Lewy Body Dementias: Controversies and Drug Development.
Ontology highlight
ABSTRACT:
SUBMITTER: Chiu SY
PROVIDER: S-EPMC9130410 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
Publications
Lewy Body Dementias: Controversies and Drug Development.
Chiu Shannon Y SY Bowers Dawn D Armstrong Melissa J MJ
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20211202 1
Lewy body dementia (LBD) is one of the most common neurodegenerative dementias. Clinical trials for symptomatic and disease-modifying therapies in LBD remain a national research priority, but there are many challenges in both past and active drug developments in LBD. This review highlights the controversies in picking the appropriate populations, interventions, target selections, and outcome measures, which are all critical components of clinical trial implementation in LBD. The heterogeneity of ...[more]
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Project description:ObjectiveLewy body dementias (LBD) include both dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), and the differentiation of LBD from other neurodegenerative dementias can be difficult. Currently, there are few biomarkers which might assist early diagnosis, map onto LBD symptom severity, and provide metrics of treatment response. Traditionally, biomarkers in LBD have focussed on neuroimaging modalities; however, as biomarkers need to be simple, inexpensive and non-invasive, neurophysiological approaches might also be useful as LBD biomarkers.MethodsIn this review, we searched PubMED and PsycINFO databases in a semi-systematic manner in order to identify potential neurophysiological biomarkers in the LBDs.ResultsWe identified 1491 studies; of these, 37 studies specifically examined neurophysiological biomarkers in LBD patients. We found that there was substantial heterogeneity with respect to methodologies and patient cohorts.ConclusionGenerally, many of the findings have yet to be replicated, although preliminary findings reinforce the potential utility of approaches such as quantitative electroencephalography and motor cortical stimulation paradigms.SignificanceVarious neurophysiological techniques have the potential to be useful biomarkers in the LBDs. We recommend that future studies focus on maximising the diagnostic specificity and sensitivity of the most promising neurophysiological biomarkers.
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Project description:Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on α-synuclein markers.
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Project description:IntroductionDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored.MethodsWe performed a cross-sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals.ResultsDLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants.DiscussionOur study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers.
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Project description:IntroductionWe aimed to identify unique proteomic signatures of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD).MethodsWe conducted a comparative proteomic analysis of 33 post mortem brains from AD, DLB, and PDD individuals without dementia focusing on prefrontal, cingulate, and parietal cortices, using weighted gene co-expression network analyses with differential enrichment analysis.ResultsNetwork modules revealed hub proteins common to all dementias. Lewy body dementias differed from AD by reduced levels of the autophagy protein p62 (SQSTM1), whereas DLB was distinguished from both AD and PDD by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) across brain regions. An increase in mitochondrial and synaptic proteins was related to better cognition whereas enrichment in the extracellular matrix, complement system, and autophagy proteins was associated with greater cognitive impairment.DiscussionOur study offers valuable insights into the network-based biomarker characterization of molecular signatures of AD, DLB, and PDD.HighlightsReduced levels of the autophagy protein p62 (SQSTM1) differentiated Lewy body dementias from Alzheimer's disease (AD) across multiple brain regions. Dementia with Lewy bodies (DLB) was distinguished from both AD and Parkinson's disease dementia (PDD) by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) levels across brain regions. Key mitochondrial oxidative phosphorylation proteins (e.g., COX7A2, TOMM40L, NDUFV1), and synaptic proteins (e.g., GABRB3, GABRB2, GLUA3, GLUA4, SNAP47, dynamin1) were more abundant in preserved cognitive states. Extracellular matrix proteins and members of the complement system (decorin, biglycan, C4A, C4B) showed a strong positive correlation with cognitive decline.
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Project description:Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.
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Project description:Lewy body dementias are the second most common cause of neurodegenerative dementia in the elderly after Alzheimer's disease (AD). The two clinical subgroups of Lewy body dementias, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), are differentiated by the chronology of cognitive symptoms relative to parkinsonism. At present, there remains a debate on whether DLB and PDD are separate disease entities, or fall within the same spectrum of Lewy body dementias. In this study, we compared the detergent-soluble proteome via an 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) analysis of pooled lysates from the prefrontal cortex (BA9) of DLB (n = 19) and PDD (n = 21) patients matched a priori for amyloid (total Aβ42) burden, semi-quantitative scores for Lewy bodies and neurofibrillary tangles together with age-matched control (n = 21) subjects. A total of 1914 proteins were confidently identified by iTRAQ (false discovery rate = 0%). None of the proteins showed a significant yet opposite regulation in between DLB and PDD when compared to aged controls in the proteomic data set as well as following immunoblot analysis of the pooled and individual lysates involving all 61 subjects. The postsynaptic protein, synaptopodin (SYNPO) was significantly down-regulated in both DLB and PDD subgroups, suggesting a defective synaptic transmission in the demented patients. In conclusion, the largely similar proteome of DLB and PDD matched for amyloid burden suggests that variations in concomitant AD-related pathology, abnormal post-translational modifications or protein-protein interactions, defective intracellular trafficking or misfolding of proteins could play a part in driving the clinically observed differences between these two subgroups of Lewy body dementias. This further indicates that amyloid-targeting therapeutic strategies may show different efficacies in DLB versus PDD.
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