Kelsey Research Foundation

BackgroundThe U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a Phase 3, multicenter, 2‐year, randomized controlled trial assessing the effects of two multidomain lifestyle interventions on cognition in older adults at risk for cognitive decline due to well‐established factors such as sedentary behavior, suboptimal diet, and suboptimal cardiometabolic health. A key aim was to test the generalizability of the FINGER findings in a diverse, representative U.S. cohort. Interventions were modeled on FINGER, adapted to U.S. culture, and delivered in collaboration with community partners.MethodParticipants aged 60‐79 years meeting pre‐specified risk criteria for cognitive decline were randomized (1:1) at five sites to one of two intervention arms. Both arms targeted physical activity, nutrition, cognitive/social challenge and cardiometabolic risk management, but differed in intensity and accountability. The Structured arm (STR) included frequent peer team meetings, regular exercise, the MIND diet, BrainHQ cognitive training, social/cognitive challenge, and monthly blood pressure monitoring. The Self‐Guided arm (SG) included fewer peer team meetings and general health education with support to encourage health behaviors. The primary outcome, assessed at baseline and every six months, was change in global cognition, measured using a composite score based on tests of executive function, episodic memory, and processing speed. Secondary outcomes included domain‐specific cognitive scores, Clinical Dementia Rating‐Sum of Boxes, functional ability, frailty, and intervention response by subgroups (e.g., APOE4 carriers).ResultA total of 2,111 participants (mean age 68±5 years, 69% female, 31% from minoritized ethnoracial groups) were randomized. Retention exceeded 94%, and intervention adherence remained high throughout the 2‐year intervention period. Topline findings on intervention effects for primary and secondary outcomes will be presented. Additionally, two participants will share testimonials about their trial experiences.ConclusionU.S. POINTER, the largest lifestyle intervention trial globally, successfully met ambitious recruitment goals and engaged a diverse, at‐risk cohort while maintaining high retention and participation rates. The topline results will provide pivotal evidence on the effectiveness of multidomain interventions to improve cognition or slow decline in older U.S. adults, with high potential to inform public health initiatives aimed at reducing Alzheimer's disease and related dementia risk.

BackgroundU.S. POINTER was a multisite randomized controlled trial testing the impact of multidomain lifestyle intervention on cognitive function in cognitively unimpaired older adults at risk for cognitive decline and dementia. Here we present the intervention adherence data.MethodsU.S. POINTER randomly assigned over 2000 participants to one of two intervention arms, both targeting physical activity, nutrition, cognitive/social challenge and cardiometabolic risk reduction, but differing in intensity and accountability. The intervention prescription for the Structured (STR) arm included frequent peer team meetings (weekly for 16 weeks, bimonthly for 2 months, monthly thereafter), a structured exercise program using community facilities, a nutrition prescription modeled on the MIND diet, BrainHQ computerized cognitive training, regular cognitive/social challenge, and frequent monitoring of cardiometabolic health. The Self‐guided (SG) arm included a total of six peer team meetings, general health education covering all intervention domains, and gift cards to encourage healthy behaviors. Treatment fidelity assessments, guided by recommendations of the NIH Behavior Change Consortium, were conducted via annual site visits. Implementation of the intervention protocol was regularly monitored via monthly meetings with site intervention leadership to ensure consistency across study sites.ResultsAdherence tracking for the STR intervention arm included team meeting attendance (%), Fitbit activity (mean very active minutes/week), self‐reported exercise (aerobic, resistance, and balance mean minutes/week), MIND diet adherence (mean score/week), cognitive training (mean BrainHQ levels completed/week), cognitive/social activity (% of goal completed/week), and blood pressure checks (% of goal completed/month). SG intervention adherence was tracked using team meeting attendance. This topline presentation of U.S. POINTER's intervention adherence will provide metrics for the entire cohort and by subgroups based on age, biological sex, race, ethnicity, APOE genotype, baseline cardiometabolic health status, and baseline cognitive function.ConclusionU.S. POINTER's adherence metrics obtained in an ethnoracially and geographically diverse cohort (31% from underrepresented groups at 5 sites across the U.S.) will significantly inform our understanding of how to effectively facilitate behavior change to support brain health for older Americans at risk for Alzheimer's disease and related dementia.

U.S. POINTER is a Phase 3, multicenter, randomized 2-year clinical trial of two multidomain lifestyle interventions in 2111 older adults who are at increased risk of cognitive decline and dementia due sedentary lifestyle, poor diet, and other factors such as family history of memory impairment and suboptimum cardiovascular health. Enrollment took place at five geographically diverse sites, beginning in 2019 and completing in early 2023. Participants are randomly assigned to one of two lifestyle intervention groups that differ in format, intensity, and accountability. Those randomized to the Self-Guided Lifestyle Intervention receive annual medical monitoring and health education information, tools, and support to encourage increased physical and cognitive activity and a healthier diet through 2-3 annual group meetings. Those randomized to the Structured Lifestyle Intervention receive frequent medical monitoring of cardiovascular health and a structured program of exercise (primarily aerobic), nutritional counseling, cognitive training and social engagement initially through weekly and then monthly group meetings. U.S. POINTER includes partnerships with local chapters of the Alzheimer's Association and lifestyle specialists to assist with intervention delivery. The primary outcome is 2-year change in cognitive function measured with a global cognition composite score that permits harmonization with FINGER and other trials. Secondary and tertiary outcomes include measures of executive function and episodic memory, physical activity, diet, cognitive and physical activity, cardiometabolic disease risks, mood, quality of life, health care costs, and health care utilization. U.S. POINTER is generating a richly phenotyped cohort that will provide a rigorous comparison of two lifestyle interventions designed to preserve cognitive function. It has nurtured 4 ancillary studies to assess intervention effects on outcomes related to sleep quality, brain structure and pathology, peripheral and neurovascular function, and the microbiome. It also partners with clinical trials within the World-Wide FINGERS international network. The study is generating an archive of biospecimens and de-identified public use data. Plans for a post-intervention observational study of the U.S. POINTER cohort are underway. U.S. POINTER provides an important national resource to advance the field in understanding the role of nonpharmacological interventions in reducing risk for cognitive decline and Alzheimer's disease and related dementia.

Rifaximin-α is a gut-targeted antibiotic indicated for numerous gastrointestinal and liver diseases. Its multifaceted mechanism of action goes beyond direct antimicrobial effects, including alterations in bacterial virulence, cytoprotective effects on host epithelial cells, improvement of impaired intestinal permeability, and reduction of proinflammatory cytokine expression via activation of the pregnane X receptor. Rifaximin-α is virtually non-absorbed, with low systemic drug levels contributing to its excellent safety profile. While there are high concentrations of drug in the colon, low water solubility leads to low colonic drug bioavailability, protecting the gut microbiome. Rifaximin-α appears to be more active in the bile-rich small bowel. Its important biologic effects are largely at sub-inhibitory concentration. Although in vitro testing of clinical isolates from rifaximin recipients has revealed rifaximin-resistant strains in some studies, the risk of emergent rifaximin-α resistance appears to be lower than for many other antibiotics. Rifaximin-α has been used for many years for traveler's diarrhea with no apparent increase in resistance levels in causative pathogens. Further, rifaximin-α retains its efficacy after long-term and recurrent usage in chronic gastrointestinal disorders. There are numerous reasons why the risk of microbial resistance to rifaximin-α may be lower than that for other agents, including low intestinal bioavailability in the aqueous colon, the mechanisms of action of rifaximin-α not requiring inhibitory concentrations of drug, and the low risk of cross transmission of rifaximin-α resistance between bacterial species. Reported emergence of vancomycin-resistant Enterococcus in liver-disease patients maintained on rifaximin needs to be actively studied. Further studies are required to assess the possible correlation between in vitro resistance and rifaximin-α efficacy.

The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease. This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months). Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks (p = 0.008) and 13 weeks (p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index (p = 0.0374) were improved in the FMT group. Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms. ClinicalTrial.gov, identifier: NCT03671785.

Secretory IgA (SIgA) is released into mucosal surfaces where its function extends beyond that of host defense to include the shaping of resident microbial communities by mediating exclusion/inclusion of respective microbes and regulating bacterial gene expression. In this capacity, SIgA acts as the fulcrum on which host immunity and the health of the microbiota are balanced. We recently completed an analysis of the gut and salivary IgA-Biomes (16S rDNA sequencing of SIgA-coated/uncoated bacteria) in Mexican-American adults that identified IgA-Biome differences across the glycemic spectrum. As Th17:Treg ratio imbalances are associated with gut microbiome dysbiosis and chronic inflammatory conditions such as type 2 diabetes, the present study extends our prior work by examining the impact of Th17:Treg ratios (pro-inflammatory:anti-inflammatory T-cell ratios) and the SIgA response (Th17:Treg-SIgA axis) in shaping microbial communities. Examining the impact of Th17:Treg ratios (determined by epigenetic qPCR lymphocyte subset quantification) on the IgA-Biome across diabetes phenotypes identified a proportional relationship between Th17:Treg ratios and alpha diversity in the stool IgA-Biome of those with dysglycemia, significant changes in community composition of the stool and salivary microbiomes across glycemic profiles, and genera preferentially abundant by T-cell inflammatory phenotype. This is the first study to associate epigenetically quantified Th17:Treg ratios with both the larger and SIgA-fractionated microbiome, assess these associations in the context of a chronic inflammatory disease, and offers a novel frame through which to evaluate mucosal microbiomes in the context of host responses and inflammation.

BackgroundReduced microbiota diversity (dysbiosis) in people with HIV (PWH) can damage the intestinal barrier and increase microbial translocation, resulting in inflammation, a driver of morbidity and mortality. We hypothesized that fecal microbiota transplants (FMT) would reverse dysbiosis in PWH.MethodsWe administered 6 weekly oral doses of a novel lyophilized fecal microbiota product from 2 healthy donors to 6 men who have sex with men with HIV on suppressive ART. Shotgun sequencing on stool before, after 6 weekly FMT, and 20 weeks after the last FMT (Weeks 0, 6 and 26), and from donors, was performed to determine bacterial community profiles. Biomarkers were measured by Luminex assays and ELISAs. All comparisons used Wilcoxon matched-pairs signed rank test.ResultsMedian age at Week 0 was 41 years, CD4+ T-cell count 504 cells/mm3, VL < 20 copies/mL. Mean α diversity by observed species index increased from Week 0 to 6 (61.2 to 70.2, P = 0.29; Figure 1) and decreased by Week 26 (70.2 to 52.2, P = 0.33) to be similar to the donors’ (63.5, P = 0.86). Microbiome distribution by principal component analysis shifted toward the donors’ distribution in most participants at Week 6 but shifted away by Week 26 (Figure 2). Biomarkers did not change significantly during the study. PID3, with HIV > 35 years, had chronic constipation that resolved with FMT with a large shift in distribution but recurred at Week 26. Fusobacterium gonidiaformans, Porphyromonas somerae, and Haemophilus parainfluenzae comprised 27% of his microbiome at Week 0 but 0.73% at Week 6; untyped Bacteroides comprised 35% at Week 6. I-FABP (6,899 to 2,736 pg/mL), sCD14 (1.67 to 1.31 μg/mL), IL-6 (1.51 to 1.13 pg/mL) and sTNFRII (11,659 to 8,300 pg/mL) levels decreased in PID3; Week 0 levels in PID3 were higher than in other recipients. No related serious adverse events occurred.ConclusionWeekly FMT resulted in increased intestinal microbiome α diversity and a shift in microbiome distribution in most participants. These changes did not persist after stopping FMT. PWH with long-term HIV and/or greater inflammation or gut damage may be most likely to benefit from FMT. The effects of recurrent FMT were transient, suggesting longer duration of treatment or intermittent FMT boosting may be required to maintain its benefits.DisclosuresAll authors: No reported disclosures.

Historically, the beneficial effects of the nonsystemic oral agent rifaximin on various gastrointestinal (GI) disorders have been attributed to direct antibiotic activity on gut microbiota. However, data are accumulating to suggest that other nonantibacterial effects may be involved in rifaximin efficacy. To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis complications, inflammatory bowel diseases, and irritable bowel syndrome with diarrhoea. Gastroenterology experts convened a round-table discussion to address clinical and pre-clinical rifaximin data pertaining to select GI diseases and the potential mechanisms of action that underlie rifaximin efficacy profiles. As preparation, the literature was searched for publications related to rifaximin, its mechanisms of action, and its efficacy in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis-related complications, inflammatory bowel diseases and irritable bowel syndrome. Gut microbiota dysbiosis and proinflammatory activities are thought to significantly contribute to disease pathophysiology of these conditions. Rifaximin may resolve gut microbiota dysbiosis by promoting GI colonisation of beneficial bacterial species without drastic alterations in overall diversity. Rifaximin-induced changes in the production and metabolism of bacteria-produced agents (e.g. deoxycholic acid, lipopolysaccharides) also may help preserve normal gut microbiota. Rifaximin may suppress local and systemic inflammatory processes by preserving epithelial function (e.g. limiting bacterial translocation), modulating bacterial virulence and reducing proinflammatory cytokine production. The commonality of pathological mechanisms underlying multiple GI diseases and the ability of rifaximin to modulate the gut microenvironment (i.e. gut microenvironment modulator) may explain its diverse efficacy profile.

Background. Infants born to mothers who are colonized with group B streptococcus (GBS) but received <4 hours of intrapartum antibiotic prophylaxis (IAP) are at-risk for presenting later with sepsis. We assessed if <4 hours of maternal IAP for GBS are associated with an increased incidence of clinical neonatal sepsis. Materials and Methods. A retrospective cohort study of women-infant dyads undergoing IAP for GBS at ≥37-week gestation who presented in labor from January 1, 2003 through December 31, 2007 was performed. Infants diagnosed with clinical sepsis by the duration of maternal IAP received (< or ≥4-hours duration) were determined. Results. More infants whose mothers received <4 hours of IAP were diagnosed with clinical sepsis, 13 of 1,149 (1.1%) versus 15 of 3,633 (0.4%), P = .03. Multivariate logistic regression analysis showed that treatment with ≥4 hours of IAP reduced the risk of infants being diagnosed with clinical sepsis by 65%, adjusted relative risk 0.35, CI 0.16–0.79, and P = .01. Conclusion. The rate of neonatal clinical sepsis is increased in newborns of GBS colonized mothers who receive <4 hours compared to ≥4 hours of IAP.