Materiały źródłowe

• #1 Dementia with Lewy bodies: an update and outlook | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0306-8

  Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated -synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinsons disease (PD). […] The central role of -syn in LBD originated from almost simultaneous findings of mutations in the gene encoding for -syn (SNCA) in familial forms of PD, and of -syn comprising the major protein component of Lewy bodies. […] Increasing recognition of DLB as a distinct and prevalent age-associated neurodegenerative dementia has stimulated increasing numbers of high-quality studies on its aetiology and pathogenesis. Here, we summarise contemporary findings from this rapidly expanding field, focusing on genetics, diagnostic biomarkers and molecular mechanisms.

• #2 Dementia with Lewy bodies – Wikipedia

  https://en.wikipedia.org/wiki/Dementia_with_Lewy_bodies

  Dementia with Lewy bodies (DLB) is characterized by the development of abnormal collections of alpha-synuclein protein within diseased brain neurons, manifesting as Lewy bodies and Lewy neurites. […] The precise mechanisms contributing to DLB are not well understood and are a matter of some controversy. […] The role of alpha-synuclein deposits is unclear, because individuals with no signs of DLB have been found on autopsy to have advanced alpha-synuclein pathology. […] The relationship between Lewy pathology and widespread cell death is contentious. […] It is not known if the pathology spreads between cells or follows another pattern. […] The mechanisms that contribute to cell death, how the disease advances through the brain, and the timing of cognitive decline are all poorly understood.

• #3 Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies – UpToDate

  https://www.uptodate.com/contents/epidemiology-pathology-and-pathogenesis-of-dementia-with-lewy-bodies

  Dementia with Lewy bodies (DLB) is one of the most common causes of dementia after Alzheimer disease (AD) and vascular dementia. […] This topic will describe the epidemiology, neuropathologic findings, and potential pathogenic mechanisms of DLB. […] DLB has been given various names over the years, which in part reflects the uncertainty as to whether it is one of several distinct disease entities with the shared common finding of limbic and cerebral cortical Lewy bodies, or whether it represents one point on a spectrum of Lewy body disease. […] More recently there has been an effort to apply the term „Lewy body disease” as a collective description of the various entities characterized pathologically by Lewy body formation (Parkinson disease [PD], PD dementia [PDD], and DLB), the terms „diffuse Lewy body disease” and „neocortical Lewy body disease” to describe the finding of Lewy bodies in neocortical neurons, and the term „DLB” to describe the clinical syndrome.

• #4 Lewy Body Dementia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482441/

  Lewy Body Dementia (LBD) encompasses two clinical entities: dementia with Lewy bodies and Parkinson disease dementia. It is a progressive degenerative brain disorder characterized by dementia, psychosis, and features of parkinsonism. Symptoms fluctuate with time and vary among different individuals. Diagnosis of LBD requires thorough clinical examination, as many of its features overlap with other dementia disorders. […] It is characterized by the deposition of Lewy bodies in the brain, which are intraneuronal cytoplasmic inclusion bodies with alpha-synuclein and ubiquitin aggregates. […] The etiology of LBD is still unknown; however, genetics, environmental factors, and changes linked to aging may have a role and still require further research. […] Like Alzheimer disease, LBD presents with acetylcholine deficiency, but it is more pronounced in LBD. Decreased levels of acetylcholine in the temporal and parietal cortex result in visual hallucinations (a prominent feature of LBD), while up-regulation of muscarinic M1 receptors in the temporal lobe results in delusions.

• #5 Lewy body dementia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/lewy-body-dementia/symptoms-causes/syc-20352025

  Lewy body dementia is characterized by the buildup of proteins into masses known as Lewy bodies. This protein also is associated with Parkinson’s disease. People who have Lewy bodies in their brains also have the plaques and tangles associated with Alzheimer’s disease. […] Protein deposits called Lewy bodies develop in nerve cells in the brain. The protein deposits affect brain regions involved in thinking, memory and movement. This condition is also known as dementia with Lewy bodies.

• #6 Lewy body – Wikipedia

  https://en.wikipedia.org/wiki/Lewy_body

  Lewy bodies are the inclusion bodies abnormal aggregations of protein that develop inside neurons affected by Parkinson’s disease (PD), the Lewy body dementias (Parkinson’s disease dementia and dementia with Lewy bodies (DLB)), and some other disorders. […] A Lewy body is composed of the protein -synuclein associated with other proteins, such as ubiquitin. […] Alpha-synuclein modulates DNA repair processes, including repair of DNA double-strand breaks (DSBs) by the process of non-homologous end joining. The repair function of alpha-synuclein appears to be greatly reduced in Lewy body bearing neurons, and this reduction may trigger cell death. […] Lewy bodies are believed to represent an aggresome response in the cell. […] Aggregation is believed to occur when there is a high amount of misfolded proteins in the ubiquitin-proteasome pathway, which are then brought to a resulting aggresome so they can be organized into one place. […] Despite their differences, there is evidence that a particular protein family, called 14-3-3, plays a role in the formation of both cortical and classical Lewy bodies. […] In histopathology, cortical Lewy bodies are a distinguishing feature for dementia with Lewy bodies.

• #7 Lewy Body Dementia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482441/

  The key feature of LBD is the presence of alpha-synuclein, a presynaptic protein whose function remains debatable. Other findings include the presence of ubiquitin and neurofilament proteins. […] The pathology of LBD overlaps that of Parkinson disease and Alzheimer disease. Neuronal cytoplasmic inclusion bodies, called Lewy bodies (comprising aggregates of ubiquitin and alpha-synuclein) and found within the brain parenchyma (mainly in the brainstem, limbic system, and cerebral cortex), are characteristic of LBD. […] Genetic mutations, environmental toxins, and the aging process can lead to alpha-synuclein misfolding and its accumulation in Lewy bodies via oxidative stress and mitochondrial dysfunction. […] The location of Lewy bodies determines the clinical presentation. If Lewy bodies develop initially in the brainstem and cerebral cortex, then dementia sets on early, and we call it dementia with Lewy bodies; however, if Lewy bodies develop initially in the brain stem only and extend to the cerebral cortex later, then dementia occurs late in the disease process, and we call it Parkinson disease dementia.

• #8 Pathogenesis of the Lewy body (Chapter 24) – Dementia with Lewy Bodies

  https://www.cambridge.org/core/books/dementia-with-lewy-bodies/pathogenesis-of-the-lewy-body/09B6D4B4276AEF92E6D8AE8882835DC9

  The constitutive fibrils of the Lewy body contain all three neurofilament subunits in an altered form. Our recent in situ hybridization studies of the low molecular weight subunit of the neurofilament suggest that altered neurofilament expression is not implicated in the formation of the Lewy body. […] We propose a speculative model of Lewy body pathogenesis in which neurofilaments are assembled normally and subsequently undergo phosphorylation, proteolysis and crosslinking at a post-translational/post-assembly stage. […] The presence of ubiquitin, ubiquitin-C-terminal hydrolase and ingestin (multicatalytic proteinase or proteasome) in the LB also suggests that proteolysis is implicated in its pathogenesis. Finally, the detergent-insolubility of these fibrils indicates that the NF proteins which form the LB are further altered and probably crosslinked. Taken together, these studies suggest that altered phosphorylation/dephosphorylation and proteolysis of NF are key post-translational events in LB pathogenesis.

• #9 Dementia with Lewy bodies: an update and outlook | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0306-8

  Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated -synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinsons disease (PD). […] The central role of -syn in LBD originated from almost simultaneous findings of mutations in the gene encoding for -syn (SNCA) in familial forms of PD, and of -syn comprising the major protein component of Lewy bodies. […] Increasing recognition of DLB as a distinct and prevalent age-associated neurodegenerative dementia has stimulated increasing numbers of high-quality studies on its aetiology and pathogenesis. Here, we summarise contemporary findings from this rapidly expanding field, focusing on genetics, diagnostic biomarkers and molecular mechanisms.

• #10 Lewy Body Dementia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482441/

  The key feature of LBD is the presence of alpha-synuclein, a presynaptic protein whose function remains debatable. Other findings include the presence of ubiquitin and neurofilament proteins. […] The pathology of LBD overlaps that of Parkinson disease and Alzheimer disease. Neuronal cytoplasmic inclusion bodies, called Lewy bodies (comprising aggregates of ubiquitin and alpha-synuclein) and found within the brain parenchyma (mainly in the brainstem, limbic system, and cerebral cortex), are characteristic of LBD. […] Genetic mutations, environmental toxins, and the aging process can lead to alpha-synuclein misfolding and its accumulation in Lewy bodies via oxidative stress and mitochondrial dysfunction. […] The location of Lewy bodies determines the clinical presentation. If Lewy bodies develop initially in the brainstem and cerebral cortex, then dementia sets on early, and we call it dementia with Lewy bodies; however, if Lewy bodies develop initially in the brain stem only and extend to the cerebral cortex later, then dementia occurs late in the disease process, and we call it Parkinson disease dementia.

• #11 Dementia with Lewy bodies: an update and outlook | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0306-8

  The aggregation of -syn is considered a central process in all synucleinopathies. The aggregation of -syn follows a two-step process, initiated by a rate limiting nucleation phase in which soluble monomers associate into transient intermediate oligomers, which are built upon during the exponential elongation phase, producing primary filaments that are in turn integrated into fibrillary assembles. […] The suggestion that -syn may spread like a prion is an attractive hypothesis, as it may explain the stereotyped topography of Lewy pathology and clinical heterogeneity across LBD. Importantly, it has also considerable translational potential. […] The relevance of Lewy pathology to the patho-mechanisms responsible for eliciting the clinical phenotype is still controversial. Numerous clinico-pathological studies have failed to correlate LB density with disease duration, age of onset, presence or absence of cognitive fluctuations, visual hallucinations, delusions, recurrent falls, severity of parkinsonism or cognitive decline.

• #12 Dementia with Lewy bodies: an update and outlook | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0306-8

  The aggregation of -syn is considered a central process in all synucleinopathies. The aggregation of -syn follows a two-step process, initiated by a rate limiting nucleation phase in which soluble monomers associate into transient intermediate oligomers, which are built upon during the exponential elongation phase, producing primary filaments that are in turn integrated into fibrillary assembles. […] The suggestion that -syn may spread like a prion is an attractive hypothesis, as it may explain the stereotyped topography of Lewy pathology and clinical heterogeneity across LBD. Importantly, it has also considerable translational potential. […] The relevance of Lewy pathology to the patho-mechanisms responsible for eliciting the clinical phenotype is still controversial. Numerous clinico-pathological studies have failed to correlate LB density with disease duration, age of onset, presence or absence of cognitive fluctuations, visual hallucinations, delusions, recurrent falls, severity of parkinsonism or cognitive decline.

• #13 Dementia with Lewy bodies: an update and outlook | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0306-8

  Despite the stable prominent nature of -syn fibrils, it is likely that toxicity is instead driven by a pool of ill-defined heterogeneous oligomers. These oligomers may dynamically shift in equilibrium, altering their properties and substrates, either acting as intermediates of aggregation (on-pathway oligomers) or terminal assemblies (off-pathway oligomers) from which fibrillation is no longer favorable.

• #14 Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5346561/

  The goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology. […] The main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively.

• #15 Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5346561/

  The goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology. […] The main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively.

• #16 Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5346561/

  Therefore, the present observations point to altered mitochondrial function in frontal cortex as a major factor in the pathogenesis of DLB and rpDLB. […] Present findings show marked alterations in the expression of enzymes involved in purine metabolism in the frontal cortex in DLB and rpDLB. […] The present study reveals disease-specific alterations when comparing the present results in DLB with available data for AD in the same region, the frontal cortex, at similar stages of disease progression. […] These observations in AD are in contrast with the extensive deregulation of ORs and TASRs in the frontal cortex in DLB, thus indicating marked differences in the regulation of these brain receptors in DLB when compared with AD.

• #17 Lewy Body Dementia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482441/

  The key feature of LBD is the presence of alpha-synuclein, a presynaptic protein whose function remains debatable. Other findings include the presence of ubiquitin and neurofilament proteins. […] The pathology of LBD overlaps that of Parkinson disease and Alzheimer disease. Neuronal cytoplasmic inclusion bodies, called Lewy bodies (comprising aggregates of ubiquitin and alpha-synuclein) and found within the brain parenchyma (mainly in the brainstem, limbic system, and cerebral cortex), are characteristic of LBD. […] Genetic mutations, environmental toxins, and the aging process can lead to alpha-synuclein misfolding and its accumulation in Lewy bodies via oxidative stress and mitochondrial dysfunction. […] The location of Lewy bodies determines the clinical presentation. If Lewy bodies develop initially in the brainstem and cerebral cortex, then dementia sets on early, and we call it dementia with Lewy bodies; however, if Lewy bodies develop initially in the brain stem only and extend to the cerebral cortex later, then dementia occurs late in the disease process, and we call it Parkinson disease dementia.

• #18

  https://link.springer.com/article/10.1007/s11910-018-0874-y

  Dementia with Lewy bodies (DLB) is a neurodegenerative disease that can be clinically and pathologically similar to Parkinsons disease (PD) and Alzheimers disease (AD). Current understanding of DLB genetics is insufficient and has been limited by sample size and difficulty in diagnosis. […] DLB shares risk loci with AD, in the APOEE4 allele, and with PD, in variation at GBA and SNCA. Interestingly, the GWAS suggested that DLB may also have genetic risk factors that are distinct from those in AD and PD. […] Although off to a slow start, recent studies have reinvigorated the field of DLB genetics and these results enable us to start to have a more complete understanding of the genetic architecture of this disease. […] It is now clear that DLB has a strong genetic component. Although most cases are sporadic, a number of reports have demonstrated the occurrence of the disorder in families, in addition to the identification of genetic loci that modulate risk for the development of DLB.

• #19

  https://link.springer.com/article/10.1007/s11910-018-0874-y

  Despite the fact that we now know that genetics plays a role in the disease, genes that cause DLB are still to be identified. […] DLB is difficult to diagnose, as phenotypic overlaps with other neurodegenerative diseases can diminish chances of an accurate diagnosis. […] Genetic studies have already shown that DLB shares genetic risk factors with AD and PD; however, recent findings suggest that DLB may also have a unique genetic architecture. […] To date, only three genes have been convincingly established to be involved in DLB: APOE, GBA and SNCA. […] The anatomical distribution of Lewy-related pathology is often widespread to limbic and neocortical areas in DLB and PDD, and at end stage, the diseases are indistinguishable. […] Genetic variation at two SNPs (rs429358 and rs7412) in the APOE gene result in three alleles, of which the 4 allele is well established to increase the risk of developing Alzheimers disease in a dose-dependent manner.

• #20

  https://link.springer.com/article/10.1007/s11910-018-0874-y

  Despite the fact that we now know that genetics plays a role in the disease, genes that cause DLB are still to be identified. […] DLB is difficult to diagnose, as phenotypic overlaps with other neurodegenerative diseases can diminish chances of an accurate diagnosis. […] Genetic studies have already shown that DLB shares genetic risk factors with AD and PD; however, recent findings suggest that DLB may also have a unique genetic architecture. […] To date, only three genes have been convincingly established to be involved in DLB: APOE, GBA and SNCA. […] The anatomical distribution of Lewy-related pathology is often widespread to limbic and neocortical areas in DLB and PDD, and at end stage, the diseases are indistinguishable. […] Genetic variation at two SNPs (rs429358 and rs7412) in the APOE gene result in three alleles, of which the 4 allele is well established to increase the risk of developing Alzheimers disease in a dose-dependent manner.

• #21 Parkinson’s disease dementia and dementia with lewy bodies differences and similarities

  https://www.neuroscigroup.us/articles/OJPDT-6-113.php

  The combination of Lewy pathology and AD pathology predicts dementia in PD better than the severity of any single pathology. […] There is little evidence that cerebrovascular pathology contributes substantially to cognitive impairment in PDD or DLB. […] The genetics of dementia with Lewy bodies (DLB), PDD, PD, and AD is overlapping. […] The homozygous mutations in GBA cause a lysosomal storage disorder called Gaucher disease. […] The presence of at least one APOE 4 allele and extrapyramidal signs are found to be strong predictors of mortality and long-term care placement. […] The genetic studies regarding distinctively DLB are few, as previous researchers focused on Lewy body disease (PD, PDD, and DLB) as a whole. […] There are only three genes that have been convincingly established to be involved in DLB: APOE, GBA, and SNCA, meaning a strong risk for dementia with Lewy bodies.

• #22

  https://link.springer.com/article/10.1007/s11910-018-0874-y

  Homozygous mutations in the GBA gene cause Gaucher disease (GD); through astute clinical observation, it was noted that some GD patients showed parkinsonian features, and that heterozygous carriers of these variants had a higher prevalence of PD, leading to the discovery that heterozygous variants in GBA can predispose to PD, with an odds ratio (OR) of 5.43. This was also shown to be true for DLB, with an OR of 8.28, where GBA variants are linked to earlier disease onset and death.

• #23 Dementia with Lewy bodies: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/dementia-with-lewy-bodies/

  Changes in these four genes can lead to the formation of Lewy bodies, which are clusters of alpha-synuclein protein. SNCA gene variants result in misshapen alpha-synuclein proteins that cluster together (aggregate). SNCB gene variants lead to the production of an altered beta-synuclein protein that allows accumulation of alpha-synuclein. GBA1 gene variants are thought to disrupt the normal function of lysosomes. Research suggests that malfunctioning lysosomes impair the breakdown of alpha-synuclein, increasing the risk of its accumulation and the formation of Lewy bodies. […] In dementia with Lewy bodies, alpha-synuclein clusters accumulate inside and outside of neurons throughout the brain where they impair cell function and ultimately cause cell death. Neurons that produce the neurotransmitter dopamine seem to be particularly vulnerable to Lewy bodies. Dopamine has many important functions, including playing complex roles in cognition, motivation, behavior, and control of movement. Over time, the loss of dopamine-producing neurons can increasingly impair intellectual and motor function and the regulation of emotions, resulting in the signs and symptoms of dementia with Lewy bodies.

• #24 Revolutionizing Lewy Body Dementia Research – Toffler Trust

  https://tofflertrust.org/revolutionizing-lewy-body-dementia-research/

  In the paper, researchers had identified a gene called glucosylceramidase beta 1 (GBA1) as the most common genetic risk factor for Lewy body dementia. This means that scientists can now explore new avenues for understanding the mechanism of Lewy body dementia and develop potential treatments to slow its progression. […] By identifying that the mutation in GBA1 disrupts the function of the Golgi apparatus, leading to the generation of a pathologic form of amyloid beta, the team has shed light on the mechanism behind the combined Parkinsons and Alzheimers-like pathology found in Lewy body dementia. […] The presence of Lewy bodies composed of -Synuclein is a hallmark of the disease and provides a key clue for scientists to investigate. […] Understanding the underlying mechanisms behind this shared pathology could hold the key to unlocking novel treatments for both diseases.

• #25 Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science

  https://www.mdpi.com/2073-4409/13/3/223

  Variants within SNCA, GBA, APOE, SNCB, and MAPT have been shown to be associated with DLB in repeated genomic studies. Transcriptomic analysis, conducted predominantly on candidate genes, has identified signatures of synuclein aggregation, protein degradation, amyloid deposition, neuroinflammation, mitochondrial dysfunction, and the upregulation of heat-shock proteins in DLB. Yet, the understanding of DLB molecular pathology is incomplete. This precipitates the current clinical position whereby there are no available disease-modifying treatments or blood-based diagnostic biomarkers. […] The role of the SNCA variants within DLB pathology is unclear. It has been hypothesised that these variants increase the propensity of α-synuclein to aggregate and inhibit membrane binding activity. Further investigation is needed to understand the functional outcomes of these variants. The pathogenesis of GBA variants is poorly understood. Individuals with GBA variants have been associated with an earlier onset of DLB and a shorter life expectancy. It has been hypothesised that GBA variants impede the production of glucosylceramidase, reducing the degradation of α-synuclein within lysosomes. Without sufficient degradation, α-synuclein accumulates and aggregates, precipitating DLB pathology.

• #26 Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science

  https://www.mdpi.com/2073-4409/13/3/223

  The MAPT variants likely contribute to the hyperphosphorylation and aggregation of tau into neurofibrillary tangles. These aggregates are known to precipitate Lewy body formation and DLB pathology. The H1 haplotype refers to the direct orientation of MAPT, which increases the expression of transcripts with four repeats (4R). 4R MAPT transcripts are associated with elevated hyperphosphorylation and aggregation of tau. […] Genomic and transcriptomic analyses have identified several pathways and genes of interest that may be pathogenic within DLB. The aggregation of α-synuclein is a key component of DLB pathology. Increased SNCA expression has been suspected as a potential cause for α-synuclein aggregation for some time. The upregulation of SNCA-98 and SNCA-112 may therefore promote synuclein aggregation. Conversely, SNCA-126 downregulation has been detected in the prefrontal cortices and peripheral leukocytes of individuals with DLB. The downregulation of this transcript, combined with the upregulation of transcripts that promote aggregation, highlights an alternative splicing mechanism that may trigger synuclein dysfunction, aggregation, and consequent Lewy pathology.

• #27 Lewy Body Dementia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482441/

  The key feature of LBD is the presence of alpha-synuclein, a presynaptic protein whose function remains debatable. Other findings include the presence of ubiquitin and neurofilament proteins. […] The pathology of LBD overlaps that of Parkinson disease and Alzheimer disease. Neuronal cytoplasmic inclusion bodies, called Lewy bodies (comprising aggregates of ubiquitin and alpha-synuclein) and found within the brain parenchyma (mainly in the brainstem, limbic system, and cerebral cortex), are characteristic of LBD. […] Genetic mutations, environmental toxins, and the aging process can lead to alpha-synuclein misfolding and its accumulation in Lewy bodies via oxidative stress and mitochondrial dysfunction. […] The location of Lewy bodies determines the clinical presentation. If Lewy bodies develop initially in the brainstem and cerebral cortex, then dementia sets on early, and we call it dementia with Lewy bodies; however, if Lewy bodies develop initially in the brain stem only and extend to the cerebral cortex later, then dementia occurs late in the disease process, and we call it Parkinson disease dementia.

• #28 Dementia with Lewy Bodies and Parkinson’s Disease-Dementia: Current Perspectives

  https://www.clinmedjournals.org/articles/ijnn/international-journal-of-neurology-and-neurotherapy-ijnn-5-076.php?jid=ijnn

  The clinicopathological features of DLB, PDD and other synucleinopathies are highly variable and heterogenous, documented by 4 current staging systems in use for LB disorders, one for PD, another one for DLB, revised guidelines, and a recent one. […] Transcellular propagation of protein aggregate „seeds” has been proposed to mediate the progression of neurodegeneration in tauopathies and synucleinopathies. This „prion-like” transmission of αSyn and other pathological proteins, appears also essential for the pathogenesis of both PDD and DLB. […] It has been suggested that distinct species of αSyn are responsible for propagation and differences of regional distribution of lesions in various synucleinopathies, and that different strains of pathological αSyn are involved in the heterogeneity of synucleinopathies.

• #29 Dementia with Lewy Bodies and Parkinson’s Disease-Dementia: Current Perspectives

  https://www.clinmedjournals.org/articles/ijnn/international-journal-of-neurology-and-neurotherapy-ijnn-5-076.php?jid=ijnn

  The clinicopathological features of DLB, PDD and other synucleinopathies are highly variable and heterogenous, documented by 4 current staging systems in use for LB disorders, one for PD, another one for DLB, revised guidelines, and a recent one. […] Transcellular propagation of protein aggregate „seeds” has been proposed to mediate the progression of neurodegeneration in tauopathies and synucleinopathies. This „prion-like” transmission of αSyn and other pathological proteins, appears also essential for the pathogenesis of both PDD and DLB. […] It has been suggested that distinct species of αSyn are responsible for propagation and differences of regional distribution of lesions in various synucleinopathies, and that different strains of pathological αSyn are involved in the heterogeneity of synucleinopathies.

• #30 Parkinson’s disease dementia and dementia with lewy bodies differences and similarities

  https://www.neuroscigroup.us/articles/OJPDT-6-113.php

  The second most common neurodegenerative disease causing dementia in the population over 65 years is Parkinsons Disease Dementia (PDD), sharing many clinical, genetic, pathophysiological, imaging, and morphological features with Dementia with Lewy Bodies (DLB). […] The differences are rather few and many authors tend to believe that PDD and DLB may be manifestations of the same neurodegenerative disorder. […] Synucleinopathies are the second most common process of neurodegenerative disorders after Alzheimers disease that can lead to dementia. […] They are characterized by the accumulation of aggregated protein alfa-synuclein ( -syn) in both neuronal and non-neuronal cells in the brain. […] The Braak hypothesis says that Lewy pathology primarily occurs in the lower brainstem, successively spreading up to the striatum and to the cortex.

• #31 Parkinson’s disease dementia and dementia with lewy bodies differences and similarities

  https://www.neuroscigroup.us/articles/OJPDT-6-113.php

  These spreads are prion-like, transferring misfolded proteins from cell to cell. […] However, the latest theories say that the propagation of the disease observed by Braak and colleagues is reflecting the vulnerability of specific cells that are first engaged in PD. […] It is not completely known how -syn spreads in the brain. […] It is not clearly shown whether LB and LN have a neuroprotective or neurotoxic role. […] It is assumed that LB and LN in the neocortex are not associated with neuron loss or atrophy but there is a correlation between total -syn burden and neuronal loss. […] Conversely, AD pathology (neurofibrillary tangles and amyloid pathology) that often coexist in DLB and PDD, leads to cortical neuronal loss. […] The presence of cortical neurofibrillary tangles and beta-amyloid pathology leads to more advanced dementia, implying that the two pathologies work together.

• #32 Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

  https://www.mdpi.com/1422-0067/24/15/12116

  Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). […] Evidence from in vitro or animal disease models, direct examination of human postmortem brain parenchyma, and in vivo biofluid or imaging studies suggests an important relationship between α-synuclein, inflammation, and LBD pathogenesis. […] The potentially central role of inflammatory pathways in dementia pathogenesis, and therefore the measurement of inflammatory molecules as markers of disease activity, is one avenue of exploration towards addressing these challenges. […] Initiation of innate inflammatory mechanisms through α-synuclein-related glial cell activation and inflammatory cytokine production is one proposed mechanism of neurodegeneration in LBD.

• #33 Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

  https://www.mdpi.com/1422-0067/24/15/12116

  Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). […] Evidence from in vitro or animal disease models, direct examination of human postmortem brain parenchyma, and in vivo biofluid or imaging studies suggests an important relationship between α-synuclein, inflammation, and LBD pathogenesis. […] The potentially central role of inflammatory pathways in dementia pathogenesis, and therefore the measurement of inflammatory molecules as markers of disease activity, is one avenue of exploration towards addressing these challenges. […] Initiation of innate inflammatory mechanisms through α-synuclein-related glial cell activation and inflammatory cytokine production is one proposed mechanism of neurodegeneration in LBD.

• #34 Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

  https://www.mdpi.com/1422-0067/24/15/12116

  The variability in microglial profiles over the disease course is an important recent development in the study of LBD pathobiology. […] Astrocytes, another glial cell population integral to CNS immune responses and widely investigated in neurodegenerative diseases, were also identified in this review as likely contributing to inflammatory signals in LBD. […] T lymphocytes, particularly CD4+ helper T cells, may contribute to chronic inflammatory processes in LBD. […] The impact of AD-type co-pathology, hyperphosphorylated tau (p-tau), and amyloid-β may be important in the inflammatory signals detected in clinical LBD studies. […] This review identifies some discordant signals in inflammatory profiles between DLB and PDD from different cohorts; however, varying methodologies between studies and a lack of direct comparison between DLB and PDD groups in all but 12 studies limit the conclusions that can be drawn.

• #35 Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

  https://www.mdpi.com/1422-0067/24/15/12116

  The variability in microglial profiles over the disease course is an important recent development in the study of LBD pathobiology. […] Astrocytes, another glial cell population integral to CNS immune responses and widely investigated in neurodegenerative diseases, were also identified in this review as likely contributing to inflammatory signals in LBD. […] T lymphocytes, particularly CD4+ helper T cells, may contribute to chronic inflammatory processes in LBD. […] The impact of AD-type co-pathology, hyperphosphorylated tau (p-tau), and amyloid-β may be important in the inflammatory signals detected in clinical LBD studies. […] This review identifies some discordant signals in inflammatory profiles between DLB and PDD from different cohorts; however, varying methodologies between studies and a lack of direct comparison between DLB and PDD groups in all but 12 studies limit the conclusions that can be drawn.

• #36 Immune system may play harmful role in Lewy body dementia

  https://www.alzheimers.gov/news/immune-system-may-play-harmful-role-lewy-body-dementia

  T cells, which are key players in the bodys immune system, may be involved in the degeneration of neurons in Lewy body dementia, according to an NIA-supported study. […] Previous research found that people with Lewy body dementia had T cells in their blood that were able to react against alpha-synuclein. This finding suggested that rather than protecting the body from foreign invaders, the immune system could play a part in causing Lewy body dementia. […] The team proposed how these T cells could travel to the brain, react against the abnormal alpha-synuclein deposits, and secrete an inflammatory substance, leading to neurodegeneration in people with Lewy body dementia. […] This new information about the disease process could help investigators find effective treatments for Lewy body dementia.

• #37 Immune system may play harmful role in Lewy body dementia

  https://www.alzheimers.gov/news/immune-system-may-play-harmful-role-lewy-body-dementia

  T cells, which are key players in the bodys immune system, may be involved in the degeneration of neurons in Lewy body dementia, according to an NIA-supported study. […] Previous research found that people with Lewy body dementia had T cells in their blood that were able to react against alpha-synuclein. This finding suggested that rather than protecting the body from foreign invaders, the immune system could play a part in causing Lewy body dementia. […] The team proposed how these T cells could travel to the brain, react against the abnormal alpha-synuclein deposits, and secrete an inflammatory substance, leading to neurodegeneration in people with Lewy body dementia. […] This new information about the disease process could help investigators find effective treatments for Lewy body dementia.

• #38

  https://link.springer.com/article/10.1385/JMN:17:2:225

  Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinsons disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimers disease (AD). […] The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by A-amyloid over-production. […] The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. […] Further investigation of -synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.

• #39 Parkinson’s disease dementia and dementia with lewy bodies differences and similarities

  https://www.neuroscigroup.us/articles/OJPDT-6-113.php

  The combination of Lewy pathology and AD pathology predicts dementia in PD better than the severity of any single pathology. […] There is little evidence that cerebrovascular pathology contributes substantially to cognitive impairment in PDD or DLB. […] The genetics of dementia with Lewy bodies (DLB), PDD, PD, and AD is overlapping. […] The homozygous mutations in GBA cause a lysosomal storage disorder called Gaucher disease. […] The presence of at least one APOE 4 allele and extrapyramidal signs are found to be strong predictors of mortality and long-term care placement. […] The genetic studies regarding distinctively DLB are few, as previous researchers focused on Lewy body disease (PD, PDD, and DLB) as a whole. […] There are only three genes that have been convincingly established to be involved in DLB: APOE, GBA, and SNCA, meaning a strong risk for dementia with Lewy bodies.

• #40 Dementia with Lewy bodies and Parkinson’s disease-dementia: Current perspectives – Atlas of Science

  https://atlasofscience.org/dementia-with-lewy-bodies-and-parkinsons-disease-dementia-current-perspectives/

  Dementia with Lewy bodies (DLB) and Parkinsons disease-dementia (PDD) are two closely related major neurocognitive disorders with Lewy bodies of unknown etiology. […] Both disorders are characterized morphologically by widespread cortical and subcortical -synuclein/Lewy bodies plus Alzheimer-related -amyloid and tau pathology. […] These changes may account for earlier onset and greater severity of cognitive defects in DLB. […] Cognitive impairment is not only induced by -synuclein-caused neurodegeneration but by multiple regional pathological scores. […] Recent animal models and human post-mortem studies have provided important insights into the pathophysiology of DLB/PDD showing some differences, e.g., different spreading patterns of -synuclein pathology, but the basic pathogenic mechanisms leading to the heterogeneity between both disorders deserve further elucidation. […] In view of the controversies about the nosology and pathogenesis of both syndromes, there remains a pressing need to differentiate them more clearly and to understand the processes leading these synucleinopathies to cause one disorder or the other.

• #41 Parkinson’s disease dementia and dementia with lewy bodies differences and similarities

  https://www.neuroscigroup.us/articles/OJPDT-6-113.php

  The combination of Lewy pathology and AD pathology predicts dementia in PD better than the severity of any single pathology. […] There is little evidence that cerebrovascular pathology contributes substantially to cognitive impairment in PDD or DLB. […] The genetics of dementia with Lewy bodies (DLB), PDD, PD, and AD is overlapping. […] The homozygous mutations in GBA cause a lysosomal storage disorder called Gaucher disease. […] The presence of at least one APOE 4 allele and extrapyramidal signs are found to be strong predictors of mortality and long-term care placement. […] The genetic studies regarding distinctively DLB are few, as previous researchers focused on Lewy body disease (PD, PDD, and DLB) as a whole. […] There are only three genes that have been convincingly established to be involved in DLB: APOE, GBA, and SNCA, meaning a strong risk for dementia with Lewy bodies.

• #42 Pathophysiology of dementia

  https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia

  The pathophysiology of dementia is broadly thought to be related to the aggregation and accumulation of misfolded proteins (termed proteinopathies) and/or associated with cerebrovascular disease (CVD). The most common cause of late-onset dementia is AD, followed by dementia with Lewy bodies (DLB), vascular dementia and frontotemporal dementia (FTD). […] After AD, DLB is the second most common form of neurodegenerative dementia in older adults. […] Pathologically, DLB is characterised by the accumulation of the synaptic protein -synuclein into Lewy bodies and Lewy neurites in the brain. […] Comorbid AD-related proteinopathies (A plaques and neurofibrillary tangles) are frequently detected in people with DLB. […] Similar to AD, CVDs, including CAA, have been investigated in people with DLB, but their prevalence and clinical implications in DLB are not well understood.

• #43 Clinical, neuropathological, and molecular characteristics of rapidly progressive dementia with Lewy bodies: a distinct clinicopathological entity? | Alzheimer’s Research & Therapy | Full Text

  https://alzres.biomedcentral.com/articles/10.1186/s13195-024-01565-x

  Multiple pathologies are common, including CAA, SVD, VBI, TDP-43 inclusions, and argyrophilic grain disease. […] Our data suggest that in the context of an RPD, an acute confusional state onset should raise the index of suspicion for underlying LBP. […] This result suggests that, within the limitations of our small case series and intrinsic to the assays ability to distinguish different Syn conformers, the physiochemical properties of Syn are not significantly different between rpDLB and typical DLB. […] Future studies should address this issue.

• #44 Diagnostic Criteria for Dementia with Lewy Bodies: Updates and Future Directions

  https://www.e-jmd.org/journal/view.php?number=267

  Pathological studies with autopsy samples from the general population showed that Lewy body pathology, found in 22.5% of the general population and 41.4% of the demented subjects, often coexists with AD pathology, and aging and AD have strong effects on the evolution of DLB pathology, influencing clinical severity and prognosis. […] These findings indicate the limitation of current diagnostic criteria and biomarkers to sensitively detect patients with DLB or the mixed dementia of DLB and AD. […] The complexity of the pathophysiology of Lewy body diseases is linked to considerable variations in clinical manifestations and courses, showing multiple phenotypes, such as PD, PDD, and DLB. […] The revised consensus criteria for the clinical diagnosis of DLB were reported with the incorporation of new information about DLB in 2017. Future directions include the development of the criteria for early diagnosis and the establishment of biomarkers directly indicative of Lewy-related pathology.

• #45 Lewy Body Dementia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482441/

  Lewy Body Dementia (LBD) encompasses two clinical entities: dementia with Lewy bodies and Parkinson disease dementia. It is a progressive degenerative brain disorder characterized by dementia, psychosis, and features of parkinsonism. Symptoms fluctuate with time and vary among different individuals. Diagnosis of LBD requires thorough clinical examination, as many of its features overlap with other dementia disorders. […] It is characterized by the deposition of Lewy bodies in the brain, which are intraneuronal cytoplasmic inclusion bodies with alpha-synuclein and ubiquitin aggregates. […] The etiology of LBD is still unknown; however, genetics, environmental factors, and changes linked to aging may have a role and still require further research. […] Like Alzheimer disease, LBD presents with acetylcholine deficiency, but it is more pronounced in LBD. Decreased levels of acetylcholine in the temporal and parietal cortex result in visual hallucinations (a prominent feature of LBD), while up-regulation of muscarinic M1 receptors in the temporal lobe results in delusions.

• #46 Dementia with Lewy bodies: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/dementia-with-lewy-bodies/

  Changes in these four genes can lead to the formation of Lewy bodies, which are clusters of alpha-synuclein protein. SNCA gene variants result in misshapen alpha-synuclein proteins that cluster together (aggregate). SNCB gene variants lead to the production of an altered beta-synuclein protein that allows accumulation of alpha-synuclein. GBA1 gene variants are thought to disrupt the normal function of lysosomes. Research suggests that malfunctioning lysosomes impair the breakdown of alpha-synuclein, increasing the risk of its accumulation and the formation of Lewy bodies. […] In dementia with Lewy bodies, alpha-synuclein clusters accumulate inside and outside of neurons throughout the brain where they impair cell function and ultimately cause cell death. Neurons that produce the neurotransmitter dopamine seem to be particularly vulnerable to Lewy bodies. Dopamine has many important functions, including playing complex roles in cognition, motivation, behavior, and control of movement. Over time, the loss of dopamine-producing neurons can increasingly impair intellectual and motor function and the regulation of emotions, resulting in the signs and symptoms of dementia with Lewy bodies.

• #47 Causes of Dementia with Lewy bodies (DLB) | Stanford Health Care

  https://stanfordhealthcare.org/medical-conditions/brain-and-nerves/dementia-with-lewy-bodies/causes.html

  Dementia with Lewy bodies (DLB) is caused by degeneration of brain tissue. Lewy bodies in the brain affect substances called neurotransmitters. A neurotransmitter is a chemical that helps to transmit signals from one nerve cell to another. […] Lewy bodies interfere with the production of dopamine. A lack of dopamine causes movement problems such as those seen in Parkinson’s disease (PD). […] When Lewy bodies build up in these areas, they lead to a deficiency in acetylcholine, causing symptoms of dementia.

• #48 Causes of Dementia with Lewy bodies (DLB) | Stanford Health Care

  https://stanfordhealthcare.org/medical-conditions/brain-and-nerves/dementia-with-lewy-bodies/causes.html

  Dementia with Lewy bodies (DLB) is caused by degeneration of brain tissue. Lewy bodies in the brain affect substances called neurotransmitters. A neurotransmitter is a chemical that helps to transmit signals from one nerve cell to another. […] Lewy bodies interfere with the production of dopamine. A lack of dopamine causes movement problems such as those seen in Parkinson’s disease (PD). […] When Lewy bodies build up in these areas, they lead to a deficiency in acetylcholine, causing symptoms of dementia.

• #49 CervoMed Announces Positive Results from the Extension

  https://www.globenewswire.com/news-release/2025/03/10/3040150/0/en/CervoMed-Announces-Positive-Results-from-the-Extension-Phase-of-its-Phase-2b-Clinical-Study-of-Neflamapimod-in-Patients-with-Dementia-with-Lewy-Bodies.html

  Dementia with Lewy bodies (DLB) is the third most common degenerative disease of the brain. Patients with this disease accumulate protein deposits, called Lewy bodies, in the brains nerve cells. This negatively affects cognitive ability, including attention, judgement, and reasoning, along with motor function. […] Neflamapimod is an investigational, orally administered small molecule brain penetrant drug that inhibits alpha isoform of the p38MAP kinase. In preclinical studies, neflamapimod reversed synaptic dysfunction, including and particularly within the part of the brain most impacted in DLB the basal forebrain cholinergic system. […] The results from the extension phase of the RewinD-LB study are highly persuasive. It is rare in dementia clinical research to see results with the magnitude of effect and statistical strength as was seen on the CDR-SB.

• #50 Dementia with Lewy Bodies and Parkinson’s Disease-Dementia: Current Perspectives

  https://www.clinmedjournals.org/articles/ijnn/international-journal-of-neurology-and-neurotherapy-ijnn-5-076.php?jid=ijnn

  Dementia with Lewy bodies (DLB) and Parkinson’s disease-dementia (PDD) are two closely related major neurocognitive disorders with Lewy bodies of unknown etiology, showing notable overlap in their clinical presentation, pathological features, biochemistry, and genetic risk factors. […] Recent intra vitam neuroimaging, clinico-pathological studies and animal models suggest that DLB and PDD represent closely related but different, heterogenic subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases) or parts of a continuum with PDD at the mild end of the spectrum, DLB in the middle, and DLB+AD at the more severe end. […] The neurobiological basis for cognitive impairment in DLB and PDD is multifocal, related to a synergistic effect of both αSyn/LB and AD pathologies and dysfunction of dopaminergic, noradrenalinergic, serotonergic, and cholinergic systems.

• #51 Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential | Communications Biology

  https://www.nature.com/articles/s42003-022-03965-x

  Dementia with Lewy bodies (DLB) is a common form of dementia with known genetic and environmental interactions. However, the underlying epigenetic mechanisms which reflect these gene-environment interactions are poorly studied. […] Overall, our study highlights previously unreported DMCs offering insights into DLB pathogenesis with the possibility that some of these could be used as biomarkers of DLB in the future. […] Currently, the exact cause of DLB is still largely unknown, but it has been suggested that both genetic and environmental factors contribute to the disease pathogenesis. […] Epigenetic mechanisms including the methylation of CpG dinucleotides on genomic DNA are known to mediate the gene-environment interactions, and are thought to be involved in the development of the disease.

• #52 Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential | Communications Biology

  https://www.nature.com/articles/s42003-022-03965-x

  Dementia with Lewy bodies (DLB) is a common form of dementia with known genetic and environmental interactions. However, the underlying epigenetic mechanisms which reflect these gene-environment interactions are poorly studied. […] Overall, our study highlights previously unreported DMCs offering insights into DLB pathogenesis with the possibility that some of these could be used as biomarkers of DLB in the future. […] Currently, the exact cause of DLB is still largely unknown, but it has been suggested that both genetic and environmental factors contribute to the disease pathogenesis. […] Epigenetic mechanisms including the methylation of CpG dinucleotides on genomic DNA are known to mediate the gene-environment interactions, and are thought to be involved in the development of the disease.

• #53 Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential | Communications Biology

  https://www.nature.com/articles/s42003-022-03965-x

  These studies represent the early efforts to explore DNA methylation sites in DLB. […] Our analyses provide insights into the epigenetic architecture of DLB and catalogues for the underlying DNA methylation changes that occur in the etiopathophysiology of DLB. […] In this study, we performed an epigenome-wide association study to identify differentially methylated CpGs in post-mortem brain tissue from DLB cases and control subjects. […] This provides independent supportive evidence that aberrant DNA methylation occurs in subjects with DLB pathology, and some of the methylation sites are likely to be epigenetic mechanisms, which may contribute to the development of the disease. […] Interestingly, in DLB cases more significant DMCs were observed to be hypo-methylated compared with controls. […] Together, these indicate aberrant PAK6 methylation sites provide additional information regarding the etiology and pathogenesis of DLB.

• #54 Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential | Communications Biology

  https://www.nature.com/articles/s42003-022-03965-x

  The potential role of the interplay between DNA methylation and chromatin remodeling in mediating the disease development may open new lines of research enquiry into mechanisms of DLB pathophysiology. […] Overall, a larger sample size and meta-analysis with other cohorts would help corroborate the findings reported herein.

• #55 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230228/Three-intestinal-bacteria-associated-with-dementia-with-Lewy-bodies-discovered.aspx

  Dementia with Lewy bodies (DLB), one of the most common forms of dementia, has no cure. […] Now, a group led by researchers at the Nagoya University Graduate School of Medicine in Japan has identified three bacteria involved in DLB: Collinsella, Ruminococcus, and Bifidobacterium. Their findings, reported in npj Parkinson’s Disease, suggest new avenues for diagnosis and treatment. […] The onset of DLB is associated with abnormal deposits of alpha-synuclein, a protein in the brain that plays a role in the transmission of signals between neurons. […] This may suggest possible ways of diagnosing and treating this neurodegenerative disease. […] The researchers also found similarities between the gut bacteria involved in Parkinson’s disease and DLB. […] „Decreases in SCFA-producing bacteria have been repeatedly reported in Parkinson’s disease, Alzheimer’s disease, and ALS,” explains Ohno. „This suggests that it is a common feature of neurodegenerative diseases.”

• #56 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230228/Three-intestinal-bacteria-associated-with-dementia-with-Lewy-bodies-discovered.aspx

  The presence of intestinal bacteria unique to DLB may explain why some patients develop Parkinson’s disease and others develop DLB first. […] Therapeutic intervention to increase Bifidobacterium may delay the onset and progression of DLB and reduce cognitive dysfunction. […] Our findings may pave the way for the discovery of new and completely different therapeutics.

• #57 Lewy body disease or diseases with Lewy bodies? | npj Parkinson’s Disease

  https://www.nature.com/articles/s41531-021-00273-9

  Given the growing knowledge in the field of cell and molecular biology and molecular genetics, it seems that LBs as such do not play a major role in the pathological process and are rather an indirect indicator of these diseases. […] The combination of LBs and AD pathology predicts dementia in PD much better than the severity of any single pathology. […] The presence of at least one parkinsonian sign is among the core clinical features of the newly established disorder that has been named MCI-LB and that represents the initial phase of DLB. […] The anatomical configuration of neurons (especially those with long hyperbranched axons that project widely to innervate multiple brain regions) is thought to be one of its causes. […] The synapse is another potential location for early involvement. […] The genetic differences between PDD and DLB have, so far, not been studied in detail. […] In our opinion, the current pieces of knowledge suggest that PD, PDD, and DLB represent closely related but different, heterogeneous subtypes of an -synuclein-associated disease spectrum.

• #58 Lewy body dementias | Dementia Australia

  https://www.dementia.org.au/about-dementia/lewy-body-dementias

  Lewy body disease is an age-related degenerative brain disease. It causes gradual brain damage, resulting in changes in movements, thinking, and behaviour. […] Lewy bodies are an abnormal accumulation in cells of a naturally occurring protein called alpha-synuclein. This causes brain cells to die. The majority of cases are sporadic with only a few known cases of inherited Lewy body disease. […] A Lewy body is a tiny tangle of protein called alpha-synuclein inside brain cells. These tangled proteins cause damage that affects your movement, thinking and behaviour. […] Right now, we dont understand well why Lewy bodies form. […] Lewy body dementia can damage your autonomic nervous system, which is the part of you that controls your bodily functions. […] Lewy body dementia can make your speech slower and less clear.

• #59 RAB39B involved in the pathogenesis of dementia with Lewy bodies – VJNeurology

  https://www.vjneurology.com/video/95x-0hqkjne-rab39b-involved-in-the-pathogenesis-of-dementia-with-lewy-bodies/

  Mutations within the vesicular trafficking protein RAB39B are associated with rare X-linked Parkinsons disease. […] Results support the involvement of RAB39B in the pathogenesis of dementia with Lewy bodies. […] Therefore, RAB39B and its associated functional pathways may be considered potential targets for therapeutic interventions in Lewy body diseases.

• #60 Cognition Therapeutics Reports Topline Results Showing Oral

  https://www.globenewswire.com/news-release/2025/05/08/3077141/0/en/Cognition-Therapeutics-Reports-Topline-Results-Showing-Oral-Zervimesine-CT1812-Reduced-Lesion-Growth-in-Phase-2-Study-in-Geographic-Atrophy.html

  To date, we have observed evidence of robust slowing of disease progression with zervimesine treatment in Phase 2 studies in Alzheimers disease and dementia with Lewy bodies […] Zervimesine (CT1812) is an investigational oral, once-daily pill being developed for the treatment of CNS diseases such as Alzheimers disease and dementia with Lewy bodies (DLB). While these diseases have different symptoms, both are associated with the buildup of certain proteins in the brain – A and -synuclein. As these proteins bind to neurons, they can damage and ultimately destroy the neurons. This results in a progressive loss in a persons ability to learn, recall memories, move efficiently, or communicate. These diseases progress relentlessly and ultimately result in death. If zervimesine can interrupt the toxic effects of these proteins, it may be able to slow progression of disease and improve the lives of those suffering from Alzheimers and DLB. […] We believe zervimesine can regulate pathways that are impaired in these diseases though its interaction with the sigma-2 receptor, a mechanism that is functionally distinct from other approaches for the treatment of degenerative diseases.

• #61 CervoMed Announces Positive Results from the Extension

  https://www.globenewswire.com/news-release/2025/03/10/3040150/0/en/CervoMed-Announces-Positive-Results-from-the-Extension-Phase-of-its-Phase-2b-Clinical-Study-of-Neflamapimod-in-Patients-with-Dementia-with-Lewy-Bodies.html

  Dementia with Lewy bodies (DLB) is the third most common degenerative disease of the brain. Patients with this disease accumulate protein deposits, called Lewy bodies, in the brains nerve cells. This negatively affects cognitive ability, including attention, judgement, and reasoning, along with motor function. […] Neflamapimod is an investigational, orally administered small molecule brain penetrant drug that inhibits alpha isoform of the p38MAP kinase. In preclinical studies, neflamapimod reversed synaptic dysfunction, including and particularly within the part of the brain most impacted in DLB the basal forebrain cholinergic system. […] The results from the extension phase of the RewinD-LB study are highly persuasive. It is rare in dementia clinical research to see results with the magnitude of effect and statistical strength as was seen on the CDR-SB.

• #62 Immune system may play harmful role in Lewy body dementia

  https://www.alzheimers.gov/news/immune-system-may-play-harmful-role-lewy-body-dementia

  T cells, which are key players in the bodys immune system, may be involved in the degeneration of neurons in Lewy body dementia, according to an NIA-supported study. […] Previous research found that people with Lewy body dementia had T cells in their blood that were able to react against alpha-synuclein. This finding suggested that rather than protecting the body from foreign invaders, the immune system could play a part in causing Lewy body dementia. […] The team proposed how these T cells could travel to the brain, react against the abnormal alpha-synuclein deposits, and secrete an inflammatory substance, leading to neurodegeneration in people with Lewy body dementia. […] This new information about the disease process could help investigators find effective treatments for Lewy body dementia.

• #63 Diagnostic Criteria for Dementia with Lewy Bodies: Updates and Future Directions

  https://www.e-jmd.org/journal/view.php?number=267

  Pathological studies with autopsy samples from the general population showed that Lewy body pathology, found in 22.5% of the general population and 41.4% of the demented subjects, often coexists with AD pathology, and aging and AD have strong effects on the evolution of DLB pathology, influencing clinical severity and prognosis. […] These findings indicate the limitation of current diagnostic criteria and biomarkers to sensitively detect patients with DLB or the mixed dementia of DLB and AD. […] The complexity of the pathophysiology of Lewy body diseases is linked to considerable variations in clinical manifestations and courses, showing multiple phenotypes, such as PD, PDD, and DLB. […] The revised consensus criteria for the clinical diagnosis of DLB were reported with the incorporation of new information about DLB in 2017. Future directions include the development of the criteria for early diagnosis and the establishment of biomarkers directly indicative of Lewy-related pathology.

• #64 Lewy Body Dementia

  https://practicalneurology.com/articles/2019-june/lewy-body-dementia-1

  Lewy body disorders are a common cause of dementia in the elderly, characterized by varying degrees of cognitive, behavioral, affective, movement, and autonomic dysfunction in older adults. LBD are associated with the accumulation of LBs in subcortical, limbic, and neocortical regions and are characterized clinically by progressive dementia, parkinsonism, cognitive fluctuations, visual hallucinations and RBD. Whether or not PDD and DLB reflect the same underlying disorder whose differences in symptom presentation are merely the end product of the underlying brain region(s) affected earlier or later in the disease course, is the subject of much controversy. […] Continued phenotypic characterization of prodromal stages of disease (RBD, autonomic dysfunction, anosmia) may improve our understanding of the earliest clinicopathological changes associated with LBD. Use of composite risk scores and assessment toolkits should help improve diagnosis in the clinical setting and could potentially be used for inclusion/exclusion criteria for LBD clinical trials. The expanding use of indicative biomarkers will enable clinicians and researchers to diagnose these disorders earlier, as well as aid in the prediction and monitoring of treatment response and development of more selective therapeutic agents.

• #65 Lewy Body Dementia

  https://practicalneurology.com/articles/2019-june/lewy-body-dementia-1

  Lewy body disorders are a common cause of dementia in the elderly, characterized by varying degrees of cognitive, behavioral, affective, movement, and autonomic dysfunction in older adults. LBD are associated with the accumulation of LBs in subcortical, limbic, and neocortical regions and are characterized clinically by progressive dementia, parkinsonism, cognitive fluctuations, visual hallucinations and RBD. Whether or not PDD and DLB reflect the same underlying disorder whose differences in symptom presentation are merely the end product of the underlying brain region(s) affected earlier or later in the disease course, is the subject of much controversy. […] Continued phenotypic characterization of prodromal stages of disease (RBD, autonomic dysfunction, anosmia) may improve our understanding of the earliest clinicopathological changes associated with LBD. Use of composite risk scores and assessment toolkits should help improve diagnosis in the clinical setting and could potentially be used for inclusion/exclusion criteria for LBD clinical trials. The expanding use of indicative biomarkers will enable clinicians and researchers to diagnose these disorders earlier, as well as aid in the prediction and monitoring of treatment response and development of more selective therapeutic agents.

• #66 Lewy body disease or diseases with Lewy bodies? | npj Parkinson’s Disease

  https://www.nature.com/articles/s41531-021-00273-9

  The current nosological concept of -synucleinopathies characterized by the presence of Lewy bodies (LBs) includes Parkinsons disease (PD), Parkinsons disease dementia (PDD), and dementia with Lewy bodies (DLB), for which the term Lewy body disease (LBD) has recently been proposed due to their considerable clinical and pathological overlap. […] In light of todays knowledge, the role of LBs in the pathogenesis and classification of these nosological entities remains somewhat uncertain. An increasingly more important role is attributed to other factors as the presence of various LBs precursors, post-translational Syn modifications, various Syn strains, the deposition of other pathological proteins (particularly -amyloid), and the discovery of selective vulnerability of specific cells due to anatomical configuration or synaptic dysfunction.

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