Alpha-synuclein in the Cerebrospinal Fluid Differentiates Synucleinopathies (Parkinson Disease, Dementia With Lewy Bodies, Multiple System Atrophy) From Alzheimer Disease

2012 ◽  
Vol 26 (3) ◽  
pp. 213-216 ◽  
Author(s):  
Fuyuki Tateno ◽  
Ryuji Sakakibara ◽  
Takayuki Kawai ◽  
Masahiko Kishi ◽  
Takeyoshi Murano
Keyword(s):  
Cerebrospinal Fluid ◽  
Alzheimer Disease ◽  
Multiple System Atrophy ◽  
Parkinson Disease ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Alpha Synuclein

scholarly journals Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy

2019 ◽  
Vol 78 (10) ◽  
pp. 877-890 ◽  
Author(s):  
Norihito Uemura ◽  
Maiko T Uemura ◽  
Angela Lo ◽  
Fares Bassil ◽  
Bin Zhang ◽  
...  
Keyword(s):  
White Matter ◽  
Multiple System Atrophy ◽  
Parkinson Disease ◽  
Mouse Models ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Wild Type ◽  
Time Points ◽  
Progressive Accumulation

Abstract Synucleinopathies are composed of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Alpha-synuclein (α-Syn) forms aggregates mainly in neurons in PD and DLB, while oligodendroglial α-Syn aggregates are characteristic of MSA. Recent studies have demonstrated that injections of synthetic α-Syn preformed fibrils (PFFs) into the brains of wild-type (WT) animals induce intraneuronal α-Syn aggregates and the subsequent interneuronal transmission of α-Syn aggregates. However, injections of α-Syn PFFs or even brain lysates of patients with MSA have not been reported to induce oligodendroglial α-Syn aggregates, raising questions about the pathogenesis of oligodendroglial α-Syn aggregates in MSA. Here, we report that WT mice injected with mouse α-Syn (m-α-Syn) PFFs develop neuronal α-Syn pathology after short postinjection (PI) intervals on the scale of weeks, while oligodendroglial α-Syn pathology emerges after longer PI intervals of several months. Abundant oligodendroglial α-Syn pathology in white matter at later time points is reminiscent of MSA. Furthermore, comparison between young and aged mice injected with m-α-Syn PFFs revealed that PI intervals rather than aging correlate with oligodendroglial α-Syn aggregation. These results provide novel insights into the pathological mechanisms of oligodendroglial α-Syn aggregation in MSA.

scholarly journals Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

2021 ◽  
pp. 19-25
Author(s):  
Lynn Marie Trotti ◽  
Donald L. Bliwise ◽  
Glenda L. Keating ◽  
David B. Rye ◽  
William T. Hu
Keyword(s):  
Cerebrospinal Fluid ◽  
Alzheimer Disease ◽  
Cholinesterase Inhibitor ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Cognitively Normal ◽  
Dementia Patients ◽  
Sleep Questionnaires ◽  
Sleep Alterations ◽  
Normal Controls

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

scholarly journals Rapid and ultra-sensitive quantitation of disease-associated α-synuclein seeds in brain and cerebrospinal fluid by αSyn RT-QuIC

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Bradley R. Groveman ◽  
Christina D. Orrù ◽  
Andrew G. Hughson ◽  
Lynne D. Raymond ◽  
Gianluigi Zanusso ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Parkinson Disease ◽  
Real Time ◽  
Sensitivity And Specificity ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Diagnostic Sensitivity ◽  
Diagnosis And Treatment ◽  
Specific Detection ◽  
End Point

Abstract The diagnosis and treatment of synucleinopathies such as Parkinson disease and dementia with Lewy bodies would be aided by the availability of assays for the pathogenic disease-associated forms of α-synuclein (αSynD) that are sufficiently sensitive, specific, and practical for analysis of accessible diagnostic specimens. Two recent αSynD seed amplification tests have provided the first prototypes for ultrasensitive and specific detection of αSynD in patients’ cerebrospinal fluid. These prototypic assays require 5–13 days to perform. Here, we describe an improved α-synuclein real time quaking-induced conversion (αSyn RT-QuIC) assay that has similar sensitivity and specificity to the prior assays, but can be performed in 1–2 days with quantitation. Blinded analysis of cerebrospinal fluid from 29 synucleinopathy cases [12 Parkinson’s and 17 dementia with Lewy bodies] and 31 non-synucleinopathy controls, including 16 Alzheimer’s cases, yielded 93% diagnostic sensitivity and 100% specificity for this test so far. End-point dilution analyses allowed quantitation of relative amounts of αSynD seeding activity in cerebrospinal fluid samples, and detection in as little as 0.2 μL. These results confirm that αSynD seeding activity is present in cerebrospinal fluid. We also demonstrate that it can be rapidly detected, and quantitated, even in early symptomatic stages of synucleinopathy.

Alpha-Synucleinopathies

2021 ◽  
pp. 387-410
Author(s):  
Carlos Henrique Ferreira Camargo ◽  
Marcus Vinicius Della-Coletta ◽  
Delson José da Silva ◽  
Hélio A. G. Teive
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Disorders ◽  
Dementia With Lewy Bodies ◽  
Therapeutic Targets ◽  
Lewy Bodies ◽  
Lysosomal Storage Diseases ◽  
Alpha Synuclein ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Abnormal Accumulation

Alpha-synuclein is a protein that forms a major component of abnormal neuronal aggregates known as Lewy bodies. A particular group of neurodegenerative disorders (NDs) is characterized by the abnormal accumulation of α-synuclein; termed the α-synucleinopathies, this group includes Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Lysosomal storage diseases have also been linked to α-synuclein toxicity. Several therapeutic targets have been chosen among steps of metabolism of α-synuclein. Reducing α-synuclein synthesis or expression and increasing the clearance can be achieved in many ways. The development of immunotherapeutic approaches targeting α-synuclein has received considerable attention in recent years. The aim of this chapter is to present the α-synucleinopathies, as well as to present the most recent researches about treatment of synucleinopathies based on knowledge of the pathophysiology of α-synuclein pathways.

scholarly journals Depression and Synaptic Zinc Regulation in Alzheimer Disease, Dementia with Lewy Bodies, and Parkinson Disease Dementia

2015 ◽  
Vol 23 (2) ◽  
pp. 141-148 ◽  
Author(s):  
David R. Whitfield ◽  
Julie Vallortigara ◽  
Amani Alghamdi ◽  
Tibor Hortobágyi ◽  
Clive Ballard ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Parkinson Disease ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies

scholarly journals Meta-analysis of Cerebrospinal Fluid Neuron-specific Enolase Levels in Alzheimer’s Disease, Parkinson’s Disease, Dementia With Lewy Bodies, and Multiple System Atrophy

2020 ◽  
Author(s):  
Takayuki Katayama ◽  
Jun Sawada ◽  
Kae Takahashi ◽  
Osamu Yahara ◽  
Naoyuki Hasebe
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Multiple System Atrophy ◽  
Dementia With Lewy Bodies ◽  
Meta Analysis ◽  
Neuron Specific Enolase ◽  
Lewy Bodies ◽  
Meta Regression

Abstract Background: To investigate the usefulness of cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels as a candidate biomarker of neurodegeneration in Alzheimer’s disease (AD), Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).Methods: We performed a systematic search of PubMed, the Cochrane Library, SCOPUS, and Google Scholar to find studies that investigated the CSF levels of NSE in AD, PD, DLB, and/or MSA. For each disease, we pooled all available data and performed a meta-analysis, and meta-regression analyses of age and sex were conducted when significant in the main analysis.Results: Twenty studies were included (13 for AD, 8 for PD/PDD/DLB, and 4 for MSA). Significantly elevated CSF NSE levels were detected in AD (Hedges’ g = 0.822, 95% confidence interval [95%CI]: 0.332 to 1.311, p = 0.0010), but the data exhibited high heterogeneity (I2 = 88.43%, p<0.001). The meta-regression analysis of AD showed that age (p<0.001), but not sex, had a significant effect on NSE. A meta-analysis of all the pooled data for PD/PDD/DLB did not show any significant changes in the CSF NSE level, but a sub-group analysis of PDD/DLB revealed significantly elevated CSF NSE levels (Hedges’ g = 0.507, 95%CI: 0.020 to 0.993, p = 0.0412). No significant changes in CSF NSE levels were detected in MSA.Conclusions: This study provided evidence about the usefulness of CSF NSE levels as a biomarker in AD and PDD/DLB, and age was found to affect the CSF NSE levels of AD patients.

scholarly journals Total alpha-synuclein assay in cerebrospinal fluid is of interest in the differential diagnosis between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage

2020 ◽  
Author(s):  
Olivier BOUSIGES ◽  
Nathalie Philippi ◽  
Thomas Lavaux ◽  
Armand Perret-Liaudet ◽  
Ingolf Lachmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Differential Diagnosis ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Prodromal Stage ◽  
Significant Difference

Abstract Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d) and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer’s biomarkers (t-Tau, P-Tau, Aβ42 and Aβ40) were also measured.Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB. Furthermore, alpha-synuclein levels were elevated not only in AD patients with a typical “Alzheimer” profile (i.e. 2 or 3 pathological biomarkers) but also in AD patients with an atypical “Alzheimer” profile (i.e. one or no pathological biomarkers).Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. Moreover, alpha-synuclein assay appears to be of particular interest in the differential diagnosis of AD in cases where the Alzheimer biomarkers do not have a typical profile of the disease, i.e. when there is only one or no pathological biomarkers.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identifier: NCT01876459)

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