Citations

Abstract Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500

Abstract Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their selective vulnerability are not well defined. In naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampus-adjacent white matter. Through gold-standard gene expression and immunolabeling combined with high-dimensional spatial mapping, we identified microglial cell fates in aged white matter characterized by aberrant morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/Lgals3), B-cell lymphoma 2 (Bcl2), and cyclin dependent kinase inhibitors, including Cdkn2a/p16ink4a. Pharmacogenetic or pharmacological targeting of p16ink4a or BCL2 reduced white matter GAL3+ DAM abundance and rejuvenated microglial fimbria organization. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic intervention to promote homeostatic maintenance in the aged brain.

ABSTRACT The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had an unprecedented impact on human health and highlights the need for genomic epidemiology studies to increase our understanding of virus evolution and spread and to inform policy decisions. We sequenced viral genomes from over 22,000 patient samples tested at Mayo Clinic Laboratories between 2020 and 2022 and used Bayesian phylodynamics to describe county and regional spread in Minnesota. The earliest calculated introduction into Minnesota was to Hennepin County from a domestic source around 22 January 2020; 6 weeks before the first confirmed case in the state. This led to the virus spreading to Northern Minnesota and, eventually, the rest of the state. International introductions were most abundant in Hennepin (home to the Minneapolis/St. Paul International Airport) totaling 45 (out of 107) over the 2-year period. Southern Minnesota counties were most common for domestic introductions, with 19 (out of 64), potentially driven by bordering states such as Iowa and Wisconsin as well as Illinois, which is nearby. Hennepin also was, by far, the most dominant source of in-state transmissions to other Minnesota locations ( n = 772) over the 2-year period. We also analyzed the diversity of the location source of SARS-CoV-2 viruses in each county and noted the timing of state-wide policies as well as trends in clinical cases. Neither the number of clinical cases nor the major policy decisions, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, appeared to have an impact on virus diversity across each individual county. IMPORTANCE We analyzed over 22,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes of patient samples tested at Mayo Clinic Laboratories during a 2-year period in the COVID-19 pandemic, which included Alpha, Delta, and Omicron variants of concern to examine the roles and relationships of Minnesota virus transmission. We found that Hennepin County, the most populous county, drove the transmission of SARS-CoV-2 viruses in the state after including the formation of earlier clades including 20A, 20C, and 20G, as well as variants of concern Alpha and Delta. We also found that Hennepin County was the source for most of the county-to-county introductions after an initial predicted introduction with the virus in early 2020 from an international source, while other counties acted as transmission “sinks.” In addition, major policies, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, did not appear to have an impact on virus diversity across individual counties.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Introduction: The differential diagnosis of a spinal intradural extramedullary mass lesion is broad and includes meningioma, schwannoma, neurofibroma, leptomeningeal metastasis, and myxopapillary ependymoma. Though rare, lymphoma should be included in the differential diagnosis of a dural mass lesion. Case Report: A 38-year-old man presented with back pain that progressed over 1 month with associated focal tenderness over his mid to lower thoracic spine. He developed intermittent numbness of the bilateral lower extremities, nuchal rigidity, difficulty sleeping, and night sweats. A magnetic resonance imaging of the thoracic spine demonstrated a dorsal intradural extramedullary enhancing lesion from T7 to T10 extending outside the spinal canal. Dural thickening across the entire circumference of the spinal cord was noted. Computed tomography (CT)-guided biopsy of the thoracic lesion was performed, and pathology was consistent with follicular lymphoma. Fluorodeoxyglucose positron emission tomography:CT demonstrated no systemic disease. Bone marrow biopsy was negative for malignancy. Symptoms resolved with dexamethasone therapy. He was treated with bendamustine and rituximab with follow-up positron emission tomography:CT 2 months later demonstrating a complete response. Conclusions: Lymphoma can rarely present as an isolated dural lesion and should be considered in the differential diagnosis of intradural extramedullary spinal mass lesions. Prompt diagnosis and initiation of treatment can lead to complete response and resolution of symptoms.

INTRODUCTION: Liver disease is a significant public health problem in the United States, with notable racial disparities in mortality. This study examines liver disease mortality trends among Black and White populations during 1999–2020. METHODS: We used CDC WONDER database to ascertain liver disease age-standardized mortality rates in Black and White Americans. Annual percent change was calculated. Age-standardized absolute rate difference and rate ratios were computed by subtracting and dividing the White population's rate from that of the Black population. RESULTS: Liver diseases accounted for 171,627 Black and 1,314,903 White deaths during 1999–2020. Age-standardized mortality rates for Blacks decreased from 22.5 to 20.1 per 100,000 person-years (annual percentage change −0.4%, −0.6% to −0.2%), whereas an increase was observed for Whites, from 17.9 to 25.3 per 100,000 person-years (annual percentage change 1.4%, 1.4% to 1.7%). The rate ratio decreased from 1.26 (1.22–1.29) in 1999 to 0.79 (0.78–0.81) in 2020. This pattern was evident in all census regions, more pronounced among the younger (age 25–64 years) than older (age 65+ years) population and observed across different urbanization levels. The pattern may be attributable to increasing alcohol-related liver disease and metabolic dysfunction–associated steatotic liver disease–related deaths in Whites and tapering in viral hepatitis and primary liver cancer–related deaths in Blacks. Despite notable improvement, racial disparities persist in primary liver cancer and viral hepatitis among the Black population. DISCUSSION: The rise in alcohol-related liver disease and metabolic dysfunction–associated steatotic liver disease–related deaths among Whites, and enduring liver cancer and viral hepatitis disparities in the Black population, underscores the urgent need for tailored public health interventions.

We report a case highlighting key clinical, CSF, and imaging findings of recurrent pleomorphic xanthoastrocytoma with leptomeningeal spread.