👤 A R Winslow

We investigated the relationship between cerebrospinal fluid (CSF) and plasma biomarkers of inflammation, neurodegeneration, and neurocognitive performance in people with HIV (PWH), using longitudinal samples from two previously published cohorts: ACTG A5090 (virally suppressed on antiretroviral therapy, ART) and A736 (ART-naïve or failing). We analyzed paired CSF and plasma samples, as well as 7-domain standardized neurocognitive test scores, at baseline and 24 weeks. Biomarkers included markers of inflammation (e.g., TNF-α, IL-6, IP-10) and neurodegeneration (e.g., NFL, p-Tau217, Aβ42), which were quantified via high-sensitivity immunoassays. Associations with cognition were tested using regression, mediation, and interaction models. Cross-sectional analyses revealed nominal associations between inflammatory markers and cognitive performance, with plasma IL-6 and IP-10 at baseline, and CSF TNFα at week 24 showing the strongest correlations (p < 0.05, uncorrected); however, none survived correction for multiple comparisons. Conversely, higher CSF Aβ42 and plasma BDNF were positively associated with memory and executive function. Longitudinally, biomarker changes did not significantly predict change in global cognition (ΔNPZ-8); the strongest trend (p-Tau217, ρ = -0.12, p = 0.38) was not statistically significant, and multivariate models failed to identify robust predictors (R These results suggest a potential role of CSF TNFα in mediating the neurocognitive effects of HIV and highlight compartment-specific inflammatory dynamics. Plasma TNFα, GFAP, and NFL may serve as peripheral indicators of CNS pathology, though with only moderate concordance. Astrocyte-tau interactions require cautious interpretation pending replication in larger cohorts. Show less

Glyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that C57BL/6J mice dosed with glyphosate for 14 days showed glyphosate and its major metabolite aminomethylphosphonic acid present in brain tissue, with corresponding increases in pro-inflammatory cytokine tumor necrosis factor-⍺ (TNF-⍺) in the brain and peripheral blood plasma. Since TNF-⍺ is elevated in neurodegenerative disorders such as Alzheimer's Disease (AD), in this study, we asked whether glyphosate exposure serves as an accelerant of AD pathogenesis. Additionally, whether glyphosate and aminomethylphosphonic acid remain in the brain after a recovery period has yet to be examined. We hypothesized that glyphosate exposure would induce neuroinflammation in control mice, while exacerbating neuroinflammation in AD mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. We dosed 4.5-month-old 3xTg-AD and non-transgenic (NonTg) control mice with either 0, 50 or 500 mg/kg of glyphosate daily for 13 weeks followed by a 6-month recovery period. We found that aminomethylphosphonic acid was detectable in the brains of 3xTg-AD and NonTg glyphosate-dosed mice despite the 6-month recovery. Glyphosate-dosed 3xTg-AD mice showed reduced survival, increased thigmotaxia in the Morris water maze, significant increases in the beta secretase enzyme (BACE-1) of amyloidogenic processing, amyloid-β (Aβ) 42 insoluble fractions, Aβ 42 plaque load and plaque size, and phosphorylated tau (pTau) at epitopes Threonine 181, Serine 396, and AT8 (Serine 202, Threonine 205). Notably, we found increased pro- and anti-inflammatory cytokines and chemokines persisting in both 3xTg-AD and NonTg brain tissue and in 3xTg-AD peripheral blood plasma. Taken together, our results are the first to demonstrate that despite an extended recovery period, exposure to glyphosate elicits long-lasting pathological consequences. As glyphosate use continues to rise, more research is needed to elucidate the impact of this herbicide and its metabolites on the human brain, and their potential to contribute to dysfunctions observed in neurodegenerative diseases. Show less

Notification by emergency medical services (EMS) to the destination hospital of an incoming suspected stroke patient is associated with timelier in-hospital evaluation and treatment. Current data on adherence to this evidence-based best practice are limited, however. We examined the frequency of EMS stroke prenotification in North Carolina by community socioeconomic status (SES) and rurality. Using a statewide database of EMS patient care reports, we selected 9-1-1 responses in 2019 with an EMS provider impression of stroke or documented stroke care protocol use. Eligible patients were 18 years old and older with a completed prehospital stroke screen. Incident street addresses were geocoded to North Carolina census tracts and linked to American Community Survey socioeconomic data and urban-rural commuting area codes. High, medium, and low SES tracts were defined by SES index tertiles. Tracts were classified as urban, suburban, and rural. We used multivariable logistic regression to estimate independent associations between tract-level SES and rurality with EMS prenotification, adjusting for patient age, sex, and race/ethnicity; duration of symptoms; incident day of week and time of day; 9-1-1 dispatch complaint; EMS provider primary impression; and prehospital stroke screen interpretation. The cohort of 9527 eligible incidents was mostly at least 65 years old (65%), female (55%), and non-Hispanic White (71%). EMS prenotification occurred in 2783 (29%) patients. Prenotification in low SES tracts (27%) occurred less often than in medium (30%) and high (32%) SES tracts. Rural tracts had the lowest frequency (21%) compared with suburban (28%) and urban (31%) tracts. In adjusted analyses, EMS prenotification was less likely in low SES (vs high SES; odds ratio 0.76, 95% confidence interval 0.67-0.88) and rural (vs urban; odds ratio 0.64, 95% confidence interval 0.52-0.77) tracts. Across a large, diverse population, EMS prenotification occurred in only one-third of suspected stroke patients. Furthermore, low SES and rural tracts were independently associated with a lower likelihood of prehospital notification. These findings suggest the need for education and quality improvement initiatives to increase EMS stroke prenotification, particularly in underserved communities. Show less

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted. Show less