 DOI: 10.1038/s41531-022-00357-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/24/2022] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10–15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between aSyn and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers for early diagnosis of PD and differentiate it from other synucleinopathies. In this review, we (1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; (2) present comparative and critical analysis of previous studies that measured total aSyn as well as other species such as modified and aggregated forms of aSyn in different biological fluids; and (3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers; and (4) outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating biochemical, aggregation and structure features of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to develop robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathies. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.
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17
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Petricca L, Chiki N, Hanna-El-Daher L, Aeschbach L, Burai R, Stoops E, Fares MB, Lashuel HA. Comparative Analysis of Total Alpha-Synuclein (αSYN) Immunoassays Reveals That They Do Not Capture the Diversity of Modified αSYN Proteoforms. JOURNAL OF PARKINSON'S DISEASE 2022; 12:1449-1462. [PMID: 35527570 PMCID: PMC9398082 DOI: 10.3233/jpd-223285] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background: The development of therapeutics for Parkinson’s disease (PD) requires the establishment of biomarker assays to enable stratifying patients, monitoring disease progression, and assessing target engagement. Attempts to develop diagnostic assays based on detecting levels of the α-synuclein (αSYN) protein, a central player in the pathogenesis of PD, have yielded inconsistent results. Objective: To determine whether the three commercial kits that have been extensively used for total αSYN quantification in human biological fluids (from Euroimmun, MSD, and Biolegend) are capable of capturing the diversity and complexity of relevant αSYN proteoforms. Methods: We investigated and compared the ability of the different assays to detect the diversity of αSYN proteoforms using a library of αSYN proteins that comprise the majority of disease-relevant αSYN variants and post-translational modifications (PTMs). Results: Our findings showed that none of the three tested immunoassays accurately capture the totality of relevant αSYN species, and that these assays are unable to recognize most disease-associated C-terminally truncated variants of αSYN. Moreover, several N-terminal truncations and phosphorylation/nitration PTMs differentially modify the level of αSYN detection and recovery by different immunoassays, and a CSF matrix effect was observed for most of the αSYN proteoforms analyzed by the three immunoassays. Conclusion: Our results show that the tested immunoassays do not capture the totality of the relevant αSYN species and therefore may not be appropriate tools to provide an accurate measure of total αSYN levels in samples containing modified forms of the protein. This highlights the need for next generation αSYN immunoassays that capture the diversity of αSYN proteoforms.
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Affiliation(s)
| | - Nour Chiki
- ND Biosciences SA, Epalinges, Switzerland
| | - Layane Hanna-El-Daher
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute,Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Lorène Aeschbach
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute,Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Ritwik Burai
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute,Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Erik Stoops
- ADx NeuroSciences NV, Technologiepark 94 - Bio Incubator, Gent, Belgium
| | | | - Hilal A Lashuel
- ND Biosciences SA, Epalinges, Switzerland.,Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute,Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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18
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Shakya S, Prevett J, Hu X, Xiao R. Characterization of Parkinson's Disease Subtypes and Related Attributes. Front Neurol 2022; 13:810038. [PMID: 35677337 PMCID: PMC9167933 DOI: 10.3389/fneur.2022.810038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
Parkinson's disease is a progressive neurodegenerative disease with complex, heterogeneous motor and non-motor symptoms. The current evidence shows that there is still a marked heterogeneity in the subtyping of Parkinson's disease using both clinical and data-driven approaches. Another challenge posed in PD subtyping is the reproducibility of previously identified PD subtypes. These issues require additional results to confirm previous findings and help reconcile discrepancies, as well as establish a standardized application of cluster analysis to facilitate comparison and reproducibility of identified PD subtypes. Our study aimed to address this gap by investigating subtypes of Parkinson's disease using comprehensive clinical (motor and non-motor features) data retrieved from 408 de novo Parkinson's disease patients with the complete clinical data in the Parkinson's Progressive Marker Initiative database. A standardized k-means cluster analysis approach was developed by taking into consideration of common practice and recommendations from previous studies. All data analysis codes were made available online to promote data comparison and validation of reproducibility across research groups. We identified two distinct PD subtypes, termed the severe motor-non-motor subtype (SMNS) and the mild motor- non-motor subtype (MMNS). SMNS experienced symptom onset at an older age and manifested more intense motor and non-motor symptoms than MMNS, who experienced symptom onset at a younger age and manifested milder forms of Parkinson's symptoms. The SPECT imaging makers supported clinical findings such that the severe motor-non-motor subtype showed lower binding values than the mild motor- non-motor subtype, indicating more significant neural damage at the nigral pathway. In addition, SMNS and MMNS show distinct motor (ANCOVA test: F = 47.35, p< 0.001) and cognitive functioning (F = 33.93, p< 0.001) progression trends. Such contrast between SMNS and MMNS in both motor and cognitive functioning can be consistently observed up to 3 years following the baseline visit, demonstrating the potential prognostic value of identified PD subtypes.
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Affiliation(s)
| | - Julia Prevett
- School of Nursing, Duke University, Durham, NC, United States
| | - Xiao Hu
- School of Nursing, Emory University, Atlanta, GA, United States
- Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, United States
- Department of Computer Science, College of Arts and Sciences, Emory University, Atlanta, GA, United States
| | - Ran Xiao
- School of Nursing, Duke University, Durham, NC, United States
- *Correspondence: Ran Xiao
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19
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Engelender S, Stefanis L, Oddo S, Bellucci A. Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation? Mov Disord 2022; 37:1346-1359. [PMID: 35579450 DOI: 10.1002/mds.29058] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 12/16/2022] Open
Abstract
Neurodegenerative proteinopathies are defined as a class of neurodegenerative disorders, with either genetic or sporadic age-related onset, characterized by the pathological accumulation of aggregated protein deposits. These mainly include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) as well as frontotemporal lobar degeneration (FTLD). The deposition of abnormal protein aggregates in the brain of patients affected by these disorders is thought to play a causative role in neuronal loss and disease progression. On that account, the idea of improving the clearance of pathological protein aggregates has taken hold as a potential therapeutic strategy. Among the possible approaches to pursue for reducing disease protein accumulation, there is the stimulation of the main protein degradation machineries of eukaryotic cells: the ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Of note, several clinical trials testing the efficacy of either UPS- or ALP-active compounds are currently ongoing. Here, we discuss the main gaps and controversies emerging from experimental studies and clinical trials assessing the therapeutic efficacy of modulators of either the UPS or ALP in neurodegenerative proteinopathies, to gather whether they may constitute a real gateway from these disorders. © 2022 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Simone Engelender
- Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa, Israel
| | - Leonidas Stefanis
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Salvatore Oddo
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Messina, Italy
| | - Arianna Bellucci
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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20
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Blanc F, Bousiges O. Biomarkers and diagnosis of dementia with Lewy bodies including prodromal: Practical aspects. Rev Neurol (Paris) 2022; 178:472-483. [PMID: 35491246 DOI: 10.1016/j.neurol.2022.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/20/2022] [Accepted: 03/21/2022] [Indexed: 10/18/2022]
Abstract
Dementia with Lewy Bodies (DLB) is a common form of cognitive neurodegenerative disease. More than half of the patients affected are not or misdiagnosed because of the clinical similarity with Alzheimer's disease (AD), Parkinson's disease but also psychiatric diseases such as depression or psychosis. In this review, we evaluate the interest of different biomarkers in the diagnostic process: cerebrospinal fluid (CSF), brain MRI, FP-CIT SPECT, MIBG SPECT, perfusion SPECT, FDG-PET by focusing more specifically on differential diagnosis between DLB and AD. FP-CIT SPECT is of high interest to discriminate DLB and AD, but not at the prodromal stage. Brain MRI has shown differences in group study with lower grey matter concentration of the Insula in prodromal DLB, but its interest in clinical routine is not demonstrated. Among the AD biomarkers (t-Tau, phospho-Tau181, Aβ42 and Aβ40) used routinely, t-Tau and phospho-Tau181 have shown excellent discrimination whatever the clinical stages severity. CSF Alpha-synuclein assay in the CSF has also an interest in the discrimination between DLB and AD but not in segregation between DLB and healthy elderly subjects. CSF synuclein RT-QuIC seems to be an excellent biomarker but its application in clinical routine remains to be demonstrated, given the non-automation of the process.
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Affiliation(s)
- F Blanc
- Hôpitaux Universitaire de Strasbourg, CM2R (Centre Mémoire de Ressource et de Recherche), Hôpital de jour, pôle de Gériatrie, Strasbourg, France; CNRS, laboratoire ICube UMR 7357 et FMTS (Fédération de Médecine Translationnelle de Strasbourg), équipe IMIS, Strasbourg, France.
| | - O Bousiges
- CNRS, laboratoire ICube UMR 7357 et FMTS (Fédération de Médecine Translationnelle de Strasbourg), équipe IMIS, Strasbourg, France; Hôpitaux Universitaire de Strasbourg, Laboratoire de Biochimie et Biologie Moléculaire, Strasbourg, France
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21
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Goldoni R, Dolci C, Boccalari E, Inchingolo F, Paghi A, Strambini L, Galimberti D, Tartaglia GM. Salivary biomarkers of neurodegenerative and demyelinating diseases and biosensors for their detection. Ageing Res Rev 2022; 76:101587. [PMID: 35151849 DOI: 10.1016/j.arr.2022.101587] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/11/2021] [Accepted: 02/07/2022] [Indexed: 01/08/2023]
Abstract
Salivary analysis is gaining increasing interest as a novel and promising field of research for the diagnosis of neurodegenerative and demyelinating diseases related to aging. The collection of saliva offers several advantages, being noninvasive, stress-free, and repeatable. Moreover, the detection of biomarkers directly in saliva could allow an early diagnosis of the disease, leading to timely treatments. The aim of this manuscript is to highlight the most relevant researchers' findings relatively to salivary biomarkers of neurodegenerative and demyelinating diseases, and to describe innovative and advanced biosensing strategies for the detection of salivary biomarkers. This review is focused on five relevant aging-related neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Multiple Sclerosis) and the salivary biomarkers most commonly associated with them. Advanced biosensors enabling molecular diagnostics for the detection of salivary biomarkers are presented, in order to stimulate future research in this direction and pave the way for their clinical application.
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Affiliation(s)
- Riccardo Goldoni
- Department of Biomedical, Surgical and Dental Sciences, School of Dentistry, University of Milan, Italy
| | - Carolina Dolci
- Department of Biomedical, Surgical and Dental Sciences, School of Dentistry, University of Milan, Italy
| | - Elisa Boccalari
- Department of Biomedical, Surgical and Dental Sciences, School of Dentistry, University of Milan, Italy
| | - Francesco Inchingolo
- Department of Interdisciplinary Medicine, University of Medicine Aldo Moro, 70124 Bari, Italy
| | - Alessandro Paghi
- Dipartimento di Ingegneria dell'Informazione, Università di Pisa, Via G. Caruso 16, Pisa, Italy
| | - Lucanos Strambini
- Istituto di Elettronica e di Ingegneria dell'Informazione e delle Telecomunicazioni, Consiglio Nazionale delle Ricerche, Via G. Caruso 16, Pisa, Italy
| | - Daniela Galimberti
- Department of Biomedical, Surgical and Dental Sciences, School of Dentistry, University of Milan, Italy; Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Gianluca Martino Tartaglia
- Department of Biomedical, Surgical and Dental Sciences, School of Dentistry, University of Milan, Italy; UOC Maxillo-Facial Surgery and Dentistry, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, 20100 Milan, Italy.
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22
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The Role of Tau beyond Alzheimer’s Disease: A Narrative Review. Biomedicines 2022; 10:biomedicines10040760. [PMID: 35453510 PMCID: PMC9026415 DOI: 10.3390/biomedicines10040760] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 02/01/2023] Open
Abstract
Nowadays, there is a need for reliable fluid biomarkers to improve differential diagnosis, prognosis, and the prediction of treatment response, particularly in the management of neurogenerative diseases that display an extreme variability in clinical phenotypes. In recent years, Tau protein has been progressively recognized as a valuable neuronal biomarker in several neurological conditions, not only Alzheimer’s disease (AD). Cerebrospinal fluid and serum Tau have been extensively investigated in several neurodegenerative disorders, from classically defined proteinopathy, e.g., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), but also in inflammatory conditions such as multiple sclerosis (MS), as a marker of axonal damage. In MS, total Tau (t-Tau) may represent, along with other proteins, a marker with diagnostic and prognostic value. In ALS, t-Tau and, mainly, the phosphorylated-Tau/t-Tau ratio alone or integrated with transactive DNA binding protein of ~43 kDa (TDP-43), may represent a tool for both diagnosis and differential diagnosis of other motoneuron diseases or tauopathies. Evidence indicated the crucial role of the Tau protein in the pathogenesis of PD and other parkinsonian disorders. This narrative review summarizes current knowledge regarding non-AD neurodegenerative diseases and the Tau protein.
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Barba L, Paolini Paoletti F, Bellomo G, Gaetani L, Halbgebauer S, Oeckl P, Otto M, Parnetti L. Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers. Mov Disord 2022; 37:669-683. [PMID: 35122299 PMCID: PMC9303453 DOI: 10.1002/mds.28941] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/21/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
The synuclein family includes three neuronal proteins, named α‐synuclein, β‐synuclein, and γ‐synuclein, that have peculiar structural features. α‐synuclein is largely known for being a key protein in the pathophysiology of Parkinson's disease (PD) and other synucleinopathies, namely, dementia with Lewy bodies and multisystem atrophy. The role of β‐synuclein and γ‐synuclein is less well understood in terms of physiological functions and potential contribution to human diseases. α‐synuclein has been investigated extensively in both cerebrospinal fluid (CSF) and blood as a potential biomarker for synucleinopathies. Recently, great attention has been also paid to β‐synuclein, whose CSF and blood levels seem to reflect synaptic damage and neurodegeneration independent of the presence of synucleinopathy. In this review, we aim to provide an overview on the pathophysiological roles of the synucleins. Because γ‐synuclein has been poorly investigated in the field of synucleinopathy and its pathophysiological roles are far from being clear, we focus on the interactions between α‐synuclein and β‐synuclein in PD. We also discuss the role of α‐synuclein and β‐synuclein as potential biomarkers to improve the diagnostic characterization of synucleinopathies, thus highlighting their potential application in clinical trials for disease‐modifying therapies. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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Affiliation(s)
- Lorenzo Barba
- Section of Neurology, Laboratory of Clinical Neurochemistry, Department of Medicine and Surgery University of Perugia Perugia Italy
- Department of Neurology University of Ulm Ulm Germany
- Department of Neurology Martin‐Luther‐University Halle‐Wittenberg Halle/Saale Germany
| | - Federico Paolini Paoletti
- Section of Neurology, Laboratory of Clinical Neurochemistry, Department of Medicine and Surgery University of Perugia Perugia Italy
| | - Giovanni Bellomo
- Section of Neurology, Laboratory of Clinical Neurochemistry, Department of Medicine and Surgery University of Perugia Perugia Italy
| | - Lorenzo Gaetani
- Section of Neurology, Laboratory of Clinical Neurochemistry, Department of Medicine and Surgery University of Perugia Perugia Italy
| | | | - Patrick Oeckl
- Department of Neurology University of Ulm Ulm Germany
- German Center for Neurodegenerative Disorders Ulm (DZNE e. V.) Ulm Germany
| | - Markus Otto
- Department of Neurology University of Ulm Ulm Germany
- Department of Neurology Martin‐Luther‐University Halle‐Wittenberg Halle/Saale Germany
| | - Lucilla Parnetti
- Section of Neurology, Laboratory of Clinical Neurochemistry, Department of Medicine and Surgery University of Perugia Perugia Italy
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24
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Siddique Y. Neurodegenerative Disorders and the Current State, Pathophysiology, and Management of Parkinson's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2022; 21:574-595. [PMID: 34477534 DOI: 10.2174/1871527320666210903101841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 12/14/2020] [Accepted: 02/13/2021] [Indexed: 06/13/2023]
Abstract
In the last few decades, major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson's Disease (PD). Based on neurotoxicological studies and postmortem investigations, there is a general concept of how environmental toxicants (neurotoxins, pesticides, insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of the midbrain and modulate cellular processes leading to the pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils, is associated with cellular dysfunction and neuronal death, thus possibly contributing to PD propagation. With advances made in identifying loci that contribute to PD, molecular pathways involved in disease pathogenesis are now clear, and introducing therapeutic strategy at the right time may delay the progression. Biomarkers for PD have helped monitor PD progression; therefore, personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, independent validation of biomarkers is required.
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Affiliation(s)
- Yasir Siddique
- Drosophila Transgenic Laboratory, Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India
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25
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Pan L, Meng L, He M, Zhang Z. Tau in the Pathophysiology of Parkinson's Disease. J Mol Neurosci 2021; 71:2179-2191. [PMID: 33459970 PMCID: PMC8585831 DOI: 10.1007/s12031-020-01776-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022]
Abstract
The pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs) in remaining neurons. LBs primarily consist of aggregated α-Synuclein (α-Syn). However, accumulating evidence suggests that Tau, which is associated with tauopathies such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and argyrophilic grain disease, is also involved in the pathophysiology of PD. A genome-wide association study (GWAS) identified MAPT, the gene encoding the Tau protein, as a risk gene for PD. Autopsy of PD patients also revealed the colocalization of Tau and α-Syn in LBs. Experimental evidence has shown that Tau interacts with α-Syn and influences the pathology of α-Syn in PD. In this review, we discuss the structure and function of Tau and provide a summary of the current evidence supporting Tau's involvement as either an active or passive element in the pathophysiology of PD, which may provide novel targets for the early diagnosis and treatment of PD.
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Affiliation(s)
- Lina Pan
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Lanxia Meng
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Mingyang He
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zhentao Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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26
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Narasimhan M, Schwartz R, Halliday G. Parkinsonism and cerebrovascular disease. J Neurol Sci 2021; 433:120011. [PMID: 34686356 DOI: 10.1016/j.jns.2021.120011] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/01/2021] [Accepted: 09/29/2021] [Indexed: 11/27/2022]
Abstract
The relationship between cerebrovascular disease and parkinsonism is commonly seen in everyday clinical practice but remains ill-defined and under-recognised with little guidance for the practising neurologist. We attempt to define this association and to illustrate key clinical, radiological and pathological features of the syndrome of Vascular Parkinsonism (VaP). VaP is a major cause of morbidity in the elderly associated with falls, hip fractures and cognitive impairment. Although acute parkinsonism is reported in the context of an acute cerebrovascular event, the vast majority of VaP presents as an insidious syndrome usually in the context of vascular risk factors and radiological evidence of small vessel disease. There may be an anatomic impact on basal ganglia neuronal networks, however the effect of small vessel disease (SVD) on these pathways is not clear. There are now established reporting standards for radiological features of SVD on MRI. White matter hyperintensities and lacunes have been thought to be the representative radiological features of SVD but other features such as the perivascular space are gaining more importance, especially in context of the glymphatic system. It is important to consider VaP in the differential diagnosis of Parkinson disease (PD) and in these situations, neuroimaging may offer diagnostic benefit especially in those patients with atypical presentations or refractoriness to levodopa. Proactive management of vascular risk factors, monitoring of bone density and an exercise program may offer easily attainable therapeutic targets in PD and VaP. Levodopa therapy should be considered in patients with VaP, however the dose and effect may be different from use in PD. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.
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Affiliation(s)
- Manisha Narasimhan
- Brain and Mind Centre and Faculty of Health and Medical Sciences, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
| | - Raymond Schwartz
- Brain and Mind Centre and Faculty of Health and Medical Sciences, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
| | - Glenda Halliday
- Brain and Mind Centre and Faculty of Health and Medical Sciences, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
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27
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Kayed R, Dettmer U, Lesné SE. Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk. JOURNAL OF PARKINSON'S DISEASE 2021; 10:791-818. [PMID: 32508330 PMCID: PMC7458533 DOI: 10.3233/jpd-201965] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
There is growing recognition in the field of neurodegenerative diseases that mixed proteinopathies are occurring at greater frequency than originally thought. This is particularly true for three amyloid proteins defining most of these neurological disorders, amyloid-beta (Aβ), tau, and alpha-synuclein (αSyn). The co-existence and often co-localization of aggregated forms of these proteins has led to the emergence of concepts positing molecular interactions and cross-seeding between Aβ, tau, and αSyn aggregates. Amongst this trio, αSyn has received particular attention in this context during recent years due to its ability to modulate Aβ and tau aggregation in vivo, to interact at a molecular level with Aβ and tau in vivo and to cross-seed tau in mice. Here we provide a comprehensive, critical, and accessible review about the expression, role and nature of endogenous soluble αSyn oligomers because of recent developments in the understanding of αSyn multimerization, misfolding, aggregation, cross-talk, spreading and cross-seeding in neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, and Huntington's disease. We will also discuss our current understanding about the relative toxicity of endogenous αSyn oligomers in vivo and in vitro, and introduce potential opportunities to counter their deleterious effects.
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Affiliation(s)
- Rakez Kayed
- Departments of Neurology & Neuroscience & Cell Biology & Anatomy, University of Texas Medical Branch Galveston, Galveston, TX, USA,George and Cynthia Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch Galveston, Galveston, TX, USA
| | - Ulf Dettmer
- Department of Neurology, Harvard Medical School, Boston, MA, USA,Ann Romney Center for Neurologic Diseases, Harvard Medical School, Boston, MA, USA
| | - Sylvain E. Lesné
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA,Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA,Correspondence to: Sylvain E. Lesné, PhD, University of Minnesota, Wallin Medical Biosciences Building (Room 4-114), 2101 Sixth Street SE, CDC 2641, Minneapolis, MN 55414, USA. Tel.: +1 612 626 8341; E-mail: ; Website: https://lesnelab.org
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28
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Ganguly U, Singh S, Pal S, Prasad S, Agrawal BK, Saini RV, Chakrabarti S. Alpha-Synuclein as a Biomarker of Parkinson's Disease: Good, but Not Good Enough. Front Aging Neurosci 2021; 13:702639. [PMID: 34305577 PMCID: PMC8298029 DOI: 10.3389/fnagi.2021.702639] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/07/2021] [Indexed: 12/15/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder of the elderly, presenting primarily with symptoms of motor impairment. The disease is diagnosed most commonly by clinical examination with a great degree of accuracy in specialized centers. However, in some cases, non-classical presentations occur when it may be difficult to distinguish the disease from other types of degenerative or non-degenerative movement disorders with overlapping symptoms. The diagnostic difficulty may also arise in patients at the early stage of PD. Thus, a biomarker could help clinicians circumvent such problems and help them monitor the improvement in disease pathology during anti-parkinsonian drug trials. This review first provides a brief overview of PD, emphasizing, in the process, the important role of α-synuclein in the pathogenesis of the disease. Various attempts made by the researchers to develop imaging, genetic, and various biochemical biomarkers for PD are then briefly reviewed to point out the absence of a definitive biomarker for this disorder. In view of the overwhelming importance of α-synuclein in the pathogenesis, a detailed analysis is then made of various studies to establish the biomarker potential of this protein in PD; these studies measured total α-synuclein, oligomeric, and post-translationally modified forms of α-synuclein in cerebrospinal fluid, blood (plasma, serum, erythrocytes, and circulating neuron-specific extracellular vesicles) and saliva in combination with certain other proteins. Multiple studies also examined the accumulation of α-synuclein in various forms in PD in the neural elements in the gut, submandibular glands, skin, and the retina. The measurements of the levels of certain forms of α-synuclein in some of these body fluids or their components or peripheral tissues hold a significant promise in establishing α-synuclein as a definitive biomarker for PD. However, many methodological issues related to detection and quantification of α-synuclein have to be resolved, and larger cross-sectional and follow-up studies with controls and patients of PD, parkinsonian disorders, and non-parkinsonian movement disorders are to be undertaken.
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Affiliation(s)
- Upasana Ganguly
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Sukhpal Singh
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Soumya Pal
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Suvarna Prasad
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Bimal K. Agrawal
- Department of General Medicine, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Reena V. Saini
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Sasanka Chakrabarti
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
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29
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Abdi IY, Majbour NK, Willemse EAJ, van de Berg WDJ, Mollenhauer B, Teunissen CE, El-Agnaf OM. Preanalytical Stability of CSF Total and Oligomeric Alpha-Synuclein. Front Aging Neurosci 2021; 13:638718. [PMID: 33762924 PMCID: PMC7982944 DOI: 10.3389/fnagi.2021.638718] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/08/2021] [Indexed: 12/14/2022] Open
Abstract
Background: The role of cerebrospinal fluid (CSF) alpha-synuclein as a potential biomarker has been challenged mainly due to variable preanalytical measures between laboratories. To evaluate the impact of the preanalytical factors contributing to such variability, the different subforms of alpha-synuclein need to be studied individually. Method: We investigated the effect of exposing CSF samples to several preanalytical sources of variability: (1) different polypropylene (PP) storage tubes; (2) use of non-ionic detergents; (3) multiple tube transfers; (4) multiple freeze-thaw cycles; and (5) delayed storage. CSF oligomeric- and total-alpha-synuclein levels were estimated using our in-house sandwich-based enzyme-linked immunosorbent assays. Results: Siliconized tubes provided the optimal preservation of CSF alpha-synuclein proteins among other tested polypropylene tubes. The use of tween-20 detergent significantly improved the recovery of oligomeric-alpha-synuclein, while multiple freeze-thaw cycles significantly lowered oligomeric-alpha-synuclein in CSF. Interestingly, oligomeric-alpha-synuclein levels remained relatively stable over multiple tube transfers and upon delayed storage. Conclusion: Our study showed for the first-time distinct impact of preanalytical factors on the different forms of CSF alpha-synuclein. These findings highlight the need for special considerations for the different forms of alpha-synuclein during CSF samples' collection and processing.
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Affiliation(s)
- Ilham Y Abdi
- Neurological Disorders Research Centre, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, Qatar
| | - Nour K Majbour
- Neurological Disorders Research Centre, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, Qatar
| | - Eline A J Willemse
- Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, Netherlands
| | - Wilma D J van de Berg
- Section Clinical Neuroanatomy and Biobanking, Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam University Medical Center, Vrije University Amsterdam, Amsterdam, Netherlands
| | - Brit Mollenhauer
- Paracelsus-Elena-Klinik, Klinikstraße, Kassel, Germany.,Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Charlotte E Teunissen
- Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, Netherlands
| | - Omar M El-Agnaf
- Neurological Disorders Research Centre, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, Qatar
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30
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Morató X, Garcia-Esparcia P, Argerich J, Llorens F, Zerr I, Paslawski W, Borràs E, Sabidó E, Petäjä-Repo UE, Fernández-Dueñas V, Ferrer I, Svenningsson P, Ciruela F. Ecto-GPR37: a potential biomarker for Parkinson's disease. Transl Neurodegener 2021; 10:8. [PMID: 33637132 PMCID: PMC7908677 DOI: 10.1186/s40035-021-00232-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/08/2021] [Indexed: 11/15/2022] Open
Abstract
Objective α-Synuclein has been studied as a potential biomarker for Parkinson’s disease (PD) with no concluding results. Accordingly, there is an urgent need to find out reliable specific biomarkers for PD. GPR37 is an orphan G protein-coupled receptor that toxically accumulates in autosomal recessive juvenile parkinsonism. Here, we investigated whether GPR37 is upregulated in sporadic PD, and thus a suitable potential biomarker for PD. Methods GPR37 protein density and mRNA expression in postmortem substantia nigra (SN) from PD patients were analysed by immunoblot and RT-qPCR, respectively. The presence of peptides from the N-terminus-cleaved domain of GPR37 (i.e. ecto-GPR37) in human cerebrospinal fluid (CSF) was determined by liquid chromatography-mass spectrometric analysis. An engineered in-house nanoluciferase-based immunoassay was used to quantify ecto-GPR37 in CSF samples from neurological control (NC) subjects, PD patients and Alzheimer’s disease (AD) patients. Results GPR37 protein density and mRNA expression were significantly augmented in sporadic PD. Increased amounts of ecto-GPR37 peptides in the CSF samples from PD patients were identified by mass spectrometry and quantified by the in-house ELISA method. However, the CSF total α-synuclein level in PD patients did not differ from that in NC subjects. Similarly, the cortical GPR37 mRNA expression and CSF ecto-GPR37 levels in AD patients were also unaltered. Conclusion GPR37 expression is increased in SN of sporadic PD patients. The ecto-GPR37 peptides are significantly increased in the CSF of PD patients, but not in AD patients. These results open perspectives and encourage further clinical studies to confirm the validity and utility of ecto-GPR37 as a potential PD biomarker. Supplementary Information The online version contains supplementary material available at 10.1186/s40035-021-00232-7.
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Affiliation(s)
- Xavier Morató
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Spain.,Neuroscience Program, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Spain.,Section of Neurology, Department of Clinical Neuroscience, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Paula Garcia-Esparcia
- Neuroscience Program, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Spain.,Neuropathology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Spain.,CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Madrid, Spain
| | - Josep Argerich
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Spain.,Neuroscience Program, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Franc Llorens
- Neuroscience Program, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Spain.,Neuropathology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Spain.,CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Madrid, Spain.,Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany
| | - Inga Zerr
- Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.,German Center for Neurodegenerative Diseases, Göttingen, Germany
| | - Wojciech Paslawski
- Section of Neurology, Department of Clinical Neuroscience, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Eva Borràs
- Proteomics Unit, Center for Genomic Regulation, Barcelona, Spain.,Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain
| | - Eduard Sabidó
- Proteomics Unit, Center for Genomic Regulation, Barcelona, Spain.,Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain
| | - Ulla E Petäjä-Repo
- Research Unit of Biomedicine, Medical Research Center Oulu, University of Oulu, Oulu, Finland
| | - Víctor Fernández-Dueñas
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Spain.,Neuroscience Program, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Isidro Ferrer
- Neuroscience Program, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Spain.,Neuropathology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Spain.,CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Madrid, Spain
| | - Per Svenningsson
- Section of Neurology, Department of Clinical Neuroscience, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Francisco Ciruela
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat, Spain. .,Neuroscience Program, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Spain.
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Kokkinou M, Beishon LC, Smailagic N, Noel-Storr AH, Hyde C, Ukoumunne O, Worrall RE, Hayen A, Desai M, Ashok AH, Paul EJ, Georgopoulou A, Casoli T, Quinn TJ, Ritchie CW. Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting. Cochrane Database Syst Rev 2021; 2:CD010945. [PMID: 33566374 PMCID: PMC8078224 DOI: 10.1002/14651858.cd010945.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. OBJECTIVES To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. SEARCH METHODS We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. SELECTION CRITERIA We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. DATA COLLECTION AND ANALYSIS Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. MAIN RESULTS We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. AUTHORS' CONCLUSIONS Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.
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Affiliation(s)
- Michelle Kokkinou
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Lucy C Beishon
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Nadja Smailagic
- Institute of Public Health, University of Cambridge , Cambridge, UK
| | | | - Chris Hyde
- Exeter Test Group, College of Medicine and Health, University of Exeter Medical School, University of Exeter, Exeter , UK
| | - Obioha Ukoumunne
- NIHR CLAHRC South West Peninsula (PenCLAHRC), University of Exeter Medical School, Exeter, UK
| | | | - Anja Hayen
- Department of Psychology and Clinical Language Sciences, University of Reading, Reading, UK
| | - Meera Desai
- Department of Experimental Psychology, University of Oxford, Oxford, UK
| | - Abhishekh Hulegar Ashok
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College , London, UK
| | - Eleanor J Paul
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK
| | | | - Tiziana Casoli
- Center for Neurobiology of Aging, IRCCS INRCA, Ancona, Italy
| | - Terry J Quinn
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Craig W Ritchie
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
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Murakami H, Ono K, Shiraishi T, Umehara T, Omoto S, Iguchi Y. Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease. Front Aging Neurosci 2021; 12:616357. [PMID: 33551789 PMCID: PMC7859256 DOI: 10.3389/fnagi.2020.616357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/29/2020] [Indexed: 11/13/2022] Open
Abstract
The level of α-synuclein, a component of Lewy bodies, in cerebrospinal fluid (CSF) in Parkinson's disease (PD) has attracted recent attention. Most meta-analyses conclude that CSF levels of α-synuclein are decreased in PD. Patients with PD present with cognitive impairment, including frontal/executive dysfunction in the early phase and later emergence of visuospatial and mnemonic deficits. To examine whether CSF α-synuclein levels reflect the activities of various cognitive domains, we reviewed reports examining the association of these levels with cognitive performance in each domain in PD. Among 13 cross-sectional studies, five showed that a lower CSF α-synuclein level was associated with worse cognitive function. In four of these five reports, frontal/executive function showed this association, suggesting a link of the pathophysiology with Lewy bodies. In three other reports, a higher CSF α-synuclein level was associated with temporal-parieto-occipital cognitive deterioration such as memory. In the other five reports, the CSF α-synuclein level did not correlate with cognitive performance for any domain. In four longitudinal studies, a higher baseline CSF α-synuclein level was associated with a worse cognitive outcome, including cognitive processing speed, visuospatial function and memory in two, but not with any cognitive outcome in the other two. The different associations may reflect the heterogeneous pathophysiology in PD, including different pathogenic proteins, neurotransmitters. Thus, more studies of the association between cognitive domains and CSF levels of pathogenic proteins are warranted.
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Affiliation(s)
- Hidetomo Murakami
- Department of Neurology, School of Medicine, The Jikei University, Tokyo, Japan
| | - Kenjiro Ono
- Department of Neurology, School of Medicine, Showa University, Tokyo, Japan
| | - Tomotaka Shiraishi
- Department of Neurology, School of Medicine, The Jikei University, Tokyo, Japan
| | - Tadashi Umehara
- Department of Neurology, School of Medicine, The Jikei University, Tokyo, Japan
| | - Shusaku Omoto
- Department of Neurology, School of Medicine, The Jikei University, Tokyo, Japan
| | - Yasuyuki Iguchi
- Department of Neurology, School of Medicine, The Jikei University, Tokyo, Japan
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Constantinides VC, Majbour NK, Paraskevas GP, Abdi I, Safieh-Garabedian B, Stefanis L, El-Agnaf OM, Kapaki E. Cerebrospinal Fluid α-Synuclein Species in Cognitive and Movements Disorders. Brain Sci 2021; 11:brainsci11010119. [PMID: 33477387 PMCID: PMC7830324 DOI: 10.3390/brainsci11010119] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 12/12/2022] Open
Abstract
Total CSF α-synuclein (t-α-syn), phosphorylated α-syn (pS129-α-syn) and α-syn oligomers (o-α-syn) have been studied as candidate biomarkers for synucleinopathies, with suboptimal specificity and sensitivity in the differentiation from healthy controls. Studies of α-syn species in patients with other underlying pathologies are lacking. The aim of this study was to investigate possible alterations in CSF α-syn species in a cohort of patients with diverse underlying pathologies. A total of 135 patients were included, comprising Parkinson's disease (PD; n = 13), multiple system atrophy (MSA; n = 9), progressive supranuclear palsy (PSP; n = 13), corticobasal degeneration (CBD; n = 9), Alzheimer's disease (AD; n = 51), frontotemporal degeneration (FTD; n = 26) and vascular dementia patients (VD; n = 14). PD patients exhibited higher pS129-α-syn/α-syn ratios compared to FTD (p = 0.045), after exclusion of samples with CSF blood contamination. When comparing movement disorders (i.e., MSA vs. PD vs. PSP vs. CBD), MSA patients had lower α-syn levels compared to CBD (p = 0.024). Patients with a synucleinopathy (PD and MSA) exhibited lower t-α-syn levels (p = 0.002; cut-off value: ≤865 pg/mL; sensitivity: 95%, specificity: 69%) and higher pS129-/t-α-syn ratios (p = 0.020; cut-off value: ≥0.122; sensitivity: 71%, specificity: 77%) compared to patients with tauopathies (PSP and CBD). There are no significant α-syn species alterations in non-synucleinopathies.
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Affiliation(s)
- Vasilios C. Constantinides
- Neurochemistry and Biomarkers Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, 11528 Athens, Greece; (G.P.P.); (E.K.)
- Ward of Cognitive and movement Disorders, 1st Department of Neurology, National and Kapodistrian University of Athens, 11528 Athens, Greece;
- Correspondence: ; Tel.: +30-2107289285
| | - Nour K. Majbour
- Neurological Disorders Research Centre, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar; (N.K.M.); (I.A.); (O.M.E.-A.)
| | - George P. Paraskevas
- Neurochemistry and Biomarkers Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, 11528 Athens, Greece; (G.P.P.); (E.K.)
| | - Ilham Abdi
- Neurological Disorders Research Centre, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar; (N.K.M.); (I.A.); (O.M.E.-A.)
| | | | - Leonidas Stefanis
- Ward of Cognitive and movement Disorders, 1st Department of Neurology, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Omar M. El-Agnaf
- Neurological Disorders Research Centre, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar; (N.K.M.); (I.A.); (O.M.E.-A.)
| | - Elisabeth Kapaki
- Neurochemistry and Biomarkers Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, 11528 Athens, Greece; (G.P.P.); (E.K.)
- Ward of Cognitive and movement Disorders, 1st Department of Neurology, National and Kapodistrian University of Athens, 11528 Athens, Greece;
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Hadi F, Akrami H, Totonchi M, Barzegar A, Nabavi SM, Shahpasand K. α-synuclein abnormalities trigger focal tau pathology, spreading to various brain areas in Parkinson disease. J Neurochem 2021; 157:727-751. [PMID: 33264426 DOI: 10.1111/jnc.15257] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 07/28/2020] [Accepted: 11/30/2020] [Indexed: 12/21/2022]
Abstract
Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2~3% in the population over 65. α-Synuclein aggregation is the major pathological hallmark of PD. However, recent studies have demonstrated enhancing evidence of tau pathology in PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further investigate the development of α-synuclein and tau pathology. We employed various PD models, including cultured neurons treated with either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or with recombinant α-synuclein. Also, we studied dopaminergic neurons of cytokine Interferon-β knock-out. Moreover, we examined rats treated with 6-hydroxydopamine, Rhesus monkeys administrated with MPTP neurotoxin, and finally, human post-mortem brains. We found the α-synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α-synuclein with prion-like nature in various brain areas. We optionally removed P-tau or P-α-synuclein from cytokine interferon-β knock out with respective monoclonal antibodies. We found that tau immunotherapy suppressed neurodegeneration more than α-synuclein elimination. Our findings indicate that the pathogenic tau could be one of the leading causes of comprehensive neurodegeneration triggered by PD. Thus, we can propose an efficient therapeutic target to fight the devastating disorder.
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Affiliation(s)
- Fatemeh Hadi
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
| | - Hassan Akrami
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
| | - Mehdi Totonchi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute, ACECR, Tehran, Iran
| | | | - Seyed Massood Nabavi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute, ACECR, Tehran, Iran
| | - Koorosh Shahpasand
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute, ACECR, Tehran, Iran
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Byeon H. Best early-onset Parkinson dementia predictor using ensemble learning among Parkinson's symptoms, rapid eye movement sleep disorder, and neuropsychological profile. World J Psychiatry 2020; 10:245-259. [PMID: 33269221 PMCID: PMC7672787 DOI: 10.5498/wjp.v10.i11.245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/27/2020] [Accepted: 10/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite the frequent progression from Parkinson’s disease (PD) to Parkinson’s disease dementia (PDD), the basis to diagnose early-onset Parkinson dementia (EOPD) in the early stage is still insufficient.
AIM To explore the prediction accuracy of sociodemographic factors, Parkinson's motor symptoms, Parkinson’s non-motor symptoms, and rapid eye movement sleep disorder for diagnosing EOPD using PD multicenter registry data.
METHODS This study analyzed 342 Parkinson patients (66 EOPD patients and 276 PD patients with normal cognition), younger than 65 years. An EOPD prediction model was developed using a random forest algorithm and the accuracy of the developed model was compared with the naive Bayesian model and discriminant analysis.
RESULTS The overall accuracy of the random forest was 89.5%, and was higher than that of discriminant analysis (78.3%) and that of the naive Bayesian model (85.8%). In the random forest model, the Korean Mini Mental State Examination (K-MMSE) score, Korean Montreal Cognitive Assessment (K-MoCA), sum of boxes in Clinical Dementia Rating (CDR), global score of CDR, motor score of Untitled Parkinson’s Disease Rating (UPDRS), and Korean Instrumental Activities of Daily Living (K-IADL) score were confirmed as the major variables with high weight for EOPD prediction. Among them, the K-MMSE score was the most important factor in the final model.
CONCLUSION It was found that Parkinson-related motor symptoms (e.g., motor score of UPDRS) and instrumental daily performance (e.g., K-IADL score) in addition to cognitive screening indicators (e.g., K-MMSE score and K-MoCA score) were predictors with high accuracy in EOPD prediction.
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Affiliation(s)
- Haewon Byeon
- Department of Medical Big Data, College of AI Convergence, Inje University, Gimhae 50834, Gyeonsangnamdo, South Korea
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Shim KH, Kim SC, Youn YC, Sung YH, An SSA. Decreased plasma α-synuclein in idiopathic Parkinson’s disease patients after adjusting hemolysis factor. Mol Cell Toxicol 2020. [DOI: 10.1007/s13273-020-00104-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Farotti L, Paolini Paoletti F, Simoni S, Parnetti L. Unraveling Pathophysiological Mechanisms of Parkinson's Disease: Contribution of CSF Biomarkers. Biomark Insights 2020; 15:1177271920964077. [PMID: 33110345 PMCID: PMC7555566 DOI: 10.1177/1177271920964077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 09/14/2020] [Indexed: 01/08/2023] Open
Abstract
Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer's disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.
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Affiliation(s)
- Lucia Farotti
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy
| | | | - Simone Simoni
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Lucilla Parnetti
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy
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Polissidis A, Petropoulou-Vathi L, Nakos-Bimpos M, Rideout HJ. The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson's Disease. Biomolecules 2020; 10:E912. [PMID: 32560161 PMCID: PMC7355671 DOI: 10.3390/biom10060912] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 12/13/2022] Open
Abstract
Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson's disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2) and glucocerebrosidase (GBA1). Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements.
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Affiliation(s)
| | | | | | - Hardy J. Rideout
- Laboratory of Neurodegenerative Diseases, Centre for Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece; (A.P.); (L.P.-V.); (M.N.-B.)
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The Challenge of Disease-Modifying Therapies in Parkinson's Disease: Role of CSF Biomarkers. Biomolecules 2020; 10:biom10020335. [PMID: 32092971 PMCID: PMC7072459 DOI: 10.3390/biom10020335] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/16/2020] [Accepted: 02/17/2020] [Indexed: 01/22/2023] Open
Abstract
The development of disease modifying strategies in Parkinson's disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be a "single entity". Conversely, in front of the common feature of nigro-striatal degeneration, PD is pathogenically heterogeneous with a series of several biological and molecular pathways that differently contribute to clinical development and progression. Currently available diagnostic criteria for PD mainly rely on clinical features and imaging biomarkers, thus missing to identify the contribution of pathophysiological pathways, also failing to catch abnormalities occurring in the early stages of disease. Cerebrospinal fluid (CSF) is a promising source of biomarkers, with the high potential for reflecting early changes occurring in PD brain. In this review, we provide an overview on CSF biomarkers in PD, discussing their association with different molecular pathways involved either in pathophysiology or progression in detail. Their potential application in the field of disease modifying treatments is also discussed.
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Schaeffer E, Postuma RB, Berg D. Prodromal PD: A new nosological entity. PROGRESS IN BRAIN RESEARCH 2020; 252:331-356. [PMID: 32247370 DOI: 10.1016/bs.pbr.2020.01.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Recent years have brought a rapid growth in knowledge of the prodromal phase of Parkinson's disease (PD). It is now clear that the clinical phase of PD is preceded by a phase of progressing neurodegeneration lasting many years. This involves not only central nervous system structures outside the substantia nigra and neurotransmitter systems other than the dopaminergic system, but also the peripheral nervous systems. Different ways of alpha-synuclein spreading are presumed, corresponding to typical prodromal non-motor symptoms like constipation, REM sleep behavior disorder (RBD) and hyposmia. Moreover, many risk and prodromal markers have been identified and combined in the prodromal research criteria, which can be used to calculate an individual's probability of being in the prodromal phase of PD. Apart from specific genetic risk markers, including most importantly GBA- and LRRK2 mutations, RBD is currently the most important prodromal marker, predicting PD with a very high likelihood. This makes individuals with RBD a promising cohort for future clinical trials to detect and treat PD in its prodromal phase. New markers, especially those derived from tissue biopsies, quantitative motor assessment and imaging, appear very promising; these are paving the way for a better understanding of the prodromal phase and its potential clinicopathological subtypes, and a more precise probability calculation.
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Affiliation(s)
- Eva Schaeffer
- Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany.
| | - Ronald B Postuma
- Department of Neurology, Montreal General Hospital, Montreal, QC, Canada
| | - Daniela Berg
- Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany
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Manne S, Kondru N, Jin H, Anantharam V, Huang X, Kanthasamy A, Kanthasamy AG. α-Synuclein real-time quaking-induced conversion in the submandibular glands of Parkinson's disease patients. Mov Disord 2020; 35:268-278. [PMID: 31758740 PMCID: PMC7102508 DOI: 10.1002/mds.27907] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Identification of a peripheral biomarker is a major roadblock in the diagnosis of PD. Immunohistological identification of p-serine 129 α-synuclein in the submandibular gland tissues of PD patients has been recently reported. OBJECTIVE We report on a proof-of-principle study for using an ultra-sensitive and specific, real-time quaking-induced conversion assay to detect pathological α-synuclein in the submandibular gland tissues of PD patients. METHODS The α-synuclein real-time quaking-induced conversion assay was used to detect and quantify pathological α-synuclein levels in PD, incidental Lewy body disease, and control submandibular gland tissues as well as in formalin-fixed paraffin-embedded sections. RESULTS We determined the quantitative seeding kinetics of pathological α-synuclein present in submandibular gland tissues from autopsied subjects using the α-synuclein real-time quaking-induced conversion assay. A total of 32 cases comprising 13 PD, 3 incidental Lewy body disease, and 16 controls showed 100% sensitivity and 94% specificity. Interestingly, both PD and incidental Lewy body disease tissues showed 100% concordance for elevated levels of pathological α-synuclein seeding activity compared to control tissues. End-point dilution kinetic analyses revealed that the submandibular gland had a wide dynamic range of pathological α-synuclein seeding activity. CONCLUSIONS Our results are the first to demonstrate the utility of using the real-time quaking-induced conversion assay on peripherally accessible submandibular gland tissues and formalin-fixed paraffin-embedded tissue sections to detect PD-related pathological changes with high sensitivity and specificity. Additionally, the detection of seeding activity from incidental Lewy body disease cases containing immunohistochemically undetected pathological α-synuclein demonstrates the α-synuclein real-time quaking-induced conversion assay's potential utility for identifying prodromal PD in submandibular gland tissues. © 2019 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Sireesha Manne
- Department of Biomedical Sciences, Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011
| | - Naveen Kondru
- Department of Biomedical Sciences, Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011
| | - Huajun Jin
- Department of Biomedical Sciences, Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011
| | - Vellareddy Anantharam
- Department of Biomedical Sciences, Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011
| | - Xuemei Huang
- Departments of Neurology and Pharmacology, Neurosurgery, Radiology, and Kinesiology, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, USA
| | - Arthi Kanthasamy
- Department of Biomedical Sciences, Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011
| | - Anumantha G. Kanthasamy
- Department of Biomedical Sciences, Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011
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Cerebrospinal fluid levels of alpha-synuclein, amyloid β, tau, phosphorylated tau, and neuron-specific enolase in patients with Parkinson's disease, dementia with Lewy bodies or other neurological disorders: Their relationships with cognition and nuclear medicine imaging findings. Neurosci Lett 2020; 715:134564. [PMID: 31733322 DOI: 10.1016/j.neulet.2019.134564] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/29/2019] [Accepted: 10/14/2019] [Indexed: 11/21/2022]
Abstract
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders, but no established biochemical markers for these diseases have been identified. We enrolled 78 subjects (27 patients with PD/DLB, 34 patients with non-PD/DLB neurodegenerative disorders [non-PD/DLB], and 17 controls). Cerebrospinal fluid (CSF) was collected via the standard lumbar puncture technique. The CSF levels of alpha-synuclein, amyloid β40, amyloid β42, tau, phosphorylated tau (p-tau), neuron-specific enolase (NSE), and hemoglobin were measured with enzyme-linked immunosorbent assays. Dopamine transporter imaging with 123I-ioflupane was also performed. The PD/DLB patients exhibited significantly lower CSF alpha-synuclein levels than non-PD/DLB group. Significantly elevated CSF levels of tau, p-tau, and NSE were detected in the non-PD/DLB group. Multivariate analysis revealed that the mini-mental state examination score was correlated with the CSF amyloid β42 level. The specific binding ratio on 123I-ioflupane imaging was decreased in the PD/DLB group, but it was not correlated with the CSF alpha-synuclein level. These results indicate that (1) the CSF alpha-synuclein level is a useful biomarker of PD/DLB; (2) the CSF levels of tau, p-tau, and NSE can be used to discriminate PD/DLB from non-PD/DLB; and (3) the CSF amyloid β42 level is an independent predictor of cognitive decline in neurological disorders.
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Bougea A, Stefanis L, Emmanouilidou E, Vekrelis K, Kapaki E. High discriminatory ability of peripheral and CFSF biomarkers in Lewy body diseases. J Neural Transm (Vienna) 2020; 127:311-322. [PMID: 31912280 DOI: 10.1007/s00702-019-02137-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 12/27/2019] [Indexed: 11/30/2022]
Abstract
Differential diagnosis between Parkinson's disease (PD) Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), namely spectrum of Lewy bodies disorders (LBDs), may be challenging, and their common underlying pathophysiology is debated. Our aim was to examine relationships among neurodegenerative biomarkers [alpha-synuclein (α-Syn), Alzheimer's Disease (AD)-related (beta-amyloid Aβ42, tau [total τΤ and phosphorylated τp-181]), dopaminergic imaging (DATSCAN-SPECT)] and spectrum of LBD. This is a cross-sectional prospective study in 30 PD, 18 PDD, 29 DLB patients and 30 healthy controls. We compared α-Syn in CSF, plasma and serum and CSF Aβ42, τΤ and τp-181 across these groups. Correlations between such biomarkers and motor, cognitive/neuropsychiatric tests, and striatal asymmetry indexes were examined. CSF α-Syn was higher in DLB versus PD/PDD/controls, and lower in PD and PDD patients compared to controls (all p < 0.001). Serum α-Syn levels were higher in all patient groups compared to controls. After excluding those DLB patients with CSF AD profile, plasma and serum Syn levels were higher in the LBD group as a whole compared to controls. The combination of CSF α-Syn, serum α-Syn and Aβ42 for comparison between PD and DLB [AUC = 0.96 (95% CI 0.90-1.00)] was significantly better when compared to serum α-Syn alone (p < 0.001). Correlation analyses of biomarkers with cognitive/neuropsychiatric scales revealed some associations, but no consistent, cohesive picture. Peripheral biomarkers such as serum α-Syn, and CSF α-Syn and Aβ42 may contribute as potential biomarkers to separate LBDs from controls and to differentiate DLB from the other LBDs with high sensitivity and specificity among study groups.
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Affiliation(s)
- Anastasia Bougea
- 1st Department of Neurology, Memory and Movement Disorder Clinic, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Vassilisis Sophias Avenue 72-74, 11528, Athens, Greece. .,Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
| | - Leonidas Stefanis
- 1st Department of Neurology, Memory and Movement Disorder Clinic, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Vassilisis Sophias Avenue 72-74, 11528, Athens, Greece.,Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Evangelia Emmanouilidou
- Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Kostas Vekrelis
- Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Elisabeth Kapaki
- 1st Department of Neurology, Memory and Movement Disorder Clinic, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Vassilisis Sophias Avenue 72-74, 11528, Athens, Greece
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Bakulski KM, Seo YA, Hickman RC, Brandt D, Vadari HS, Hu H, KyunPark S. Heavy Metals Exposure and Alzheimer's Disease and Related Dementias. J Alzheimers Dis 2020; 76:1215-1242. [PMID: 32651318 PMCID: PMC7454042 DOI: 10.3233/jad-200282] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer's disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer's disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer's disease specifically though two studies have reported a link between cadmium and Alzheimer's disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer's disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer's disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer's disease and related dementias and makes recommendations of critical areas of future investment.
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Affiliation(s)
- Kelly M. Bakulski
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Young Ah Seo
- Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Ruby C. Hickman
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Daniel Brandt
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Harita S. Vadari
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Howard Hu
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Sung KyunPark
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
- Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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Mesa-Herrera F, Taoro-González L, Valdés-Baizabal C, Diaz M, Marín R. Lipid and Lipid Raft Alteration in Aging and Neurodegenerative Diseases: A Window for the Development of New Biomarkers. Int J Mol Sci 2019; 20:E3810. [PMID: 31382686 PMCID: PMC6696273 DOI: 10.3390/ijms20153810] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/1970] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 12/13/2022] Open
Abstract
Lipids in the brain are major components playing structural functions as well as physiological roles in nerve cells, such as neural communication, neurogenesis, synaptic transmission, signal transduction, membrane compartmentalization, and regulation of gene expression. Determination of brain lipid composition may provide not only essential information about normal brain functioning, but also about changes with aging and diseases. Indeed, deregulations of specific lipid classes and lipid homeostasis have been demonstrated in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, recent studies have shown that membrane microdomains, named lipid rafts, may change their composition in correlation with neuronal impairment. Lipid rafts are key factors for signaling processes for cellular responses. Lipid alteration in these signaling platforms may correlate with abnormal protein distribution and aggregation, toxic cell signaling, and other neuropathological events related with these diseases. This review highlights the manner lipid changes in lipid rafts may participate in the modulation of neuropathological events related to AD and PD. Understanding and characterizing these changes may contribute to the development of novel and specific diagnostic and prognostic biomarkers in routinely clinical practice.
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Affiliation(s)
- Fátima Mesa-Herrera
- Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology
| | - Lucas Taoro-González
- Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Section of Medicine, Faculty of Health Sciences, University of La Laguna, Sta. Cruz de Tenerife 38200, Spain
| | - Catalina Valdés-Baizabal
- Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Section of Medicine, Faculty of Health Sciences, University of La Laguna, Sta. Cruz de Tenerife 38200, Spain
| | - Mario Diaz
- Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology
- Associate Research Unit ULL-CSIC "Membrane Physiology and Biophysics in Neurodegenerative and Cancer Diseases", University of La Laguna, Sta. Cruz de Tenerife 38200, Spain
| | - Raquel Marín
- Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Section of Medicine, Faculty of Health Sciences, University of La Laguna, Sta. Cruz de Tenerife 38200, Spain.
- Associate Research Unit ULL-CSIC "Membrane Physiology and Biophysics in Neurodegenerative and Cancer Diseases", University of La Laguna, Sta. Cruz de Tenerife 38200, Spain.
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Fayyad M, Salim S, Majbour N, Erskine D, Stoops E, Mollenhauer B, El-Agnaf OMA. Parkinson's disease biomarkers based on α-synuclein. J Neurochem 2019; 150:626-636. [PMID: 31265130 DOI: 10.1111/jnc.14809] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/05/2019] [Accepted: 06/26/2019] [Indexed: 12/20/2022]
Abstract
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and is estimated to affect approximately 1-4% of individuals aged over 60 years old. Although considerable efforts have been invested into developing disease-modifying therapies for Parkinson's disease, such efforts have been confounded by the difficulty in accurately diagnosing Parkinson's disease during life to enable accurate patient stratification for clinical trialling of candidate therapeutics. Therefore, the search for effective biomarkers that can be accurately evaluated during life with non-invasive means is a pressing issue in the field. Since the discovery of α-synuclein (α-syn) as a protein linked to a familial form of Parkinson's disease, later identified as the major protein component of the neuropathological hallmark of idiopathic Parkinson's disease, considerable interest has focused on this protein and its distinct conformers. We describe here the progress that has been made in the area of Parkinson's disease biomarker discovery with a focus on α-synuclein. In particular, we highlight the novel assays that have been employed and the increasing complexity in evaluating α-synuclein with regard to the considerable diversity of conformers that exist in the biofluids and peripheral tissues under disease conditions. "This article is part of the Special Issue Synuclein."
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Affiliation(s)
- Muneera Fayyad
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Safa Salim
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Nour Majbour
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Daniel Erskine
- Institute of Neuroscience, Ageing Research Laboratories Newcastle University, Newcastle upon Tyne, UK
| | | | | | - Omar M A El-Agnaf
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
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Førland MG, Tysnes OB, Aarsland D, Maple-Grødem J, Pedersen KF, Alves G, Lange J. The value of cerebrospinal fluid α-synuclein and the tau/α-synuclein ratio for diagnosis of neurodegenerative disorders with Lewy pathology. Eur J Neurol 2019; 27:43-50. [PMID: 31293044 DOI: 10.1111/ene.14032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 07/05/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND PURPOSE Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are three of the most common neurodegenerative disorders. Up to 20% of these patients have the wrong diagnosis, due to overlapping symptoms and shared pathologies. A cerebrospinal fluid (CSF) biomarker panel for AD is making its way into the clinic, but an equivalent panel for PD and DLB and for improved differential diagnoses is still lacking. Using well-defined, community-based cohorts and validated analytical methods, the diagnostic value of CSF total-α-synuclein (t-α-syn) alone and in combination with total tau (t-tau) in newly diagnosed patients with PD, DLB and AD was determined. METHODS Cerebrospinal fluid concentrations of t-α-syn were assessed using our validated in-house enzyme-linked immunosorbent assay in 78 PD patients, 20 AD patients, 19 DLB patients and 32 controls. t-tau was measured using a commercial assay. Diagnostic performance was assessed by receiver operating characteristic curve analysis. RESULTS Compared to controls (mean 517 pg/ml), significantly lower levels of CSF t-α-syn in patients with PD (434 pg/ml, 16% reduction, P = 0.036), DLB (398 pg/ml, 23% reduction, P = 0.009) and AD (383 pg/ml, 26% reduction, P = 0.014) were found. t-α-syn levels did not differ significantly between PD, DLB and AD. The t-tau/t-α-syn ratio showed an improved performance compared to the single markers. CONCLUSION This is the first study to compare patients with PD, DLB and AD at the time of diagnosis. It was found that t-α-syn can contribute as a teammate with tau in a CSF biomarker panel for PD and DLB, and strengthen the existing biomarker panel for AD.
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Affiliation(s)
- M G Førland
- Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Centre for Organelle Research, University of Stavanger, Stavanger, Norway
| | - O-B Tysnes
- Department of Neurology, Haukeland University Hospital, Bergen, Norway.,Institute for Clinical Medicine, University of Bergen, Bergen, Norway
| | - D Aarsland
- Centre for Age-related Medicine, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway.,Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK
| | - J Maple-Grødem
- Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - K F Pedersen
- Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Department of Neurology, Stavanger University Hospital, Stavanger, Norway
| | - G Alves
- Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.,Department of Neurology, Stavanger University Hospital, Stavanger, Norway
| | - J Lange
- Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Centre for Organelle Research, University of Stavanger, Stavanger, Norway
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Vaikath NN, Hmila I, Gupta V, Erskine D, Ingelsson M, El-Agnaf OMA. Antibodies against alpha-synuclein: tools and therapies. J Neurochem 2019; 150:612-625. [PMID: 31055836 DOI: 10.1111/jnc.14713] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/20/2019] [Accepted: 04/24/2019] [Indexed: 01/04/2023]
Abstract
Synucleinopathies including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterized by the abnormal accumulation and propagation of α-synuclein (α-syn) pathology in the central and peripheral nervous system as Lewy bodies or glial cytoplasmic inclusions. Several antibodies against α-syn have been developed since it was first detected as the major component of Lewy bodies and glial cytoplasmic inclusions. Over the years, researchers have generated specific antibodies that alleviate the accumulation of intracellular aggregated α-syn and associated pathology in cellular and preclinical models of synucleinopathies. So far, antibodies have been the first choice as tools for research and diagnosis and currently, a wide variety of antibody fragments have been developed as an alternative to full-length antibodies for increasing its therapeutic usefulness. Recently, conformation specific antibody-based approaches have been found to be promising as therapeutic strategies, both to block α-syn aggregation and ameliorate the resultant cytotoxicity, and as diagnostic tools. In this review, we summarize different α-syn specific antibodies and provide their usefulness in tackling synucleinopathies. This article is part of the Special Issue "Synuclein".
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Affiliation(s)
- Nishant N Vaikath
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Issam Hmila
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Vijay Gupta
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Daniel Erskine
- Institute of Neuroscience, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK
| | - Martin Ingelsson
- Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden
| | - Omar M A El-Agnaf
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
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Abstract
Following the development of the first methods to measure the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer’s Disease, we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42, the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies.
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Affiliation(s)
- Kaj Blennow
- Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Henrik Zetterberg
- Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
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50
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Parkinson's and Lewy body dementia CSF biomarkers. Clin Chim Acta 2019; 495:318-325. [PMID: 31051162 DOI: 10.1016/j.cca.2019.04.078] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 04/24/2019] [Accepted: 04/24/2019] [Indexed: 11/24/2022]
Abstract
The clinical diagnosis of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) is challenging due to highly variable clinical presentation and clinical and pathological overlap with other neurodegenerative diseases. Since cerebrospinal fluid (CSF) mirrors the pathological changes taking place in the brain, it represents a promising source of biomarkers. With respect to classical AD biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment in PD and DLB. In the differential diagnosis between AD and DLB, a potential role of t-tau, p-tau and Aβ42/Aβ38 ratio has been demonstrated. Regarding CSF α-synuclein (α-syn) species, lower levels of total α-synuclein (t-α-syn) and higher concentration of oligomeric-α-synuclein (o-α-syn) and phosphorylated α-synuclein (p-α-syn) have been observed in PD. Furthermore, the detection of "pro-aggregating" α-synuclein has enabled the discrimination of patients affected by synucleinopathies with high sensitivity and specificity. New promising biomarkers are emerging: GCase activity (reduced in PD and DLB patients vs. controls), CSF/serum albumin ratio (increased in PD and DLB), fatty-acid-binding protein (increased in AD and DLB vs. PD), visinin-like protein-1 (increased in AD vs. DLB) and monoamines (useful in differential diagnosis among PD and DLB). These encouraging results need to be confirmed by future studies.
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