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The Lancet. Neurology Feb 2020Dementia with Lewy bodies and Parkinson's disease dementia, jointly known as Lewy body dementia, are common neurodegenerative conditions. Patients with Lewy body... (Review)
Review
Dementia with Lewy bodies and Parkinson's disease dementia, jointly known as Lewy body dementia, are common neurodegenerative conditions. Patients with Lewy body dementia present with a wide range of cognitive, neuropsychiatric, sleep, motor, and autonomic symptoms. Presentation varies between patients and can vary over time within an individual. Treatments can address one symptom but worsen another, which makes disease management difficult. Symptoms are often managed in isolation and by different specialists, which makes high-quality care difficult to accomplish. Clinical trials and meta-analyses now provide an evidence base for the treatment of cognitive, neuropsychiatric, and motor symptoms in patients with Lewy body dementia. Furthermore, consensus opinion from experts supports the application of treatments for related conditions, such as Parkinson's disease, for the management of common symptoms (eg, autonomic dysfunction) in patients with Lewy body dementia. However, evidence gaps remain and future clinical trials need to focus on the treatment of symptoms specific to patients with Lewy body dementia.
Topics: Dementia; Humans; Lewy Bodies; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease
PubMed: 31519472
DOI: 10.1016/S1474-4422(19)30153-X -
Disease-a-month : DM May 2023Lewy Body Dementia is the second most frequent neurodegenerative illness proven to cause dementia, after Alzheimer's disease (AD). It is believed to be vastly... (Review)
Review
Lewy Body Dementia is the second most frequent neurodegenerative illness proven to cause dementia, after Alzheimer's disease (AD). It is believed to be vastly underdiagnosed, as there is a significant disparity between the number of cases diagnosed clinically and those diagnosed via neuropathology at the time of postmortem autopsy. Strikingly, many of the pharmacologic treatments used to treat behavioral and cognitive symptoms in other forms of dementia exacerbate the symptoms of DLB. Therefore, it is critical to accurately diagnose DLB as these patients require a specific treatment approach. This article focuses on its pathophysiology, risk factors, differentials, and its diverse treatment modalities. In this study, an English language literature search was conducted on Medline, Cochrane, Embase, and Google Scholar till April 2022. The following search strings and Medical Subject Headings (MeSH) terms were used: "Lewy Body Dementia," "Dementia with Lewy bodies," and "Parkinson's Disease Dementia." We explored the literature on Lewy Body Dementia for its epidemiology, pathophysiology, the role of various genes and how they bring about the disease, biomarkers, its differential diagnoses and treatment options.
Topics: Humans; Lewy Body Disease; Dementia; Parkinson Disease; Alzheimer Disease; Diagnosis, Differential
PubMed: 35690493
DOI: 10.1016/j.disamonth.2022.101441 -
Molecular Neurodegeneration Dec 2021Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of... (Review)
Review
Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.
Topics: Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies; alpha-Synuclein
PubMed: 34922583
DOI: 10.1186/s13024-021-00501-z -
Neuron Aug 2019Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this...
Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).
Topics: Animals; Axonal Transport; Brain Chemistry; Dopaminergic Neurons; Duodenum; Humans; Injections, Intramuscular; Lewy Bodies; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Neurological; Muscle, Smooth; Nesting Behavior; Parkinsonian Disorders; Phosphorylation; Protein Aggregates; Protein Processing, Post-Translational; Pylorus; Rotarod Performance Test; Vagotomy; Vagus Nerve; alpha-Synuclein
PubMed: 31255487
DOI: 10.1016/j.neuron.2019.05.035 -
Neurobiology of Disease Jan 2023Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and... (Review)
Review
Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and subsequent aggregation of alpha-synuclein (α-syn) that accumulates in cytoplasmic inclusions bodies in the cells of affected brain regions. Since the seminal report of likely-aggregated α-syn presence within the Lewy bodies by Spillantini et al. in 1997, the keyword "synuclein aggregation" has appeared in over 6000 papers (Source: PubMed October 2022). Studying, observing, describing, and quantifying α-syn aggregation is therefore of paramount importance, whether it happens in tubo, in vitro, in post-mortem samples, or in vivo. The past few years have witnessed tremendous progress in understanding aggregation mechanisms and identifying various polymorphs. In this context of growing complexity, it is of utmost importance to understand what tools we possess, what exact information they provide, and in what context they may be applied. Nonetheless, it is also crucial to rationalize the relevance of the information and the limitations of these methods for gauging the final result. In this review, we present the main techniques that have shaped the current views about α-syn structure and dynamics, with particular emphasis on the recent breakthroughs that may change our understanding of synucleinopathies.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Parkinson Disease; Multiple System Atrophy; Lewy Bodies
PubMed: 36527982
DOI: 10.1016/j.nbd.2022.105966 -
International Journal of Geriatric... Oct 2022Lewy body dementia (LBD) refers to both dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Sleep disturbances are common in LBD, and can... (Review)
Review
BACKGROUND
Lewy body dementia (LBD) refers to both dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Sleep disturbances are common in LBD, and can include poor sleep quality, excessive daytime sleepiness (EDS), and rapid eye movement behaviour disorder (RBD). Despite the high clinical prevalence of sleep disturbances in LBD, they are under-studied relative to other dementias. The aim of the present systematic review was to examine the nature of sleep disturbances in LBD, summarise the effect of treatment studies upon sleep, and highlight specific and necessary directions for future research.
METHODS
Published studies in English were located by searching PubMED and PSYCArticles databases (until 10 June 2022). The search protocol was pre-registered in PROSPERO (CRD42021293490) and performed in accordance with PRISMA guidelines.
RESULTS
Following full-text review, a final total of 70 articles were included. These included 20 studies focussing on subjective sleep, 14 on RBD, 8 on EDS, 7 on objective sleep, and 1 on circadian rhythms. The majority of the 18 treatment studies used pharmacological interventions (n = 12), had an open-label design (n = 8), and were of low-to-moderate quality. Most studies (n = 55) included only patients with DLB. Due to the heterogeneity of the studies, we reported a narrative synthesis without meta-analysis.
CONCLUSIONS
At least one form of sleep disturbance may be present in as many as 90% of people with LBD. Subjectively poor sleep quality, excessive daytime sleepiness, and RBD are more common and severe in LBD relative to other dementias.
Topics: Alzheimer Disease; Disorders of Excessive Somnolence; Humans; Lewy Body Disease; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders
PubMed: 36168299
DOI: 10.1002/gps.5814 -
Progress in Neurobiology Jul 2022Aggregation of specific proteins are histopathological hallmarks of several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles... (Review)
Review
Aggregation of specific proteins are histopathological hallmarks of several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions of ratiometric 3 repeat (3 R) and 4 repeat (4 R) tau isoforms in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) and dystrophic Lewy neurites (LNs) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, mixed brain protein pathologies have been frequently observed in many of these diseases and in normal aging brains, among which Aβ/tau and tau/α-Syn crosstalks have received increased attention. Interestingly, studies have also shown synergistic interplay among Aβ, tau, and α-Syn in several neurodegenerative diseases, suggesting a protein triumvirate. In this review, we summarize the emerging evidence of Aβ, tau, and α-Syn aggregation in pathophysiology, and their overlap in a spectrum of neurodegenerative diseases including AD, PSP, PiD, CBD, PD and DLB. We discuss the prognostic advancements made in biomarker and imaging techniques in the triumvirate proteinopathies. Finally, we discuss the combined therapeutic modality involving biomarkers and imaging techniques for future combinatorial immunotherapeutic targeting more than one protein aggregates. We hope that such a multitarget therapeutic approach will have synergistic or additive effects to manage neurodegenerative diseases with two or more protein pathologies that might uncover a promising strategy for personalized combination therapies. Managing neurodegenerative diseases by optimizing the diagnostic criteria and the correct combination of immunotherapies will be a key factor in the success of future treatment.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease; Plaque, Amyloid; Protein Aggregation, Pathological; alpha-Synuclein; tau Proteins
PubMed: 35447272
DOI: 10.1016/j.pneurobio.2022.102270 -
Annals of Clinical and Translational... Jun 2023LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence... (Review)
Review
LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence of Lewy bodies and marked Alzheimer's disease pathology. The mechanisms underlying LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested, among others. As novel therapies targeting LRRK2 are under development, understanding the role and function of LRRK2 in PD is becoming increasingly important. Here, we outline the epidemiological, pathophysiological, and clinical features of LRRK2-PD, and discuss the arising therapeutic approaches targeting LRRK2 and possible future directions for research.
Topics: Humans; Parkinson Disease; Lewy Bodies; Alzheimer Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
PubMed: 37021623
DOI: 10.1002/acn3.51776 -
Biomolecules Oct 2021Parkinson's Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic... (Review)
Review
Parkinson's Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.
Topics: Biomarkers; Dopaminergic Neurons; Humans; Lewy Bodies; Mitochondria; Neuroinflammatory Diseases; Parkinson Disease; Protein Aggregates; Proteostasis Deficiencies; Reactive Oxygen Species; alpha-Synuclein
PubMed: 34680141
DOI: 10.3390/biom11101508 -
Journal of Parkinson's Disease 2023The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from... (Review)
Review
The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from the earliest stages of pathology to manifest disease. Despite progress, a biologically based PD staging system does not exist. Such staging would be a useful framework within which to model the disease, develop and validate biomarkers, guide therapeutic development, and inform clinical trials design. We propose that the presence of aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, and clinical signs and symptoms identifies a group of individuals that have Lewy body pathology, which in early stages manifests with what is now referred to as prodromal non-motor features and later stages with the manifestations of PD and related Lewy body diseases as defined by clinical diagnostic criteria. Based on the state of the field, we herein propose a definition and staging of PD based on biology. We present the biologic basis for such a staging system and review key assumptions and evidence that support the proposed approach. We identify gaps in knowledge and delineate crucial research priorities that will inform the ultimate integrated biologic staging system for PD.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Lewy Body Disease; Lewy Bodies; Nerve Degeneration; Biomarkers; Prodromal Symptoms; Biological Products
PubMed: 37066922
DOI: 10.3233/JPD-225111