ABSTRACT
Introduction: Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial (RCT) to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage Alzheimer's disease (AD). AD results from the interplay of multiple interacting dysfunctional biological systems. Specific causes of AD differ between individuals. Personalized, multimodal therapies are needed to best prevent and treat AD. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic and microbiome data at multiple timepoints across two years for each participant. These data enable systems-biology analyses. We report analyses of the first COCOA data freeze. This analysis includes an evaluation of the effect of the intervention on outcome measures. It also includes systems analyses to identify molecular mediators that convey the effect of personalized multimodal lifestyle interventions on amelioration of cognitive trajectory. Methods. A total of 55 participants with early-stage AD from Southern California were randomized into two parallel arms. Arm 1 (control; N=24) received standard of care. Arm 2 (intervention; N=31) also received telephonic personalized coaching for multiple lifestyle interventions including diet, exercise, and cognitive training. COCOA's overarching aim was to gather dense molecular data from an AD cohort to improve understanding of pathophysiology and advance treatment. For the RCT, COCOA's objective was to test the hypothesis that the Memory Performance Index (MPI) trajectory would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test (FAST) was assessed for a secondary outcome. Assessments were blinded. The nature of the intervention precluded participant blinding. Results. The intervention arm ameliorated 2.6 ± 0.8 MPI points (p = 0.0007; N = 48) compared to the control arm over the two-year intervention. Top-ranked candidate mediators included: albumin, propionylcarnitine, sphingomyelin, hexadecanedioate, acetylkynurenine, tiglylcarnitine, IL18R1, palmitoyl-sphingosine-phosphoethanolamine, acetyltryptophan, and IL17D. These individual molecules implicated inflammatory and nitrogen/tryptophan metabolism pathways. No important adverse events or side effects were observed. Conclusions. Clinical trials should include frequent assessment of dense data to maximize knowledge gained. Such knowledge is useful not only in testing a primary hypothesis, but also in advancing basic biological and pathophysiological knowledge, understanding mechanisms explaining trial results, generating synergistic knowledge tangential to preconceived hypotheses, and refining interventions for clinical translation. Data from every trial should allow an intervention to be refined and then tested in future trials, driving iterative improvement. Multimodal lifestyle interventions are effective for ameliorating cognitive decline and may have an effect size larger than pharmacological interventions. Effects may be molecularly idiosyncratic; personalization of interventions is important. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.
Subject(s)
Alzheimer DiseaseABSTRACT
The immunological picture of how different patients recover from COVID-19, and how those recovery trajectories are influenced by infection severity, remain unclear. We investigated 140 COVID-19 patients from diagnosis to convalescence using clinical data, viral load assessments, and multi-omic analyses of blood plasma and circulating immune cells. Immune-phenotype dynamics resolved four recovery trajectories. One trajectory signals a return to pre-infection healthy baseline, while the other three are characterized by differing fractions of persistent cytotoxic and proliferative T cells, distinct B cell maturation processes, and memory-like innate immunity. We resolve a small panel of plasma proteins that, when measured at diagnosis, can predict patient survival and recovery-trajectory commitment. Our study offers novel insights into post-acute immunological outcomes of COVID-19 that likely influence long-term adverse sequelae.
Subject(s)
COVID-19ABSTRACT
Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of 221,748 PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.
Subject(s)
COVID-19ABSTRACT
Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.