ABSTRACT
BACKGROUND: Cognitive, global and functional instruments have been extensively investigated for correlations with neuropathological changes such as neurofibrillary tangles (NFTs), plaques, and synapse loss in the brain. OBJECTIVE: Our objective is to correlate the functional, global and cognitive decline assessed clinically with the neuropathological changes observed in a large prospectively characterized cohort of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: We examined 150 subjects (16 MCI and 134 AD) that were prospectively assessed and longitudinally followed to autopsy. MCI subjects clinically met Petersen criteria for single or multi-domain amnestic MCI. AD subjects clinically met NINCDS-ADRDA criteria for probable or possible AD. All subjects received the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and the Mini Mental State Examination (MMSE) ante-mortem. Plaque and tangle counts were gathered for hippocampus, entorhinal cortex, frontal, temporal and parietal cortices. Braak staging was performed as well. RESULTS: The GDS, FAST and MMSE correlated with plaque counts in all regions. The GDS, FAST and MMSE correlated with tangle counts in in all regions. The three instruments also correlated with the Braak score. The MMSE and GDS correlate better than the FAST in most regions. CONCLUSIONS: Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress from MCI through AD.
Subject(s)
Alzheimer Disease/pathology , Cognition Disorders/pathology , Aged, 80 and over , Alzheimer Disease/physiopathology , Alzheimer Disease/psychology , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Cognition Disorders/physiopathology , Cognition Disorders/psychology , Cohort Studies , Disability Evaluation , Disease Progression , Entorhinal Cortex/pathology , Entorhinal Cortex/physiopathology , Female , Hippocampus/pathology , Hippocampus/physiopathology , Humans , Longitudinal Studies , Male , Neurofibrillary Tangles/pathology , Neuropsychological Tests/statistics & numerical data , Plaque, Amyloid/pathology , Predictive Value of Tests , Prognosis , Prospective Studies , Severity of Illness IndexABSTRACT
Although considered selective for its natural substrate, 4-aminobutyrate, gab permease was inhibited by 1,2,3,6-tetrahydro-3-pyridinecarboxylate and 1,2,3,6-tetrahydro-4-pyridinecarboxylate. The former is a transported substrate, since its preloading into metabolically poisoned cells stimulated transient accumulation of 4-aminobutyrate via counterflow.
Subject(s)
Escherichia coli/enzymology , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Membrane Transport Proteins/metabolism , Nicotinic Acids/pharmacology , Organic Anion Transporters , Proline/analogs & derivatives , Biological Transport , Escherichia coli/genetics , Escherichia coli Proteins , GABA Plasma Membrane Transport Proteins , Genes, Bacterial , Nipecotic Acids/metabolism , Piperidines/pharmacology , Substrate Specificity , gamma-Aminobutyric Acid/metabolismABSTRACT
4-aminobutyrate metabolism in Escherichia coli begins with transport across the cytoplasmic membrane via the GabP, which is encoded by gabP. Although GabP is specific and exhibits poor affinity for many cellular constituents such as the alpha-amino acids, the range of compounds recognized with high affinity has yet to be investigated. In order to address this gap in knowledge, we developed a gabP-negative host strain, which permits evaluation of test compounds for inhibitory effects on cloned GabP (expression inducible by isopropyl-1-thio-beta-D-galactopyranoside). Using this inducible expression system, three structurally distinct categories of high affinity transport inhibitor were identified. The structural dissimilarity of these inhibitors significantly alters our view of ligand recognition by GabP. Any complete model must now account for the observation that inhibition of 4-aminobutyrate transport can be mediated either (i) by open chain analogs of 4-aminobutyrate, (ii) by cyclic amino acid analogs, or (iii) by planar heterocyclic compounds lacking a carboxyl group. Such results do not support a previously sustainable view of GabP that features a restrictive ligand recognition domain, unable to accommodate structures that differ very much from the native substrate, 4-aminobutyrate.
