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Parkinsonism & Related Disorders Nov 2022Alpha-synuclein(αSyn) aggregates are definite pathological hallmarks of α-synucleinopathies. Seeding amplification assays (SAAs) have been developed to detect trace... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Alpha-synuclein(αSyn) aggregates are definite pathological hallmarks of α-synucleinopathies. Seeding amplification assays (SAAs) have been developed to detect trace amounts of αSyn oligomers in vivo.. Herein, we assessed the diagnostic accuracy of the αSyn-SAAs across biospecimens, diagnostic references, methods, and subtypes.
METHODS
A systematic literature search yielded 36 eligible studies for a meta-analysis of the sensitivity and specificity of αSyn-SAAs in patients with α-synucleinopathies(n = 2722) and controls(n = 2278). Pooled sensitivities and specificities with 95% confidence intervals (CIs) were calculated using bivariate random-effects models and a meta-regression analysis was performed.
RESULTS
The summary sensitivity and specificity of αSyn-SAAs positivity for the diagnosis of α-synucleinopathies were 0.88(95% CIs = 0.84-0.91) and 0.95(0.93-0.97), respectively. Two covariates (biospecimen and diagnostic reference) were significant in fitting the meta-regression model (likelihood-ratio test for sensitivity and specificity, p < 0.01, p = 0.01, respectively). Skin αSyn-SAAs exhibited the highest sensitivity 0.92(0.87-0.95), which was not different from that of cerebrospinal fluid (CSF)(0.90(0.86-0.93), p = 0.39). Olfactory mucosa αSyn-SAAs exhibited a lower sensitivity 0.64(0.49-0.76) than those of the other two specimens(p = 0.02, 0.01, compared to CSF and skin, respectively). Application of pathological diagnostic standards were associated with a higher specificity of αSyn-SAAs compared to clinical diagnosis (p < 0.01). The diagnostic sensitivity and specificity of CSF αSyn-SAAs were 0.91(0.87-0.94) and 0.96(0.93-0.98) for Lewy body disease, 0.90(0.79-0.95) and 0.96(0.90-0.98) for prodromal α-synucleinopathies, and 0.63(0.24-0.90) and 0.97(0.93-0.99) for multiple system atrophy.
CONCLUSIONS
αSyn-SAAs are promising in vivo detectors of abnormal αSyn aggregates and may aid the early diagnosis of α-synucleinopathies.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Lewy Body Disease; Multiple System Atrophy; Sensitivity and Specificity
PubMed: 36289019
DOI: 10.1016/j.parkreldis.2022.10.007 -
CNS Neuroscience & Therapeutics Jan 2023Recent advances have highlighted the relationships between gut dysbiosis and Parkinson's disease (PD). Microbiota transplantation from PD patients to mice can induce... (Review)
Review
INTRODUCTION
Recent advances have highlighted the relationships between gut dysbiosis and Parkinson's disease (PD). Microbiota transplantation from PD patients to mice can induce increased alpha-synuclein-mediated motor deficits. Human studies have identified differences in the gut microbiota of PD patients compared to healthy controls. We undertook a systematic review to evaluate the available evidence for the involvement of gut bacteria in the etiology of PD.
METHODS
The PubMed databank, the China National Knowledge Infrastructure databank, and Wanfang Data were searched from inception until June 2021 to identify human case-control studies that investigated relationships between PD and microbiota quantified from feces. We evaluated the resulting studies focusing on bacterial taxa that were different between PD patients and healthy controls.
RESULTS
Twenty-six studies were found in which 53 microbial families and 98 genera exhibited differences between patients with PD and healthy controls. The genera identified by more than two studies as increased in PD were Bifidobacterium, Alistipes, Christensenella, Enterococcus, Oscillospira, Bilophila, Desulfovibrio, Escherichia/Shigella, and Akkermansia, while Prevotella, Blautia, Faecalibacterium, Fusicatenibacter, and Haemophilus had three or more reports of being lower in PD patients. More than one report demonstrated that Bacteroides, Odoribacter, Parabacteroides, Butyricicoccus, Butyrivibrio, Clostridium, Coprococcus, Lachnospira, Lactobacillus, Megasphaera, Phascolarctobacterium, Roseburia, Ruminococcus, Streptococcus, and Klebsiella were altered in both directions.
CONCLUSION
Our review shows that the involvement of the gut microbiome in the etiology of PD may involve alterations of short-chain fatty acids (SCFAs)-producing bacteria and an increase in putative gut pathobionts. SCFAs-producing bacteria may vary above or below an "optimal range," causing imbalances. Considering that Bifidobacterium, Lactobacillus, and Akkermansia are beneficial for human health, increased Bifidobacterium and Lactobacillus in the PD gut microbiome may be associated with PD medications, especially COMT inhibitors, while a high level of Akkermansia may be associated with aging.
Topics: Humans; Animals; Mice; Parkinson Disease; Gastrointestinal Microbiome; Bacteria; Feces; Fatty Acids, Volatile
PubMed: 36284437
DOI: 10.1111/cns.13990 -
Ageing Research Reviews Dec 2022Recently, there has been growing interest in exosomal biomarkers for their active targeting and specificity for delivering their cargos (proteins, lipids, nucleic acids)... (Meta-Analysis)
Meta-Analysis Review
Recently, there has been growing interest in exosomal biomarkers for their active targeting and specificity for delivering their cargos (proteins, lipids, nucleic acids) from the parent cell to the recipient cell. Currently, the clinical diagnosis of Parkinson's disease (PD) is mainly based on a clinician's neuropsychological examination and motor symptoms (e.g., bradykinesia, rigidity, postural instability, and resting tremor). However, this diagnosis method is not accurate due to overlapping criteria of other neurodegenerative diseases. Exosomes are differentially expressed in PD and a combination of types and contents of exosomes might be used as a biomarker in PD. Here, we systematically reviewed and meta-analyzed exosomal contents, types and sources of exosomes, method of isolation, and protein quantification tools to determine the optimum exosome-related attributes for PD diagnosis. Pubmed, Embase, and ISI Web of Science were searched for relevant studies. 25 studies were included in the meta-analysis. The Ratio of Mean (RoM) with 95% confidence intervals (CI) was calculated to estimate the effect size. Biomarker performances were rated by random-effects meta-analysis with the Restricted Maximum Likelihood (REML) method. The study protocol is available at PROSPERO (CRD42022331885). Exosomal α-synuclein (α-Syn) was significantly altered in PD patients from healthy controls [RoM = 1.67, 95% CI (0.99 to 2.35); p = 0.00] followed by tau [RoM = 1.33, 95% CI (0.79 to 1.87); p = 0.00], PS-129 [RoM = 0.97, 95% CI (0.54 to 1.40); p = 0.00], and DJ-1/PARK7 [RoM = 0.93, 95% CI (0.64 to 1.21); p = 0.00]. Central nervous system derived L1CAM exosome [RoM = 1.24, 95% CI (1.04 to 1.45); p = 0.00] from either plasma [RoM = 1.35, 95% CI (1.09 to 1.61); p = 0.00]; or serum [RoM = 1.47, 95% CI (1.05 to 1.90); p = 0.00] has been found the optimum type of exosome. The exosome isolation by ExoQuick [RoM = 1.16, 95% CI (0.89 to 1.43); p = 0.00] and protein quantification method by ELISA [RoM = 1.28, 95% CI (1.15 to 1.41); p = 0.00] has been found the optimum isolation and quantification method, respectively for PD diagnosis. This meta-analysis suggests that α-Syn in L1CAM exosome derived from blood, isolated by ExoQuick kit, and quantified by ELISA can be used for PD diagnosis.
Topics: Humans; Parkinson Disease; Neural Cell Adhesion Molecule L1; alpha-Synuclein; Biomarkers; Exosomes; Central Nervous System
PubMed: 36273807
DOI: 10.1016/j.arr.2022.101764 -
Movement Disorders : Official Journal... Jan 2023Studies on dementia with Lewy bodies (DLB) have mainly focused on the degeneration of distinct cortical and subcortical regions related to the deposition of Lewy bodies.... (Review)
Review
Studies on dementia with Lewy bodies (DLB) have mainly focused on the degeneration of distinct cortical and subcortical regions related to the deposition of Lewy bodies. In view of the proposed trans-synaptic spread of the α-synuclein pathology, investigating the disease only in this segregated fashion would be detrimental to our understanding of its progression. In this systematic review, we summarize findings on structural and functional brain connectivity in DLB, as connectivity measures may offer better insights on how the brain is affected by the spread of the pathology. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched Web of Science, PubMed, and SCOPUS for relevant articles published up to November 1, 2021. Of 1215 identified records, we selected and systematically reviewed 53 articles that compared connectivity features between patients with DLB and healthy controls. Structural and functional magnetic resonance imaging, positron emission tomography, single-positron emission computer tomography, and electroencephalography assessments of patients revealed widespread abnormalities within and across brain networks in DLB. Frontoparietal, default mode, and visual networks and their connections to other brain regions featured the most consistent disruptions, which were also associated with core clinical features and cognitive impairments. Furthermore, graph theoretical measures revealed disease-related decreases in local and global network efficiency. This systematic review shows that structural and functional connectivity characteristics in DLB may be particularly valuable at early stages, before overt brain atrophy can be observed. This knowledge may help improve the diagnosis and prognosis in DLB as well as pinpoint targets for future disease-modifying treatments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Lewy Body Disease; Lewy Bodies; Brain; Electroencephalography; Positron-Emission Tomography; Alzheimer Disease
PubMed: 36253921
DOI: 10.1002/mds.29248 -
Frontiers in Aging Neuroscience 2022Nilotinib, which inhibits cellular Abelson tyrosine kinase, may be an effective treatment for patients with Parkinson's disease (PD). The purpose of this study is to...
BACKGROUND
Nilotinib, which inhibits cellular Abelson tyrosine kinase, may be an effective treatment for patients with Parkinson's disease (PD). The purpose of this study is to evaluate the outcomes of different doses of nilotinib in patients with PD.
METHODS
We searched PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Clinical Trials from inception to 7 March 2022 to identify all randomized controlled trials (RCTs) of nilotinib reporting outcomes of interest in patients with PD. Outcomes included tolerability, efficacy, safety, and CSF biomarker levels. Review manager 5.4 software was used to analyze all data.
RESULTS
Three RCTs with a total of 163 patients were included. No significant difference was found between 150 mg nilotinib or 300 mg nilotinib and placebo in terms of tolerability, adverse events, or HVA levels. 300 mg nilotinib showed significantly higher Movement Disorder Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS III) scores [SMD = 0.52, 95%CI = (0.12, 0.92), = 0.01] and 3,4-dihydroxyphenylacetic acid (DOPAC) levels [SMD = 0.52, 95%CI = (0.12, 0.92), = 0.01], and lower α-synuclein levels [SMD = -2.16, 95%CI = (-3.38, -1.84), < 0.00001] compared with placebo. And compared with 150 mg nilotinib, 300 mg nilotinib showed significantly lower α-synuclein levels [SMD = -1.16, 95%CI = (-1.70, -0.61), < 0.0001].
CONCLUSIONS
Although our study demonstrated favorable tolerability and safety of different doses of nilotinib, and improvement in part of CSF biomarker levels of 300 mg nilotinib, the poor efficacy on motor outcomes indicated that nilotinib had no advantages in the clinic.
PubMed: 36248007
DOI: 10.3389/fnagi.2022.996217 -
International Journal of Molecular... Sep 2022Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder, characterized by the misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies... (Review)
Review
Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder, characterized by the misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The urge for an early diagnosis biomarker comes from the fact that clinical manifestations of PD are estimated to appear once the substantia nigra has deteriorated and there has been a reduction of the dopamine levels from the striatum. Nowadays, extracellular vesicles (EVs) play an important role in the pathogenesis of neuro-degenerative diseases as PD. A systematic review dated August 2022 was carried out with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses with the aim to analyze the potential role of EVs as biomarkers for PD. From a total of 610 articles retrieved, 29 were eligible. This review discusses the role of EVs biochemistry and their cargo proteins, such as α-syn and DJ-1 among others, detected by a proteomic analysis as well as miRNAs and lncRNAs, as potential biomarkers that can be used to create standardized protocols for early PD diagnosis as well as to evaluate disease severity and progression.
Topics: Biomarkers; Dopamine; Dopaminergic Neurons; Extracellular Vesicles; Humans; MicroRNAs; Parkinson Disease; Proteomics; RNA, Long Noncoding; alpha-Synuclein
PubMed: 36232833
DOI: 10.3390/ijms231911508 -
Alzheimer Disease and Associated...This study investigated whether α-synuclein and tau in cerebrospinal fluid (CSF) can be used as biomarkers to diagnose dementia with Lewy bodies (DLB). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study investigated whether α-synuclein and tau in cerebrospinal fluid (CSF) can be used as biomarkers to diagnose dementia with Lewy bodies (DLB).
MATERIALS AND METHODS
We retrieved 3303 studies with "Dementia with Lewy bodies," "α-synuclein," and "tau" as keywords. We formulated screening criteria, and 2 researchers completed the screening, quality evaluation, and data extraction tasks. Finally, 35 studies related to tau, and 14 studies related to α-synuclein were included. Review Manager 5.4 and Stata16 were used for meta-analysis. Subgroup, sensitivity, and meta-regression analyses were performed to identify sources of heterogeneity and strengthen the results.
RESULTS
Compared with the control group, DLB patients showed significantly higher CSF levels of tau [weighted mean difference=81.36 (59.82, 102.91); Z =7.40; P <0.00001], and lower CSF levels of α-synuclein [weighted mean difference=-95.25 (-162.02, -28.48); Z =2.80; P =0.005]. Mini-Mental State Examination (MMSE) score, male ratio, and disease duration were not sources of heterogeneity on subgroup and meta-regression analyses. Sensitivity analysis revealed no significant differences.
CONCLUSIONS
Higher levels of tau and lower levels of α-synuclein were found in the CSF of patients with DLB compared with the control group. Therefore, CSF tau and α-synuclein levels may be diagnostic biomarkers for DLB.
Topics: Humans; Male; alpha-Synuclein; Lewy Body Disease; tau Proteins; Alzheimer Disease; Biomarkers; Amyloid beta-Peptides
PubMed: 36183420
DOI: 10.1097/WAD.0000000000000516 -
Biomolecules Aug 2022α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning... (Review)
Review
α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson's disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.
Topics: Axons; Humans; Lewy Bodies; Parkinson Disease; Synapses; alpha-Synuclein
PubMed: 36139038
DOI: 10.3390/biom12091199 -
Frontiers in Aging Neuroscience 2022Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to...
Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models.
PubMed: 35966779
DOI: 10.3389/fnagi.2022.909273 -
Nutritional Neuroscience Oct 2023The pathology underlying cognitive changes in people with Parkinson's disease (PD) is not well understood. In healthy older adults, gut microbiome composition has been...
BACKGROUND
The pathology underlying cognitive changes in people with Parkinson's disease (PD) is not well understood. In healthy older adults, gut microbiome composition has been associated with cognitive function. In people with PD, preliminary evidence suggests that cortical spreading of abnormal alpha-synuclein aggregates may be associated with cognitive impairment. As changes in the gut have been linked to PD onset and associated Lewy body pathology, an investigation of the gut microbiome and cognition in PD is warranted.
OBJECTIVE
To synthesise existing evidence on the relationship between the gut microbiome and cognitive function in PD.
METHODS
A systematic review was conducted to search for peer-reviewed articles and grey literature published to July 2021 across seven electronic databases (MEDLINE, EMBASE, PsycINFO, Scopus, Cochrane Library, ProQuest, and ProQuest Dissertations and Theses). English language articles reporting the relationship between cognition and the gut microbiome in human participants with PD were considered for inclusion. Results were qualitatively synthesised and evidence quality was assessed using the QualSyst tool for quantitative studies.
RESULTS
Five cross-sectional studies reporting the association between the gut microbiome and cognition in 395 participants with PD were included. Studies provided preliminary evidence of a relationship between cognition and gut microbiota within the and phyla, however, associations with specific genera were inconsistent across studies.
CONCLUSIONS
Some species of short-chain fatty acid-producing bacteria (e.g. acetate, butyrate, and propionate producers) appear to be reduced in participants with PD with cognitive impairment. More research with larger samples and more consistent methodology is needed to substantiate these findings.
Topics: Humans; Aged; Gastrointestinal Microbiome; Parkinson Disease; Cross-Sectional Studies; Cognition; Cognitive Dysfunction
PubMed: 35965446
DOI: 10.1080/1028415X.2022.2110189