ABSTRACT
BACKGROUND: Knowledge of Alzheimer's disease (AD) manifestation in the pre-dementia stage facilitates the selection of appropriate measures for early detection and disease progression. OBJECTIVE: To examine the trajectories of cognitive performance, gray matter volume (GMV), and cerebrospinal fluid (CSF) biomarkers, together with the influence of apolipoprotein E (APOE) in subjects with amyloid-ß (Aß) deposits across the pre-clinical to dementia stages of AD. METHODS: 356 subjects were dichotomized into Aß+ and Aß- groups based on their CSF Aß1-42 level. We derived AD-related atrophic regions (AD-ROIs) using the voxel-based morphometry approach. We characterized the trajectories of cognitive scores, GMV at AD-ROIs, and CSF biomarkers from preclinical to disease stages in Aß+ subjects. The effect of APOE ε4 genotype on these trajectories was examined. RESULTS: Impairments in executive functioning/processing speed (EF/PS) and atrophy at the right supramarginal/inferior parietal gyrus were detected in cognitively normal Aß+ subjects. Together with the APOE ε4 carrier status, these measures showed potential to identify cognitively normal elderly with abnormal CSF Aß1-42 level in another independent cohort. Subsequently, impairment in memory, visuospatial, language, and attention as well as atrophy in the temporal lobe, thalamus, and mid-cingulate cortex were detectable in Aß+ mild cognitive impairment (MCI) subjects. In MCI and dementia Aß+ subjects, ε4 carriers had more severe atrophy of the medial temporal lobe and memory impairment but higher EF/PS compared to non-carriers. CONCLUSIONS: EF/PS decline and right parietal atrophy might act as non-invasive screening tests for abnormal amyloid deposition in cognitively normal elderly. APOE modulation on subsequent trajectories in cognition and atrophy should be taken into account when analyzing disease progression.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoproteins E/genetics , Brain/pathology , Cognition Disorders/etiology , Dementia/diagnosis , Peptide Fragments/cerebrospinal fluid , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/complications , Alzheimer Disease/genetics , Analysis of Variance , Atrophy/complications , Atrophy/pathology , Biomarkers/cerebrospinal fluid , Cohort Studies , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Neuropsychological Tests , Psychiatric Status Rating ScalesABSTRACT
Bioartificial liver (BAL) system is promising as an alternative treatment for liver failure. We have developed a bioreactor with stacked sandwich culture plates for the application of BAL. This bioreactor design addresses some of the persistent problems in flat-bed bioreactors through increasing cell packing capacity, eliminating dead flow, regulating shear stress, and facilitating the scalability of the bioreactor unit. The bioreactor contained a stack of twelve double-sandwich-culture plates, allowing 100 million hepatocytes to be housed in a single cylindrical bioreactor unit (7 cm of height and 5.5 cm of inner diameter). The serial flow perfusion through the bioreactor increased cell-fluid contact area for effective mass exchange. With the optimal perfusion flow rate, shear stress was minimized to achieve high and uniform cell viabilities across different plates in the bioreactor. Our results demonstrated that hepatocytes cultured in the bioreactor could re-establish cell polarity and maintain liver-specific functions (e.g. albumin and urea synthesis, phase I&II metabolism functions) for seven days. The single bioreactor unit can be readily scaled up to house adequate number of functional hepatocytes for BAL development.
