a positron emission tomographic study of resting cerebral glucose metabolism in the early diagnosis...

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THIRD INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE S15 Spectra were quanti!ied by integrating curve-fitted peaks. Resting regional metabolic rates for glucose (ICMRglc) were obtained using PET with (18F)-2-flooro-2-dtoxy-D-glueose (FDG) in 7 of the DAT patients (5 male, 2 female) and 7 of the age&x matched controls (5 male, 2 female). Mean age (2 SD) of Ihe patients and contmls WBS 59 f 9 yr and 62 f 10 respectively. Studies were performed on a Scandiuonix PC-1024-7B tomograph (Uppsala. Sweden). All scans were carried out with lights dimmed and the patient’s eyes and ears covered Data from PET slices corresponding to the MRS ROI was statistically analysed. Slices were 7 mm thick and 35,45,50, and 65 mm above the IOM Glucose metabolism in the ROI used for MRS was sianificandy lower in DAT patients (p-z 0.01) than controls. Mean (iS.D) rCMRglc in DAfpatienta hd controls WBS 5.01 + 0.9 and 6.08 + 0.6 ma/lOOa/min rewectivelv. However. we found no sianificant group difference in any phosphorus metadolite &ncenUatio&tio. and no co&lation behveen any phosphorus me&&l& coocemration/ratio and severity of dementia or glucose metabolism. For example mean (k S.D) PME concentration (mgkg brain matter) in DAT patients and controls was 3.86 f1.86 and 3.03 + 1.06, respectively We suggest that: (i) in DAT glucose metabolism is affected early in the disease process. reflecting decreased basal synaptic functioning, and (ii) changes in glucose metabolism precede significant changes in ATF' storage or phospholipid metabolism in neural elements per unit volume of brain matter. 61 A POSITRON EMISSION TOMOGRAPHIC STUDY OF RESTING CEREBRAL GLUCOSE METABOLISM IN THE EARLY DIAGNOSIS OF ALZHEIMER'S DIASEASE: USEFULNESS OF ALTERNATIVE METHODS OFANALYSWP. Pietrini. N.P. Azari. CL. Grady, J.A. Salerno, A. Gonzales-Aviles. L. Heston. K.D. Pettigrew. B. Horwitz, J.V. Haxby. M.B. Schapiro. Laboratory of Neurosciences. National Institute on Aging, NIH. Bethesda MD, USA. Patients with mild Alzhcimer’s disease (AD) show a pattern of reduced cerebral metabolic rate for glucose (rCMRglc) in parietal and temporal association COrteX. as measured by positron emission tomography (PET) and [18-Fl-fluoro-2-deoxy-D-glucose (FDG). To verify if a similar rCMRglc pattern is present in subjects “at risk” for probable AD. we longitudinally measured rCMRglc and neuropsychological function in a 65 y.o. man with isolated memory impairment and family history for autosomal dominant AD. Two PET examinations one year apart (Scanditronix PC1024-7B. Uppsala, Sweden; FWHM 6mm) were performed in the “resting state” (ears plugged/eyes covered, minimal ambient noise) with FDG. Sixteen sex- and age-matched healthy volunteers were used for comparison. Initial neuropsychological testing was normal except for the WAIS delayed memory. which were 2 SD lower than the control mean. To reduce inter-subject variability, absolute (mg/lOOg tissue/mitt) rCMRglc values were also “normalized” to the mean whole grey matter rCMRglc (rCMRglc/globalCMRglc). as well as to the mean sensorimotor rCMRglc (rCMRglc/SmCMRglc). PET data were analyzed in two ways: a) patient-control group mean comparisons of rCMRglc values (Z-score analysis; values > 2SD were considered significantly different). Initial rCMRglc data did not reveal any consistent abnormality in absolute or normalized rCMRglc values as compared to controls. However, one year later. a follow-up evaluation did reveal rCMRglc reductions in parietal regions (areas usually affected in AD), in coincidence with worsening of cognitive impairment (initial WAIS IQ=ISO; follow-up WAIS IQ=l36). Neither hippocampus. nor any other subcortical region showed any significant rCMRglc reduction at either evaluation; b) application of a previously determined discriminant function (Azari et al.. J Neuroimaging 1992; 1: 55) that successfully distinguished 17 mild/moderate AD patients from 16 matched healthy controls. When this discriminant function was applied to variables that represent the subject’s patterns of regional brain interactions. the subject was correctly identified as an AD patient with 100% probability on both PET scans. These results emphasize the importance of alternative methods of analysis to increase usefulness of resting PET data in the early detection of AD. 62 POSITRON EMISSION TOMOGRAPHY WITH ‘%LABELLED SERUM AMYLOID P COMPONENT IN SYSTEMIC AND CEREBRAL AMYLOIDOSIS, P.N. Hawkins, T. Jones, P. Tyrrell, M.N. Rossor, M. Myers, P. Roques, R. Larnbrecht, S. Richardson and M.B. Pepys. Immunological Medicine Unit, and MRC Cyclotron Unit, Royal Postgraduate Medical School, and Department of Neurology, St Mary’s Hospital, London, UK. The characteristic pathology of Alzheimer’s disease (AD) includes localised deposits of p-amyloid in the intracerebral plaques and leptomeningeal blood vessels. These deposits contain small quantities of amyloid P component (AP) which is a universal non-fibrillar constituent of all types of amyloid. AP is directly derived from the normal plasma protein serum amyloid P component (SAP) which binds to amyloid tibrils in a specific calcium-dependent manner. We have developed a quantitative scintigraphic method for imaging systemic amyloid deposits with ‘“I-labelled SAP as a specific molecular probe, and report here positron emission tomography studies in systemic and cerebral amyloid using ‘?-labelled protein. Eight patients were studied at intervals of up to 6 days following i.v. injection of ‘“I SAP: 2 patients with systemic amyloid (AA and AL type, 1 patient each); 2 patients with familial AD; 3 patients with Icelandic type of hereditary cerebral haemorrhage with amyloidosis (HCHWA), a disorder characterised by cerebrovascular deposits of cystatin C amyloid; 1 non-demented individual with a family history of AD. Extremely high resolution images offering tine anatomical detail, were obtained of renal AA and cardiac AL deposits. Quantitative cranial images in all other subjects demonstrated localisation and persistence of tracer in a rim surrounding the brain as well as degrees of intracerebral activity. The latter phenomenon was most markedinone of theAD subjects. However, as generally similar results were obtained in AD, HCHWA and one apparently normal 52 year old individual, the significance of the findings is unclear. Work is underway to conjugate SAP to other positron emitting isotopes with safer and more suitable emission profiles which would permit extension of the studies, including further control subjects. 63 ALZHEIMER AND AUTONOMIC NERVOUS SYSTEM G.Cometti, P.Cortelll*, F.Di Cesare, A.Mustafl, S.Pugliese, G.Savorani and S.Semeraro. V Geriatric Ward S.Orsola-Malpighi Hospital - Bologna *Department of Neurology University of Bologna A positive diagnosis of Alzheimer's disease. especially in it$ early stages, is of vital importance in correctly following di- sease evolution. Since cl' lnlcal diagnostic markers do not exist in Alzheimer's disease, various research study groups base their study protocols on patient history, the neurological examination, neuropsychological testing, instrumental examinations (MNR, CAT scan, SPECT) and laboratory data. The DSM III R criteria was often utilized. The aim of ow study was to investigate the auto- nomic nervous system in a group of patients in initial phase Al- zheimer's disease. Since it is known that during disease progres- sion, autonomic deflclt may develop, and if this occurs early in the disease, we may be able to search for possible clinical mar- kers that would enable us to make and confirm a" early diagnosis. Sixteen patients made up our case study: 6 SDAT, 5 MID and 5 heal thy controls (all patients about the same age). The internationa; ly accepted autonomic nervous system protocol will be briefly described below. PROTOCOL -Measurements: EEG. electrooculogram, blood pressure (FL napres). continuous HR, breathing oro-nasal and thoracic, finger plethysmography, plasma NA at rest and after 10 min of tilt. -Cardiovascular reflexes: head-up tilt, Valsalva manoeuvre, deep breathing, cold face test, CFT + voluntary apnoea, sustained handgrip. Cardiac arrythmias were frequently observed in AD in comparison to the other two groups of patients studied. We suppose that a" autonomic nervous system dysfunction in patients with SDAT can in some way determine such arrythmias. If our data can be confirmed by studies of a wider group of patients, we may be able to fur- ther study autonomic nervous system dysfunction, and eventually isolate a clinical marker. thereby enabling us to make an early diagnosis in initial phase Alzheimer'sdisease. 64 THE CONTRIBUTION OF NEUROIMAGING TO THE DIFFERENTIAL DIAGNOSIS OF EARLY DEMENTIA IN A MEMORY CLINIC. A. Spand*, H. Ftirstl, O.P. Almeida and R. Levy, Inet. of Gerontology*, University of Modena; Section of Old Age Psychiatry, Institute of Psychiatry, London SE5 BAF, UK. We examined the contribution of quantitative CT-scan analysis to the differential diagnosis of early dementing conditions in patients seen at a *Memory Clinic'. Seventy-eight consecutive referrals (39 m; 49 f; range 52 to 84 years, mean 69.2) underwent a standardised psychiatric, physical and laboratory a8sesement including unenhanced CT-scans. Vascular changes were readily identified in the scans from 13 patients with a history and

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Page 1: A positron emission tomographic study of resting cerebral glucose metabolism in the early diagnosis of Alzheimer's diasease: Usefulness of alternative methods of analysis

THIRD INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE S15

Spectra were quanti!ied by integrating curve-fitted peaks. Resting regional metabolic rates for glucose (ICMRglc) were obtained using PET with (18F)-2-flooro-2-dtoxy-D-glueose (FDG) in 7 of the DAT patients (5 male, 2 female) and 7 of the age&x matched controls (5 male, 2 female). Mean age (2 SD) of Ihe patients and contmls WBS 59 f 9 yr and 62 f 10 respectively. Studies were performed on a Scandiuonix PC-1024-7B tomograph (Uppsala. Sweden). All scans were carried out with lights dimmed and the patient’s eyes and ears covered Data from PET slices corresponding to the MRS ROI was statistically analysed. Slices were 7 mm thick and 35,45,50, and 65 mm above the IOM

Glucose metabolism in the ROI used for MRS was sianificandy lower in DAT patients (p-z 0.01) than controls. Mean (iS.D) rCMRglc in DAfpatienta hd controls WBS 5.01 + 0.9 and 6.08 + 0.6 ma/lOOa/min rewectivelv. However. we found no sianificant group difference in any phosphorus metadolite &ncenUatio&tio. and no co&lation behveen any phosphorus me&&l& coocemration/ratio and severity of dementia or glucose metabolism. For example mean (k S.D) PME concentration (mgkg brain matter) in DAT patients and controls was 3.86 f1.86 and 3.03 + 1.06, respectively

We suggest that: (i) in DAT glucose metabolism is affected early in the disease process. reflecting decreased basal synaptic functioning, and (ii) changes in glucose metabolism precede significant changes in ATF' storage or phospholipid metabolism in neural elements per unit volume of brain matter.

61 A POSITRON EMISSION TOMOGRAPHIC STUDY OF RESTING CEREBRAL GLUCOSE METABOLISM IN THE EARLY DIAGNOSIS OF ALZHEIMER'S DIASEASE: USEFULNESS OF ALTERNATIVE METHODS OFANALYSWP. Pietrini. N.P. Azari. CL. Grady, J.A. Salerno, A. Gonzales-Aviles. L. Heston. K.D. Pettigrew. B. Horwitz, J.V. Haxby. M.B. Schapiro. Laboratory of Neurosciences. National Institute on Aging, NIH. Bethesda MD, USA. Patients with mild Alzhcimer’s disease (AD) show a pattern of reduced cerebral metabolic rate for glucose (rCMRglc) in parietal and temporal association COrteX. as measured by positron emission tomography (PET) and [18-Fl-fluoro-2-deoxy-D-glucose (FDG). To verify if a similar rCMRglc pattern is present in subjects “at risk” for probable AD. we longitudinally measured rCMRglc and neuropsychological function in a 65 y.o. man with isolated memory impairment and family history for autosomal dominant AD. Two PET examinations one year apart (Scanditronix PC1024-7B. Uppsala, Sweden; FWHM 6mm) were performed in the “resting state” (ears plugged/eyes covered, minimal ambient noise) with FDG. Sixteen sex- and age-matched healthy volunteers were used for comparison. Initial neuropsychological testing was normal except for the WAIS delayed memory. which were 2 SD lower than the control mean. To reduce inter-subject variability, absolute (mg/lOOg tissue/mitt) rCMRglc values were also “normalized” to the mean whole grey matter rCMRglc (rCMRglc/globalCMRglc). as well as to the mean sensorimotor rCMRglc (rCMRglc/SmCMRglc). PET data were analyzed in two ways: a) patient-control group mean comparisons of rCMRglc values (Z-score analysis; values > 2SD were considered significantly different). Initial rCMRglc data did not reveal any consistent abnormality in absolute or normalized rCMRglc values as compared to controls. However, one year later. a follow-up evaluation did reveal rCMRglc reductions in parietal regions (areas usually affected in AD), in coincidence with worsening of cognitive impairment (initial WAIS IQ=ISO; follow-up WAIS IQ=l36). Neither hippocampus. nor any other subcortical region showed any significant rCMRglc reduction at either evaluation; b) application of a previously determined discriminant function (Azari et al.. J Neuroimaging 1992; 1: 55) that successfully distinguished 17 mild/moderate AD patients from 16 matched healthy controls. When this discriminant function was applied to variables that represent the subject’s patterns of regional brain interactions. the subject was correctly identified as an AD patient with 100% probability on both PET scans. These results emphasize the importance of alternative methods of analysis to increase usefulness of resting PET data in the early detection of AD.

62 POSITRON EMISSION TOMOGRAPHY WITH ‘%LABELLED SERUM AMYLOID P COMPONENT IN SYSTEMIC AND CEREBRAL AMYLOIDOSIS, P.N. Hawkins, T. Jones, P. Tyrrell, M.N. Rossor, M. Myers, P. Roques, R. Larnbrecht, S. Richardson and M.B. Pepys. Immunological Medicine Unit, and MRC Cyclotron Unit, Royal Postgraduate Medical School, and Department of Neurology, St Mary’s Hospital, London, UK.

The characteristic pathology of Alzheimer’s disease (AD) includes

localised deposits of p-amyloid in the intracerebral plaques and leptomeningeal blood vessels. These deposits contain small quantities of amyloid P component (AP) which is a universal non-fibrillar constituent of all types of amyloid. AP is directly derived from the normal plasma protein serum amyloid P component (SAP) which binds to amyloid tibrils in a specific calcium-dependent manner. We have developed a quantitative scintigraphic method for imaging systemic amyloid deposits with ‘“I-labelled SAP as a specific molecular probe, and report here

positron emission tomography studies in systemic and cerebral amyloid using ‘?-labelled protein. Eight patients were studied at intervals of up to 6 days following i.v. injection of ‘“I SAP: 2 patients with systemic amyloid (AA and AL type, 1 patient each); 2 patients with familial AD; 3 patients with Icelandic type of hereditary cerebral haemorrhage with amyloidosis (HCHWA), a disorder characterised by cerebrovascular deposits of cystatin C amyloid; 1 non-demented individual with a family history of AD. Extremely high resolution images offering tine anatomical detail, were obtained of renal AA and cardiac AL deposits. Quantitative cranial images in all other subjects demonstrated localisation and persistence of tracer in a rim surrounding the brain as well as degrees of intracerebral activity. The latter phenomenon was most marked in one of the AD subjects. However, as generally similar results were obtained in AD, HCHWA and one apparently normal 52 year old individual, the significance of the findings is unclear. Work is underway to conjugate SAP to other positron emitting isotopes with safer and more suitable emission profiles which would permit extension of the studies, including further control subjects.

63 ALZHEIMER AND AUTONOMIC NERVOUS SYSTEM G.Cometti, P.Cortelll*, F.Di Cesare, A.Mustafl, S.Pugliese, G.Savorani and S.Semeraro. V Geriatric Ward S.Orsola-Malpighi Hospital - Bologna *Department of Neurology University of Bologna

A positive diagnosis of Alzheimer's disease. especially in it$ early stages, is of vital importance in correctly following di- sease evolution. Since cl' lnlcal diagnostic markers do not exist in Alzheimer's disease, various research study groups base their study protocols on patient history, the neurological examination, neuropsychological testing, instrumental examinations (MNR, CAT scan, SPECT) and laboratory data. The DSM III R criteria was often utilized. The aim of ow study was to investigate the auto- nomic nervous system in a group of patients in initial phase Al- zheimer's disease. Since it is known that during disease progres- sion, autonomic deflclt may develop, and if this occurs early in the disease, we may be able to search for possible clinical mar- kers that would enable us to make and confirm a" early diagnosis. Sixteen patients made up our case study: 6 SDAT, 5 MID and 5 heal thy controls (all patients about the same age). The internationa; ly accepted autonomic nervous system protocol will be briefly described below. PROTOCOL -Measurements: EEG. electrooculogram, blood pressure (FL napres). continuous HR, breathing oro-nasal and thoracic, finger plethysmography, plasma NA at rest and after 10 min of tilt. -Cardiovascular reflexes: head-up tilt, Valsalva manoeuvre, deep breathing, cold face test, CFT + voluntary apnoea, sustained handgrip. Cardiac arrythmias were frequently observed in AD in comparison to the other two groups of patients studied. We suppose that a" autonomic nervous system dysfunction in patients with SDAT can in some way determine such arrythmias. If our data can be confirmed by studies of a wider group of patients, we may be able to fur- ther study autonomic nervous system dysfunction, and eventually isolate a clinical marker. thereby enabling us to make an early diagnosis in initial phase Alzheimer's disease.

64 THE CONTRIBUTION OF NEUROIMAGING TO THE DIFFERENTIAL DIAGNOSIS OF EARLY DEMENTIA IN A MEMORY CLINIC. A. Spand*, H. Ftirstl, O.P. Almeida and R. Levy, Inet. of Gerontology*, University of Modena; Section of Old Age Psychiatry, Institute of Psychiatry, London SE5 BAF, UK.

We examined the contribution of quantitative CT-scan analysis to the differential diagnosis of early dementing conditions in patients seen at a *Memory Clinic'. Seventy-eight consecutive referrals (39 m; 49 f; range 52 to 84 years, mean 69.2) underwent a standardised psychiatric, physical and laboratory a8sesement including unenhanced CT-scans.

Vascular changes were readily identified in the scans from 13 patients with a history and