- Email: [email protected]
The human hypothalamus and Alzheimer symptoms
THIRD INTERNATIONAL
ral, and occipital lobes were used for neuropathological evaluation. The temporal preparation ran through the uncal portion of the Ammons'horn and included entorhinal/transentorhinal regions and the adjoining temporal isocortex. Neurofibrillary tangles and neuropil threads (but not neuritic plaques) displayed a consistent pattern of distribution throughout cortical areas and subcortical nuclei which rendered differentiation of six stages possible. Amyloid deposits were found in both non-demented and demented individuals. Neuritic plaques were not considered in the differentiation of stages. Stages I and II were characterized by lesions virtually confined to the transentorhinal region. None of the cases classified as stage I or II had obvious impairments of intellectual capabilities. Stages I and II may, therefore, correspond to a clinically silent period of Alzheimer‘s disease. Stages III and IV were marked by severe affliction of the entorhinal cortex and a few other areas and nuclei of the limbic system. Cases classified as stages III and IV showed impairments of cognition and personality changes and were considered to represent clinically incipient Alzheimer's disease. The hallmark of the final stages V and VI was destruction of the isocortex. All cases classified as stages V and VI were severely demented. The neuropathological stageing correlated linearly with status (r-=0.669; evaluations of the intellectual df=26; p=O.OOOl: stage = 5.02 - 0.11 BTS). Supported by the Deutsche Forschungsgemeinschaft
171 lwEHu.mN-AND-K. Ic@a12, P.J. D.F. swaad-, I. czU&e-Iqbal2, -1, F.c. -1, R. Ravidl, J.A.P. van de N&,3 1.NetherlandsInstitutzforBrain~,*ibezvdreef 33, 1105 AZ zu&em%m, TiXaWet&rl.aI&.2.Institute for Basic &search in ~svmlcanental Disabilities, 1050 Forest Bill Ilmd, Staten I&&, NY 10314, U.S.A. 3. Valerius Clinic, Free vniversity, Amsterdam. Ibe Netherlards. Sclwaclinical syl@ars of Alzbeinmr'sdisease (AD) may havetheiriX3sisindsgenzative,&ngesinhy@ialemic nuclei. DisaFpearance Of Circacllan rtrytlnrs ard ni&tlY re&lessnessinADsear!stoberelatsdtooelldeatiin the suprachiasmatic nucleus. Eating dishnbances and [email protected]~staining of ec neurites and cell bodies found with antibcdiesagai&tauandubiquitininthslXIslls tuberalis lat.eralis. Iicwevz, ti all cell gralpa shar signs of &~nsraticsr in the v chnirqagw raaainilitXtand.?XeVen andinAD.sCmecellgKUp6 activated, es is evident fran an inzease in cell, nucleolus and Golgi apparatus size. This is true for the in the supracptic andpataventricuv_inneJRons larnucleus (PVW) andtheaX%iuotrcpinreleasinghornKJr@a(C=D neurons in the PVW. Activation of the hypethalanu-pititaryadrenal(BPA)-ax.i.sinag~andADis alsoreflectedin pc&r&em~inaIfluidMis notdirectlyrelatedtothe ~OfAD~. Various obeervationsintbsby@halamicrnzleidonot tally with the generally w sequence 0feventsi.n AD, i.e. that amyloid deposition wcul.d lead to cytoskeletal changes follcwsdbycelldeati.Ourocservathat the activation &served tions indicate,~, may~themfmadeinsaeahy&d?alamicneUons VtiiXg in aging and AD. (D.F. Swaab, Nsurobiolcgyof wil-rg12, 317-324, 1991). Braintissue wasabtainsdfrcmtbeNetherlandsBrs.inBank.
172 RESPONSES OF SURVIVING CELLS THROUGH THE DEATH OF THEIR NEIGHBOR NEURONS. P-D. Coleman, D.G. Flood, M.R. Martzen, M.K. O'Banion, J.R. Slemmon, T. Wengenack. Depts of Neurobiology & Anatomy, Biochemistry, University Neurology; of Rochester, Rochester, NY 14642. Neuron death in the normally aging brain initiates a cascade of responses which include a complex set of
CONFERENCE
ON ALZHEIMER’S
DISEASE
glial responses of surviving neurons. A model system of intercellular signalling is proposed in which signals released by dying and dead neurons act on glia to alter the glial expression of neurotrophic, neurotoxic and neurite elongation factors. Peptides associated with neuron death in-vitro and in animal model systems will be described. Differences between in vitro and in viva systems will be discussed. Alterations in levels of these peptides in Alzheimer's disease will be presented. Supported by: LEAD Award - AG09016; AG01121; AG03644; and the American Health Assistance Foundation
173 A PROSPECTIVE STUDY ON THE PA-I-TERNSOF CELL LOSS AND THEIR ASSOCIATION WITH COGNITIVE AND NON-COGNITIVE FEATURES IN VERIFIED ALZHEIMER’S DISEASE, H. Forstl, A. Burns, R. Levy and N. Cairns. Central Institute of Mental Health P.0.B 122 120,680O Mannheim 1, Germany, Section of Old Age Psychiatry and Department of Neuropathology, Institute of Psychiatry, London. UK. 178 demented patients satisfying NINCDS-ADRDA criteria for ‘probable’ and ‘possible’ Alzheimer’s disease (AD) were enrolled in this longitudinal study. The diagnosis of AD was confirmed neuropathologically in 56 of the first 65 patients who came to post-mortem examination. In these patients (13e432; age 67 - 96, mean 83.1 years) the number of large neurons (>20pm maximum diameter) per mm* wascounted in cortical layers Ill and IV of the frontal (area 32) and parietal cortex (area 7), in the parahippocampal gyrus. in the pyramidal cell layer of the hippocampus (CAl) and in the basal nucleus of Meynert. The total number of neurons per horizontal section was counted in the substantia nigra, locus coeruleus and dorsal raphe nucleus. Cognitive performance as measured by the ‘CAMCOG’ was correlated significantly with the pyramidal cell counts in CA1 (Kendall’s tg = 0.20 [54] p = 0.020); the closest correlation was found with the subscore for recent memory (t 0.26 1541 0.012). These counts correlated inversely with the subscores for Phvsical Disabilitv, m and Communication Failure from the ‘Stockton Geriatric Rating Scale’ (t -0.16 [53] 0.044) and they were lower in patients with misidentifications (e.g. ‘mirror sign’, ‘phantom boarder syndrome’, etc.; U = 161.5 [42,13] 0.027). Features of the Kluver- Bucysyndrome were not associated with lower counts in the hippocampus or basal nucleus of Meynert. but with lower neuron counts in the temporoparietal cortex. Lower cell counts in the dorsal raphe nucleus were found in patients with delusions (U 99.0 [43,91 0.022) and auditorv hallucinations (U 88.5 [45,7] 0.064) as examined with the ‘Geriatric Mental State Schedule’. Patients satisfying DSM-IIIR criteria for ‘primary degenerative dementia of the Alzheimer tJpe with depression’ had lower neuron counts in the locus coeruleus (U 185.0 L39.1410.037), but not in the dorsal raphe nucleus or substantia nigra. Cogwheel rioidiD/ was associated with the presence of Lewy-bodies (X2 4.44 [l] 0.035) and lower cell counts in the substantia nigra (U 151.0 [29,1610.027). These findings suggest that the heterogenous clinical features in AD are associated with different patterns of cell loss.
174 A BIOCHEMICAL CELL MEMBRANE LESION SPECIFIC TO ALZHEIMER’S DISEASE, R.M. Nitsch. R.J. Wurtman and J.H.Growdon. Dept. of Neurology, Mass. General Hospital, Harvard Medical School, ACC 830. Boston, MA; and Dept. of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. The major structural membrane molecules, phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PldEtn) account for 7580% of the total phospholipid content in braincell membranes. In order to establish the biochemical membrane alterations which accompany neurodegeneration in Alzheimer’s disease, we measured levels of phospholipids and their metabolites in various brain regions of 10 histopathologically confirmed AD patients and 10 normal control subjects, matched according to age of death and postmortem time intervall. In AD brains, tissue levels of PtdCho and PdtEtn were decreased significantly (P < 0.05) by 15 to 20% in the frontal and parietal cortex, compared to controls. This depletion of membrane molecules was accompanied by a concomitant stoichiometric accumulation of the phospholipd catabolite. glycerophosphocholine (GPC), which was increased twofold in AD brains This stoichiometric
ral, and occipital lobes were used for neuropathological evaluation. The temporal preparation ran through the uncal portion of the Ammons'horn and included entorhinal/transentorhinal regions and the adjoining temporal isocortex. Neurofibrillary tangles and neuropil threads (but not neuritic plaques) displayed a consistent pattern of distribution throughout cortical areas and subcortical nuclei which rendered differentiation of six stages possible. Amyloid deposits were found in both non-demented and demented individuals. Neuritic plaques were not considered in the differentiation of stages. Stages I and II were characterized by lesions virtually confined to the transentorhinal region. None of the cases classified as stage I or II had obvious impairments of intellectual capabilities. Stages I and II may, therefore, correspond to a clinically silent period of Alzheimer‘s disease. Stages III and IV were marked by severe affliction of the entorhinal cortex and a few other areas and nuclei of the limbic system. Cases classified as stages III and IV showed impairments of cognition and personality changes and were considered to represent clinically incipient Alzheimer's disease. The hallmark of the final stages V and VI was destruction of the isocortex. All cases classified as stages V and VI were severely demented. The neuropathological stageing correlated linearly with status (r-=0.669; evaluations of the intellectual df=26; p=O.OOOl: stage = 5.02 - 0.11 BTS). Supported by the Deutsche Forschungsgemeinschaft
171 lwEHu.mN-AND-K. Ic@a12, P.J. D.F. swaad-, I. czU&e-Iqbal2, -1, F.c. -1, R. Ravidl, J.A.P. van de N&,3 1.NetherlandsInstitutzforBrain~,*ibezvdreef 33, 1105 AZ zu&em%m, TiXaWet&rl.aI&.2.Institute for Basic &search in ~svmlcanental Disabilities, 1050 Forest Bill Ilmd, Staten I&&, NY 10314, U.S.A. 3. Valerius Clinic, Free vniversity, Amsterdam. Ibe Netherlards. Sclwaclinical syl@ars of Alzbeinmr'sdisease (AD) may havetheiriX3sisindsgenzative,&ngesinhy@ialemic nuclei. DisaFpearance Of Circacllan rtrytlnrs ard ni&tlY re&lessnessinADsear!stoberelatsdtooelldeatiin the suprachiasmatic nucleus. Eating dishnbances and [email protected]~staining of ec neurites and cell bodies found with antibcdiesagai&tauandubiquitininthslXIslls tuberalis lat.eralis. Iicwevz, ti all cell gralpa shar signs of &~nsraticsr in the v chnirqagw raaainilitXtand.?XeVen andinAD.sCmecellgKUp6 activated, es is evident fran an inzease in cell, nucleolus and Golgi apparatus size. This is true for the in the supracptic andpataventricuv_inneJRons larnucleus (PVW) andtheaX%iuotrcpinreleasinghornKJr@a(C=D neurons in the PVW. Activation of the hypethalanu-pititaryadrenal(BPA)-ax.i.sinag~andADis alsoreflectedin pc&r&em~inaIfluidMis notdirectlyrelatedtothe ~OfAD~. Various obeervationsintbsby@halamicrnzleidonot tally with the generally w sequence 0feventsi.n AD, i.e. that amyloid deposition wcul.d lead to cytoskeletal changes follcwsdbycelldeati.Ourocservathat the activation &served tions indicate,~, may~themfmadeinsaeahy&d?alamicneUons VtiiXg in aging and AD. (D.F. Swaab, Nsurobiolcgyof wil-rg12, 317-324, 1991). Braintissue wasabtainsdfrcmtbeNetherlandsBrs.inBank.
172 RESPONSES OF SURVIVING CELLS THROUGH THE DEATH OF THEIR NEIGHBOR NEURONS. P-D. Coleman, D.G. Flood, M.R. Martzen, M.K. O'Banion, J.R. Slemmon, T. Wengenack. Depts of Neurobiology & Anatomy, Biochemistry, University Neurology; of Rochester, Rochester, NY 14642. Neuron death in the normally aging brain initiates a cascade of responses which include a complex set of
CONFERENCE
ON ALZHEIMER’S
DISEASE
glial responses of surviving neurons. A model system of intercellular signalling is proposed in which signals released by dying and dead neurons act on glia to alter the glial expression of neurotrophic, neurotoxic and neurite elongation factors. Peptides associated with neuron death in-vitro and in animal model systems will be described. Differences between in vitro and in viva systems will be discussed. Alterations in levels of these peptides in Alzheimer's disease will be presented. Supported by: LEAD Award - AG09016; AG01121; AG03644; and the American Health Assistance Foundation
173 A PROSPECTIVE STUDY ON THE PA-I-TERNSOF CELL LOSS AND THEIR ASSOCIATION WITH COGNITIVE AND NON-COGNITIVE FEATURES IN VERIFIED ALZHEIMER’S DISEASE, H. Forstl, A. Burns, R. Levy and N. Cairns. Central Institute of Mental Health P.0.B 122 120,680O Mannheim 1, Germany, Section of Old Age Psychiatry and Department of Neuropathology, Institute of Psychiatry, London. UK. 178 demented patients satisfying NINCDS-ADRDA criteria for ‘probable’ and ‘possible’ Alzheimer’s disease (AD) were enrolled in this longitudinal study. The diagnosis of AD was confirmed neuropathologically in 56 of the first 65 patients who came to post-mortem examination. In these patients (13e432; age 67 - 96, mean 83.1 years) the number of large neurons (>20pm maximum diameter) per mm* wascounted in cortical layers Ill and IV of the frontal (area 32) and parietal cortex (area 7), in the parahippocampal gyrus. in the pyramidal cell layer of the hippocampus (CAl) and in the basal nucleus of Meynert. The total number of neurons per horizontal section was counted in the substantia nigra, locus coeruleus and dorsal raphe nucleus. Cognitive performance as measured by the ‘CAMCOG’ was correlated significantly with the pyramidal cell counts in CA1 (Kendall’s tg = 0.20 [54] p = 0.020); the closest correlation was found with the subscore for recent memory (t 0.26 1541 0.012). These counts correlated inversely with the subscores for Phvsical Disabilitv, m and Communication Failure from the ‘Stockton Geriatric Rating Scale’ (t -0.16 [53] 0.044) and they were lower in patients with misidentifications (e.g. ‘mirror sign’, ‘phantom boarder syndrome’, etc.; U = 161.5 [42,13] 0.027). Features of the Kluver- Bucysyndrome were not associated with lower counts in the hippocampus or basal nucleus of Meynert. but with lower neuron counts in the temporoparietal cortex. Lower cell counts in the dorsal raphe nucleus were found in patients with delusions (U 99.0 [43,91 0.022) and auditorv hallucinations (U 88.5 [45,7] 0.064) as examined with the ‘Geriatric Mental State Schedule’. Patients satisfying DSM-IIIR criteria for ‘primary degenerative dementia of the Alzheimer tJpe with depression’ had lower neuron counts in the locus coeruleus (U 185.0 L39.1410.037), but not in the dorsal raphe nucleus or substantia nigra. Cogwheel rioidiD/ was associated with the presence of Lewy-bodies (X2 4.44 [l] 0.035) and lower cell counts in the substantia nigra (U 151.0 [29,1610.027). These findings suggest that the heterogenous clinical features in AD are associated with different patterns of cell loss.
174 A BIOCHEMICAL CELL MEMBRANE LESION SPECIFIC TO ALZHEIMER’S DISEASE, R.M. Nitsch. R.J. Wurtman and J.H.Growdon. Dept. of Neurology, Mass. General Hospital, Harvard Medical School, ACC 830. Boston, MA; and Dept. of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. The major structural membrane molecules, phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PldEtn) account for 7580% of the total phospholipid content in braincell membranes. In order to establish the biochemical membrane alterations which accompany neurodegeneration in Alzheimer’s disease, we measured levels of phospholipids and their metabolites in various brain regions of 10 histopathologically confirmed AD patients and 10 normal control subjects, matched according to age of death and postmortem time intervall. In AD brains, tissue levels of PtdCho and PdtEtn were decreased significantly (P < 0.05) by 15 to 20% in the frontal and parietal cortex, compared to controls. This depletion of membrane molecules was accompanied by a concomitant stoichiometric accumulation of the phospholipd catabolite. glycerophosphocholine (GPC), which was increased twofold in AD brains This stoichiometric