Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Objectives Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyPeer reviewe

Киберпространство и виртуальная реальность: попытка историко-философского анализа

Материалы IV Республик. науч. конф. студентов, магистрантов и аспирантов, Гомель, 12 мая 2011 г

Association study of cholesterol-related genes in Alzheimer's disease

Alzheimer's disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some sample

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Towards an understanding of fatigue in Parkinson's disease.

OBJECTIVES: To gain an improved understanding of fatigue in Parkinson's disease (PD) by exploring possible predictors among a wide range of motor and non-motor aspects of PD. METHODS: 118 consecutive PD patients (54% men; mean age, 64 years) were assessed regarding fatigue, demographics and a range of non-motor and motor symptoms. Variables significantly associated with fatigue scores in bivariate analyses were used in multiple regression analyses with fatigue as the dependent variable. RESULTS: Fatigue was associated with increasing Hoehn & Yahr stages, specifically transition from stages I-II to stages III-V. Regression analysis identified five significant independent variables explaining 48% of the variance in fatigue scores: anxiety, depression, lack of motivation, Unified PD Rating Scale (UPDRS) motor score and pain. Gender, age, body mass index, PD duration, motor fluctuations, dyskinesias, symptomatic orthostatism, thought disorder, cognition, drug treatment, sleep quality and daytime sleepiness were not significantly associated with fatigue scores. When considering individual motor symptom clusters instead of the UPDRS motor score, only axial/postural/gait impairment was associated with fatigue. CONCLUSIONS: We found fatigue to be primarily associated with symptoms of depression and anxiety, and with compromised motivation, parkinsonism (particularly axial/postural/gait impairment) and pain. These results are in agreement with findings in other disorders and imply that fatigue should be considered a separate PD entity differing from, e.g., excessive daytime sleepiness. Fatigue may have a distinguished neurobiological background, possibly related to neuroinflammatory mechanisms. This implies that novel treatment options, including anti-inflammatory therapies, could be effective

Förskola för fler barn : En kvalitativ intervjustudie och kritisk policyanalys om synen på barn i behov av språkutveckling i det svenska språket

Denna studie syftar till att studera hur förskolans uppdrag rörande barn i behov av språkutveckling i det svenska språket beskrivs av olika aktörer som regering, riksdag och förskollärare. Detta undersöks i relation till riksdagens beslut kring Förskola för fler barn.  Studien utgår från Carol Bacchis teoretiska perspektiv “What’s the Problem (represented to be)?” som grundas i ett socialkonstruktionistiskt perspektiv med nära släktskap med olika typer av diskursanalys.  För att besvara studiens syfte har ett urval av policydokument som relaterar till beslutet Förskola för fler barn analyserats med hjälp av Carol Bacchis metod för kritisk policyanalys. Data har även samlats in genom kvalitativa semistrukturerade intervjuer med förskollärare som analyserats med hjälp av tematisk analys ifrån ett socialkonstruktionistiskt perspektiv, enligt Virginia Braun och Victoria Clarke.  Studiens resultat visade att det finns en samstämmighet kring antagandena att tidiga insatser i förskolan leder till bättre språkutveckling och skolresultat. Ett ökat deltagande i förskolan antas även förbättra både integration och jämställdhet i samhället i stort. Likheter finns även i policydokumentens och förskollärarnas uppfattningar om vikten av att ha adekvat utbildning och kompetens för att lyckas i arbetet med barns språkutveckling i det svenska språket. Relationsskapande lyfts fram som en viktig faktor i samverkan med de målgrupper som har liten erfarenhet av förskolan eller inte har svenska som modersmål. Analysen av utredningen visade även att nyanlända barn och vårdnadshavare särskiljs från andra grupper av barn och vårdnadshavare i de åtgärder som presenteras. Denna kategorisering ses inte lika tydligt i förskollärarnas utsagor. Kategoriseringen bidrar till att konstruera en bild av nämnda vårdnadshavare och barn som “de andra”. Förskolans roll blir att integrera barnen och familjerna in i det svenska samhället.

Salivary cortisol and suicidal behavior-A follow-up study.

INTRODUCTION: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis is a common finding in major depressive disorder. Similar studies on suicide attempters are less abundant, and the results are divergent. The main aim of the present study was to investigate HPA-axis parameters by the time of a suicide attempt and at follow-up in search for associations between HPA-axis function and suicidal behavior. METHODS: Thirty-five suicide attempters and 16 non-suicidal controls were admitted to a psychiatric ward between the years of 1986 and 1992. Corticotrophin-releasing hormone (CRH) in cerebrospinal fluid and urinary cortisol were obtained for the suicide attempters. The patients were followed up approximately 12 years after the index admission. Cortisol was measured in saliva, and additional suicide attempts and current psychiatric symptoms were registered. RESULTS: At follow-up, evening salivary cortisol was lower in suicide attempters compared to controls. Low cortisol levels at follow-up were associated with severe psychiatric symptoms. Among women, repeated suicide attempts were associated with low morning and lunch salivary cortisol, and in this subgroup we also found significant correlations between salivary cortisol at follow-up, and CRH as well as urinary cortisol at index. CONCLUSION: We found evidence for an association between low HPA-axis activity and suicidal behavior. This could be due to long-lasting and severe psychiatric morbidity, which in turn has exhausted the HPA-axis of these patients. The potential role of hypocortisolism should be given more attention in studies on suicidal patients

Can infections trigger alpha-synucleinopathies?

As synucleinopathies, Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that involve the spread of pathogenic alpha-synuclein (αSyn) throughout the brain. Recent studies have suggested a role for αSyn as an antimicrobial peptide in response to PD- and MSA-related infections of peripheral tissues, including those in the respiratory, gastrointestinal, and urogenital systems. In this chapter, we examine epidemiological and experimental evidence for a role of peripheral microbial infections in triggering alpha-synucleinopathies. We propose a model of how infectious triggers, in conjunction with inflammatory, environmental, and genetic facilitators, may result in transfer of pathogenic αSyn strains from the periphery to the brain, where they propagate and spread. Finally, we discuss future research challenges and programs necessary to clarify the role of infections as triggers of PD and MSA and, ultimately, to prevent the onset of these diseases by infectious triggers.status: publishe

Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood.

Low levels of vitamin D may play a role in psychiatric disorders, as cross-sectional studies show an association between vitamin D deficiency and depression, schizophrenia and psychotic symptoms. The underlying mechanisms are not well understood, although vitamin D is known to influence the immune system to promote a T helper (Th)-2 phenotype. At the same time, increased inflammation might be of importance in the pathophysiology of depression and suicide. We therefore hypothesized that suicidal patients would be deficient in vitamin D, which could be responsible for the inflammatory changes observed in these patients