Influence of apolipoprotein E ɛ4 on rates of cognitive and functional decline in mild cognitive impairment

BackgroundApolipoprotein E ?4 (APOE ?4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE ?4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE ?4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI).MethodsA total of 516 aMCI participants aged 55–90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36-month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE ?4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period.ResultsAPOE ?4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE ?4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini-Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale.ConclusionsThese findings demonstrate that APOE ?4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE ?4 status needs to be accounted for in treatment trials of MCI.     

Engineering an artificial alveolar-capillary membrane: a novel continuously perfused model within microchannels

Introduction

Pulmonary hypoplasia is a condition of the newborn that is characterized by underdeveloped lungs and poor outcome. One strategy in the treatment of patients with hypoplasia is to augment underdeveloped lungs using biocompatible artificial lung tissue. However, one central challenge in current pulmonary tissue engineering efforts remains the development of a stable bio-mimetic alveolar-capillary membrane. Accordingly, we have built a series of bio-mimetic microfluidic devices that specifically model the alveolar-capillary membrane. Current designs include a single-layer microchip that exposes alveolar and endothelial cell types to controlled fluidic stimuli. A more advanced multi-layered device allows for alveolar cells to be cultured at an air interface while allowing constant media nourishment and waste removal, thus better mimicking the physiologic milieu of the alveolar-capillary interface. Both devices possess the benefit of parallel testing.

Material and methods

Microdevices were fabricated using soft lithography in a biocompatible transparent polymeric material, polydimethyl siloxane, sealed covalently to glass. The multistage microdevice also integrated a suspended polyethylene terephthalate membrane connected via microfluidic channels to constant media and air access. Pulmonary endothelial (HMEC-1) and alveolar epithelial (A549) cell lines, along with fetal pulmonary cells (FPC) harvested from Swiss Webster mice at day 18 gestational age, were studied under multiple hydrodynamic shear conditions and liquid-to-cell ratio regimes. Cultures were examined for cell viability, function and proliferation to confluent monolayers. A549 cells cultured at an air-interface in a microdevice was also tested for their ability to maintain cell phenotype and function.

Results

The single-layer differential flow microdevice allowed for a systematic determination of the optimal growth conditions of various lung-specific cell types in a microfluidic environment. Our device showed a greater surfactant based decrease in surface tension of the alveolar hypophase in A549 cultures exposed to air as compared to submerged cultures.

Conclusions

We have successfully developed biomimetic microfluidic devices that specifically allow stable alveolar cell growth at the air-liquid interface. This work serves prerequisite towards an implantable artificial alveolar membrane.     

Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model

Previous studies have suggested that intravenous transplantation of mesenchymal stem cells (MSCs) in rat ischemia models reduces ischemia‐induced brain damage. Here, we analyzed the expression of neurotrophic factors in transplanted human MSCs and host brain tissue in rat middle cerebral artery occlusion (MCAO) ischemia model. At 1 day after transient MCAO, 3 × 10⁶ immortalized human MSC line (B10) cells or PBS was intravenously transplanted. Behavioral tests, infarction volume, and B10 cell migration were investigated at 1, 3, 7, and 14 days after MCAO. The expression of endogenous (rat origin) and exogenous (human origin) neurotorphic factors and cytokines was evaluated by quantitative real‐time RT‐PCR and Western blot analysis. Compared with PBS controls, rats receiving MSC transplantation showed improved functional recovery and reduced brain infarction volume at 7 and 14 days after MCAO. In MSC‐transplanted brain, among many neurotrofic factors, only human insulin‐like growth factor 1 (IGF‐1) was detected in the core and ischemic border zone at 3 days after MCAO, whereas host cells expressed markedly higher neurotrophic factors (rat origin) than control rats, especially vascular endothelial growth factor (VEGF) at 3 days and epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) at 7 days after MCAO. Intravenously transplanted human MSCs induced functional improvement, reduced infarct volume, and neuroprotection in ischemic rats, possibly by providing IGF‐1 and inducing VEGF, EGF, and bFGF neurotrophic factors in host brain. © 2009 Wiley‐Liss, Inc.