Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease.

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with higher risk of dementia, and, consequently, be not rarely misdiagnosed. In this review, we summarize the state-of-the-art on LBD-AD by discussing the synergistic effects between AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment in LBD-AD and their possible diagnostic and prognostic value. AD pathology can be suspected in vivo by means of CSF, MRI and PET markers, whereas α-synuclein seed amplification assays (SAAs) represent to date the most promising technique to identify Lewy pathology in different biological tissues. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity like in pure AD. The implementation of blood-based biomarkers of AD might allow the fast screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account for the differential diagnosis of dementia syndromes, for the prognostic evaluation on an individual level and for guiding symptomatic and disease-modifying therapies.

CSF1R mutation presenting as dementia with Lewy bodies.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult-onset autosomal dominant leukoencephalopathy resulting from mutations affecting the tyrosine kinase domain of the colony stimulating factor receptor 1 protein (encoded by CSF1R). The clinical phenotypes reported with CSF1R mutations are variable. We present a case of a patient with a pathogenic variant in the CSF1R gene with clinical and imaging features suggestive of Dementia with Lewy Bodies (DLB). This case expands the known clinical presentations associated with CSF1R mutations.

Corticobasal syndrome with visual hallucinations and probable REM-sleep behavior disorder: an autopsied case report of a patient with CBD and LBD pathology.

Corticobasal syndrome and dementia with Lewy bodies are clinical presentations with unique and overlapping features but distinct pathological substrates. We report the case of an 80 year-old man who presented with apraxia, rigidity, slowness, right arm myoclonus, a 10-year history of probable REM-sleep behavior disorder, and later developed visual hallucinations. At autopsy, he had pathological features of corticobasal degeneration, and Lewy body disease confined to the brainstem. This report highlights the importance of considering co-existing pathologies when a clinical presentation defies categorization, and demonstrates that salient features of dementia with Lewy bodies may result from pathology limited to the brainstem.

Distinct α-Synuclein strains and implications for heterogeneity among α-Synucleinopathies.

The deposition of misfolded ß-sheet enriched amyloid protein is a shared feature of many neurodegenerative diseases. Recent studies demonstrated the existence of conformationally diverse strains as a common property for multiple amyloidogenic proteins including α-Synuclein (α-Syn). α-Syn is misfolded and aggregated in a group of neurodegenerative diseases collectively known as α-Synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy body, multiple system atrophy and also a subset of Alzheimer's disease patients with concomitant PD-like Lewy bodies and neurites. While sharing the same pathological protein, different α-Synucleinopathies demonstrate distinct clinical and pathological phenotypes, which could result from the existence of diverse pathological α-Syn strains in patients. In this review, we summarized the characteristics of different α-Synucleinopathies and α-Syn strains generated with recombinant α-Syn monomers. We also make predictions of α-Syn strains that could potentially exist in patients based on the knowledge from other amyloid proteins and the clinical and pathological features of different α-Synucleinopathies.

Is Lewy pathology in the human nervous system chiefly an indicator of neuronal protection or of toxicity?

Misfolded α-synuclein accumulates in histological inclusions constituting "Lewy pathology" found in idiopathic Parkinson disease, Parkinson disease dementia and dementia with Lewy body. The mechanism inducing α-synuclein misfolding is still unknown. The misfolded molecules form oligomers that organize into fibrils. α-Synuclein fibrils, in vitro, are capable of initiating an auto-replicating process, transforming normal molecules into misfolded molecules that aggregate. Fibrils can cross the neuronal membrane and recruit α-synuclein molecules in connected neurons. Such properties of seeding and propagation, shared with prion proteins, belong to "tissular propagons". Lewy bodies isolate harmful species from the cytoplasm and have been thought to be protective. In PRKN gene mutations, however, the absence of Lewy bodies is not associated with a more aggressive course. In idiopathic Parkinson disease, the proportion of neurons with Lewy bodies in the substantia nigra remains stable despite the progression of neuronal loss. This stable proportion suggests that Lewy bodies are eliminated at the rate at which neurons are lost because Lewy bodies cause, or invariably accompany, neuronal loss. Experimentally, cellular death selectively occurs in inclusion-bearing neurons. This set of data indicates that α-synuclein misfolding is the essential mechanism causing the lesions of Parkinson disease and dementia with Lewy body. Lewy pathology is a direct and visible evidence of α-synuclein misfolding and, as such, is an accurate marker for assessing the presence of α-synuclein misfolding even if the inclusions themselves may not be as directly causative as the molecules they accumulate.

Alpha event-related synchronization after eye closing differs in Alzheimer's disease and dementia with Lewy bodies: a magnetoencephalography study.

BACKGROUND: The electroencephalography (EEG) abnormalities found in patients with dementia with Lewy bodies (DLB) are conflicting. In this study, we used magnetoencephalography, which has higher spatial resolution than electroencephalography, to explore neurophysiological features of DLB that may aid in the differential diagnosis. METHODS: Six patients with DLB, 11 patients with Alzheimer's disease, and 11 age-matched normal subjects were recruited. We investigated alterations in the ratio of event-related synchronization (ERS) in the alpha band after eye-closing. RESULTS: Although the averaged ratio change of alpha ERS after eye-closing appeared predominantly in the posterior brain regions in all study groups, DLB patients had the weakest ratio change of alpha ERS. In particular, DLB patients exhibited a significantly reduced ratio change of alpha ERS in the bilateral inferior temporal gyrus, right occipital pole, and left parieto-occipital cortex compared to Alzheimer's disease patients or normal controls. CONCLUSION: Our findings indicated that a reduced ratio change of alpha ERS in the posterior brain regions elicited by eye-closing is a brain electromagnetic feature of DLB.

Altered Expression of Human Mitochondrial Branched Chain Aminotransferase in Dementia with Lewy Bodies and Vascular Dementia.

Cytosolic and mitochondrial human branched chain aminotransferase (hBCATc and hBCATm, respectively) play an integral role in brain glutamate metabolism. Regional increased levels of hBCATc in the CA1 and CA4 region of Alzheimer's disease (AD) brain together with increased levels of hBCATm in frontal and temporal cortex of AD brains, suggest a role for these proteins in glutamate excitotoxicity. Glutamate toxicity is a key pathogenic feature of several neurological disorders including epilepsy associated dementia, AD, vascular dementia (VaD) and dementia with Lewy bodies (DLB). To further understand if these increases are specific to AD, the expression profiles of hBCATc and hBCATm were examined in other forms of dementia including DLB and VaD. Similar to AD, levels of hBCATm were significantly increased in the frontal and temporal cortex of VaD cases and in frontal cortex of DLB cases compared to controls, however there were no observed differences in hBCATc between groups in these areas. Moreover, multiple forms of hBCATm were observed that were particular to the disease state relative to matched controls. Real-time PCR revealed similar expression of hBCATm mRNA in frontal and temporal cortex for all cohort comparisons, whereas hBCATc mRNA expression was significantly increased in VaD cases compared to controls. Collectively our results suggest that hBCATm protein expression is significantly increased in the brains of DLB and VaD cases, similar to those reported in AD brain. These findings indicate a more global response to altered glutamate metabolism and suggest common metabolic responses that might reflect shared neurodegenerative mechanisms across several forms of dementia.

Insights into the management of Lewy body dementia: a scoping review.

Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal protein in the brain, namely, the Lewy body causes disturbances in typical neural functioning, leading to a range of cognitive, motor, and mental symptoms that have a substantial influence on the overall well-being and quality of life of affected individuals. There is no definitive cure for the disease; however, several nonpharmacological and pharmacological modalities have been tried with questionable efficacies. The aim of this study is to figure out the role of different interventional strategies in the disease. Donepezil, rivastigmine, memantine, and galantamine were the commonly used drugs for LBD. Together with that, levodopa, antipsychotics, armodafinil, piracetam, and traditional medications like yokukansan were also used, when indicated. Talking about nonpharmacological measures, exercise, physical therapy, multicomponent therapy, occupational therapy, psychobehavioral modification, transcranial stimulation, and deep brain stimulation have been used with variable efficacies. Talking about recent advances in the treatment of LBD, various disease-modifying therapies like ambroxol, neflamapimod, irsenontrine, nilotinib, bosutinib, vodobatinib, clenbuterol, terazosin, elayta, fosgonimeton, and anle138b are emerging out. However, there drugs are still in the different phases of clinical trials and are not commonly used in clinical practice. With the different pharmacological and nonpharmacological modalities we have for treatment of LBD, all of them offer symptomatic relief only. Being a degenerative disease, definite cure of the disease can only be possible with regenerative measures.

Incident anti-LGI1 autoimmune encephalitis during dementia with Lewy bodies: when Occam razor is a double-edged sword.

In Dementia with Lewy bodies (DLB), rapid cognitive decline and seizures seldom complicate the typical clinical course. Nevertheless, concurrent, treatable conditions may be responsible. We report a case of DLB with superimposed anti-LGI1 encephalitis, emphasizing the importance of thorough diagnostic reasoning beyond the simplest explanation amid distinct clinical cues.

A systematic literature review of fMRI and EEG resting-state functional connectivity in Dementia with Lewy Bodies: Underlying mechanisms, clinical manifestation, and methodological considerations.

Previous studies suggest that there may be important links between functional connectivity, disease mechanisms underpinning the Dementia with Lewy Body (DLB) and the key clinical symptoms, but the exact relationship remains unclear. We performed a systematic literature review to address this gap by summarising the research findings while critically considering the impact of methodological differences on findings. The main methodological choices of fMRI articles included data-driven, seed-based or regions of interest approaches, or their combinations. Most studies focused on examining large-scale resting-state networks, which revealed a consistent decrease in connectivity and some associations with non-cognitive symptoms. Although the inter-network connectivity showed mixed results, the main finding is consistent with theories positing disconnection between visual and attentional areas of the brain implicated in the aetiology of psychotic symptoms in the DLB. The primary methodological choice of EEG studies was implementing the phase lag index and using graph theory. The EEG studies revealed a consistent decrease in connectivity on alpha and beta frequency bands. While the overall trend of findings showed decreased connectivity, more subtle changes in the directionality of connectivity were observed when using a hypothesis-driven approach. Problems with cognition were also linked with greater functional connectivity disturbances. In summary, connectivity measures can capture brain disturbances in the DLB and remain crucial in uncovering the causal relationship between the networks' disorganisation and underlying mechanisms resulting in psychotic, motor, and cognitive symptoms of the DLB.

Dysphagia in a Patient With Lewy Body Dementia and Incidental Anterior Cervical Osteophyte: A Case Report.

One of the common problems affecting the elderly is dysphagia, which can be brought on by several things, including the presence of anterior cervical osteophytes. In this case study, a patient with Lewy body dementia is shown to have a case of dysphagia. The patient's primary complaint was dysphagia, which prompted questions regarding the development of underlying Lewy body dementia combined with gradual cognitive deterioration and motor control problems. An upper GI endoscopy was conducted during the patient's hospitalization after a barium swallow suggested esophageal obstruction but found no internal obstruction or any other abnormalities. Following the endoscopic procedure, the patient complained of neck aches. An anterior cervical osteophyte was subsequently discovered by computed tomography, which may have been the primary cause of the patient's dysphagia. The importance of considering coexisting medical conditions in elderly individuals, as well as the significance of promptly assessing and diagnosing dysphagia in the presence of neurodegenerative disorders such as Lewy body dementia, is emphasized by this example.

Is the clinical phenotype impact the prognosis in dementia with Lewy bodies?

INTRODUCTION: The first predominant clinical symptoms of dementia with Lewy bodies (DLB) are highly variable; however, the prognosis based on initial predominant symptoms remains poorly understood. METHODS: Multicenter retrospective study in 4 French expert neurological centers. Patients were categorized in 3 groups according to their first more predominant symptoms: cognitive, psychiatric, or motor. RESULTS: Analysis of 310 DLB patients. The mean age was 73.5 years old (SD 7.5) including 32.3% of women. The mean follow-up was 7.25 years (SD 3.6). We observed that the full clinical picture was more frequent in the motor group than in the cognitive group (p = 0.01); male gender and age at onset were associated with a significant excess risk of instantaneous mortality (p = 0.01). CONCLUSION: Initial symptoms may affect the clinical course of patients, but no significant difference in mortality was observed.

A Unique Perspective on Lead Compounds for Dementia with the Lewy Body.

Dementia with Lewy Bodies is a neurodegenerative disorder characterised by abnormal α-Synuclein aggregate accumulation in Lewy Bodies and Lewy Neurites and the most common form of dementia after Alzheimer's disease. The presynaptic protein alpha-synuclein (α-Syn) regulates synaptic vesicle trafficking and the subsequent release of neurotransmitters in the brain. These aggregates go through a number of crucial stages, such as aggregation, oligomerization, and fibrillation. Treatment of this disorder is generally symptomatic. This necessitates the development of cutting-edge therapeutic approaches that can either stop or change the course of the diseases. Many studies have shown that α-synuclein is a significant therapeutic target and that inhibiting α-synuclein aggregation, oligomerization, and fibrillation is an important disease-modifying strategy. Since α-syn is a defining feature of Parkinson's disease, the current review provides an overview of plant phytochemicals and synthetic heterocyclic compounds that target α-syn in Parkinson's disease in order to develop new drugs for Dementia with Lewy Bodies.

Optimal Protocol and Clinical Usefulness of 123I-MIBG Cardiac Scintigraphy for Differentiation of Parkinson's Disease and Dementia with Lewy Body from Non-Parkinson's Diseases.

Purpose: 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy was a useful imaging modality for the diagnosis of Parkinson's disease, but its diagnostic performances were variably reported. This retrospective study compared the diagnostic performances and investigated the optimal imaging protocol of 123I-MIBG cardiac scintigraphy at various imaging time points in patients suspected of Parkinson's disease in clinical practice. Methods: In patients suspected of Parkinson's disease, clinical records, autonomic function tests, and 123I-MIBG cardiac scintigraphy were retrospectively reviewed. Semi-quantitative parameters such as heart-to-mediastinum ratio (HMR) and washout rate (WR) were calculated and compared at 15 min, 1 h, 2 h, 3 h, and 4 h post-injection (p.i.). of 123I-MIBG cardiac scintigraphy. Group A consisted of Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy body (DLB), and group B consisted of non-Parkinson's diseases such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), drug-induced parkinsonism (DIP), essential tremor (ET), Parkinson-plus syndrome (PPS), and unspecified secondary parkinsonism (NA). The diagnostic performances of HMR and WR were compared for differentiation of group A from group B, and their clinical usefulness and optimal imaging time points were explored. Results: Seventy-eight patients were included in group A (67 PD, 7 PDD, 4 DLB), and 18 patients were included in group B (5 MSA, 3 PSP, 2 DIP, 2 ET, 1 PPS, and 1 NA). Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value of HMR and WR were maximized at 4 h p.i., (82.1%, 85.7%, 82.6%, 97.0%, and 46.2%; cutoff threshold < 1.717; area under curve 0.8086) and at the time interval between 1 and 4 h p.i. (65.4%, 85.7%, 68.5%, 96.2%, and 30.8%; cutoff threshold > 24.1%; area under curve 0.8246), respectively, and PPVs of both HMR and WR persistently showed greater than 92.7% at earlier time points and shorter time intervals. Conclusion: This study reassured that 4-h-delayed imaging is recommended for the best diagnostic performances in 123I-MIBG cardiac scintigraphy. Although it showed suboptimal diagnostic performances to differentiate PD, PDD, and DLB from non-Parkinson's diseases, it can be useful as an auxiliary measure for the differential diagnosis in usual clinical practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13139-023-00790-w.

Long-term outcomes with pimavanserin for psychosis in clinical practice.

Introduction: Pimavanserin is the only medication FDA-approved for the treatment of Parkinson disease (PD) psychosis (PDP), but reports of long-term, real-world clinical experience are lacking. Methods: A retrospective chart review of all patients treated with pimavanserin was conducted at our large Movement Disorders practice in Providence, Rhode Island, USA. Demographic and clinical data for each patient were collected and descriptive analyses were performed. Results: We identified 54 patients (23 female) who initiated pimavanserin, whose median age was 70 years (range 44-87 years) and the median duration of pimavanserin therapy was 26 weeks. Initial improvement was seen in 47% of the entire group, and 50% of the DLB patients. Additional antipsychotic medication was needed concomitantly with pimavanserin to maintain a positive response for 40% of patients. Only 15% of the entire group had effective treatment of their condition with pimavanserin monotherapy over a median of 52 weeks. Among the initial responders, 32% continued on pimavanserin monotherapy. Among the non-responders, the mean trial period for patients who did not improve was 27 weeks, for patients who worsened was 16 weeks, and for those who experienced adverse effects was 1-2 weeks. Reported sex was similar across responders (60%), non-responders (56%), and the overall cohort (57%). Conclusion: Our real-world experience shows that pimavanserin is safe and tolerable, with a lower response rate than reported in other publications. While it has been proven to be effective in short-duration clinical trials, our clinical experiences, however, demonstrate less promising results in the long term.

Association between prevalence rate of dementia with Lewy bodies and sleep characteristics in Chinese old adults.

Introduction: Few studies are available on the prevalence and sleep-related factors of dementia with Lewy bodies (DLB) in Chinese older adults, aiming to explore the associations between sleep characteristics and DLB. Methods: A cross-sectional study with 7,528 individuals aged ≥65 years in 106 communities in Northern China was conducted from April 2019 to January 2020. Questionaries (including demographic characteristics, comorbidities, lifestyles, and sleep characteristics) were administered, and neuropsychological assessments and physical examination were conducted in phase I; screening for probable DLB was done in phase II. Logistic regressions were used to assess associations. Results: A total of 919 (12.2%, 919/7,528) participants had dementia, and 101 (1.3%, 101/7,528) participants were diagnosed with DLB. The prevalence of dementia and DLB were slightly higher or equal in women, increased with age, and roughly decreased with nighttime sleep duration. Of the 101 participants, all of them (100.0%) had cognitive impairment, 46 (44.54%) displayed fluctuating cognition, 72 (71.29%) of them showed visual hallucination, 22 (21.78%) individuals reported RBD, and 27.71% showed Parkinsonism. Sleeping for <5 h (adjusted OR = 1.795, 95%CI: 1.055-3.054, p < 0.05) or having hypersomnolence (adjusted OR = 31.213, 95% CI: 17.618-55.301, p < 0.001) were significantly associated with the occurrence of DLB. Sleep duration of <5 h or >8 h had combined diagnostic value for DLB (AUC = 0.783, 95%CI: 0.734-0.831, p < 0.001). Conclusions: The current prevalence of DLB is 1.3% in Northern China. Short or long nighttime sleep duration is independently associated with the occurrence of dementia and DLB.

Large-scale network dysfunction in α-Synucleinopathy: A meta-analysis of resting-state functional connectivity.

BACKGROUND: Although dysfunction of large-scale brain networks has been frequently demonstrated in patients with α-Synucleinopathy (α-Syn, i.e., Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy), a consistent pattern of dysfunction remains unclear. We aim to investigate network dysfunction in patients with α-Syn through a meta-analysis. METHODS: Whole-brain seed-based resting-state functional connectivity studies (published before September 1st, 2020 in English) comparing α-Syn patients with healthy controls (HC) were retrieved from electronic databases (PubMed, Web of Science, and EMBASE). Seeds from each study were categorized into networks by their location within a priori functional networks. Seed-based effect size mapping with Permutation of Subject Images analysis of between-group effects identified the network systems in which α-Syn was associated with hyperconnectivity (increased connectivity in α-Syn vs. HC) or hypoconnectivity (decreased connectivity in α-Syn vs. HC) within and between each seed-network. This study was registered on PROSPERO (CRD42020210133). FINDINGS: In total, 136 seed-based voxel-wise resting-state functional connectivity datasets from 72 publications (3093 α-Syn patients and 3331 HC) were included in the meta-analysis. We found that α-Syn patients demonstrated imbalanced connectivity among subcortical network, cerebellum, and frontal parietal networks that involved in motor functioning and executive control. The patient group was associated with hypoconnectivity in default mode network and ventral attention network that involved in cognition and attention. Additionally, the patient group exhibited hyperconnectivity between neural systems involved in top-down emotion regulation and hypoconnectivity between networks involved in bottom-up emotion processing. INTERPRETATION: These findings supported neurocognitive models in which network dysfunction is tightly linked to motor, cognitive and psychiatric symptoms observed in α-Syn patients. FUNDING: This study was partially supported by the Research Grants Council of Hong Kong (Grant No. RGC14116121).

A Comparison of Cerebrospinal Fluid Beta-Amyloid and Tau in Idiopathic Normal Pressure Hydrocephalus and Neurodegenerative Dementias.

Purpose: Idiopathic normal pressure hydrocephalus (iNPH) is the leading reversible cause of cognitive impairment and gait disturbance that has similar clinical manifestations and accompanies to major neurodegenerative disorders in older adults. We aimed to investigate whether cerebrospinal fluid (CSF) biomarker for Alzheimer's disease (AD) may be useful in the differential diagnosis of iNPH. Patients and Methods: Amyloid-beta (Aß) 42 and 40, total tau (t-tau), phosphorylated tau (p-tau) were measured via ELISA in 192 consecutive CSF samples of patients with iNPH (n=80), AD (n=48), frontotemporal dementia (FTD) (n=34), Lewy body diseases (LBDs) (n=30) consisting of Parkinson's disease dementia and dementia with Lewy bodies. Results: The mean age of the study population was 75.6±7.7 years, and 54.2% were female. CSF Aß42 levels were significantly higher, and p-tau and t-tau levels were lower in iNPH patients than in those with AD and LBDs patients. Additionally, iNPH patients had significantly higher levels of t-tau than those with FTD. Age and sex-adjusted multi-nominal regression analysis revealed that the odds of having AD relative to iNPH decreased by 37% when the Aß42 level increased by one standard deviation (SD), and the odds of having LBDs relative to iNPH decreased by 47%. The odds of having LBDs relative to iNPH increased 76% when the p-tau level increased 1SD. It is 2.5 times more likely for a patient to have LBD relative to NPH and 2.1 times more likely to have AD relative to iNPH when the t-tau value increased 1SD. Conclusion: Our results suggest that levels of CSF Aß42, p-tau, and t-tau, in particularly decreased t-tau, are of potential value in differentiating iNPH from LBDs and also confirm previous studies reporting t-tau level is lower and Aß42 level is higher in iNPH than in AD.

Cell-Type Specific Changes in DNA Methylation of SNCA Intron 1 in Synucleinopathy Brains.

Parkinson's disease (PD) and dementia with Lewy body (DLB) are the most common synucleinopathies. SNCA gene is a major genetic risk factor for these diseases group, and dysregulation of its expression has been implicated in the genetic etiologies of several synucleinopathies. DNA methylation at CpG island (CGI) within SNCA intron 1 has been suggested as a regulatory mechanism of SNCA expression, and changes in methylation levels at this region were associated with PD and DLB. However, the role of DNA methylation in the regulation of SNCA expression in a cell-type specific manner and its contribution to the pathogenesis of PD and DLB remain poorly understood, and the data are conflicting. Here, we employed a bisulfite pyrosequencing technique to profile the DNA methylation across SNCA intron 1 CGI in PD and DLB compared to age- and sex-matched normal control subjects. We analyzed homogenates of bulk post-mortem frozen frontal cortex samples and a subset of neuronal and glia nuclei sorted by the fluorescence-activated nuclei sorting (FANS) method. Bulk brain tissues showed no significant difference in the overall DNA methylation across SNCA intron 1 CGI region between the neuropathological groups. Sorted neuronal nuclei from PD frontal cortex showed significant lower levels of DNA methylation at this region compared to normal controls, but no differences between DLB and control, while sorted glia nuclei exhibited trends of decreased overall DNA methylation in DLB only. In conclusion, our data suggested disease-dependent cell-type specific differential DNA methylation within SNCA intron 1 CGI. These changes may affect SNCA dysregulation that presumably mediates disease-specific risk. Our results can be translated into the development of the SNCA intron 1 CGI region as an attractive therapeutics target for gene therapy in patients who suffer from synucleinopathies due to SNCA dysregulation.