scholarly journals Bridging Molecular Genetics and Biomarkers in Lewy Body and Related Disorders

2011 ◽  
Vol 2011 ◽  
pp. 1-18 ◽  
Author(s):  
Gilbert J. Ho ◽  
Willie Liang ◽  
Masaaki Waragai ◽  
Kazunari Sekiyama ◽  
Eliezer Masliah ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Biological Fluids ◽  
Lewy Bodies ◽  
Underlying Disease ◽  
Genetic Alterations ◽  
Diagnostic Tools ◽  
Common Disease ◽  
Disease Mechanisms

Recent advances have been made in defining the genetic and molecular basis of dementia with Lewy bodies (DLBs) and related neurodegenerative disorders such as Parkinson's disease (PD) and Parkinson's disease dementia (PDD) which comprise the spectrum of “Lewy body disorders” (LBDs). The genetic alterations and underlying disease mechanisms in the LBD overlap substantially, suggesting common disease mechanisms. As with the other neurodegenerative dementias, early diagnosis in LBD or even identification prior to symptom onset is key to developing effective therapeutic strategies, but this is dependent upon the development of robust, specific, and sensitive biomarkers as diagnostic tools and therapeutic endpoints. Recently identified mutations in the synucleins and other relevant genes in PD and DLB as well as related biomolecular pathways suggest candidate markers from biological fluids and imaging modalities that reflect the underlying disease mechanisms. In this context, several promising biomarkers for the LBD have already been identified and examined, while other intriguing possible candidates have recently emerged. Challenges remain in defining their correlation with pathological processes and their ability to detect DLB and related disorders, and perhaps a combined array of biomarkers may be needed to distinguish various LBDs.

scholarly journals Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

2021 ◽  
Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy M. Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Subsequent Development ◽  
Lewy Body Dementia ◽  
Anterior Cingulate ◽  
Lewy Body Diseases

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

scholarly journals Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

2021 ◽  
Author(s):  
Maarten C Hardenberg ◽  
Tessa Sinnige ◽  
Sam Casford ◽  
Samuel Dada ◽  
Chetan Poudel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Self Assembly ◽  
Lewy Body ◽  
Amyloid Fibrils ◽  
Liquid Droplet ◽  
Large Body ◽  
Lewy Bodies ◽  
Cellular Components

Abstract Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson’s disease. A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here we show, both in vitro and in a Caenorhabditis elegans model of Parkinson’s disease, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.

scholarly journals Motor and Nonmotor Symptoms of Parkinson’s Disease: Antagonistic Pleiotropy Phenomena Derived from α-Synuclein Evolvability?

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiki Takamatsu ◽  
Masayo Fujita ◽  
Gilbert J. Ho ◽  
Ryoko Wada ◽  
Shuei Sugama ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Gastrointestinal Symptoms ◽  
Lewy Bodies ◽  
Antagonistic Pleiotropy ◽  
Nonmotor Symptoms ◽  
Novel Therapy ◽  
Wide Range ◽  
Lewy Body Diseases

Lewy body diseases, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α-synuclein (αS) and amyloid-β (Aβ) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.

scholarly journals It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra

2021 ◽  
Vol 15 ◽  
Author(s):  
Noritaka Wakasugi ◽  
Takashi Hanakawa
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Continuous Spectrum ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Lewy Body Disease ◽  
Common Mechanism ◽  
Protein Accumulation ◽  
The Brain

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.

scholarly journals Insular cortex sub-region-dependent distribution pattern of α-synuclein immunoreactivity in Parkinson’s disease and dementia with Lewy bodies

2017 ◽  
Author(s):  
Yasmine Y. Fathy ◽  
Frank Jan de Jong ◽  
Anne-Marie van Dam ◽  
Annemieke J.M. Rozemuller ◽  
Wilma D.J. van de Berg
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Distribution Pattern ◽  
Lewy Body ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Insular Cortex ◽  
Disease Stage ◽  
Incidental Lewy Body Disease ◽  
Lewy Body Diseases

AbstractThe insular cortex is a heterogeneous and widely connected brain region. It plays a role in autonomic, cognitive, emotional and somatosensory functions. Its complex and unique cytoarchitecture includes a periallocortical agranular, pro-isocortical dysgranular, and isocortical granular sub-regions. In Parkinson’s disease (PD), the insula shows α-synuclein inclusions in advanced stages of the disease and its atrophy correlates with cognitive deficits. However, little is known regarding its regional neuropathological characteristics and vulnerability in Lewy body diseases. The aim of this study is to assess the distribution pattern of α-synuclein pathology in the insular sub-regions and the selective vulnerability of its different cell types in PD and dementia with Lewy bodies (DLB). Human post-mortem insular tissues from 10 donors with incidental Lewy body disease (iLBD), PD, DLB, and age-matched controls were immunostained for α-synuclein and glial fibrillary acid protein (GFAP). Results showed that a decreasing gradient of α-synuclein pathology was present from agranular to granular sub-regions in iLBD, PD and PD with dementia (PDD) donors. The agranular insula was heavily inflicted, revealing various α-synuclein immunoreactive morphological structures, predominantly Lewy neurites (LNs), and astroglial synucleinopathy. While dysgranular and granular sub-regions showed a decreasing gradient of inclusions and more Lewy bodies (LBs) in deeper layers. In DLB, this gradient was less pronounced and severe pathology was observed in the granular insula compared to PDD and regardless of disease stage. Protoplasmic astrocytes showed α-synuclein inclusions and severe degenerative changes increasing with disease severity. While few von Economo neurons (VENs) in the fronto-insular region revealed inclusions, particularly in PDD patients. Our study reports novel findings on the differential involvement of the insular sub-regions in PD and particular involvement of the agranular sub-region, VENs and astrocytes. Thus, the differential cellular architecture of the insular sub-regions portrays the topographic variation and vulnerability to α-synuclein pathology in Lewy body diseases.

scholarly journals Clinical diagnosis of Lewy body dementia

BJPsych Open ◽  
2020 ◽  
Vol 6 (4) ◽  
Author(s):  
Ajenthan Surendranathan ◽  
Joseph P. M. Kane ◽  
Allison Bentley ◽  
Sally A. H. Barker ◽  
John-Paul Taylor ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Dopamine Transporter ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Final Diagnosis ◽  
Dopamine Transporter Imaging ◽  
The Uk

Background Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series. Aims This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences. Method We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions. Results The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs. Conclusions Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.

scholarly journals Progress in Clinical Neurosciences: Parkinson's Disease with Dementia and Dementia with Lewy Bodies

2004 ◽  
Vol 31 (1) ◽  
pp. 7-21 ◽  
Author(s):  
Richard Camicioli ◽  
Nancy Fisher
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Imaging Findings ◽  
Functional Impact ◽  
Assessment And Treatment ◽  
Parkinson’S Disease With Dementia ◽  
One Year

Dementia occurs in up to 30% of people with Parkinson's disease and is a major cause of disability. Pathologically, Parkinson's dementia, where dementia follows the onset of parkinsonism by at least one year, overlaps with dementia with Lewy bodies. We review the functional impact, definitions, neuropsychology, epidemiology and pathophysiology of Parkinson's dementia, dementia with Lewy bodies and their overlap. Associated psychiatric and imaging findings are also considered. Lastly, current and emerging approaches to assessment and treatment in patients with these Lewy body associated dementias are presented.

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