Sex differences in brain atrophy in dementia with Lewy bodies

Oltra, Javier; Habich, Annegret; Schwarz, Christopher G.; Nedelska, Zuzana; Przybelski, Scott A.; Inguanzo, Anna; Diaz‐Galvan, Patricia; Lowe, Val J.; Oppedal, Ketil; Gonzalez, Maria C.; Philippi, Nathalie; Blanc, Frederic; Barkhof, Frederik; Lemstra, Afina W.; Hort, Jakub; Padovani, Alessandro; Rektorova, Irena; Bonanni, Laura; Massa, Federico; Kramberger, Milica G.; Taylor, John‐Paul; Snædal, Jon G.; Walker, Zuzana; Antonini, Angelo; Dierks, Thomas; Segura, Barbara; Junque, Carme; Westman, Eric; Boeve, Bradley F.; Aarsland, Dag; Kantarci, Kejal; Ferreira, Daniel

doi:10.1002/alz.13571

Cited by 5 publications

(2 citation statements)

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“…The incidence of DLB is greater in men than in women but pathology and clinical features vary with gender (Oltra et al, 2024 ). One recent study using a mouse model of PD showed that α-syn accumulation was age-dependent, but with male mice being more severely affected by α-syn toxicity than females (Lamontagne-Proulx et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

Al-Musawi,

Dennis,

Clowry

et al. 2024

Front. Dement.

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IntroductionNeuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals.MethodsPrevious studies have shown early hyperexcitability in the hippocampal CA3 region in male A30P mice at 2–4 months of age, therefore, in the current study we have immunostained this region for markers of neuronal activity (c-Fos), reactive astrocytes (glial fibrillary acidic protein, GFAP), microglia (ionizing calcium binding adapter protein 1, Iba-1) and reactive microglia (inducible nitric oxide synthase, iNOS).ResultsWe found an interesting biphasic change in the expression of c-Fos in A30P mice with high expression at 1 month, consistent with early onset of hyperexcitability, but lower expression from 2–4 months in male A30P mice compared to wild-type (WT) controls, possibly indicating chronic hyperexcitability. Neuroinflammation was indicated by significant increases in the % area of GFAP and the number of Iba-1+ cells that expressed iNOS immunoreactivity in the CA3 region in 2–4 months A30P male mice compared to WT controls. A similar increase in % area of GFAP was observed in female A30P mice, however, the Iba-1 count was not different between female WT and A30P mice. In WT mice aged 2–4 months only 4.6% of Iba-1+ cells co-expressed iNOS. In contrast, in age matched A30P mice 87% of cells co-expressed Iba-1 and iNOS. Although there was no difference in GFAP immunoreactivity at 1 month, Iba-1/iNOS co-expression was also increased in a cohort of 1 month old A30P mice.DiscussionAbnormal hα-syn expression in A30P mice caused early changes in network excitability, as indicated by c-Fos expression, and neuroinflammation which might contribute to disease progression.

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Section: Discussionmentioning

confidence: 99%

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

Al-Musawi,

Dennis,

Clowry

et al. 2024

Front. Dement.

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“…In contrast, the prevalence of AD is higher in women [ 197 ]. Sex and gender differences in AD and DLB are not limited to prevalence [ 184 , 198 , 199 ]. Women with LB pathology are at greater risk of underdiagnosis or misdiagnosis [ 184 , 190 ].…”

Section: Call For Diversitymentioning

confidence: 99%

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer’s Disease: A Pragmatic Review for Clinicians

Wyman-Chick,

Chaudhury,

Bayram

et al. 2024

Neurol Ther

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This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and K. A. Wyman-Chick (*)

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Epigenetic and Metabolic Landscape of Dementia with Lewy Bodies

Vishweswaraiah,

Yilmaz,

Gordevicius

et al. 2024

Movement Disorders

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BackgroundLewy body diseases, including dementia with Lewy bodies (DLB), are characterized by α‐synuclein accumulation, leading to dementia. Previous studies suggest distinct epigenetic and metabolomic profiles in DLB.ObjectiveThis study aims to identify diagnostic biomarkers by analyzing the methylome and metabolome in the Brodmann area 7 of postmortem brain tissues from DLB patients and control subjects using multiomics approaches.MethodsMethylation analysis was performed using the Illumina EPIC array, and metabolomics profiling was conducted via 1H nuclear magnetic resonance (NMR) and direct injection/liquid chromatography coupled with mass spectrometry. Differential methylation and metabolite analysis were conducted, followed by pathway enrichment to explore biological relevance.ResultsWe identified 3478 significantly differentially methylated cytosines, mostly hypermethylated, enriched in CpG islands near transcription start sites. Pathway enrichment analysis showed significant pathways, primarily linked to olfactory and synaptic functions. Metabolomics profiling identified 15 significantly altered metabolites, with Phosphatidylethanolamine (PE) Biosynthesis being the most affected pathway. Key correlations between differentially methylated cytosines and metabolites, particularly in the PE Biosynthesis pathway involving PTDSS1 and PCYT2 genes, were observed.ConclusionsNotably, sex‐specific differences were found, with females exhibiting more epigenetic and metabolomic changes than males. Increased hypermethylation, linked to transcriptional silencing, and disruptions in PE biosynthesis suggest a role in synaptic dysfunction and olfactory deficits. In addition, α‐aminoadipic acid was strongly associated with vascular functions, hinting at a possible overlap between vascular health and DLB. This study provides new insights into DLB mechanisms and potential therapeutic targets. © 2024 International Parkinson and Movement Disorder Society.

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Sex differences in brain atrophy in dementia with Lewy bodies

Cited by 5 publications

References 75 publications

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer’s Disease: A Pragmatic Review for Clinicians

Epigenetic and Metabolic Landscape of Dementia with Lewy Bodies

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