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.

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 REM sleep behavior in Parkinson disease: Frequent, particularly with higher age

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243454
Author(s):  
Heide Baumann-Vogel ◽  
Hyun Hor ◽  
Rositsa Poryazova ◽  
Philipp Valko ◽  
Esther Werth ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Parkinson Disease ◽  
Progressive Supranuclear Palsy ◽  
Rem Sleep ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Corticobasal Degeneration ◽  
Sleep Behavior

This retrospective single-center polysomnography-based study was designed to assess the frequency of REM sleep behavior disorder (RBD) in consecutive patients with Parkinsonism, including Parkinson disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. We observed RBD in 77% of 540 Parkinson patients, with rising frequency at higher age and regardless of sex, in >89% of 89 patients with dementia with Lewy bodies or multiple system atrophy, and in <15% of 42 patients with progressive supranuclear palsy or corticobasal degeneration. Thus, the prevalence of RBD in sporadic Parkinson disease might be higher than previously assumed, particularly in elderly patients.

Alpha-Synucleinopathies

2019 ◽  
pp. 274-297
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.

Diagnosis and Therapy for Lewy Body Dementia

2017 ◽  
Author(s):  
Bela R. Turk ◽  
Ali Fatemi
Keyword(s):  
Adverse Reaction ◽  
Parkinson Disease ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
The Elderly ◽  
Alpha Synuclein ◽  
Accurate Diagnosis ◽  
Degenerative Diseases ◽  
Severe Adverse Reaction

Almost undistinguished some 30 years ago, dementia with Lewy bodies is now shown to be the second most common neurodegenerative cause of dementia in the elderly. A host of neuroinflammatory mechanisms are attributed to Lewy bodies and their component alpha synuclein, a common pathology shared by Parkinson disease and Parkinson disease with dementia. Accurate diagnosis of patients is essential, as they show unique impairment patterns, which differ from other forms of dementia and show severe adverse reaction to neuroleptic medication, a common treatment in other degenerative diseases.

scholarly journals Correlation of Microglial Activation with White Matter Changes in Dementia with Lewy Bodies

2019 ◽  
Author(s):  
Nicolas Nicastro ◽  
Elijah Mak ◽  
Guy B. Williams ◽  
Ajenthan Surendranathan ◽  
William Richard Bevan-Jones ◽  
...  
Keyword(s):  
White Matter ◽  
Dementia With Lewy Bodies ◽  
Microglial Activation ◽  
Diffusion Tensor ◽  
Lewy Bodies ◽  
Structural Mri ◽  
Alpha Synuclein ◽  
Variable Degree ◽  
Degenerative Dementia ◽  
Alzheimer's Disase

ABSTRACTDementia with Lewy bodies (DLB) is the second-leading degenerative dementia after Alzheimer’s disase. Neuropathologically, it is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer pathology. Neuroinflammation is increasingly recognized as a significant contributor of degeneration.Objectiveto examine the relationship between microglial activation as measured with [11C]-PK11195 brain PET and MR diffusion tensor imaging (DTI) in DLB.Methodsnineteen clinically probable DLB and 20 similarly aged controls underwent structural MRI with T1-weighted and 3T DTI sequences. Eighteen DLB subjects also underwent [11C]-PK11195 PET imaging. Tract-Based Spatial Statistics (TBSS) were performed to compare DTI parameters in DLB relative to controls and identify associations of [11C]-PK11195 binding with white matter integrity.ResultsTBSS showed widespread changes in all DTI parameters in the DLB group compared to controls (Threshold Free Cluster Enhancement (TFCE) p < 0.05). [11C]-PK11195 binding in parietal cortices also correlated with widespread lower mean and radial diffusivity (TFCE p < 0.05).ConclusionOur study demonstrates that higher PK11195 binding is associated with a relative preservation of white matter, positioning neuroinflammation as a potential early marker in the DLB pathogenic cascade.

scholarly journals Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential

2021 ◽  
Author(s):  
Nelson Ferreira ◽  
Hjalte Gram ◽  
Zachary A. Sorrentino ◽  
Emil Gregersen ◽  
Sissel Ida Schmidt ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Protein Misfolding ◽  
Resonance Energy Transfer ◽  
Lewy Bodies ◽  
Resonance Energy ◽  
Alpha Synuclein ◽  
Striatal Neurons ◽  
End Stage ◽  
Intracellular Aggregates

AbstractPathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a “tropism” for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy.

scholarly journals Levodopa-induced dyskinesia in dementia with Lewy bodies and Parkinson disease with dementia

2019 ◽  
Vol 10 (2) ◽  
pp. 156-161
Author(s):  
Pierpaolo Turcano ◽  
Cole D. Stang ◽  
James H. Bower ◽  
J. Eric Ahlskog ◽  
Bradley F. Boeve ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Population Based ◽  
Olmsted County ◽  
Levodopa Dosage ◽  
Younger Age ◽  
Increased Risk ◽  
Incident Cohort ◽  
Median Interval

ObjectiveTo investigate the frequency of levodopa-induced dyskinesia in dementia with Lewy bodies (DLBs) and Parkinson disease with dementia (PDD) and compare these frequencies with patients with incident Parkinson disease (PD) through a population-based cohort study.MethodsWe identified all patients with DLB, PDD, and PD without dementia in a 1991–2010 population-based parkinsonism-incident cohort, in Olmsted County, Minnesota. We abstracted information about levodopa-induced dyskinesia. We compared patients with DLB and PDD with dyskinesia with patients with PD from the same cohort.ResultsLevodopa use and dyskinesia data were available for 141/143 (98.6%) patients with a diagnosis of either DLB or PDD; 87 (61.7%), treated with levodopa. Dyskinesia was documented in 12.6% (8 DLB and 3 PDD) of levodopa-treated patients. Among these patients, median parkinsonism diagnosis age was 74 years (range: 64–80 years); 63.6%, male. The median interval from levodopa initiation to dyskinesia onset was 2 years (range: 3 months–4 years); the median daily levodopa dosage was 600 mg (range: 50–1,600 mg). Dyskinesia severity led to levodopa adjustments in 5 patients, and all improved. Patients with dyskinesia were diagnosed with parkinsonism at a significantly younger age compared with patients without dyskinesia (p < 0.001). Levodopa dosage was unrelated to increased risk of dyskinesias among DLB and PDD. In contrast, 30.1% of levodopa-treated patients with PD developed dyskinesia. In age-, sex-, and levodopa dosage–adjusted models, Patients with DLB and PDD each had lower odds of developing dyskinesia than patients with PD (odds ratio = 0.42, 95% CI 0.21–0.88; p = 0.02).ConclusionsThe dyskinesia risk for levodopa-treated patients with DLB or PDD was substantially less than for levodopa-treated patients with PD.

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