scholarly journals An analytical solution simulating growth of Lewy bodies

2021 ◽  
Author(s):  
Ivan A Kuznetsov ◽  
Andrey V Kuznetsov

This paper reports a minimal model simulating the growth of a Lewy body (LB). The LB is assumed to consist of a central spherical core, which is composed of membrane fragments and various dysfunctional intracellular organelles, and a halo, which is composed of alpha-synuclein fibrils. Membrane fragments and alpha-synuclein monomers are assumed to be produced in the soma at constant rates. The growth of the core and the halo are simulated by the Finke-Watzky model. Analytical solutions describing the growth of the core and the halo are obtained.

Author(s):  
James E. Galvin ◽  
Jose Tomas Bras

Lewy body dementia (LBD) is the second most common form of neurocognitive disorder after Alzheimer’s disease and covers two related diagnoses: Dementia with Lewy Bodies and Parkinson’s Disease Dementia. Despite being a common disorder, diagnosis outside expert academic centers remains a significant challenge. The core pathological feature of LBD is the cortical Lewy body; however, many cases will have coexistent Alzheimer disease pathology. Genetic risk factors for LBD include mutations in genes for alpha-synuclein (SNCA) and galactocerbrosidase (GBA). Dopamine transporter imaging remains the most sensitive but platforms for measuring alpha-synuclein are being developed. Current therapies focus on symptomatic relief but experimental cell and animal models are providing new insights for the development of disease-modifying therapeutics.


2021 ◽  
Vol 13 ◽  
Author(s):  
Nelson de Oliveira Manzanza ◽  
Lucia Sedlackova ◽  
Raj N. Kalaria

Lewy Body Disorders (LBDs) lie within the spectrum of age-related neurodegenerative diseases now frequently categorized as the synucleinopathies. LBDs are considered to be among the second most common form of neurodegenerative dementias after Alzheimer's disease. They are progressive conditions with variable clinical symptoms embodied within specific cognitive and behavioral disorders. There are currently no effective treatments for LBDs. LBDs are histopathologically characterized by the presence of abnormal neuronal inclusions commonly known as Lewy Bodies (LBs) and extracellular Lewy Neurites (LNs). The inclusions predominantly comprise aggregates of alpha-synuclein (aSyn). It has been proposed that post-translational modifications (PTMs) such as aSyn phosphorylation, ubiquitination SUMOylation, Nitration, o-GlcNacylation, and Truncation play important roles in the formation of toxic forms of the protein, which consequently facilitates the formation of these inclusions. This review focuses on the role of different PTMs in aSyn in the pathogenesis of LBDs. We highlight how these PTMs interact with aSyn to promote misfolding and aggregation and interplay with cell membranes leading to the potential functional and pathogenic consequences detected so far, and their involvement in the development of LBDs.


2021 ◽  
Author(s):  
Rosaleena Mohanty ◽  
Daniel Ferreira ◽  
Simon Frerich ◽  
J-Sebastian Muehlboeck ◽  
Michel Grothe ◽  
...  

AbstractObjectivesTo investigate whether antemortem atrophy-based subtypes of Alzheimer’s disease (AD) may be differentially susceptible to individual or concomitance of AD and non-AD (co)-pathologies, assessed neuropathologically at postmortem.MethodsWe selected 31 individuals from the AD neuroimaging initiative with: an antemortem magnetic resonance imaging scan evaluating brain atrophy available within two years before death; an antemortem diagnosis of AD dementia or prodromal AD; and postmortem neuropathological confirmation of AD. Antemortem atrophy-based subtypes was modeled as a continuous phenomenon in terms of two recently proposed dimensions: typicality (ranging from limbic-predominant AD to hippocampal-sparing AD subtypes) and severity (ranging from typical AD to minimal atrophy AD subtypes). Postmortem neuropathological evaluation included global and regional outcomes: AD hallmark pathologies of amyloid-beta and tau; non-AD co-pathologies of alpha-synuclein Lewy body and TDP-43; and the overall concomitance across these four (co)-pathologies. Partial correlation and linear regression models were used to assess the association between antemortem atrophy-based subtypes and postmortem neuropathological outcomes.ResultsWe observed significant global and regional associations between antemortem typicality and postmortem (co)-pathologies including tau, alpha-synuclein Lewy bodies and TDP-43. Antemortem typicality demonstrated stronger regional associations with concomitance of multiple postmortem (co)-pathologies in comparison to antemortem severity. Our findings suggest the following susceptibilities of atrophy-based subtypes: limbic-predominant AD towards higher burden of tau and TDP-43 pathologies while hippocampal-sparing AD towards lower burdens; limbic-predominant AD and typical AD towards higher burden of alpha-synuclein Lewy body pathology while hippocampal-sparing AD and minimal-atrophy AD towards lower burdens.DiscussionThrough a direct antemortem-to-postmortem validation, our study highlights the importance of understanding heterogeneity in AD in relation to concomitance of AD and non-AD pathologies. Our findings provide a deeper understanding of both global and regional vulnerabilities of the biological subtypes of AD brain towards (co)-pathologies. Relative involvement of both AD hallmark and non-AD (co)-pathologies will enhance prevailing knowledge of biological heterogeneity in AD and could thus, contribute towards tracking disease progression and designing clinical trials in the future.


2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Kathrin Brockmann ◽  
Corinne Quadalti ◽  
Stefanie Lerche ◽  
Marcello Rossi ◽  
Isabel Wurster ◽  
...  

AbstractThe clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.


2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Geidy E Serrano ◽  
David Shprecher ◽  
Michael Callan ◽  
Brett Cutler ◽  
Michael Glass ◽  
...  

Abstract Comorbid Lewy body pathology is very common in Alzheimer’s disease and may confound clinical trial design, yet there is no in vivo test to identify patients with this. Tissue (and/or radioligand imaging) studies have shown cardiac sympathetic denervation in Parkinson’s disease and dementia with Lewy bodies, but this has not been explored in Alzheimer’s subjects with Lewy bodies not meeting dementia with Lewy bodies clinicopathological criteria. To determine if Alzheimer’s disease with Lewy bodies subjects show sympathetic cardiac denervation, we analysed epicardial and myocardial tissue from autopsy-confirmed cases using tyrosine hydroxylase and neurofilament immunostaining. Comparison of tyrosine hydroxylase fibre density in 19 subjects with Alzheimer’s disease/dementia with Lewy bodies, 20 Alzheimer’s disease with Lewy bodies, 12 Alzheimer’s disease subjects without Lewy body disease, 19 Parkinson’s disease, 30 incidental Lewy body disease and 22 cognitively normal without Alzheimer’s disease or Lewy body disease indicated a significant group difference (P < 0.01; Kruskal–Wallis analysis of variance) and subsequent pair-wise Mann–Whitney U tests showed that Parkinson’s disease (P < 0.05) and Alzheimer’s disease/dementia with Lewy bodies (P < 0.01) subjects, but not Alzheimer’s disease with Lewy bodies subjects, had significantly reduced tyrosine hydroxylase fibre density as compared with cognitively normal. Both Parkinson’s disease and Alzheimer’s disease/dementia with Lewy bodies subjects also showed significant epicardial losses of neurofilament protein-immunoreactive nerve fibre densities within the fibre bundles as compared with cognitively normal subjects (P < 0.01) and both groups showed high pathologic alpha-synuclein densities (P < 0.0001). Cardiac alpha-synuclein densities correlated significantly with brain alpha-synuclein (P < 0.001), while cardiac tyrosine hydroxylase and neurofilament immunoreactive nerve fibre densities were negatively correlated with the densities of both brain and cardiac alpha-synuclein, as well as Unified Parkinson’s Disease Rating Scale scores (P < 0.05). The clear separation of Alzheimer’s disease/dementia with Lewy bodies subjects from Alzheimer’s disease and cognitively normal, based on cardiac tyrosine hydroxylase fibre density, is the first report of a statistically significant difference between these groups. Our data do not show significant sympathetic cardiac denervation in Alzheimer’s disease with Lewy bodies, but strongly confirm that cardiac nuclear imaging with a noradrenergic radioligand is worthy of further study as a potential means to separate Alzheimer’s disease from Alzheimer’s disease/dementia with Lewy bodies during life.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
André D. G. Leitão ◽  
Paulina Rudolffi-Soto ◽  
Alexandre Chappard ◽  
Akshay Bhumkar ◽  
Derrick Lau ◽  
...  

AbstractThe aggregation of alpha-synuclein (α-SYN) follows a cascade of oligomeric, prefibrillar and fibrillar forms, culminating in the formation of Lewy Bodies (LB), the pathological hallmarks of Parkinson’s Disease. Although LB contain over 70 proteins, the potential for interactions along the aggregation pathway of α-SYN is unknown. Here we propose a map of interactions of 65 proteins against different species of α-SYN. We measured binding to monomeric α-SYN using AlphaScreen, a sensitive nano-bead luminescence assay for detection of protein interactions. To access oligomeric species, we used the pathological mutants of α-SYN (A30P, G51D and A53T) which form oligomers with distinct properties. Finally, we generated amyloid fibrils from recombinant α-SYN. Binding to oligomers and fibrils was measured by two-color coincidence detection (TCCD) on a single molecule spectroscopy setup. Overall, we demonstrate that LB components are recruited to specific steps in the aggregation of α-SYN, uncovering future targets to modulate aggregation in synucleinopathies.


SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A330-A330
Author(s):  
Rupa Koothirezhi ◽  
Pratibha Anne ◽  
Minh Tam Ho ◽  
Brittany Monceaux ◽  
Cesar Liendo ◽  
...  

Abstract Introduction Dementia with Lewy bodies (DLB) is one of the most common types of degenerative dementia after Alzheimer’s dementia. The core clinical features for diagnosis includes cognitive fluctuations, visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and parkinsonism. Other symptoms include daytime drowsiness, longer daytime naps, prolonged staring spells, and episodes of disorganized speech. REM behavioral disorder (RBD) is commonly associated with DLB, occurring in 85 percent of individuals, often early in the course of the disease. It can precede the clinical diagnosis of DLB by up to 20 years. Report of case(s) A seventy-six-year-old female with a history of well controlled obstructive sleep apnea was diagnosed with REM behavioral disorder in 2012. She had presented with episodes of screaming, attempt to ambulate during sleep, resulting in injury. Her polysomnogram revealed evidence of REM without atonia and a screaming episode during REM. Her RBD symptoms were controlled with clonazepam and melatonin with less frequency of the RBD episodes. The patient gradually started noticing memory issues and by January 2020 she was diagnosed with dementia and was initiated on Aricept. Within 7 months of diagnosis of dementia, she started reporting vivid hallucinations that were not threatening or violent compared to her violent content of RBD. Physical exam revealed impaired cognitive function and mild intermittent resting tremor of the right hand. The neurological exam was normal including normal tone, strength, and gait. She also reported repeated falls and fractures. The diagnosis of Lewy body dementia was made based on the presence of 2 core clinical features. Conclusion The current management of these conditions is mainly symptomatic. In the evolution of neurodegenerative disorder, RBD precedes other conditions like LBD, parkinsonism, etc. Research suggests that alpha-synuclein neurodegeneration is the common pathology behind these conditions. The understanding that RBD presents at the beginning of the evolution, provides us with a unique opportunity for preemptive treatment to prevent further degeneration in turn preventing the debilitation consequence like dementia, parkinsonism, neuroleptic sensitivity, and dysautonomia. Further research is needed for developing these early interventional strategies. Support (if any) NOne


Author(s):  
Marzena Kurzawa-Akanbi ◽  
Seshu Tammireddy ◽  
Ivo Fabrik ◽  
Lina Gliaudelytė ◽  
Mary K. Doherty ◽  
...  

AbstractMutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)—collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein–ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.


2021 ◽  
Vol 22 (11) ◽  
pp. 5999
Author(s):  
David S. Goldstein

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.


Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 759
Author(s):  
Jung-Youn Han ◽  
Chaewon Shin ◽  
Young Pyo Choi

In synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy body (DLB), pathological alpha-synuclein (α-syn) aggregates are found in the gastrointestinal (GI) tract as well as in the brain. In this study, using real-time quaking-induced conversion (RT-QuIC), we investigated the presence of α-syn seeding activity in the brain and colon tissue of G2-3 transgenic mice expressing human A53T α-syn. Here we show that pathological α-syn aggregates with seeding activity were present in the colon of G2-3 mice as early as 3 months old, which is in the presymptomatic stage prior to the observation of any neurological abnormalities. In contrast, α-syn seeding activity was not detectable in 3 month-old mouse brains and only identified at 6 months of age in one of three mice. In the symptomatic stage of 12 months of age, RT-QuIC seeding activity was consistently detectable in both the brain and colon of G2-3 mice. Our results indicate that the RT-QuIC assay can presymptomatically detect pathological α-syn aggregates in the colon of G2-3 mice several months prior to their detection in brain tissue.


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