O1-01-03

S8

Oral O1-01: D&CC (Molecular Pathology/Hispathological)

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. Supported by NIH grants RO1 AG12138, RO1 AG14449, RO1 AG10161, RO1 AG10668 and P50 AG05133 O1-01-02

MITOCHONDRIAL ALTERATIONS IN RELATION TO SYNAPTIC PATHOLOGY IN ALZHEIMER’S DISEASE

Stavros I. Baloyannis, Aristotelian University, Thessaloniki, Greece. Contact e-mail: [email protected] 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 morphometric changes in the neurons of the hippocampus, the acoustic cortex, the frontal cortex, the cerebellar cortex, the climbing fibers, the thalamus, the globus palidus, the red nucleus and the locus coeruleus. Methods: Samples from fifteen brains derived from patients suffered from Alzheimer’s disease were prepared for electron microscopy. Morphological and morphometric analysis of the mitochondria and the synapses was performed. Results: The morphological alterations consisted of considerable changes of the mitochondrial cristae, accumulation of osmiophilic material, and decrease of their size, in comparison with the normal controls. Mitochondrial alterations were particularly prominent in neurons, which showed loss of dendritic spines and abbreviation of the dendritic arborization. The ultrastructural study of a large number of neurons in the thalamus and the red nucleus revealed that the mitochondrial alterations did not coexist with cytoskeletal pathology and accumulation of amyloid deposits, though they

were prominent in neurons, which demonstrated fragmentation of the cisternae of the Golgi apparatus. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer’s disease. Conclusions: The relationship between the site and extent of mitochondrial abnormalities and the synaptic alterations plead in favor of an intimate and early association between mitochondrial alteration and synaptic pathology in Alzheimer’s disease. O1-01-03

ALZHEIMER DISEASE PATHOLOGY INFLUENCES THE IMPACT OF CEREBRAL AMYLOID ANGIOPATHY ON COGNITIVE DECLINE

Magdalena Quass1, Johannes Attems1, Kurt A. Jellinger2, Felix Lintner1, 1OWS Institute of Pathology, Vienna, Austria; 2Institute of Clinical Neurobiology, Vienna, Austria. Contact e-mail: [email protected] Background: Cerebral amyloid angiopathy (CAA) is defined by ␤-amyloid peptide (A␤) depositions in cerebral vessels and is associated with Alzheimer disease (AD). It has been suggested that severe CAA is an independent risk factor for cognitive decline. However, data on the impact of CAA on cognitive decline are rare. Objective: The aim of the present study was to further evaluate the influence of AD pathology (ADP; e.g., CERAD scores, Braak stages, NIA-Reagan Institute Criteria) on the association between CAA and clinical dementia. Methods: 171 autopsy brains underwent standardized neuropathological assessment; the patients’ ages ranged from 54 to 104 years (mean age: 83.9 years, ⫹/-9.2, 59.6% female, 56.1% clinically demented). Using immunohistochemistry, the severity of CAA was assessed semiquantitatively (leptomeningeal and cortical vessels were scored separately): 0 ⫽ no A␤ positive vessels, 1 ⫽ mild (i.e., scattered positivity in few vessels), 2 ⫽ moderate (i.e., scattered positivity in many vessels or strong positivity in few vessels), 3 ⫽ severe (i.e., strong positivity in many vessels), 4 ⫽ severe with dyshoric changes (only in cortical vessels). Conclusion: CAA was present in 117 cases (68.4%), with the occipital region being affected significantly more than other regions. The overall incidence of CAA was significantly higher in cases with high grade AD pathology compared to those with low grade or no ADP. The severity of CAA significantly increased with increasing ADP, with CAA in the occipital region increasing significantly more than that in other regions. The association of CAA and clinical dementia failed to remain statistically significant when adjusting for concomitant ADP. However, in cases devoid of any ADP, CAA was significantly associated with the presence of clinical dementia. These results indicate a strong association of AD with CAA, but do not unequivocally support reports suggesting CAA to be an independent risk factor for cognitive decline, except for a subgroup of demented patients lacking any ADP. O1-01-04

INFLAMMATORY CELL INFILTRATES ARE COMMONLY ASSOCIATED WITH BRAIN VASCULATURE AND CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER’S DISEASE

Manuel Buttini1, Ming Chen1, Elizabeth Head2, Carl Cotman2, Dora Games1, 1Elan Pharmaceuticals, South San Francisco, CA, USA; 2 Institute of Brain Aging and Dementia, Univ. Calif. Irvine, Irvine, CA, USA. Contact e-mail: [email protected] Cerebral amyloid angiopathy (CAA), which is present in the majority of Alzheimer’s disease (AD) patients, is characterized by the deposition of the amyloid beta (Abeta) peptide around brain blood vessels. Brain vessel-, and especially CAA-associated inflammation, in AD is not well characterized, but it may have a role in adverse events linked to Abeta immunotherapy in a subset of patients. We asked whether brain blood vessels with and without Abeta deposits are associated with inflammatory cell infiltrates in AD and in young, non-neurological controls. The distributions of perivascular monocytic cells and T-cells were revealed by triple immunostaining with specific markers in sections of the occipital cortex: Factor