Abeta-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Abeta-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Abeta. There are also indications that clinically proven AD cases with full-blown beta-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Abeta pathology.

Background: Synaptic loss is a common feature in the neocortex and hippocampus in AD. Individuals with MCI, lacking a clinical diagnosis of AD, manifest a decline in synapse numbers in the hippocampus. It is unclear whether areas of neocortex also affected in AD display synaptic loss during this prodromal transitional stage. The inferior temporal gyrus (ITG) is considered tertiary association cortex with a special role in higher order visual function. It is an integral part of the visual association pathway that provides the anatomical substrate for the perception and memory of shapes and objects. Objective: To assess total synaptic numbers in lamina III of the ITG during the progression of AD. Methods: Tissue was examined from the Rush Religious Orders Study and from the AD Center at the University of Kentucky. All cases had detailed clinical evaluation within 12 months prior to death and were categorized as AD, MCI, or no cognitive impairment (NCI). Systematic random samples throughout the entire extent of the ITG were obtained at autopsy and processed for standard transmission electron microscopy. Unbiased stereological techniques employing the physical disector were used to estimate the total number of synapses in lamina III. Results: Preliminary results revealed that the AD group had significantly fewer synapses than NCI. The mean number of synapses in the MCI group was also lower compared to NCI but higher than the AD subjects. The total volume of the ITG appeared the same for both the NCI and MCI cases; and substantially greater than the AD group volume. There was a highly significant association between the total number of synapses in the ITG and the subject's score on the mini mental status exam (MMSE). Conclusions: This is the first study to estimate the total number of synapses in a specific region of the human neocortex. These results suggest that the ITG in individuals with MCI manifest synaptic loss that may be equivalent to some AD subjects, supporting the idea that significant synaptic loss occurs early in the progression to AD. Background: Morphological alterations of mitochondria may be related to metabolic and energy deficiency in neurons in Alzheimer's disease and other neurodegenerative disorders. Mitochondrial dysfunction is also a hallmark of A peptide induced neuronal toxicity in Alzheimer's disease. A general change in glucose utilization, increased oxidative stress, and Ca2 deregulation are additional metabolic defects in the AD brain that may also be associated with defective mitochondrial function. The result is a cycle of increased mitochondrial dysfunction causing increased oxidative damage until the cellular energy supply falls below the threshold for cellular survival. Objective(s): In a series of studies on the morphological and morphometric estimation of mitochondria in Alzheimer's disease, by electron microscopy we noticed substantial morphological and morpho-metric changes in the neurons of the hippocampus, the acoustic cortex, the frontal cortex, the cerebellar cortex, the cl...

Background and Purpose-Glutathione S-transferase omega-1 is a multifunctional enzyme. The Asp/Asp genotype of the Ala140Asp polymorphism of the GSTO1 gene has been alleged to increase the risk of vascular dementia. The objective of this study is to address the question of whether common vessel disorders known to cause vascular dementia are modified in their severity by this polymorphism. Methods-The severity and expansion of atherosclerosis in the circle of Willis vessels, cerebral small vessel disease, and cerebral amyloid angiopathy were studied in a sample of 79 autopsy cases. Genotyping of the GSTO1 Ala140Asp polymorphism as well as immunohistochemistry for glutathione S-transferase omega-1 was performed. Results-Carriers of the GSTO1 Asp/Asp genotype presented with more severe and widespread atherosclerosis than noncarriers. However, there was no effect on small vessel disease expansion and cerebral amyloid angiopathy severity.Immunohistochemically, we detected interleukin-1␣ expressing macrophages in the lipid core of atherosclerosis plaques exhibiting glutathione S-transferase omega-1-positive material. GSTO1 Asp/Asp carriers showed larger areas of atherosclerosis plaques containing interleukin-1␣-positive material than carriers of the GSTO1 Ala-allele. Key Words: atherosclerosis Ⅲ cerebral arteries Ⅲ GSTO1-1 G lutathione S-transferase omega-1 (GSTO1-1) is a member of the glutathione S-transferases family of phase II enzymes that catalyze the glutathione dependent detoxification of, eg, oxidants. 1 Recently, we have shown that the Asp/Asp genotype of the GSTO1 Ala140Asp polymorphism in exon 4 is associated with an increased risk for vascular dementia. 2 However, the relationship between this GSTO1 polymorphism and common vessel diseases is not clear. Major vessel diseases causing vascular dementia include atherosclerosis (AS) of the arteries of the circle of Willis, small vessel disease, and cerebral amyloid angiopathy. 3 Small vessel disease includes vascular lesions of arteriolosclerosis, arteriohyalinosis, lipohyalinosis, fibrohyalinosis, and arteriosclerotic intimal proliferation and fibrosis of the media in small arteries but no AS plaques. Conclusions-TheThe objective of this study was to investigate whether one of these vessel disorders is influenced by the GSTO1 Ala140Asp polymorphism. Materials and MethodsWe analyzed a sample of 79 formalin-fixed human brains from continuously collected autopsy cases of 60 years of age and older without further selection criteria (Table). We counted the number of vessels with macroscopically detectable AS plaques in relation to the total number of vessels analyzed within the circle of Willis. Vessels included in this quantification were the major branches of the vertebral, basilar, anterior cerebral, middle cerebral, posterior cere- Histopathology confirmed the diagnosis of AS. The histopathological type of AS lesions of the most severely affected artery of the circle of Willis was determined. 4 The extent of small vessel disease was determined in leptomeningeal,...