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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 -
Continuum (Minneapolis, Minn.) Apr 2016This article provides an overview of the clinical features, neuropathologic findings, diagnostic criteria, and management of dementia with Lewy bodies (DLB) and... (Review)
Review
PURPOSE OF REVIEW
This article provides an overview of the clinical features, neuropathologic findings, diagnostic criteria, and management of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), together known as the Lewy body dementias.
RECENT FINDINGS
DLB and PDD are common, clinically similar syndromes that share characteristic neuropathologic changes, including deposition of α-synuclein in Lewy bodies and neurites and loss of tegmental dopamine cell populations and basal forebrain cholinergic populations, often with a variable degree of coexisting Alzheimer pathology. The clinical constellations of DLB and PDD include progressive cognitive impairment associated with parkinsonism, visual hallucinations, and fluctuations of attention and wakefulness. Current clinical diagnostic criteria emphasize these features and also weigh evidence for dopamine cell loss measured with single-photon emission computed tomography (SPECT) imaging and for rapid eye movement (REM) sleep behavior disorder, a risk factor for the synucleinopathies. The timing of dementia relative to parkinsonism is the major clinical distinction between DLB and PDD, with dementia arising in the setting of well-established idiopathic Parkinson disease (after at least 1 year of motor symptoms) denoting PDD, while earlier cognitive impairment relative to parkinsonism denotes DLB. The distinction between these syndromes continues to be an active research question. Treatment for these illnesses remains symptomatic and relies on both pharmacologic and nonpharmacologic strategies.
SUMMARY
DLB and PDD are important and common dementia syndromes that overlap in their clinical features, neuropathology, and management. They are believed to exist on a spectrum of Lewy body disease, and some controversy persists in their differentiation. Given the need to optimize cognition, extrapyramidal function, and psychiatric health, management can be complex and should be systematic.
Topics: Autonomic Nervous System Diseases; Cognition Disorders; Disease Management; Humans; Lewy Body Disease; Mental Disorders; Parkinson Disease; REM Sleep Behavior Disorder
PubMed: 27042903
DOI: 10.1212/CON.0000000000000309 -
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 -
Journal of Cerebral Blood Flow and... Jan 2016The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease... (Review)
Review
The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer’s Disease prioritized Alzheimer’s disease-related dementias to include: Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and blood–brain barrier permeability responsible for disease etiology and progression will be discussed.
Topics: Blood-Brain Barrier; Cerebrovascular Disorders; Dementia; Humans; Lewy Bodies; Neurodegenerative Diseases; Neurogenic Inflammation; Prevalence; Risk Factors
PubMed: 26174330
DOI: 10.1038/jcbfm.2015.164 -
Brain Research Aug 2018Parkinson's disease (PD) is a debilitating neurodegenerative condition associated with tremor, rigidity, dementia, and gastrointestinal symptoms such as constipation,... (Review)
Review
Parkinson's disease (PD) is a debilitating neurodegenerative condition associated with tremor, rigidity, dementia, and gastrointestinal symptoms such as constipation, nausea and vomiting. The pathological hallmarks of PD are Lewy bodies and neurites in the brain and peripheral nerves. The major constituent of Lewy bodies is the neuronal protein α-synuclein. Misfolding of α-synuclein confers prion-like properties enabling its spread from cell to cell. Misfolded α-synuclein also serves as a template and induces misfolding of endogenous α-synuclein in recipient cells leading to the formation of oligomers that progress to fibrils and eventually Lewy bodies. Accumulating evidence suggests that PD may arise in the gut. Clinically, gastrointestinal symptoms often appear in patients before other neurological signs and aggregates of α-synuclein have been found in enteric nerves of PD patients. Importantly, patients undergoing vagotomy have a reduced risk of developing PD. Experimentally, abnormal forms of α-synuclein appear in enteric nerves before they appear in the brain and injection of abnormal α-synuclein into the wall of the intestine spreads to the vagus nerve. Ingested toxins and alterations in gut microbiota can induce α-synuclein aggregation and PD, however, it is not known how PD starts. Recently, it has been shown that sensory cells of the gut known as enteroendocrine cells (EECs) contain α-synuclein and synapse with enteric nerves, thus providing a connection from the gut to the brain. It is possible that abnormal α-synuclein first develops in EECs and spreads to the nervous system.
Topics: Animals; Enteroendocrine Cells; Gastrointestinal Tract; Humans; Lewy Bodies; Neurons; Parkinson Disease; Prions; Proteostasis Deficiencies; alpha-Synuclein
PubMed: 29360467
DOI: 10.1016/j.brainres.2018.01.010 -
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 -
Nature Reviews. Neuroscience Jan 2017Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical... (Review)
Review
Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.
Topics: Animals; Brain; Cell Death; Humans; Lewy Bodies; Neurons; Parkinson Disease; alpha-Synuclein
PubMed: 28104909
DOI: 10.1038/nrn.2016.178 -
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 -
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