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Passive digital markers (PDMs) for Early Detection of ADRD: A longitudinal approach
No full textBackground:
The timely diagnosis of Alzheimer's disease and other related dementias (ADRD) occurs two to five years after the onset of symptoms. Passive Digital Markers (PDMs) are predictive models that leverage the existing multimodal data captured and stored in the electronic health records (EHR). Our group has previously demonstrated that our PDMs can detect the risk of developing ADRD at 1‐ and 3‐year horizons. We developed and validated new PDMs to identify ADRD at 1 to 12 months prior to onset
Method:
Retrospective case control study of patients (N = 204) from Federally Qualified Primary Care Centers in Indianapolis over the age of 65 years with no history of ADRD, mild cognitive impairment, schizophrenia or bipolar disorder prior to the index date. We used XGBoost to process the passive exposure variables captured by the EHR and classify the presence or absence of ADRD against diagnosis determined by a consensus‐based cognitive diagnosis after a comprehensive cognitive assessment that included neuropsychological testing, neurological examinations, and caregiver interviews.
Result:
Among the 204 patients in our study, we found no baseline differences between patients with normal cognition, mild cognitive impairment, and dementia for mean age (69.9 years vs 69.7 years vs 72.1 years, p‐value 0.08), female gender (65.4% vs 61.4% vs 60.0%, p‐value 0.86), Black or African‐American race (36.5% vs 56.7% vs 68%, p‐value 0.08), mean number of medications (4.02 vs 4.53 vs 4.64, p‐value 0.45), or mean number of comorbidities (3.02 vs 3.43 vs 3.71, p‐value 0.11). The PDM for ADRD at a 1‐month horizon had an Area Under the Curve (AUC) of 0.77 (0.03) and 0.75 (0.04) for 1‐month and 12‐months prediction horizons, respectively.
Conclusion:
PDMs for early detection of ADRD are accurate, scalable and feasible. longitudinal follow‐up is important as accuracy improves closer to the onset by leveraging the more up‐to‐date information in the clinical notes
Association of Alzheimer's Disease Polygenic Risk Score with Concussion Severity and Recovery Metrics
No full textBackground: Identification of genetic alleles associated with both Alzheimer's disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed.
Objective: We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset.
Methods: We assessed six concussion outcomes in 931 participants, including two recovery measures (number of days to asymptomatic and to return to play (RTP)) and four severity measures (scores on SAC and BESS, SCAT symptom severity and total number of symptoms). We calculated the PRS using a published score and performed multiple linear regression to assess the relationship of the PRS with outcomes. We also used ANOVAs, t-tests, and chi-square tests to examine outcomes by APOE genotype.
Results: Higher PRS was associated with longer injury to RTP time in the normal RTP (< 24 days) subgroup (p = 0.024). A one standard deviation increase in the PRS resulted in a 9.89 hour increase to RTP time. This result was no longer significant after inclusion of covariates. There were no other consistently significant effects.
Conclusions: Our findings suggest high AD genetic risk is not associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations
Culinary Medicine Interventions Among Racial and Ethnic Minority and Underrepresented Populations: A Systematic Review
No full textIntroduction: Racial and ethnic minority populations experience a higher rate of diet-related disparities compared to the general population. Culinary medicine interventions have the potential to help improve health equity among disadvantaged groups. We examined behavioral, anthropometric, and laboratory outcomes of culinary medicine interventions among racial and ethnic minority and underrepresented populations. Methods: All articles on the PubMed database were searched to identify eligible studies with no date limitation. Articles that included a culinary medicine intervention for racial and ethnic minority and underrepresented populations were eligible for inclusion. Results: A total of 25 articles were included. There were 4186 participants with 3268 adult, 857 child, and 2452 female participants. Participants predominantly identified as Black (25.0%), South Asian (21.6%), and Hispanic (33.5%). Studies varied in design, setting, length, and outcomes (e.g., behavior, clinical). Overall, outcomes varied in significance and effect size. Risk of bias was high among studies. Discussion: Culinary medicine interventions appear to be successfully integrated across various settings and among diverse populations with variable effect on behavioral changes and anthropometric measurement changes. Conclusion: Culinary medicine interventions show promise for improving diet-related health equity; however, greater rigor and controlled study designs are needed
Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W
No full textFrontotemporal dementia (FTD) and Alzheimer’s disease (AD) are the most common forms of early-onset dementia. Unlike AD, FTD begins with behavioral changes before the development of cognitive impairment. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of FTD and parkinsonism linked to chromosome 17. These individuals develop abundant filamentous tau inclusions in brain cells in the absence of β-amyloid deposits. Here, we used cryo-electron microscopy to determine the structures of tau filaments from the brains of human MAPT mutants V337M and R406W. Both amino acid substitutions gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified another assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau (297–391) with substitution V337M had the Alzheimer fold and showed an increased rate of assembly
Longitudinal Trends in Physical Activity Among Older Adults With and Without HIV in Uganda
No full textIntroduction: Physical Activity (PA) and its links to frailty, quality of life (QoL), and other comorbidities in older Ugandans living with HIV remain under-explored.
Methods: We analyzed data from three annual assessments of older people living with HIV (PLWH) and age- and sex-similar people not living with HIV (PnLWH). We fitted linear generalized estimating equations (GEE) regression models to estimate the correlates of PA, including demographics, frailty, QoL, HIV, and other comorbidities.
Results: We enrolled 297 PLWH and 302 PnLWH. Older age (b = -157.34, 95% CI [-222.84, -91.83]), living with HIV (b = -979.88 [95% CI: -1878.48, -81.28]), frailty (b = -3011.14 [95% CI: -4665.84, -1356.45]), and comorbidities (b = -2501.75 [95% CI: -3357.44, -1646.07]) were associated with lower overall PA. Higher general QoL (b = 89.96 [95% CI: 40.99, 138.94]) was associated with higher PA.
Conclusion: PA interventions may support wellbeing of older people in the region, and tailored interventions should be explored
Understanding monocyte-driven neuroinflammation in Alzheimer's disease using human cortical organoid microphysiological systems
No full textIncreasing evidence strongly links neuroinflammation to Alzheimer's disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability. Using these models, we found that monocytes from AD patients exhibit increased infiltration ability, decreased amyloid-β clearance capacity, and stronger inflammatory response than monocytes from age-matched control donors. Moreover, we observed that AD monocytes induce pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis. Furthermore, the marked increase in IL1B and CCL3 expression underscores their pivotal role in AD monocyte-mediated neuroinflammation. Our findings provide insight into understanding monocytes' role in AD pathogenesis, and our lab-compatible MPS models may offer a promising way for studying various neuroinflammatory diseases
A Window Between Worlds Evaluation Report
No full textThis evaluation examines the implementation and outcomes of A Window Between Worlds (AWBW) within the Your Life, Your Story (YLYS) Resilience Summer Camp, funded by The Humana Foundation as part of the Healthy Minds, Healthy Families initiative. The two-week, trauma-informed, arts-based intervention was designed to strengthen resilience among Latine youth. Fifteen adolescents (ages 12–16) enrolled in the camp, and nine completed both pre- and post-assessments. Measures included Protective Childhood Experiences (PCE), the Strengths and Difficulties Questionnaire (SDQ), and child-reported trauma symptoms (CROPS), along with fidelity and satisfaction data.
Findings showed statistically significant increases in protective factors, particularly peer support, mentorship, emotional openness, and cultural/community connection. Prosocial behaviors improved, and most youth reported feeling safer expressing themselves, more hopeful about the future, and motivated to make positive changes. Trauma symptom scores did not significantly decrease; however, some increases in reported stress may reflect greater emotional awareness and trust in disclosing difficult experiences.
Fidelity to the trauma-informed model was high, and parent engagement emerged as a critical strength, supporting intergenerational resilience. Overall, results provide promising evidence that culturally grounded, relationship-first, arts-based programming can enhance protective factors and emotional wellbeing among Latine youth
Caloric Restriction Enhances the Efficacy of Anti-Androgen Therapy in Prostate Cancer by Inhibiting Androgen Receptor Translation
No full textEpidemiological studies suggest that diet can impact the incidence, progression, and response to treatment in multiple cancers, including prostate cancer (PCa). In this study, we investigated the use of dietary interventions, specifically caloric or protein restriction, in combination with anti-androgen therapy as a treatment for PCa. Caloric restriction through alternate-day fasting (ADF) reduced androgen receptor (AR) expression and signaling. This reduction in AR enhanced the anti-tumor activity of the AR antagonist enzalutamide in multiple mouse models of PCa. Mechanistic studies revealed that nutrient starvation via ADF predominantly decreased AR mRNA translation at the elongation stage due to amino acid limitation. Pharmacological agents that similarly impair translation elongation and promote ribosome collisions mimicked the AR translation reduction observed with ADF. Overall, these findings suggest that amino acid limitation through ADF impairs translation elongation in PCa, to which AR mRNA translation is susceptible, leading to a reduction in AR protein levels and enhancing AR-targeted therapy
Racial and demographic disparities in glp-1ra use among breast cancer patients with Type 2 Diabetes
No full textGlucagon-like peptide-1 receptor agonists (GLP-1RAs) offer significant benefits for patients with type 2 diabetes mellitus (T2DM), including improved glycemic control, weight reduction, cardiovascular protection, and reduced all-cause mortality, which are particularly relevant to breast cancer survivorship. Disparities in access may worsen inequities in care. Using the TriNetX national electronic health record database, we conducted a retrospective cohort study of 119,430 breast cancer patients with type 2 diabetes (2005-2024; mean age 66.1 ± 11.4 years; 67.2% White, 22.9% Black, 5.7% Asian, 4.2% Other). After propensity matching, compared with White patients, Asian (HR 0.64, 95% CI 0.58-0.71), Black (HR 0.78, 95% CI 0.75-0.81), and Other race patients (HR 0.90, 95% CI 0.83-0.97) were significantly less likely to receive GLP-1RAs. These disparities persisted among overweight and obese subgroups: Asian (HR 0.78, 95% CI 0.68-0.88), Black (HR 0.78, 95% CI 0.74-0.81), and Other patients (HR 0.83, 95% CI 0.72-0.95). These findings underscore the urgent need to address inequitable access to GLP-1RAs in breast cancer survivorship care
Acute alcohol in prefrontal cortex is characterized by enhanced inhibition that transitions to excitation
No full textAcute alcohol can have profound effects on the brain and behavior. Dorsal medial prefrontal cortex (dmPFC) function is especially sensitive to disruption from acute alcohol exposure. The acute, broadly inhibitory pharmacodynamics of alcohol in dmPFC have been well characterized in in vitro and ex vivo preparations, but seemingly contradict the stimulatory behavioral effects of alcohol at low-to-moderate doses. To determine the effects of acute alcohol on dmPFC activity, this study combined multiple routes of alcohol exposure across multiple rodent species and preparations and utilized modeling techniques to make direct predictions about brain ethanol concentrations. These findings revealed that the acute effects of alcohol on dmPFC are actually biphasic in nature, such that broad reductions in activity are immediately followed by broad increases in neural activity. Notably, these increases in neural activity were only observed in in vivo preparations, suggesting that network engagement and exposure route may be critical