scholarly journals Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology

2021 ◽  
Author(s):  
Lasse Pihlstrøm ◽  
Gemma Shireby ◽  
Hanneke Geut ◽  
Sandra Pilar Henriksen ◽  
Annemieke J.M. Rozemüller ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Frontal Cortex ◽  
Association Study ◽  
Lewy Body ◽  
Meta Analysis ◽  
Lewy Bodies ◽  
Independent Set ◽  
Risk Alleles ◽  
Lewy Body Pathology ◽  
Causal Therapy

AbstractParkinson’s disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available causal therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 219 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near SFMBT2, PHYHIP, BRF1/PACS2 and DGKG. The DGKG locus also showed evidence of DNA methylation changes in the earliest, preclinical stage of disease. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

scholarly journals Identification of 20 novel loci associated to ischemic stroke. Epigenome-Wide Association Study

2019 ◽  
Author(s):  
Carolina Soriano-Tárraga ◽  
Uxue Lazcano ◽  
Eva Giralt-Steinhauer ◽  
Carla Avellaneda-Gómez ◽  
Ángel Ois ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Ischemic Stroke ◽  
Association Study ◽  
Genetic Variants ◽  
Meta Analysis ◽  
Epigenetic Mechanism ◽  
Regulatory Sequence ◽  
Nucleotide Polymorphisms ◽  
Stroke Subtypes ◽  
Discovery Sample

ABSTRACTRationaleDNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1–2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism.ObjectiveTo detect epigenetic variants associated to stroke occurrence and stroke subtypes.Methods and ResultsA two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N=226 and N=166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which includes known genetic variants associated with stroke. The pathways associated to these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. Stratification analysis by stroke subtypes revealed distinct methylation patterns.ConclusionsWe identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.

scholarly journals Transcriptional network analysis in frontal cortex in Lewy body diseases with focus on dementia with Lewy bodies

2017 ◽  
Vol 28 (3) ◽  
pp. 315-333 ◽  
Author(s):  
Gabriel Santpere ◽  
Paula Garcia-Esparcia ◽  
Pol Andres-Benito ◽  
Belen Lorente-Galdos ◽  
Arcadi Navarro ◽  
...  
Keyword(s):  
Network Analysis ◽  
Frontal Cortex ◽  
Lewy Body ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Transcriptional Network ◽  
Lewy Body Diseases

scholarly journals A Case of Parkinson’s Disease with No Lewy Body Pathology due to a Homozygous Exon Deletion in Parkin

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Krisztina Kunszt Johansen ◽  
Sverre Helge Torp ◽  
Matthew J. Farrer ◽  
Emil K. Gustavsson ◽  
Jan O. Aasly
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Diagnostic Criteria ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Homozygous Deletion ◽  
Substantia Nigra Pars Compacta ◽  
Lewy Body Pathology ◽  
Deep Brain

Parkinson’s disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, good response to levodopa, and no other explanations of the syndrome. Earlier diagnostic criteria required autopsy for a definite diagnosis based on neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies and neurites. Here, we present a patient who developed parkinsonism around the age of 20, with an excellent response to levodopa who, at age 65, received bilateral STN deep brain stimulation (DBS). The patient died at age 79. The autopsy showed severe neuronal loss in the SN without any Lewy bodies in the brainstem or in the hemispheres. Genetic screening revealed a homozygous deletion of exon 3-4 in the Parkin gene. In this case report we discuss earlier described pathological findings in Parkin cases without Lewy body pathology, the current diagnostic criteria for PD, and their clinical relevance.

scholarly journals Dementia in Parkinson's Disease Correlates withα-Synuclein Pathology but Not with Cortical Astrogliosis

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Simone A. van den Berge ◽  
Josta T. Kevenaar ◽  
Jacqueline A. Sluijs ◽  
Elly M. Hol
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Glial Fibrillary Acidic Protein ◽  
Western Blot ◽  
Frontal Cortex ◽  
Lewy Body ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Cortical Lewy Bodies

Dementia is a common feature in Parkinson’s disease (PD) and is considered to be the result of limbic and cortical Lewy bodies and/or Alzheimer changes. Astrogliosis may also affect the development of dementia, since it correlates well with declining cognition in Alzheimer patients. Thus, we determined whether cortical astrogliosis occurs in PD, whether it is related to dementia, and whether this is reflected by the presence of glial fibrillary acidic protein (GFAP) and vimentin in cerebrospinal fluid (CSF). We have examined these proteins by immunohistochemistry in the frontal cortex and by Western blot in CSF of cases with PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and nondemented controls. We were neither able to detect an increase in cortical astrogliosis in PD, PDD, or DLB nor could we observe a correlation between the extent of astrogliosis and the degree of dementia. The levels of GFAP and vimentin in CSF did not correlate to the extent of astrogliosis or dementia. We did confirm the previously identified positive correlation between the presence of cortical Lewy bodies and dementia in PD. In conclusion, we have shown that cortical astrogliosis is not associated with the cognitive decline in Lewy body-related dementia.

scholarly journals Susceptibility to postmortem (co)-pathologies in antemortem atrophy-based subtypes of Alzheimer’s disease

2021 ◽  
Author(s):  
Rosaleena Mohanty ◽  
Daniel Ferreira ◽  
Simon Frerich ◽  
J-Sebastian Muehlboeck ◽  
Michel Grothe ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Magnetic Resonance Imaging Scan ◽  
Linear Regression Models ◽  
Lewy Body Pathology ◽  
Hippocampal Sparing ◽  
Regional Associations

AbstractObjectivesTo investigate whether antemortem atrophy-based subtypes of Alzheimer’s disease (AD) may be differentially susceptible to individual or concomitance of AD and non-AD (co)-pathologies, assessed neuropathologically at postmortem.MethodsWe selected 31 individuals from the AD neuroimaging initiative with: an antemortem magnetic resonance imaging scan evaluating brain atrophy available within two years before death; an antemortem diagnosis of AD dementia or prodromal AD; and postmortem neuropathological confirmation of AD. Antemortem atrophy-based subtypes was modeled as a continuous phenomenon in terms of two recently proposed dimensions: typicality (ranging from limbic-predominant AD to hippocampal-sparing AD subtypes) and severity (ranging from typical AD to minimal atrophy AD subtypes). Postmortem neuropathological evaluation included global and regional outcomes: AD hallmark pathologies of amyloid-beta and tau; non-AD co-pathologies of alpha-synuclein Lewy body and TDP-43; and the overall concomitance across these four (co)-pathologies. Partial correlation and linear regression models were used to assess the association between antemortem atrophy-based subtypes and postmortem neuropathological outcomes.ResultsWe observed significant global and regional associations between antemortem typicality and postmortem (co)-pathologies including tau, alpha-synuclein Lewy bodies and TDP-43. Antemortem typicality demonstrated stronger regional associations with concomitance of multiple postmortem (co)-pathologies in comparison to antemortem severity. Our findings suggest the following susceptibilities of atrophy-based subtypes: limbic-predominant AD towards higher burden of tau and TDP-43 pathologies while hippocampal-sparing AD towards lower burdens; limbic-predominant AD and typical AD towards higher burden of alpha-synuclein Lewy body pathology while hippocampal-sparing AD and minimal-atrophy AD towards lower burdens.DiscussionThrough a direct antemortem-to-postmortem validation, our study highlights the importance of understanding heterogeneity in AD in relation to concomitance of AD and non-AD pathologies. Our findings provide a deeper understanding of both global and regional vulnerabilities of the biological subtypes of AD brain towards (co)-pathologies. Relative involvement of both AD hallmark and non-AD (co)-pathologies will enhance prevailing knowledge of biological heterogeneity in AD and could thus, contribute towards tracking disease progression and designing clinical trials in the future.

scholarly journals Cardiovascular dysautonomia and cognitive impairment in Lewy body disease

2019 ◽  
Author(s):  
Hisayoshi Oka ◽  
Tadashi Umehara ◽  
Atsuo Nakahara ◽  
Hiromasa Matsuno
Keyword(s):  
Blood Pressure ◽  
Cognitive Impairment ◽  
Lewy Body ◽  
De Novo ◽  
Blood Pressure Monitoring ◽  
Lewy Bodies ◽  
Lewy Body Disease ◽  
Executive Dysfunction ◽  
Lewy Body Pathology ◽  
State Examination

Abstract Background Cognitive impairment may be correlated with cardiovascular dysautonomia, including blood pressure (BP) dysregulation, in Parkinson’s disease (PD), but the association between these factors in dementia with Lewy bodies (DLB) is uncertain. This study aimed to clarify whether cardiovascular dysautonomia had an influence on cognitive function in Lewy body disease or not. Methods 99 patients with de novo PD (n=75) and DLB (n=24) were evaluated using the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension (PPH), nocturnal BP fall in 24-hour ambulatory blood pressure monitoring (ABPM) and constipation were estimated. Associations of these factors with cognitive and executive dysfunction were examined. Results In DLB, MIBG uptake was reduced and OH, PPH and SH were severely disturbed, compared to PD. The nocturnal BP fall in ABPM was lower in DLB, and the failure of nocturnal BP fall in PD was associated with MMSE, after adjustment for other clinical features. FAB was significantly associated nocturnal BP fall, age and SH in PD, but no significant correlations among factors were found for DLB. Conclusion The significant association between nocturnal BP dysregulation and cognitive or executive decline in PD might be due to impaired microvascular circulation or invasion of α-synuclein in the CNS. The lack of a correlation of BP insufficiency with cognitive impairment in DLB suggests initial involvement of Lewy body pathology in the neocortex, regardless of Lewy body invasion of the autonomic nervous system.

scholarly journals Cardiovascular dysautonomia and cognitive impairment in Lewy body disease

2019 ◽  
Author(s):  
Hisayoshi Oka ◽  
Tadashi Umehara ◽  
Atsuo Nakahara ◽  
Hiromasa Matsuno
Keyword(s):  
Blood Pressure ◽  
Cognitive Impairment ◽  
Lewy Body ◽  
De Novo ◽  
Blood Pressure Monitoring ◽  
Lewy Bodies ◽  
Lewy Body Disease ◽  
Executive Dysfunction ◽  
Lewy Body Pathology ◽  
State Examination

Abstract Background Cognitive impairment may be correlated with cardiovascular dysautonomia, including blood pressure (BP) dysregulation, in Parkinson’s disease (PD), but the association between these factors in dementia with Lewy bodies (DLB) is uncertain. This study aimed to clarify whether cardiovascular dysautonomia had an influence on cognitive function in Lewy body disease or not. Methods 99 patients with de novo PD (n=75) and DLB (n=24) were evaluated using the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension (PPH), nocturnal BP fall in 24-hour ambulatory blood pressure monitoring (ABPM) and constipation were estimated. Associations of these factors with cognitive and executive dysfunction were examined. Results In DLB, MIBG uptake was reduced and OH, PPH and SH were severely disturbed, compared to PD. The nocturnal BP fall in ABPM was lower in DLB, and the failure of nocturnal BP fall in PD was associated with MMSE, after adjustment for other clinical features. FAB was significantly associated nocturnal BP fall, age and SH in PD, but no significant correlations among factors were found for DLB. Conclusion The significant association between nocturnal BP dysregulation and cognitive or executive decline in PD might be due to impaired microvascular circulation or invasion of α-synuclein in the CNS. The lack of a correlation of BP insufficiency with cognitive impairment in DLB suggests initial involvement of Lewy body pathology in the neocortex, regardless of Lewy body invasion of the autonomic nervous system.

scholarly journals Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure

Hypertension ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 195-205 ◽  
Author(s):  
Yisong Huang ◽  
Miina Ollikainen ◽  
Maheswary Muniandy ◽  
Tao Zhang ◽  
Jenny van Dongen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Pressure ◽  
Dna Methylation ◽  
Association Study ◽  
Meta Analysis ◽  
African Ancestry ◽  
Cpg Sites ◽  
Genome Wide ◽  
Novel Association ◽  
Peripheral Leukocytes

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P <1×10 −5 . In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated ( P <1×10 −7 ) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P <0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 ( TXNIP ) and cg00716257 ( JDP2 ) determined by environmental effects acting on both systolic BP and methylation levels.

Delirium prior to dementia as a clinical phenotype of Lewy body disease: an autopsied case report

2016 ◽  
Vol 29 (4) ◽  
pp. 687-689 ◽  
Author(s):  
Hiroshige Fujishiro ◽  
Ito Kawakami ◽  
Kenichi Oshima ◽  
Kazuhiro Niizato ◽  
Shuji Iritani
Keyword(s):  
Lewy Body ◽  
Clinical Phenotype ◽  
Lewy Bodies ◽  
Lewy Body Disease ◽  
Japanese Woman ◽  
Visual Hallucinations ◽  
Limited Information ◽  
Lewy Body Pathology ◽  
Old Japanese ◽  
The Relationship

ABSTRACTAlthough delirium shares clinical characteristics with dementia with Lewy bodies (DLB), there is limited information regarding the relationship between delirium and Lewy body pathology. Here, we report an 89-year-old Japanese woman with an episode of delirium who was pathologically confirmed to have limbic-type Lewy body disease (LBD). Although she exhibited transient visual hallucinations during the delirium, she had no overt dementia. She developed no core clinical features of DLB and died of pneumonia at the age of 90 years. This autopsied case suggests that delirium may be one of the clinical phenotypes of LBD prior to the onset of dementia.

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