- Email: [email protected]
Hippocampal atrophy in mild cognitive impairment. A population-based study
s252
111501
Poster
A CORRELATIVE OF LIMBIC IN DEMENTIA
STUDY
SYSTEM
OF VOLUME
WITH
MEASUREMENT
CLINICAL
OF ALZHEIMER’S
SCALE
MRI
EXMANIATION
TYPE.
OBJECTIVE: To study the correlationso of quantitive MRI of hippocampal formation (HF), amygadala (AM) and the temporal horn of lateral ventricle (TN) with chnical xale examinations in dementia of Alzheimer’a type. METHODS: Using Siemeny I .ST superconductive MRI scanning machine to obtain volume measurements of the HF. AM and TH on oblique coronal sections of 27 cases of dementia of Alrheimer’s type. The patients were exammed simultaneously by usmg clinical scale. RESULTS: Significant correlations were observed between the volume of AM. TH and parahippocampals with MMSE and WMS.
Poster Presentation: REGULATION PRIMARY
Angel
TYPE:
A PILOT
IN SENILE
DEMENTIA
IN
MILD
and
Cellular
Biology
IV
APOLIPOPROTEIN
Km-olinsko Frank
Kurolinska Err/in
OF
Albert,
Inst,
and Cellular Biology IV
Inst. Huddinge Chnrite,
Huddinge
E SECRETION
ASTROCYTE
Swrdrw
Anatomy,
Sweden,
IN RAT
CULTURES.
Ulrike
Berlin
Thomas
Hamker,
Germany;
George
Rydigrr Richard
Ohm,
F
Charire,
Germmy
STUDY
Objectivea: Inflammatory mechamsms contribute to the neurodegenerative process in Alzheimer’s Disease, not simply ab a response to already existing pathology, but pathognomonic as a significant source and hallmark of pathology. 1271PKI 1195 is a single photon emission computed tomography (SPECT) ligand with high selectivity and affinity (KD X.0 + 1.7 nM) for the peripheral benzodiaaepine receptor (PBR), expressed on microglia (brain resident macrophages). In viva visualization of thl\ inflammation could be helpful to understand the pathophysiology of the disease and eventually. as a tool to monitor am-inflammatory treatment. Methods: Seven patxnts w&ring from probable Alzheimer’s Disease (3 men, moderate to severe) and 5 control persons (4 men) were imaged on a triple-head gamma camera after injection of 185 MBq ‘*-‘I PKI 1195. After iterative reconstruction. normalization was done on cerebellar uptake. Within one week, a standard high-resolution ‘9’“Tc ECD perfusion SPECT war alao performed in all patienta and controls. “‘1 PKI 1195 SPECT Images were realigned by means of the transmissmn images into Thalaraich co-ordinates. Findings: The mean uptake of jz31 PK 1I 195 in patients suffering from Alzheimer’s Disease was increased as compared to controls and this in the left frontal, occipital, parietal and right frontal, parietal. occipital. temporal and medial temporal region. A decreased uptake was found in the left temporal and medial temporal region. Conclusions: ‘“I PKI I195 can be used to visualize inflammation in viva in patient\ wffering from Alzheimer’b Disease. The decreased uptake in the (pathognomonically) compromised regions l.c. left temporal and medul temporal could be due to the severity of the disease (moderate to severe) and the long disease duration. The hzterogencity between the regional “‘1 PKI 1195 uptake can be seen a~ a manifw tation of a generalized disease with temporal and regional difference\. Aa for the correlation with regional perfusion, the discrepancy between receptor and metabolism changes mw be taken into account.
HIPPOCAMPAL ATROPHY 111521 MENT. A POPULATION-BASED
Awton~),
Meske,
Molecular
HIPPOCAMPAL
Cedu:o-Mingur;. Volker
Cowburn, INFLAMMATION
Molecular
The magnitude of non-directional hippocampal asymmetry increased with decreasing cognitive state. Conclusion: Hlppocampal atrophy (HA) is a sensitive marker for MCI in the elderly. Asymmetrical HA may be an early sign of Alzheimer’s disease and MCI.
Veh,
SPECT IMAGING OF (11511 OF THE ALZHEIMER
Presentation:
COGNITIVE
IMPAIR-
STUDY.
Objective: AILheimer’s disease has been defined as a hippocampal disease. In thih study, the power of MR volumetric hippocampal measures to delineate mdd cognitive impairment (MCI) from normal cognition and mild dementia is examined in a randomly selected sample of elderly community dwellers. Subjects and Methods: A sample of 39 right-handed subjects taking part in the Leipzig Longitudinal Study of the Aged (LEILA 75+) is examined (mean age 78.4, MMSE 19.30). Clinical dementia rating (CDR) was used to assess the cognitive state of the subjects and three clinical groups were formed according to the CDR (CDR O=normal, CDR OS=MCI, and CDR I =mild dementia). For each subject, a 3D Tl-weighted high resolution MRI brain dataset was obtained. Hippocampal volumes were segmented manually in the coronal plane on both sides and normalized by the intracranial volume. Results: In MCI, a stgnificant hippocampal volume reduction of 14.3% vs.1 1.3% (left vs. right) relative to normal was found. Discriminant analysis based on four hippocampal measures resulted in a correct classification of 76.9 % of the subjects. Left-sided and posterior hlppocampal measures were more responsible for group dircrimination than right-sided and anterior measures. The physiological left-right asymmetry of the hippocampus wac preserved in MCI and normal cognition, but not In mild dementia.
Apolipoprotein E (apoE) ia an abundant hpoprotein, the iaoforma of which may hale differential effecta on a number of pathological procerses underlying Alrhemw’s disease (AD). Alternatively, recent studies suggest that the amount, rather than type. of apoE may be an important determinant for AD. Therefore, understanding the regulated synthesis of apoE may be important for determining its role in AD. In the present wdy we show that in rat primary hippocampal astrocyte cultures dibutyrylCAMP (dBcAMP) increases apoE secretion in a dose and time dependent manner and Retinoic Acid potentiates this effect. In contrast, the protein kinase C (PKC) activator phorbol 12.my&ate 13.acetate (PMA) decreased apoE secretion, and reversed the effects of dBcAMP. ApoE secretion was also modulated by agonists for receptora linked to the adenylyl cyclase/cAMP and phospholipase ClPKC signal transduction pathways. Isoprotenerol, artenerol and serotonin enhanced, while clonidine and carbachol decreased secreted apoE. Artenerol also potentiated the isoprotenerolmediated increase. Our results indicate that astrocytic apoE production can be regulated by factors that affect the intracellular concentration of cAMP and that PKC has a complex role in the regulation of this protein. Alterations in these aignalling pathways in AD brain. may have cowequences for apoE wcretion in this disorder.
INDUCTION PLASMA
Julim
J O’Rror.
Mineola.
NY;
OF
APOPTOSIS
FACTOR
Louis RnRo/ia, Trtsuo
rnvrry, NJ: Steven
FOUND
Thomus A P&in.
Shimumura,
Fishbane.
IN
John
Robert
NEURONAL
IN ALZHEIMER’S
Linda
Wood
K Moesako.
Fww.
Johnson
Winthrop
Sch
CELLS DISEASE
Winthrop
of
BY
Uni\, Ho.yp,
Medicine,
Umv Hasp,
A
(AD)
Mineolu,
PiscntNY
We demonstrated a plasma factor found in AD, identified as glutathione-independent prostaglandin D2 aynthase (PGD2S). and an end- product of the pro\taglandin D2 pathway, 15.deoxy-A ‘L.‘J-proataglandin 52 (15dPGJ2), induce apoptoais (Apoptotlc Index [AI] = Ic of cells undergoing apoptosis) in rat PC12 and human NTERA-2 neuronal cells. PC12 and NTERA-2 cells were exposed for 2 h to a I:5 dilution of AD plasma (AI: 27.223.7, 30.3k2.4). OSpg recombinant (r)PGD2S (AI: 32.654.0, 30.62 1.3). 6kglml 15dPGJ2 (AI: 31.321.7, 36.15 0.8), a I:5 dilution of control plasma (AI: 7.921.7, 10.72 1.7). or untreated cells (Al: lOSil.X, 10.711.4) respectively. The activities of AD plasma and rPGD2S, but not 15dPGJ2, were inhibited by the COX-2 specific inhibitor, NS-39X (lOkM), and IS kg of antirPGD2S antibody in PC12 cells (AI: 6.550.9, 6.0-tl.4, X.8) 1.6, 8.42 1.6 reqpectively). Apoptotic characteristics were examined using cellular ultrastructure , TUNEL activity annexin V staining , and inhibitjon of TUNEL activity by Z-DEVD-fmk, a caspase-3 inhibitor a> indicators. BRL49653, a PPARy ligand chemically unrelated to the end-product prostaglandins, which are natural ligands for PPAR?, increased AI’? measured with the TUNEL assay (PC12 Al: 2722.2: NTERA Al: 21.626.4). AI‘s were significantly (PcO.05) reduced by the transcriptional inhibitor actinomycin D (48%, 52% respectively), and by prostaglandin F2a, known to Induce MAP kinase phosphorylation of PPARy and down regulate it\ activity(34%,48% respectively). The number of PC12 cells stained with Annexin V Increased when exposed to a I:5 dilution of AD plasma (AI: 50.7?4.S), hkglml 15dPGJ (AI: 62.1 il.1). IO&M BRL49653 (AI: 53.2?1.8), IOOkM glutamate (AI: 61.5k3.9) as compared to control solvent (Al: 15.92 I .4). There was no detectable decline in cell number after exposure to apoptotic agents for four days even though the AI was increased as noted by TEM when treated with 15dPGJ2, BRL49653. or glutamate. These results indicate that the kinetics of apoptosis induced in neuronal cells by this pathway may be slower than in other cell types and has important implications with respect to apoptosis in AD. Drugs that phosphorylate PPARy might block apoptosis early on.
111501
Poster
A CORRELATIVE OF LIMBIC IN DEMENTIA
STUDY
SYSTEM
OF VOLUME
WITH
MEASUREMENT
CLINICAL
OF ALZHEIMER’S
SCALE
MRI
EXMANIATION
TYPE.
OBJECTIVE: To study the correlationso of quantitive MRI of hippocampal formation (HF), amygadala (AM) and the temporal horn of lateral ventricle (TN) with chnical xale examinations in dementia of Alzheimer’a type. METHODS: Using Siemeny I .ST superconductive MRI scanning machine to obtain volume measurements of the HF. AM and TH on oblique coronal sections of 27 cases of dementia of Alrheimer’s type. The patients were exammed simultaneously by usmg clinical scale. RESULTS: Significant correlations were observed between the volume of AM. TH and parahippocampals with MMSE and WMS.
Poster Presentation: REGULATION PRIMARY
Angel
TYPE:
A PILOT
IN SENILE
DEMENTIA
IN
MILD
and
Cellular
Biology
IV
APOLIPOPROTEIN
Km-olinsko Frank
Kurolinska Err/in
OF
Albert,
Inst,
and Cellular Biology IV
Inst. Huddinge Chnrite,
Huddinge
E SECRETION
ASTROCYTE
Swrdrw
Anatomy,
Sweden,
IN RAT
CULTURES.
Ulrike
Berlin
Thomas
Hamker,
Germany;
George
Rydigrr Richard
Ohm,
F
Charire,
Germmy
STUDY
Objectivea: Inflammatory mechamsms contribute to the neurodegenerative process in Alzheimer’s Disease, not simply ab a response to already existing pathology, but pathognomonic as a significant source and hallmark of pathology. 1271PKI 1195 is a single photon emission computed tomography (SPECT) ligand with high selectivity and affinity (KD X.0 + 1.7 nM) for the peripheral benzodiaaepine receptor (PBR), expressed on microglia (brain resident macrophages). In viva visualization of thl\ inflammation could be helpful to understand the pathophysiology of the disease and eventually. as a tool to monitor am-inflammatory treatment. Methods: Seven patxnts w&ring from probable Alzheimer’s Disease (3 men, moderate to severe) and 5 control persons (4 men) were imaged on a triple-head gamma camera after injection of 185 MBq ‘*-‘I PKI 1195. After iterative reconstruction. normalization was done on cerebellar uptake. Within one week, a standard high-resolution ‘9’“Tc ECD perfusion SPECT war alao performed in all patienta and controls. “‘1 PKI 1195 SPECT Images were realigned by means of the transmissmn images into Thalaraich co-ordinates. Findings: The mean uptake of jz31 PK 1I 195 in patients suffering from Alzheimer’s Disease was increased as compared to controls and this in the left frontal, occipital, parietal and right frontal, parietal. occipital. temporal and medial temporal region. A decreased uptake was found in the left temporal and medial temporal region. Conclusions: ‘“I PKI I195 can be used to visualize inflammation in viva in patient\ wffering from Alzheimer’b Disease. The decreased uptake in the (pathognomonically) compromised regions l.c. left temporal and medul temporal could be due to the severity of the disease (moderate to severe) and the long disease duration. The hzterogencity between the regional “‘1 PKI 1195 uptake can be seen a~ a manifw tation of a generalized disease with temporal and regional difference\. Aa for the correlation with regional perfusion, the discrepancy between receptor and metabolism changes mw be taken into account.
HIPPOCAMPAL ATROPHY 111521 MENT. A POPULATION-BASED
Awton~),
Meske,
Molecular
HIPPOCAMPAL
Cedu:o-Mingur;. Volker
Cowburn, INFLAMMATION
Molecular
The magnitude of non-directional hippocampal asymmetry increased with decreasing cognitive state. Conclusion: Hlppocampal atrophy (HA) is a sensitive marker for MCI in the elderly. Asymmetrical HA may be an early sign of Alzheimer’s disease and MCI.
Veh,
SPECT IMAGING OF (11511 OF THE ALZHEIMER
Presentation:
COGNITIVE
IMPAIR-
STUDY.
Objective: AILheimer’s disease has been defined as a hippocampal disease. In thih study, the power of MR volumetric hippocampal measures to delineate mdd cognitive impairment (MCI) from normal cognition and mild dementia is examined in a randomly selected sample of elderly community dwellers. Subjects and Methods: A sample of 39 right-handed subjects taking part in the Leipzig Longitudinal Study of the Aged (LEILA 75+) is examined (mean age 78.4, MMSE 19.30). Clinical dementia rating (CDR) was used to assess the cognitive state of the subjects and three clinical groups were formed according to the CDR (CDR O=normal, CDR OS=MCI, and CDR I =mild dementia). For each subject, a 3D Tl-weighted high resolution MRI brain dataset was obtained. Hippocampal volumes were segmented manually in the coronal plane on both sides and normalized by the intracranial volume. Results: In MCI, a stgnificant hippocampal volume reduction of 14.3% vs.1 1.3% (left vs. right) relative to normal was found. Discriminant analysis based on four hippocampal measures resulted in a correct classification of 76.9 % of the subjects. Left-sided and posterior hlppocampal measures were more responsible for group dircrimination than right-sided and anterior measures. The physiological left-right asymmetry of the hippocampus wac preserved in MCI and normal cognition, but not In mild dementia.
Apolipoprotein E (apoE) ia an abundant hpoprotein, the iaoforma of which may hale differential effecta on a number of pathological procerses underlying Alrhemw’s disease (AD). Alternatively, recent studies suggest that the amount, rather than type. of apoE may be an important determinant for AD. Therefore, understanding the regulated synthesis of apoE may be important for determining its role in AD. In the present wdy we show that in rat primary hippocampal astrocyte cultures dibutyrylCAMP (dBcAMP) increases apoE secretion in a dose and time dependent manner and Retinoic Acid potentiates this effect. In contrast, the protein kinase C (PKC) activator phorbol 12.my&ate 13.acetate (PMA) decreased apoE secretion, and reversed the effects of dBcAMP. ApoE secretion was also modulated by agonists for receptora linked to the adenylyl cyclase/cAMP and phospholipase ClPKC signal transduction pathways. Isoprotenerol, artenerol and serotonin enhanced, while clonidine and carbachol decreased secreted apoE. Artenerol also potentiated the isoprotenerolmediated increase. Our results indicate that astrocytic apoE production can be regulated by factors that affect the intracellular concentration of cAMP and that PKC has a complex role in the regulation of this protein. Alterations in these aignalling pathways in AD brain. may have cowequences for apoE wcretion in this disorder.
INDUCTION PLASMA
Julim
J O’Rror.
Mineola.
NY;
OF
APOPTOSIS
FACTOR
Louis RnRo/ia, Trtsuo
rnvrry, NJ: Steven
FOUND
Thomus A P&in.
Shimumura,
Fishbane.
IN
John
Robert
NEURONAL
IN ALZHEIMER’S
Linda
Wood
K Moesako.
Fww.
Johnson
Winthrop
Sch
CELLS DISEASE
Winthrop
of
BY
Uni\, Ho.yp,
Medicine,
Umv Hasp,
A
(AD)
Mineolu,
PiscntNY
We demonstrated a plasma factor found in AD, identified as glutathione-independent prostaglandin D2 aynthase (PGD2S). and an end- product of the pro\taglandin D2 pathway, 15.deoxy-A ‘L.‘J-proataglandin 52 (15dPGJ2), induce apoptoais (Apoptotlc Index [AI] = Ic of cells undergoing apoptosis) in rat PC12 and human NTERA-2 neuronal cells. PC12 and NTERA-2 cells were exposed for 2 h to a I:5 dilution of AD plasma (AI: 27.223.7, 30.3k2.4). OSpg recombinant (r)PGD2S (AI: 32.654.0, 30.62 1.3). 6kglml 15dPGJ2 (AI: 31.321.7, 36.15 0.8), a I:5 dilution of control plasma (AI: 7.921.7, 10.72 1.7). or untreated cells (Al: lOSil.X, 10.711.4) respectively. The activities of AD plasma and rPGD2S, but not 15dPGJ2, were inhibited by the COX-2 specific inhibitor, NS-39X (lOkM), and IS kg of antirPGD2S antibody in PC12 cells (AI: 6.550.9, 6.0-tl.4, X.8) 1.6, 8.42 1.6 reqpectively). Apoptotic characteristics were examined using cellular ultrastructure , TUNEL activity annexin V staining , and inhibitjon of TUNEL activity by Z-DEVD-fmk, a caspase-3 inhibitor a> indicators. BRL49653, a PPARy ligand chemically unrelated to the end-product prostaglandins, which are natural ligands for PPAR?, increased AI’? measured with the TUNEL assay (PC12 Al: 2722.2: NTERA Al: 21.626.4). AI‘s were significantly (PcO.05) reduced by the transcriptional inhibitor actinomycin D (48%, 52% respectively), and by prostaglandin F2a, known to Induce MAP kinase phosphorylation of PPARy and down regulate it\ activity(34%,48% respectively). The number of PC12 cells stained with Annexin V Increased when exposed to a I:5 dilution of AD plasma (AI: 50.7?4.S), hkglml 15dPGJ (AI: 62.1 il.1). IO&M BRL49653 (AI: 53.2?1.8), IOOkM glutamate (AI: 61.5k3.9) as compared to control solvent (Al: 15.92 I .4). There was no detectable decline in cell number after exposure to apoptotic agents for four days even though the AI was increased as noted by TEM when treated with 15dPGJ2, BRL49653. or glutamate. These results indicate that the kinetics of apoptosis induced in neuronal cells by this pathway may be slower than in other cell types and has important implications with respect to apoptosis in AD. Drugs that phosphorylate PPARy might block apoptosis early on.