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Diffusion tensor imaging reveals neuronal microstructural changes in myalgic encephalomyelitis/chronic fatigue syndrome.

ABSTRACT: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients suffer from a variety of physical and neurological complaints indicating the central nervous system plays a role in ME/CFS pathophysiology. Diffusion tensor imaging (DTI) has been used to study microstructural changes in neurodegenerative diseases. In this study, we evaluated DTI parameters to investigate microstructural abnormalities in ME/CFS patients. We estimated DTI parameters in 25 ME/CFS patients who met Fukuda criteria (ME/CFS_Fukuda ), 18 ME/CFS patients who met International Consensus Criteria (ICC) (ME/CFS_ICC ) only and 26 healthy control (HC) subjects. In addition to voxel-based DTI-parameter group comparisons, we performed voxel-based DTI-parameter interaction-with-group regressions with clinical and autonomic measures to test for abnormal regressions. Group comparisons between ME/CFS_ICC and HC detected significant clusters (a) with decreased axial diffusivity (p = .001) and mean diffusivity (p = .01) in the descending cortico-cerebellar tract in the midbrain and pons and (b) with increased transverse diffusivity in the medulla. The mode of anisotropy was significantly decreased (p = .001) in a cluster in the superior longitudinal fasciculus region. Voxel-based group comparisons between ME/CFS_Fukuda and HC did not detect significant clusters. For ME/CFS_ICC and HC, DTI parameter interaction-with-group regressions were abnormal for the clinical measures of information processing score, SF36 physical, sleep disturbance score and respiration rate in both grey and white matter regions. Our study demonstrated that DTI parameters are sensitive to microstructural changes in ME/CFS_ICC and could potentially act as an imaging biomarker of abnormal pathophysiology in ME/CFS. The study also shows that strict case definitions are essential in investigation of the pathophysiology of ME/CFS.

SUBMITTER: Thapaliya K

PROVIDER: S-EPMC9291819 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: ME/CFS is a lifelong debilitating disease that affects approximately 1% of the global population. Previous studies have identified dysfunctional activity in metabolic, immune and neurological pathways. The goal of this study is to identify ME/CFS specific variations in DNA methylation to determine whether the patient specific epigenetic patterns provide insight into the disease pathophysiology. Methods: DNA was extracted from the PBMCs of 10 ME/CFS patients and age/gender matched controls. After performing RRBS the sequence was aligned to hg19 genome using Bismark. The data was analyzed using first an ANOVA F test through DMAP in order to determine variation between the patient and control groups across 40-220bp fragments of the genome. Additional analysis was performed following a MethylKit pipeline, which analyzed the variation on a single CpG basis using a Fishers test. Results: From a total of 146,575 DMAP fragments we identified 76 differentially methylated fragments (P <0.05, Diff meth +/- 15%). A total of 31 were associated with gene regions (intronic/exonic). MethylKit analysis also identified a total of 394 differentially methylated cytosines (FDR corrected P <0.05, Diff meth +/- 15%) from a total of 196,172 individual analyzed cytosines, 91 of the statistically significant cytosines fell within gene regions. Comparison of both methylomes and regions where both the DMAP fragments and multiple MethylKit cytosines fell highlighted areas of the genome containing regulatory elements associated with metabolic and immune activity. Gene body pathway enrichment additionally identified immune metabolic and neurological related functions. Conclusions: Our study represents the first investigation of ME/CFS patients using reduced representation bisulfite sequencing. We identified a number of major differences between patients that distinguished them from healthy controls. Our results identified a number of differentially methylated regulatory elements and gene bodies that highlight the disturbed pathophysiology in ME/CFS. In particular the large number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology in patients.

Project description:BACKGROUND:Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study. RESULTS:DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls. CONCLUSIONS:Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.

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Diffusion tensor imaging reveals neuronal microstructural changes in myalgic encephalomyelitis/chronic fatigue syndrome.

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