Increased Aß42-α7-like nicotinic acetylcholine receptor complex level in lymphocytes is associated with apolipoprotein E4-driven Alzheimer's disease pathogenesis.

BACKGROUND: The apolipoprotein E ε4 (APOE4) genotype is a prominent late-onset Alzheimer's disease (AD) risk factor. ApoE4 disrupts memory function in rodents and may contribute to both plaque and tangle formation. METHODS: Coimmunoprecipitation and Western blot detection were used to determine: 1) the effects of select fragments from the apoE low-density lipoprotein (LDL) binding domain and recombinant apoE subtypes on amyloid beta (Aß)42-α7 nicotinic acetylcholine receptor (α7nAChR) interaction and tau phosphorylation in rodent brain synaptosomes; and 2) the level of Aß42-α7nAChR complexes in matched controls and patients with mild cognitive impairment (MCI) and dementia due to AD with known APOE genotypes. RESULTS: In an ex vivo study using rodent synaptosomes, apoE141-148 of the apoE promotes Aß42-α7nAChR association and Aß42-induced α7nAChR-dependent tau phosphorylation. In a single-blind study, we examined lymphocytes isolated from control subjects, patients with MCI and dementia due to AD with known APOE genotypes, sampled at two time points (1 year apart). APOE ε4 genotype was closely correlated with heightened Aß42-α7nAChR complex levels and with blunted exogenous Aß42 effects in lymphocytes derived from AD and MCI due to AD cases. Similarly, plasma from APOE ε4 carriers enhanced the Aß42-induced Aß42-α7nAChR association in rat cortical synaptosomes. The progression of cognitive decline in APOE ε4 carriers correlated with higher levels of Aß42-α7nAChR complexes in lymphocytes and greater enhancement by their plasma of Aß42-induced Aß42-α7nAChR association in rat cortical synaptosomes. CONCLUSIONS: Our data suggest that increased lymphocyte Aß42-α7nAChR-like complexes may indicate the presence of AD pathology especially in APOE ε4 carriers. We show that apoE, especially apoE4, promotes Aß42-α7nAChR interaction and Aß42-induced α7nAChR-dependent tau phosphorylation via its apoE141-148 domain. These apoE-mediated effects may contribute to the APOE ε4-driven neurodysfunction and AD pathologies.

Hemodynamic-guided heart-failure management using a wireless implantable sensor: Infrastructure, methods, and results in a community heart failure disease-management program.

BACKGROUND: The real-world impact of remote pulmonary artery pressure (PAP) monitoring on New York Heart Association (NYHA) class improvement and heart failure (HF) hospitalization rate is presented here from a single center. HYPOTHESIS: METHODS: Seventy-seven previously hospitalized outpatients with NYHA class III HF were offered PAP monitoring via device implantation in a multidisciplinary HF-management program. Prospective effectiveness analyses compared outcomes in 34 hemodynamically monitored patients to a group of similar patients (n = 32) who did not undergo device implantation but received usual care. NYHA class and 6-minute walk testing were assessed at baseline and 90 days. All hospitalizations were collected after 6 months of the implantation date (average follow-up, 15 months) and compared with the number of hospitalizations experienced prior to hemodynamic monitoring. RESULTS: Patients in both groups had similar distributions of age, sex, and ejection fraction. After 90 days, 61.8% of the monitored patients had NYHA class improvement of ≥1, compared with 12.5% in the controls (P < 0.001). Distance walked in 6 minutes increased by 54.5 meters in the monitored group (253.0 ± 25.6 meters to 307.4 ± 26.3 meters; P < 0.005), whereas no change was seen in the usual-care group. After implantation, 19.4% of the monitored group had ≥1 HF hospitalization, compared with 100% who had been hospitalized in the year prior to implantation. The monitored group had a significantly lower HF hospitalization rate (0.16; 95% confidence interval: 0.06-0.35 hospitalizations/patient-year) compared with the year prior (1.0 hospitalizations/patient-year; P < 0.001). CONCLUSIONS: Hemodynamic-guided HF management leads to significant improvements in NYHA class and HF hospitalization rate in a real-world setting compared with usual care delivered in a comprehensive disease-management program.