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The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

The full text of this preprint has been withdrawn by the authors while they make corrections to the work. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

Alzheimer's disease (AD) is the most common form of dementia, progressively impairing memory and cognition. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify abnormal biophysical mechanisms underlying these abnormal electrophysiological patterns, we estimated the parameters of a spectral graph-theory model (SGM). SGM is an analytic model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. The long-range excitatory time scale was associated with greater deficits in global cognition and was able to distinguish AD patients from controls with high accuracy. These results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the spatiospectral signatures and cognition in AD.

Introduction: Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available.

Objectives: To develop a model to estimate the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward.

Design and setting: A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden were estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward.

Main outcome measures: Incidence of Sanfilippo syndrome was calculated for each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. Direct and indirect costs were calculated for each simulated patient from onset of symptoms to death.

Results: From 2023-2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.04 billion USD present value (2023) with current standard of care. The burden to individual families exceeded $8 million present value from time of birth per child born with Sanfilippo syndrome.

Conclusion: Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families demonstrates a considerable cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome.

DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC arrays. We conducted a comprehensive assessment of the EPIC array probe reliability using 138 duplicated blood DNAm samples generated by the Alzheimer's Disease Neuroimaging Initiative study. We introduced a novel statistical measure, the modified intraclass correlation, to better account for the disagreement in duplicate measurements. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliable information for probes on the EPIC array, will serve as a valuable resource for future DNAm studies.

Circulating metabolites act as biomarkers of dysregulated metabolism, and may inform disease pathophysiology. A portion of the inter-individual variability in circulating metabolites is influenced by common genetic variation. We evaluated whether a genetics-based "virtual" metabolomics approach can identify novel metabolite-disease associations. We examined the association between polygenic scores for 726 metabolites (derived from OMICSPRED) with 1,247 clinical phenotypes in 57,735 European ancestry and 15,754 African ancestry participants from the BioVU DNA Biobank. We probed significant relationships through Mendelian randomization (MR) using genetic instruments constructed from the METSIM Study, and validated significant MR associations using independent GWAS of candidate phenotypes. We found significant associations between 336 metabolites and 168 phenotypes in European ancestry and 107 metabolites and 56 phenotypes among African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolite-phenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p<0.05). Validated findings included the metabolites bilirubin and X-21796 with cholelithiasis, phosphatidylcholine(16:0/22:5n3,18:1/20:4) and arachidonate(20:4n6) with inflammatory bowel disease and Crohn's disease, and campesterol with coronary artery disease and myocardial infarction. These associations may represent biomarkers or potentially targetable mediators of disease risk.

Traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function which contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham congenic donor mice into otherwise healthy, age-matched, irradiated hosts. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI showed that longer reconstitution periods were associated with increased microgliosis and leukocyte infiltration. Thus, TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in innate immunity and neurological function, as well as altered sensitivity to subsequent brain injury.