Citations

Background African American adults experience a disproportionate burden of dementia, shaped by structural and clinical factors that remain unclear. Objective To quantify associations between multimorbidity, polypharmacy, and cognition in the context of neighborhood disadvantage. Methods This study is a cross-sectional analysis of 348 African American adults aged 45–92 years (mean 64.3 years; 73.6% female) from the Aging Research Characterizing Health Exposome via Social drivers (ARCHES) cohort. Comorbidity burden was assessed using a modified Charlson Comorbidity Index (CCI), polypharmacy as ≥5 medications, and neighborhood disadvantage using the Area Deprivation Index (ADI). Linear regression estimated associations with a Preclinical Alzheimer’s Cognitive Composite (PACC). The polypharmacy model included modified CCI as a covariate, and effect modification by ADI was assessed using an interaction term between polypharmacy and ADI. Results Higher modified CCI was associated with lower cognitive performance (B = −0.071; 95% CI: −0.130, −0.012). Polypharmacy was not independently associated with cognition after modified CCI adjustment (B = −0.081; β = −0.057; p = 0.257). No significant ADI interaction was found (p = 0.064).

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactolipids, resulting in toxic psychosine accumulation and progressive demyelination of the central and peripheral nervous systems. Newborn screening (NBS) has increased recognition of later-onset Krabbe disease, although interpretation of complex GALC genotypes remains challenging, particularly in the presence of “pseudodeficiency” and modifier alleles. In this case report, we describe a child with late-infantile Krabbe disease identified through NBS with markedly reduced GALC activity and a homozygous GALC haplotype containing c.956A>G (p.Tyr319Cys; Y319C) and c.1685T>C (p.Ile562Thr; I562T), in addition to other benign variants. Retrospective analysis of the newborn screening specimen demonstrated mild psychosine elevation. Despite preserved neurodevelopment, longitudinal surveillance demonstrated progressive cerebral white matter abnormalities by 3 years and 9 months of age and psychosine elevation in erythrocytes (14 pmol/g Hb; controls < 5), prompting umbilical cord blood transplantation (UCBT). Following transplantation, GALC enzyme activity normalized, psychosine levels decreased, and serial neuroimaging demonstrated radiographic stability without neurologic regression at last follow-up (9 years old). This case expands the phenotypic spectrum associated with homozygosity for the p.Tyr319Cys variant and highlights the role of p.Ile562Thr in amplifying the pathogenic potential when in cis with p.Tyr319Cys. This GALC haplotype illustrates how “pseudodeficiency” and modifier alleles may collectively influence biochemical, radiologic, and clinical disease expression. These findings emphasize the importance of integrating genotype, psychosine, enzyme activity, and longitudinal neuroimaging when evaluating infants with NBS results positive for Krabbe disease.

Background Hearing impairment (HI) has been identified as a potentially modifiable risk factor for dementia, yet its relationship with Alzheimer's disease (AD) neuropathology and the temporal directionality remain unclear, particularly in late life. Objective To examine cross-sectional and longitudinal associations between HI, clinical cognitive status, and AD biomarkers in community-dwelling older adults. Methods We included 474 DRIVES Project participants (mean age 73.5 ± 5.2 years). Hearing was assessed using the NIH Toolbox Words-in-Noise (WIN) test. Clinical cognitive status was assessed using Clinical Dementia Rating (CDR). AD biomarkers included cerebrospinal fluid (CSF) Aβ 42 /Aβ 40 , t-tau/Aβ 42 , and p-tau/Aβ 42 ratios and amyloid PET imaging. Multivariable linear, logistic, Cox proportional hazards, and Fine–Gray competing-risk models were used. Results HI was more prevalent among participants with mild cognitive impairment (MCI; defined as CDR = 0.5) than cognitively normal individuals (50% versus 24%, p < 0.001), and MCI status was independently associated with worse baseline WIN thresholds (β = 1.55 dB SNR; 95% CI 0.72–2.37). HI was not cross-sectionally associated with CSF amyloid or tau ratios or amyloid PET positivity. Longitudinally, baseline MCI was associated with a higher risk of incident HI (Cox HR = 2.63, 95% CI 1.48–4.67; Fine–Gray sHR = 2.79, 95% CI 1.06–7.40), whereas baseline HI was not associated with subsequent CDR progression. Conclusions In older adults, HI was associated with MCI but not core AD biomarkers or future CDR progression, suggesting that late-life HI may reflect cognitive vulnerability or broader brain aging rather than independently driving AD pathology.

Objectives Long-term symptoms following infection with acute respiratory syndrome coronavirus-2 (SARS-CoV-2), termed post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID (LC), persist beyond 90 days and may impact at least 10% of patients with acute infection. The exact cause of LC remains unknown, but several theories include persistent viral particles, immune dysfunction, and autonomic nervous system (ANS) imbalance, particularly involving the vagus nerve. Given the role of the vagus nerve in inflammation regulation, vagal nerve stimulation (VNS) is being explored as a treatment option. The present study aimed to evaluate the feasibility, safety, and exploratory effects of a handheld external transcutaneous cervical non-invasive VNS (tcVNS) on the primary endpoint of Post-COVID Functional Status (PCFS) grade, alongside secondary outcomes such as LC-related fatigue and other symptoms. Methods Participants from our Post COVID Care Clinic were randomized into treatment (tcVNS treatments two minutes, three times a day) and control (no VNS) groups for a study period of 12 weeks. Participants completed validated questionnaires, PET-CT scans, and inflammatory cytokines at baseline and 12 weeks. Results All randomized patients (8 tcVNS, 10 control) completed the 12-week study. Participants randomized to tcVNS were observed to have improvements in PHQ-9, PROMIS-F, and COMPASS-31 when compared to controls, but these differences were not statistically significant. Cortisol and DHEA were also observed to increase less in the tcVNS group when compared to the control group, but these changes were also not statistically significant. Conclusions tcVNS was well tolerated and may be a promising therapeutic approach for LC, a chronic disease with no approved treatments and very low rates of complete recovery.

Objective Long COVID (LC) refers to the long-term symptoms occurring after SARS-CoV-2 infection and resolution of the initial disease prodrome. While LC is increasingly recognized, knowledge about its biomarkers is still limited. This study examines imaging findings in 18 F-FDG PET-CT scans in 40 patients with LC from an academic LC Clinic, for potential imaging biomarkers. Methods This study included patients aged 18 and older with confirmed positive SARS-CoV-2 PCR test and at least 28 days post-symptom onset. 18 F-FDG PET-CT scans were performed, and brain metabolic activity was compared to a control database to generate Z-scores. Participants were grouped based on their clinical phenotype and Z-scores of different brain regions were analyzed using t-tests. Results The study group was mainly female (70%), with a median age of 53 years, and predominantly non-Hispanic White (90%). Most had pre-existing conditions such as gastrointestinal, cardiovascular, endocrine, and psychiatric disorders. The findings showed significant cerebral hypometabolism in 29 patients with fatigue and post-exertional malaise (PEM), particularly in the left sensorimotor cortex (p=0.0253) and bilateral primary visual cortex (right: p=0.0096, left: p=0.0016), which persisted up to two years after infection. Conclusions In summary, this study identified persistent cerebral hypometabolism in LC patients, especially those with fatigue with PEM, up to two years post-infection. These results suggest that 18 F-FDG PET-CT could be a valuable tool for diagnosing and managing LC. Further research is essential to confirm these findings and improve treatment strategies for patients with LC.

Background Black adults experience disproportionately higher rates of Alzheimer's disease and related dementias (ADRD), yet remain underrepresented in blood-based biomarker research. Understanding how plasma biomarkers relate to cognitive performance is essential for equitable detection and monitoring of ADRD. Objective We examined cross-sectional and longitudinal associations of both core and non-core plasma biomarkers and cognition in a community-based cohort of Black adults. Methods Participants from the ARCHES study completed baseline plasma biomarker assessments and neuropsychological testing, including a Preclinical Alzheimer Cognitive Composite (PACC) score and the Montreal Cognitive Assessment (MoCA). Plasma biomarkers reflecting amyloid, tau, neurodegeneration, and astrocytic activation were quantified using immunoprecipitation–mass spectrometry and ultrasensitive immunoassay platforms. Linear regression was used to evaluate cross-sectional associations between biomarkers and cognition. Linear mixed-effects models examined whether baseline biomarker levels were associated with cognitive change over one year, adjusting for age, sex, and education. Results The sample included 334 participants with a mean baseline age of 64.6 years (SD = 10.1; range, 45–92.9). Cross-sectionally, higher brain-derived phosphorylated tau 181 was associated with poorer MoCA score (p = 0.04), and neurofilament light chain (NfL) level was also associated with lower PACC score (p = 0.04). Longitudinally, higher baseline NfL and glial fibrillary acidic protein (GFAP) were associated with faster cognitive decline (p < 0.001 and p = 0.018). Conclusions Non-core NfL and GFAP biomarkers are associated with both cross-sectional and longitudinal cognitive performance. These findings highlight the importance of inclusive biomarker research and suggest non-core biomarkers may be particularly informative for characterizing cognitive aging and decline in this population.