305 Clinico-pathological correlates in Alzheimer\'s disease and frontotemporal dementia

FIFTH INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE free of NFT. Immunocytochemistry was used to define whether single neurons contain NFT, followed by in situ hybridization for selected messages. Neurons bearing NFT have a many-fold reduction of message for the synapse-associated protein, synaptophysln, in comparison to NFT-free neurons from the same region of the same brain. These NFT-free neurons from AD brain express synaptophysin message at the same level as that seen in single neurons of non-demented control brains. Message for the growth-associated protein, GAP-43, is also reduced in tangle-bearing neurons relative to adjacent tangle-free neurons. These reductions in message level are not a consequence of a generalized reduction in message synthesis in tangle-bearlng neurons since a poly-U probe for total messenger RNA shows only minor differences between many tangle-bearing neurons and neighboring tangle-free neurons. In fact, the level of expression of some messages, such as the iysosomal enzyme, cathepsin D, is increased in tangle-bearlng neurons. Double immunocytochemistry for NFT and for phospho-tau combined with in situ hYbridization for synaptophysin message suggest that tau phosphorylation alone, without the formation of NFT, is not sufficient to cause a decrease in synaptophysin message. However, we have examined only a limited number of potential tau phosphorylation sites to date. These findings may be conceptualized as demonstrating that molecular expression profiles of single neurons depend on whether that neuron does or does not contain NFT. We will also present a method for obtaining expression profiles of many messages from single neurons that have been immunocytochemieally characterized and some preliminary results utilizing this method with postmortem AD brain tissue. Supported by: American Health Assistance Foundation, Markey Foundation, and the National Instltue on Aging R35 09016, P30 08665, T32 00107, ROI 01121.

SYMPOSIUM: CLINICAL COURSE DIAGNOSIS I

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306 Morphological and Functional Neuroimaging in Alzheimer's Disease K. Uemura #, M. Sasaki*, J. Hatazawa# and T. Okudera#. Department of Radiology and Nuclear Medicine, Research Institute of Brain and Blood Vessels, Akita. 6-10 Senshu-Kubota machi, Akita. Japan#, and The Center of Radiological Science, lwate Medical University, Morioka, Japan.* Patients with probable Alzheimer's disease were analyzed detailed morphological changes of the basal forebrain and temporal lobe and functional changes such as regional cerebral blood flow (CBF), blood volume (CBV) and oxygen metabolism by using a 1.5T super-conductive MRI, a positron emission computed tomograpy (PET) and single photon emission tomography (SPECT). The results are summarized as follows. 1. Although morphological changes of the nucleus basalis of Meynert in Alzheimer's disease has been intensively investigated histologically, little attention has been paid in neuro-imaging such as MRI. With our study, thinsection T2-weighted coronal MRI through the anterior commissure could demonstrate the substantia innominata as a gray matter signal intensity. The average thickness of substantia innominata of the Alzheimer patients was 2.1 mm: SD, 0.4ram, that was significantly reduced comparing to that of agematched normal control (3.0mm: SD,0.4mm). Significant volumetric reduction was also found in the parahippocampal gyrus that includes the entorhinal cortex, in where neurofibrillary change has been proved histologically from the earliest stage of this disease. 2. It has been known that CBF and metabolism in Alzheimer patients frequently decreased in the temporo-parietal lobe but oxygen extraction fraction of there has been believed to be normal. Our PET study disclosed that, in some patients, the oxygen extraction fraction increased mildly combined with decreased CBV. The finding would be caused by vaso-constriction of the small arteries in the cerebral cortex due to cholinergic denervation of the arterial smooth muscles. 3. Early diagnosis of dementia is thought to be important for control of the disease. Blood flow studies with PET and SPECT showed mild decrease of CBF in the medial temporal lobe as an early sign of Alzheimer's disease. The results shown above will contribute the differential diagnosis and patho-physiological interpretation of AIzheimer's disease.

307 305 Clinien-pathological correlates in AIzheimer's disease and Frontotemporal dementia. L. Gustafson*, U. Passant, A. Brun. Departraents of Psycbogeriatrics and Pathology, Lund University Hospital, PO Box 638, So220 09 Land, Sweden The early clinical manifestations and the course in Alzheimer's disease (AD) and frontotemporal dementia (FTD) are related to the loealisation and type of brain damage and dysfunction, but also influenced by premorbid personality and concurrent somatic and environmental conditions. This study analyses the relationship between psychiatric, neurohigieal and somatic features in two types of degenerative dementia with a largely inverse distribution of cortical and subenrtieal involvement. The study is based on a large material of cases from a long-term prospective dementia study. Patients with presenile AD and FTD were diagnosed and followed-up clinically, including measurement of regional cerebral blood flow (rCBF), neuropsyehologieal testing, in most eases CT and/or MRI, and a detailed neuropathologieal investigation in deceased eases. The engnitive and behavioural changes in the diagnostic groups and in individual cases were correlated to the distribution of enrtieal degeneration and the rCBF pattem. Deterioration of personality, emotional changes, psychotic features and dissolution of expressive language were strongly related to frontal cortical involvement and appeared early in FTD with strong impact on psychosocial competence, Differential diagnosis of FTD may be difficult not only against other types of dementia but against schizophrenia, mood disorder and personality deviations of non-organic origin. FTD is however possible to differentiate from AD, where habitual personality traits and the capacity for social interactionare comparatively spared in contrastto severe cognitive and practical impairment of tempoproparietal type. The rather consistent emotional and behavioural differences between A D and F T D are probably explained by the partly inverse distribution of degeneration in the cingulate gyrus and differences in temporal limbie

involvement in the two diseases. The clinical differences between AD and FTD are obvious when the patients axe investigated and followed under standardized and optimal ennditions. The differential diagnosis has become increasingly important for the choice of drug treatment and the development of care for these patient groups. One eenfotinding factor for the differential diagnosis between FFD and AD on one hand and vasenla? dementia on the other is the high prevalence of orthostatie hypotension and clinical signs of cerebral hypoperfusion in both. From the climeal point of view low blood pressure and orthostatie hypotension may have impact on treatment and prevention ofisehemin brain damage in all types of dementia.

Hippocampal Atrophy: An Early Brain Marker for AD and a Correlate of Memory and HPA Axis Dysfunction. M.J. de Leon*, A. Convit, S. De Senti, C. Tarshish, H. Rusinek and A.E. George. NYU Medical Center 550 First Ave. NY 10016 Post mortem studies suggest that lesions in the hippocampal formation precede neocortical lesions and dementia symptoms of AD. Recent MRI results are in agreement and expand these findings. The cross-sectional MRI data show that hippocampal formation atrophy (n=405) and volume loss (n=79) (HA) discriminate between normal elderly and elderly with mild cognitive impairments (at increased risk for AD). After controlling for age, HA is a specific anatomic predictor of memory performance. Including the lateral temporal lobe volume serves to improve the detection of patients with dementia. The longitudinal data show that baseline HA is an accurate predictor of dementia within 4 years. We now observe that many of these relationships are observable on the PET with FDG. Basic studies consistently point to relationships between HPA axis functioning and hippocampal integrity. In AD, glucose tolerance tests caused hypercortisolemia which was associated with increased HA. With the IV infusion of eortisol we observe, using PET, marked hippoeampal glucose metabolism reductions in elderly controls (n=7) but not in AD (n=8). These results contribute both to the increased understanding of normal hippocampal functioning and to the detection of early AD.

308 Diffuse Cerebral Amyloid Angiopathy-associated Vasculopathy as a Cause of Dementia: A Clinico-pathological Study J. Ogata*, J. Masuda, C. Yutani, T. Abumiya, K. Minematsu and T. Yamaguchi National Cardiovascular Center, Osaka, and Shimane Medical University, Shimane (J.M.), Japan We investigated our 892 adult autopsy cases to elucidate whether cerebral amyloid angiopathy (CAA) causes dementia in the elderly.