Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

BACKGROUND: Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated. OBJECTIVES: To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration. DESIGN: Cross-sectional and longitudinal analyses. SETTING: Community-based cohort in the city of Framingham, Massachusetts. PARTICIPANTS: 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. MEASUREMENTS: Plasma Aß40 and Aß42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aß isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aß40 (ß -0.006, p-value 0.032) at Exam-7 and plasma total-tau (ß -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: ß -0.009, p 0.0005; FWS: ß -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers; Aß42 was not associated with function. CONCLUSION: Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial.

Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).

Is There a Role for Desmopressin in Liver Transplantation? A Case Report.

Living donor liver transplantation reduces time and mortality on the waiting list. Bleeding is a serious complication; however, "overcorrection" of coagulopathy may lead to hepatic artery thrombosis. We report a case where desmopressin (DDAVP) was used in the management of persistent postreperfusion bleeding (44 red blood cell units transfused). After 1 dose of DDAVP, bleeding improved significantly and the recipient had an unremarkable recovery. DDAVP should be considered for persisting bleeding after correcting common coagulation abnormalities where complexity of the anastomosis may preclude the use of more aggressive procoagulant drugs in liver transplantation.

Central adiposity and the functional magnetic resonance imaging response to cognitive challenge.

BACKGROUND: Excessive adipose tissue, particularly with a centralized distribution, propagates hormonal and metabolic disturbance. The detrimental effects of adiposity may extend beyond the periphery and target the central nervous system, increasing vulnerability to cognitive decline. The aim of the current study was to determine how central adiposity impacts the brain at midlife by examining the blood oxygen level-dependent (BOLD) response to a challenging cognitive task. METHODS: Seventy-three adults, aged 40-60 years, completed a 2-back verbal working memory task during functional magnetic resonance imaging. Central adiposity was assessed with waist circumference. The association between waist circumference and task-related activation in a priori regions of interest was modeled using bootstrapping regression models corrected for multiple-comparisons. RESULTS: Larger waist circumference was associated with diminished working-memory-related BOLD response in the right superior frontal gyrus (ß=-0.008, P=0.001, 95% CI: -0.012 to -0.004) and left middle frontal gyrus (ß=-0.009, P=0.002, 95% CI: -0.015 to -0.003), statistically adjusting for age, sex, systolic blood pressure and total cholesterol. Reduced task-related activation in the right superior frontal gyrus (r=-0.369, P=0.002) and left middle frontal gyrus (r=-0.266, P=0.025) were related to slower reaction time on the task, controlling for age and education. CONCLUSIONS: Larger waist circumference predicted alterations in the BOLD response that coupled with decrements in task performance. While future studies are necessary, the results suggest that similar to its role in the periphery, central adiposity may be a robust predictor of metabolic and hormonal alterations that impinge upon central nervous system functioning.

Functional MR imaging evidence of altered functional activation in metabolic syndrome.

BACKGROUND AND PURPOSE: MetS is a cluster of risk factors associated with significant cardiovascular morbidity and mortality and diminished cognitive function. Given that little is known about the early signs of brain vulnerability related to persistent metabolic dysfunction, we set out to determine whether cognitively healthy middle-aged individuals with MetS exhibit an altered cerebrovascular response to a cognitive challenge relative to those without MetS. MATERIALS AND METHODS: Forty neurologically healthy adults aged 40-60 years (19 with MetS and 21 healthy controls) performed a 2-back verbal working memory task during fMRI. We compared BOLD responses between the 2 groups in 8 a priori regions of interest previously shown to be associated with the 2-back in patients with cardiovascular disease. RESULTS: Age, education level, sex distribution, cognitive and emotional functioning, and task performance (accuracy and reaction time) were not different between the groups. Compared with healthy controls, individuals with MetS demonstrated a lower 2-back-related BOLD response in the right superior frontal gyrus, right superior parietal lobule, and left inferior parietal lobule. CONCLUSIONS: This study provides preliminary evidence that cognitively intact middle-aged individuals with MetS exhibit significant alterations in cerebrovascular response to a cognitive challenge. Our results also demonstrate that fMRI may identify early brain changes associated with MetS.

Evaluation by three-dimensional anal endosonography of injectable silicone biomaterial (PTQ) implants to treat fecal incontinence: long-term localization and relation with the deterioration of the continence.

BACKGROUND: The purposes of the study were the long-term evaluation of silicone implants with three-dimensional (3D) anal endosonography and its correlation with anal incontinence. METHODS: Fifteen patients were injected with silicone because of anal incontinence and co-existing internal anal sphincter disruption (n = 8) or thinning (n = 7). The evaluation was performed with the Wexner score and 3D anal endosonographies. RESULTS: Forty-four implants were performed. The endosonography at 3 months detected that all the implants were properly located. At 24 months, it detected 37/44 implants of initially injected and 33/37 were properly located. Four of 37 implants had moved and 7/44 were neither in the anus nor in the rectum. A total of 8/15 patients had their implants correctly placed. Globally, silicone implants significantly improved fecal continence. CONCLUSIONS: The silicone implants might have moved or even be lost. The continence deterioration suffered by most patients after the first year of the injection has no relation with the localization and number of implants that the patients have.