Materiały źródłowe

• #1 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 characterized by the deposition of Lewy bodies in the brain, which are intraneuronal cytoplasmic inclusion bodies with alpha-synuclein and ubiquitin aggregates. […] The key feature of LBD is the presence of alpha-synuclein, a presynaptic protein whose function remains debatable. […] 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 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. […] Unlike Parkinson disease, the reduction in acetylcholine is much more severe in LBD. […] Postmortem examinations have revealed that LBD affects the substantia nigra, dorsal raphe, locus ceruleus, and the dorsal motor nucleus of the vagus nerve.

• #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 mechanisms that contribute to cell death, how the disease advances through the brain, and the timing of cognitive decline are all poorly understood.

• #3 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. However, the regional spread of -syn does not appear to be solely determined by the strength of anatomical connectivity or a nearest neighbor rule, indicating cell- or region- autonomous factors may govern the development of LB pathology.

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

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

  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. […] Thus, 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.

• #5 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.

• #6 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.

• #7 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.

• #8 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). […] 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. […] 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. […] Initiation of innate inflammatory mechanisms through α-synuclein-related glial cell activation and inflammatory cytokine production is one proposed mechanism of neurodegeneration in LBD.

• #9 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.

• #10 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.

• #11 Cognitive effects of Lewy body pathology in clinically unimpaired individuals | Nature Medicine

  https://www.nature.com/articles/s41591-023-02450-0

  -Synuclein aggregates constitute the pathology of Lewy body (LB) disease. […] LB pathology had independently negative effects on cross-sectional and longitudinal global cognition and memory and on longitudinal attention/executive function. […] Participants with both LB and AD (A and tau) pathology exhibited faster cognitive decline than those with only LB or AD pathology. […] LB, but not AD, pathology was associated with reduced sense of smell. […] Only LB-positive participants progressed to clinical LB disease over 10 years. […] LB pathology, the primary pathology of Lewy body disease (LBD), comprises the intraneuronal accumulation of aggregates of misfolded alpha-synuclein (-syn) as LB and neurites. […] Importantly, LB pathology is also often found as a copathology in AD. […] Because of the previous lack of accurate biomarkers for misfolded -syn, little is known about the effects of LB pathology in this preclinical (also known as presymptomatic) phase of LBD.

• #12 What Is Lewy Body Dementia?

  https://www.alzheimers.gov/alzheimers-dementias/lewy-body-dementia

  In people with LBD, abnormal clumps of a protein called alpha-synuclein accumulate in areas of the brain involved in thinking, memory, and movement. The clumps are called „Lewy bodies” after the doctor who discovered them. They build up inside neurons, or nerve cells, in the brain and cause the neurons not to work well and eventually die. Certain chemicals in the brain that act as messengers between cells are also affected. What causes these changes in the brain is not yet fully understood. […] Most cases of LBD are not inherited and rarely does more than one family member have the disease. Certain genetic variants may increase the chance of developing dementia with Lewy bodies, but having a genetic variant does not mean that a person will definitely develop the disease.

• #13

  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). […] 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. […] Despite the fact that we now know that genetics plays a role in the disease, genes that cause DLB are still to be identified. […] 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.

• #14

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

  The SNCA gene is highly relevant to synucleinopathies as its encoded protein, alpha-synuclein, aggregates within neurons to form Lewy bodies and Lewy neurites, which are the pathological hallmark of PD, PDD and DLB. […] 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. […] 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.

• #15 Dementia with Lewy bodies: MedlinePlus GeneticsLock

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

  Dementia with Lewy bodies is a nervous system disorder characterized by a decline in intellectual function (dementia), a group of movement problems known as parkinsonism, visual hallucinations, sudden changes (fluctuations) in behavior and intellectual ability, and acting out dreams while asleep (REM sleep behavior disorder). This condition typically affects older adults, most often developing between ages 50 and 85. The life expectancy of individuals with dementia with Lewy bodies varies; people typically survive about 5 to 7 years after they are diagnosed. […] Variants (also called mutations) in genes known as SNCA and SNCB can cause dementia with Lewy bodies. The SNCA and SNCB genes provide instructions for making proteins, called alpha-synuclein and beta-synuclein, respectively, that are found primarily in the brain. Alpha-synuclein plays a role in communication between nerve cells (neurons), helping to regulate the release of chemical messengers (neurotransmitters). Beta-synuclein is likely involved in a process that allows neurons to change and adapt over time, which is necessary for learning and memory. Beta-synuclein may also prevent harmful accumulation of alpha-synuclein in neurons.

• #16 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.

• #17 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.

• #18 New Genetic Loci Identified for Lewy Body Dementia

  https://frontlinegenomics.com/new-genetic-loci-identified-for-lewy-body-dementia/

  A recent study, published in Nature used Genome Wide Association Studies to identify new risk loci associated with Lewy Body Dementia, and confirmed that it genetically overlaps with both Parkinson’s Disease and Alzheimer’s Disease. […] The genetic basis of Lewy Body Dementia (LBD) is not well understood. […] Post-mortem analyses have revealed that the disorder is distinguished by widespread cortical and limbic depositions of mutated forms of alpha synuclein proteins. […] The pathogenic impacts of this gene in LBD appear to be the same as in AD. […] Thus, mitigation of BIN1-mediated endosomal dysfunction could have therapeutic implications in both neurodegenerative diseases. […] The identification of this gene underscores the role of lysosomal dysfunction in the pathogenesis of Lewy body diseases.

• #19 New Genetic Loci Identified for Lewy Body Dementia

  https://frontlinegenomics.com/new-genetic-loci-identified-for-lewy-body-dementia/

  Pathway enrichment analysis of LBD found several pathways which may be involved in LBD. These are related to the regulation of amyloid-beta formation, regulation of endocytosis, tau protein binding and others. […] These findings support the hypothesis of overlapping disease-associated pathways in these common, age-related neurodegenerative diseases. […] The study identified new loci relevant to the pathogenesis of LBD and confirmed that LBD genetically overlaps with AD and PD.

• #20 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. DLB often presents a diagnostic challenge given its clinical heterogeneity and overlap with other neurodegenerative diseases. […] 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.

• #21 Lewy Bodies, Dementia, and Parkinson’s – What Does it all Mean? | American Parkinson Disease Association

  https://www.apdaparkinson.org/article/understanding-parkinsons-disease-dementia-lewy-bodies/

  In PD, PDD, and DLB, the protein alpha-synuclein abnormally accumulates in the brain in aggregates, or clumps, called Lewy bodies. […] When Lewy bodies affect the substantia nigra, located in the midbrain portion of the brainstem, hallmark motor symptoms will emerge including resting tremor, slowness and stiffness. […] Lewy bodies can also affect areas beyond the brainstem, including the cortex or the thinking part of the brain. When this occurs, cognitive symptoms become apparent. […] In both PDD and DLB, symptoms caused by Lewy bodies in the lower brainstem (e.g. constipation, depression, sleep disorders), midbrain (e.g. resting tremor, slowness, stiffness) and cortex (e.g. cognitive difficulties, hallucinations,) can all occur. […] Technically, the difference between these two conditions lies in how quickly the cognitive difficulties and hallucinations develop in relation to the movement issues.

• #22 Lewy Bodies, Dementia, and Parkinson’s – What Does it all Mean? | American Parkinson Disease Association

  https://www.apdaparkinson.org/article/understanding-parkinsons-disease-dementia-lewy-bodies/

  However, because both DLB and PDD are characterized by abnormal accumulations of alpha-synuclein and loss of dopamine nerve endings, each of these biomarkers are abnormal in both PDD and DLB and current tests are not able to distinguish between the two. […] Treatments for DLB are similar to those for PDD and are aimed at symptom control. […] However, two anti-psychotic medications, quetiapine and clozapine, are sometimes used in PDD and DLB patients as they have less of an ability to worsen motor symptoms. […] A newer medication, pimavanserin, has a different mechanism of action, and does not block the dopamine system but rather the serotonin system, and therefore does not increase motor symptoms. […] DLB gained more visibility in the press when Robin Williams, the beloved comedian, died in 2014 with this condition.

• #23 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. […] Lewy body dementia causes a decline in mental abilities that gradually gets worse over time. […] Lewy body dementia is progressive. This means it gradually gets worse over time.

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

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

  Molecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response. […] Our hypothesis is that alterations of several metabolic pathways converge in the pathogenesis of DLB and that impaired mitochondria and energy metabolism, purine metabolism, protein synthesis, and inflammation may be important factors in the pathogenesis of DLB. […] Present biochemical studies have shown similar percentages of A40 and A42 in plaques in DLB and rpDLB abnormal solubility and aggregation of -synuclein and increased -amyloid bound to membranes in the frontal cortex in DLB and rpDLB. […] Mitochondrial alterations in the frontal cortex are prominent in DLB.

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

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

  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 selective vulnerability of specific neuronal populations is considered to be one of the factors involved in the specific distribution of pathological changes and the resulting clinical phenotype. […] The synapse is another potential location for early involvement. […] The role of genetic factors in DLB has 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.

• #25 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. […] 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 spectrum of Syn accumulations in LB disorders is much broader than the mere presence of LBs and involves also depositions in synapses and neurites.

• #26 Cognitive effects of Lewy body pathology in clinically unimpaired individuals | Nature Medicine

  https://www.nature.com/articles/s41591-023-02450-0

  However, recent advances have shown that misfolded -syn can be detected in the cerebrospinal fluid (CSF) of patients with LB pathology using in vitro seed amplification assay (SAA) of -syn. […] The coexistence of LB and AD pathologies is also important considering the many ongoing preclinical AD trials enrolling cognitively unimpaired participants with AD pathology. […] If LB pathology has cognitive effects similar to AD pathology, trials that account for the presence of LB pathology could better detect the effects of anti-A treatments. […] The effect of LB pathology on memory function had a similar magnitude to that of tau pathology, both cross-sectionally and longitudinally. […] Overall, we found that similar cognitive measures that are sensitive to changes in preclinical AD are also sensitive to LB pathology and could be suitable for preclinical LBD trials.

• #27 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20210621/Role-of-tau-in-pathogenesis-of-Lewy-body-dementias-is-distinct-from-Alzheimere28099s-disease-suggests-study.aspx

  Will a reduction in tau protein in brain neurons protect against Parkinson’s disease and Lewy body dementias? […] If this is borne out, that result differs from Alzheimer’s disease, where reducing endogenous tau levels in brain neurons is protective for multiple models of the disease – which further suggests that the role of tau in the pathogenesis of Lewy body dementias is distinct from Alzheimer’s disease. […] Here, we have shown that reduction of endogenous tau did not influence formation of templated alpha-synuclein inclusion formation or the loss of dopamine neurons. This suggests that therapeutics directed to tau for Parkinson’s disease may be more complicated than tau reduction. This is unlike Alzheimer’s disease, where tau reduction has been suggested as a possible therapy.

• #28 Lewy body diseases and the gut | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-025-00804-5

  Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. […] Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. […] The cellular and mechanistic origins of -syn propagation in disease are under intense investigation. […] Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. […] We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.

• #29 Lewy body diseases and the gut | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-025-00804-5

  The exact prevalence of -syn fibrils in the GI tract broadly across LBDs is unknown. […] Lewy pathology was first discovered in the enteric nervous system (ENS) of the gastrointestinal tract in 1984. […] Several studies report abundant Lewy pathology (primarily based on pS129–syn staining) in enteric nerves throughout the GI tract, including submandibular glands, esophagus, stomach, small intestine, colon, and rectum of PD patients. […] Pathology also occurs in the submucosa and myenteric plexi throughout the GI tract. […] The human abdominal vagus contains up to 50,000 axons which are a mixture of afferent and efferent neurons. […] The vagus nerve richly innervates the upper GI tract and provides a direct route for -syn spread to the brain. […] It is proposed that one way in which -syn spreads from the gut to the brain is via the vagus nerve, coursing through the dorsal motor nucleus of the vagus (DMV) in the medulla oblongata and from the lower brainstem to the substantia nigra and other brain regions including the cerebral cortex in both PD and DLB.

• #30 Lewy body diseases and the gut | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-025-00804-5

  Taken together, these data suggest that -syn proteins have the potential to spread from the gut to the brain via the vagus nerve. […] The role of adaptive immune cells, B and T cells, in triggering or promoting -syn pathology is less well understood compared to the function of innate immune cells. […] The hypothesis that PD pathology spreads in a prion-like manner from peripheral organs via the vagus nerve or other neurons is supported by the detection of -syn pathology in olfactory and enteric neurons, and the ability of misfolded -syn to transfer between the gut mucosa, and neurons in the enteric and central nervous system.

• #31

  https://omim.org/entry/127750

  In Lewy body diseases, including Parkinson disease with or without dementia, dementia with Lewy bodies, and Alzheimer disease with Lewy body copathology, alpha-synuclein aggregates in neurons as Lewy bodies and Lewy neurites. […] Peng et al. (2018) reported that pathologic alpha-synuclein in GCIs and Lewy bodies is conformationally and biologically distinct. GCI-alpha-synuclein forms structures that are more compact and is about 1,000-fold more potent than Lewy body alpha-synuclein in seeding alpha-synuclein aggregation, consistent with the highly aggressive nature of multiple system atrophy. […] GCI-alpha-synuclein and Lewy body alpha-synuclein show no cell-type preference in seeding alpha-synuclein pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy.

• #32

  https://omim.org/entry/127750

  Peng et al. (2018) found that oligodendrocytes, but not neurons, transform misfolded alpha-synuclein into a GCI-like strain, highlighting the fact that distinct alpha-synuclein strains are generated by different intracellular milieus. […] Moreover, GCI-alpha-synuclein maintains its high seeding activity when propagated in neurons. Thus, alpha-synuclein strains are determined by both misfolded seeds and intracellular environments.

• #33 Lewy body dementias | Dementia Australia

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

  Treating physical symptoms can happen. We talked about parkinsonism, so we tend to use other Parkinson drugs, because a number of patients will improve with physical symptoms in the response to a Parkinson’s treatment. […] In summary, DLB is common. It’s a clinical diagnosis at the moment where you can’t just have a blood test or a brain scan. There’s a significant overlap with the number of the other conditions that can get confused with DLB in the clinic. […] The prognosis, they say, normally, we talk about a survival of two to six years, but remember, many of these patients are diagnosed in their eighties, so in actual fact, they’ve already, if you like, exceeded what one might have predicted for their expected life duration. […] DLB is less so, but not exclusively less so on memory, but more on attention, working memory, visuospatial, so these non-amnestic features, but we certainly do see memory problems, especially as the disease progresses.

• #34

  https://link.springer.com/article/10.1007/s00415-018-8892-x

  Lewy body dementia (DLB) is a common form of cognitive impairment, accounting for 30% of dementia cases in ages over 65 years. […] Novel PET molecular imaging modalities, such as amyloid and tau imaging, may provide further insights into DLB pathophysiology and may aid in early diagnosis. […] Thus, the term Lewy body disease is currently used to describe neurodegenerative conditions with similar clinical phenotype (dementia combined with parkinsonism) and underlying pathophysiology. […] Aggregation of -synuclein (SNCA) in Lewy bodies and neurites often coexists with amyloid- plaques and tau neurofibrillary tangles. […] An integrated approach in these conditions that have a consecutive clinical outcome is ideal for elucidating underlying mechanisms and therefore improving diagnostic tools and therapeutic interventions.

• #35

  https://link.springer.com/article/10.1007/s00415-018-8892-x

  In respect of the former and considering that DLB diagnosis relies predominately on clinical features, neuroimaging biomarkers could aid towards an increased diagnostic certainty. […] However, the application of advanced techniques in the clinical setting requires additional validation. […] Although DLB has demonstrated some overlap with the cortical atrophy patterns seen in AD, atrophy is generally less diffuse in DLB with moderate preservation of the medial temporal lobe structures. […] These findings are in corroboration with the notion that DLB is a result of neuronal synaptic dysfunction, not neuronal loss. […] Studies have also demonstrated greater atrophy in the substantia innominate, with increased dorsal mesopontine GM atrophy distinguishing patients with clinically diagnosed DLB from AD.

• #36

  https://link.springer.com/article/10.1007/s00415-018-8892-x

  These findings may suggest a greater cholinergic dysfunction in DLB, perhaps related to the presence of midbrain synuclein pathology. […] A recent study by Shams et al. demonstrated that MRI of the swallow tail sign may have diagnostic potential in DLB, given that the largest dopamine-containing cluster within caudal and posterolateral part of the substantia nigra (nigrosome 1) is highly affected in parkinsonian syndromes. […] The finding of AD exhibiting greater temporal involvement compared to DLB has been a homogenous result across several structural imaging studies. […] Although investigations into hippocampal atrophy have revealed that DLB patients have less severe atrophy compared to AD patients, with the entorhinal cortex, CA1 and subiculum areas of the hippocampus being most affected in AD.

• #37 Dementia with Lewy bodies (DLB) | Symptoms & Causes | alz.org

  https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/dementia-with-lewy-bodies

  Most experts believe that dementia with Lewy bodies and Parkinson’s disease dementia are two different expressions of the same underlying problems with brain processing of the protein alpha-synuclein. […] Since Lewy bodies usually coexist with Alzheimer’s brain changes, it may sometimes be hard to distinguish DLB from Alzheimer’s disease, especially in the early stages. […] Researchers have not yet identified any specific causes of dementia with Lewy bodies. Most people diagnosed with DLB have no family history of the disorder, and no genes linked to DLB have been conclusively identified. […] There are no treatments that can slow or stop the brain cell damage caused by dementia with Lewy bodies. Current strategies focus on helping symptoms. […] Cholinesterase inhibitor drugs are a common approach for addressing thinking changes in Alzheimer’s. They also may help certain DLB symptoms. […] Antipsychotic drugs should be used with extreme caution in Lewy body dementia, including both dementia with Lewy bodies and Parkinson’s disease dementia. […] Like other types of dementia that destroy brain cells, dementia with Lewy bodies gets worse over time and shortens lifespan.

• #38 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. […] Right now, we dont understand well why Lewy bodies form. […] 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. […] Lewy body dementia can damage your autonomic nervous system, which is the part of you that controls your bodily functions. […] People with Lewy body dementia can have severe reactions to antipsychotic medications. […] There are ways to manage your condition, however. Your doctor might prescribe anti-depressant or anti-anxiety medication.

• #39 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

  Further, the consistency and magnitude of the clinical effect of neflamapimod on the CDR-SB are similar to our Phase 2a study results and we believe demonstrate proof-of-concept for neflamapimod as a potential treatment for dementia with Lewy bodies […] 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 […] 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 primary endpoint in the study is change in the CDR-SB, and secondary endpoints include CGIC, the TUG test, and a cognitive test battery (NTB) […] Neflamapimod has the potential to treat synaptic dysfunction, the reversible aspect of the underlying neurodegenerative processes that causes disease in DLB and certain other major neurological disorders.

• #40 Neflamapimod Displays Robust Efficacy in Pure Lewy Body Dementia Pathology

  https://www.neurologylive.com/view/neflamapimod-displays-robust-efficacy-pure-lewy-dementia-pathology

  The magnitude of neflamapimods effect on several efficacy measures proved to be consistent with the mechanism of action and prior preclinical data, with p-tau181 data suggesting a stronger effect on nonmixed Lewy body pathology. […] These findings support the notion that neflamapimod has potent and specific activity against basal forebrain cholinergic dysfunction, the underlying disease processes of DLB. […] Using a mixed model confined to patients with pure DLB, the magnitude of the treated population relative to placebo was substantial and clinically important. […] Galvin added, „combined with the scientific studies that preceded the clinical study, the results suggest that neflamapimod has the potential to change the course of the disease and significantly improve function and quality of life in patients with DLB.” […] Neflamapimod remains the first treatment with potential impact on cognition, function, and motor function in patients with DLB.

• #41 Cognition Therapeutics Reports Financial Results for the First Quarter 2025 and Provides Business Update | Taiwan News | May. 7, 2025 19:30

  https://www.taiwannews.com.tw/en/news/6104336

  Phase 2 results in dementia with Lewy bodies accepted for oral presentation at AAIC […] In January 2025 results from the Companys Phase 2 SHIMMER study were presented at the International Lewy Body Dementia Conference (ILBDC) by James E. Galvin, MD, MPH. (Director, Comprehensive Center for Brain Health at the University of Miami Miller School of Medicine; study director and principal investigator on the SHIMMER study grant from the National Institute of Aging) […] We are currently investigating our lead candidate, zervimesine (CT1812), in clinical programs in dementia with Lewy bodies (DLB) and Alzheimers disease, including the ongoing START study (NCT05531656) in early Alzheimers disease. 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.

• #42 Parkinson and Lewy Body-like Dementia Triggers

  https://www.neurologylive.com/view/parkinson-and-lewy-body-dementia-triggers

  The discovery of a possible trigger for PD and Lewy body dementia could provide a new avenue for gene therapy in these neurological conditions. […] Danish and German scientists have identified impaired cytokine interferon- (IFN-) signaling as a possible molecular trigger for Parkinson disease dementia, as well as the related neurodegenerative disorder, Lewy body dementia. […] According to the study authors, the alpha-synuclein and Lewy body accumulation are the consequence of late-stage autophagy. […] We found that IFN- is essential for neurons ability to recycle waste proteins. Without this, the waste proteins accumulate in disease-associated structures called Lewy bodies and with time the neurons die, noted Ejlerskov in a press release. […] The scientists concluded in their manuscript We showed that Ifnb gene therapy reversed pathology in a familial PD model, by promoting autophagy and a-syn clearance, which preserved DA neurons and associated neurologic deficit.

• #43 Parkinson and Lewy Body-like Dementia Triggers

  https://www.neurologylive.com/view/parkinson-and-lewy-body-dementia-triggers

  Not only did this research study identify a possible new animal model for Parkinson disease and Lewy body dementia, but it the results also suggest a potential new avenue for gene therapy in these neurological conditions. […] This is one of the first genes found to cause pathology and clinical features of non-familial PD and DLB, through accumulation of disease-causing proteins. It is independent of gene mutations known from familial PD and when we introduced IFN-gene therapy, we could prevent neuronal death and disease development.

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