Different loneliness types, cognitive function, and brain structure in midlife: Findings from the Framingham Heart Study.

Background: It remains unclear whether persistent loneliness is related to brain structures that are associated with cognitive decline and development of Alzheimer's disease (AD). This study aimed to investigate the relationships between different loneliness types, cognitive functioning, and regional brain volumes. Methods: Loneliness was measured longitudinally, using the item from the Center for Epidemiologic Studies Depression Scale in the Framingham Heart Study, Generation 3, with participants' average age of 46·3 ± 8·6 years. Robust regression models tested the association between different loneliness types with longitudinal neuropsychological performance (n = 2,609) and regional magnetic resonance imaging brain data (n = 1,829) (2002-2019). Results were stratified for sex, depression, and Apolipoprotein E4 (ApoE4). Findings: Persistent loneliness, but not transient loneliness, was strongly associated with cognitive decline, especially memory and executive function. Persistent loneliness was negatively associated with temporal lobe volume (ß = -0.18, 95%CI [-0.32, -0.04], P = 0·01). Among women, persistent loneliness was associated with smaller frontal lobe (ß = -0.19, 95%CI [-0.38, -0.01], P = 0·04), temporal lobe (ß = -0.20, 95%CI [-0.37, -0.03], P = 0·02), and hippocampus volumes (ß = -0.23, 95%CI [-0.40, -0.06], P = 0·007), and larger lateral ventricle volume (ß = 0.15, 95%CI [0.02, 0.28], P = 0·03). The higher cumulative loneliness scores across three exams, the smaller parietal, temporal, and hippocampus volumes and larger lateral ventricle were evident, especially in the presence of ApoE4. Interpretation: Persistent loneliness in midlife was associated with atrophy in brain regions responsible for memory and executive dysfunction. Interventions to reduce the chronicity of loneliness may mitigate the risk of age-related cognitive decline and AD. Funding: US National Institute on Aging.

Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous Apolipoprotein E ɛ4 Carriers.

OBJECTIVE: Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer's disease (AD) risk only in apoliprotein E4 genotype (APOE ε4) allele carriers. The objective of this study was to examine the interactive effects of plasma CRP and apoliprotein E (APOE) genotype on cognition and AD biomarkers. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study was analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., MCI and dementia due to AD); Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) Dementia Staging Instrument; cerebral spinal fluid (CSF) concentrations of amyloid-ß peptide (Aß42), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes. RESULTS: Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had one, and 70 (12.4%) had two APOE ε4 alleles. Only among participants who had two APOE ε4 alleles, elevated CRP was associated with lower MMSE at baseline [ß (95%CI): -0.52 ( -1.01, -0.12)] and 12-month follow-up [ß (95%CI): -1.09 (-1.88, -0.17)] after adjusting for sex, age and education. The interaction of two APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (ß = +11.21, SE = 3.37, p < 0.001) and p-Tau (ß = +2.74, SE = 1.14, p < 0.01). Among those who had no APOE ε4 allele, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at 12-month follow-up. CONCLUSIONS: CRP released during peripheral inflammation could be a mediator in APOE ε4 related AD neurodegeneration and serve as a drug target for AD.

Associations of loneliness with risk of Alzheimer's disease dementia in the Framingham Heart Study.

INTRODUCTION: The relationship between persistent loneliness and Alzheimer's disease (AD) is unclear. We examined the relationship between different types of mid-life loneliness and the development of dementia and AD. METHODS: Loneliness was assessed in cognitively normal adults using one item from the Center for Epidemiologic Studies Depression Scale. We defined loneliness as no loneliness, transient loneliness, incident loneliness,or persistent loneliness, and applied Cox regression models and Kaplan-Meier plots with dementia and AD as outcomes (n = 2880). RESULTS: After adjusting for demographics, social network, physical health, and apolipoprotein E ε4, persistent loneliness was associated with higher (hazard ratio [HR], 1.91; 95% confidence interval [CI] 1.25-2.90; P < .01), and transient loneliness with lower (HR, 0.34; 95% CI 0.14-0.84; P < .05), risk of dementia onset, compared to no loneliness. Results were similar for AD risk. DISCUSSION: Persistent loneliness in mid-life is an independent risk factor for dementia and AD, whereas recovery from loneliness suggests resilience to dementia risk.

Rapid Cycle Evaluation and Adaptation of an Inpatient Tobacco Treatment Service at a U.S. Safety-Net Hospital.

Background: To address disparities in smoking rates, our safety-net hospital implemented an inpatient tobacco treatment intervention: an "opt-out" electronic health record (EHR)-based Best Practice Alert + order-set, which triggers consultation to a Tobacco Treatment Consult (TTC) service for all hospitalized patients who smoke cigarettes. We report on development, implementation, and adaptation of the intervention, informed by a pre-implementation needs assessment and two rapid-cycle evaluations guided by the Consolidated Framework for Implementation Research (CFIR) and Expert Recommendations for Implementing Change (ERIC) compilation. Methods: We identified stakeholders affected by implementation and conducted a local needs assessment starting 6 months-pre-launch. We then conducted two rapid-cycle evaluations during the first 6 months post-implementation. The CFIR informed survey and interview guide development, data collection, assessment of barriers and facilitators, and selection of ERIC strategies to implement and adapt the intervention. Results: Key themes were: (1) Understanding the hospital's priority to improving tobacco performance metrics was critical in gaining leadership buy-in (CFIR Domain: Outer setting; Construct: External Policy and Incentives). (2) CFIR-based rapid-cycle evaluations allowed us to recognize implementation challenges early and select ERIC strategies clustering into 3 broad categories (conducting needs assessment; developing stakeholder relationships; training and educating stakeholders) to make real-time adaptations, creating an acceptable clinical workflow. (3) Minimizing clinician burden allowed the successful implementation of the TTC service. (4) Demonstrating improved 6-month quit rates and tobacco performance metrics were key to sustaining the program. Conclusions: Rapid-cycle evaluations to gather pre-implementation and early-implementation data, focusing on modifiable barriers and facilitators, allowed us to develop and refine the intervention to improve acceptability, adoption, and sustainability, enabling us to improve tobacco performance metrics in a short timeline. Future directions include spreading rapid-cycle evaluations to promote implementation of inpatient tobacco treatment programs to other settings and assessing long-term sustainability and return on investment of these programs.