262 NEUROBIOLOGY OF AGING, VOLUME 11, 1990 ABSTRACTS OF SECOND INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE

NEUROIMAGING/BRAIN ENERGY METABOLISM

between MID and DAT. The study shows that diffuse changes in cerebral white matter can be detected by MR in patients with dementia.

TABLE i

Cases Matched Control@ P value of

Location Mean ~.D. Mean S.D. Differencea

WM RA 922 138 831 93 0.01 RP 894 124 835 108 0.11 LA 901 107 803 98 0.01 LP 922 116 834 96 0.01

GM RA 1313 355 1099 162 0.02 LA 1316 239 1084 292 < 0.01

39

DIAGNOSTIC VALUE OF A COMBINATION OF TEMPORAL LOBE CT SCANS AND SPET STUDIES IN DEMENTIA: DEFINITION OF A SUBGROUP OF PATIENTS WITH STRUCTURAL AND METABOLIC CHANGES. *K. A. Jobat, Anslow, P.A., Barker, S., Esiri, M.M., Molyneux, A.J,, King, E., Shepstone, B.J., Smith, A., Soper, N., Sutton, L., Smith, A.D. University Department of Clinical Neurology, Department of Radiology and Department of Neuropathology, Radcliffe Infirmary, Oxford; University Department of Nuclear Medicine, John Radcliffe Hospital, Oxford; University Department of Pharmacology, South Parks Rd. Oxford, England.

The major pathological changes in Alzheimer's disease are in the medial temporal lobe with a high concentration of plaques and tangles and reduced tissue mass. However, SPET studies indicate reduced blood flow in posterior parietal/ superior temporal cortex, where there are fewer plaques and tangles. To establish the diagnostic value of SPET and CT we are studying patients with cognitive impairment who will be followed to post mortem for histological diagnosis. SPET was carried out using Tc-HMPAO and CT scanning with temporal lobe orientation. Measurements were made of the thickness of temporal lobe structures. All patients were assessed by CAMCOG and MMSE, in order to define the degree of dementia. This is a preliminary report on our first 79 patients.

Two groups were defined by their cognitive scores: for 25 patients both scores were above the cut-off values ('controls'); while for 49 both scores were below the cut-off values ('dements'). SPET showed that 4/25 controls had moderate to severe reductions in blood flow in the parietotemporal region that could not be accounted for solely by ischaemic damage; 37/49 of the dements showed reduced blood flow in these regions. Thinning of the medial temporal lobe was found by CT in 9/25 of controls and in 42/49 of dements. Thus, SPET alone is better than CT alone in identifying demented patients. However, the best discrimination was found when CT and SPET results were combined: 37/49 of dements had both reduced parletotemporal blood flow and thinning of the medial temporal lobe, while these changes only occurred together in 3/25 controls. All 37 dements who had SPET evidence of reduced parietotemporal blood flow also had atrophic medial temporal lobes. The combination of reduced parietotemporal blood flow and atrophy of the medial temporal lobe might define a subgroup of demented patients who have Alzheimer's disease.

40

PET IMAGING OF IIC-NICOTINE BINDING IN THE Hi.AN BRAIN - IMPLICATIONS FOR DRUGDEP~DmWCEANDDEMENTIADISGRDERS *H. Nyi~ck, A. Nordberg, B. IAngstr~m, C. Ralldin, P. Hartvig, A. ]&hlin G. Sedvall. Department of Psychiatry and Psychology, Karolinska Institutet, Stockholm and Departments of Pharmacology and Biochemistry, University of Uppsala, Sweden.

The cholinergic receptors of the brain are known to play an essential role in cognitive processes which are improved by nicotine and deranged by dementia disorders. In order to elaborate a method for the study of nicotinic receptors in human brain in vivo (+)- and (-)llC-nlcotine were synthesized and administered i.v. to healthy volunteers. The level of llC-radioactivity in arterial blood was measured and the uptake and distribution of the activity in various brain regions were studied during 60 min usingpositronemission tomography (PET). Both enantiomerswere rapidly taken upand distributed to various cortical and subcortical regions. The

highest radioactivity was obtained in the frontal, the temporal, the cingulate and the insular cortex. The lowest activities were in the cerebellum, the white matter and the blood. Peak activity was at 1-2 min in the blood and at 4-6 min in the brain. There were no differences in the kinetics in blood between (+)- and (-)llC-nicotine. However, the uptake of (-)llC-nicotine in the brain was higher than that of (+)llC-nicotine, particularly in smokers as compared to non-smokers. Concomitant i.v. administration of unlabelled nicotine (0.4-1.5 rag) with the tracer diminished the binding of llC-nicotine by 10-20 per cent whereas infusion of un- labelled nicotine (0.5-4.0 mg) diminished the brain uptake of (-)llC-nicotine by 50-60 per cent as evidence for competition at specific binding sites. Patients with Alzheimer's disease showed a decreased uptake of (+)- and (-)lie-nicotine as compared to age matched control subjects. These results indicate that the PET technique may be used for further understanding of nicotinic mechanisms in drug dependence as well as in neurodegenerative disorders.

41 MUSCARINIC AND NICOTINIC CONTRIBUTIONS TO THE AD CORTICAL

PERFUSION ABNORMALITY *I. Prohovnik

NYS Psychiatric Institute and Depts. Psychiatry, Neurology, and Radiology, Columbia University, NY 10032.

Alzheimer's disease (AD) is characterized by a typical cortical abnormality of perfusion and metabolism, which has been suggested to be of diagnostic value. This characteristic abnormality is clearly detectable even in patients with mild symptoms and early in the course of the disease (Prohovnik et al., 1988). The following series of experiments was performed to assess whether this common abnormality is due to a cholinergic deficit. All experiments consisted of the induction of transient memory deficit in healthy subjects by anticholinergic agents, and measuring regional Cerebral Blood Flow (rCBF) by the 133Xe inhalation technique.

In the first experiment (Honer et al., 1988), scopolamine induced a dose- and time-dependent reduction of frontal cortical perfusion (n=15). In the second experiment (n=9, Probovnik et al., 1988, unpublished), we replicated the scopolamine (7.3 ~g/Kg IV) effects, and also showed a transient reversal of both global and frontal flow deficits by physostigmine (22 Bg/Kg IV), but not by neostigmine (either 7 or 11 ~ K g IV).

Having thus confirmed the central and specific scopolamine effect, we proceeded to evaluate the hypothesis that its failure to mimic the AD perfusion pattern was due to its partial blockade of the muscarinic system: The third experiment involved blockade of muscarinic (scopolamine 7.3 ~ K g ) as well as nicotinic receptors. For nicotinic blockade, we employed mecamylamine (7.5 and 15 mg PO). Further, to evaluate age effects, this experiment included both young and elderly healthy subjects. Data analyzed so far include 3 young and 7 elderly subjects. Mecamylamine was administered first, followed two hours later by scopolamine, rCBF and BSRT were performed at baseline, one and two hours following mecamylamine, and 25 and 75 minutes following scopolamine.

As in the previous experiments, scopolamine induced a marked frontal flow deficit. Mecamylamine, in contrast, mainly affected parietotemp0ral cortex, the area most consistently implicated in functional brain imaging of AD. Using a simple index related to the parietotemporal functional lesion, there was a highly specific interaction of dose by time (F(4,24)=5.97, p<.002), demonstrating a maximal drop of this index within an hour following the high dose, but. not the low dose, of mecamylamlne.

We propose that the characteristic perfusion abnormality in AD does, in fact reflect cholinergic deficits. Further, it appears to consist of at least two componenets, reflecting systems associated with muscarinic (frontal cortex) and nicotinic (parietotemporal cortex) receptors.

42

COMPUTERIZED EEG FREQUENCY ANALYSIS AND TOPOGRAPHIC BRAIN MAPPING IN ALZHEIMER'S DISEASE AND MULTI-INFARCT DEMENTIA. *C.K. Liu, C.K. Mody, H.B. Mclntyre, B.L. Miller, Harbor- UCLA Medical Center, Torrance, California, 90509 USA.

Topographic Brain Mapping (TBM) and Computerized EEG Frequency Analysis (CEEGFA) were obtained on 20 patients (age: 64.4+ 11.2; MMSE: 17.8+ 7.0) with multl-infarct dementia (MID) and 20, age and severity matched patients (age: 66.8~ 10.6; MMSE: 17.2 ~ 7.1) with Alzheimer's Disease (AD) defined by DSM-III-R and NINCDS-ARDA criteria respectively. The basis of comparison was TBM and background activity from CEEGFA. Utilizing a QSI 9000 brain mapping instrument, compu- terized EEG data were acquired using nose and llnked'ear common references and ware interpreted blindly.

In the AD group, all 20 (100%) had generalized abnormalltie~ with maximal change over bilateral temporo-parfeto'occipital