- Email: [email protected]
P3-164 Vascular pathology in patients with dementia
Poster Session P3: Histopathology
$402
Numerous CWP, PLA, NFT and leukoencephalopathy were characteristic in this patient, suggesting dense deposition of A[3 in the cerebral parenchyma and blood vessels may have caused both AD changes and Binswanger type leukoencephalopathy. CWP occur in dementias other than familial AD of presenilin- 1 gene mutation.
~ L O S S O F PERINEURONAL NETS IN ALZHEIMER'S DISEASE IS NOT RELATED TO TAU PATHOLOGY Shabnam M. Baig*, Seth Love, Gordon K. Wilcock. University of Bristol,
Bristol, United Kingdom. Contact e-mail: Shabnam.Baig @bristol, ac. uk Background: The perineuronal net (PN) is a speciafised region of extracellular matrix (ECM) that surrounds neuronal cell bodies and dendrites. It is thought to be involved in regulating the microenvironment around neurones, in buffering of ions and maintenance of synapses. Molecules such as tenascin and hyahironan are expressed in ECM throughout the brain, whereas chondroitin sulphate proteoglycans (CSPGs) are largely confined to the PNs. Regions of cortex with high levels of CSPGs have been reported to have reduced susceptibility to neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). Objectives: To determine (i) whether there is a loss of PNs in AD, and (ii) whether the distribution of any PN loss is related to the distribution of NFTs and other tan pathology. Methods: Paraffin sections of frontal lobe from 72 cases with a pathologically confirmed diagnosis of AD and 45 normal controls were used. Perineuronal nets were labelled with lectin histochemistry for Wisteria floribunda agglutinin, which binds to the N-acetylgalactosamine residue of CSPGs. Tan was immunostained with AT8 in AD cases that showed marked variation in PN preservation between different areas in the same section. The numbers of intact PNs were counted in 10 randomly selected areas of cortex. Computer-assisted image analysis was used to measure the fraction of each area that was immunopositive for tan. Results: Significantly fewer intact PNs were present in sections from patients with AD compared to control sections (p = 0.001). AD brains also showed more marked variation in the preservation of PNs between different areas in the same section. However, there was no significant difference between the levels of tan in areas with and without intact PNs. Conclusions: There is loss of PNs in AD but this is not related to the severity of tan pathology.
•
HIGHER EXPRESSION OF ALPHA7 NICOTINIC RECEPTOR ON ASTROCYTES IN ALZHEIMER PATIENTS WITH SWEDISH APP 670/671MUTATION COMPARED TO SPORADIC ALZHEIMER'S DISEASE
Wenfeng Yu*, Zhizhong Guan, Nenad Bogdanovic, Agneta Nordberg.
Karolinska Instituter, Stockholm, Sweden. Contact e-mail: wenfeng, [email protected] Background: The nicotinic acetylcholine receptors (nAChRs) in brain is suggested to play an important role in memory processes as well as neuroprotective mechanisms. Significant losses in nAChRs especially for the alpha 4 subunit has been found in sporadic AD as well as Familiar AD carrying the Swedish amyloid precursor protein (APP) 670/671 mutation (APPswe) brains. An increase in alpha 7 nicotinic receptor has been observed in APPswe transgenic mice brains. Objective(s): In this study, we investigated the expression of nAChR subunits in astrocytes and neurons in the hippocampus and temporal cortex of APPswe, sporadic AD, and control brain and the possible correlation between changes of nAChR subunit expression and neuropathological changes in AD brains. Results: The a7 nAChR subunit, but not the ct4, c~3 or [32 subunits, was found to be express in astrocytes, while all four subunits were detected in neurons. A significant loss in the number of alpha 7 nAchR binding sites as measured by [lZSI]0t-BTX binding in the temporal cortex of APPswe brain compared to control while no significant change was observed in sporadic AD compared to control. An increased expression of ct7 nAChR was measured on astrocytes and a significant decrease of ct7 and ct4 nAChRs in neuron in the hippocampus and temporal cortex of both APPswe and sporadic
AD brains as compared to control. A significant higher expression of a7 nAChR was detected in astrocytes in the hippocampus and upper layer of the temporal cortex, as well as a larger decrease of ct7 and cx4 rlAChR subunits in neurons in the hippocampus and temporal cortex in APPswe brains compared to sporadic AD. The increased expression of a7 nAChR on astrocytes was found to correlate with the extent of neuropathological changes in the AD brains. There was a strong association between c~7 nAChR positive astrocytes and amyloid plaques cortical and hippocampus of AD brains. Conclusions: The up-regulation of c~7 nAChR in astrocytes might be involved in the A[3 cascade and formation of amyloid plaque and as such might play an important role in the pathogenesis of AD.
•
VASCULAR PATHOLOGY IN PATIENTS WITH DEMENTIA
Christine M. Hulette*, John E Ervin, Yvette Edmonds, Marl H. Szymansld, Donald E. Schmechel, Elizabeth H. Corder. Duke University Medical
Center, Durham, NC, USA. Contact e-mail: [email protected] Background: The lipid transport molecule, ApoE4, is associated with increased risk of Alzheimer's Disease (AD), vascular amyloid and coronary atherosclerosis. Objective(s): In this autopsy study, we investigated cerebrovascular and cardiovascular disease in AD patients mad Controls. Methods: First, we analyzed microvascular changes in the brains of 10 ApoFA,4 and 10 ApoE3,3 AD subjects, matched for age, sex and duration of dementia, and 20 coguitively normal controls. 10 controls exhibited Possible AD, Braak Stage less than IIL 10 were normal, Braak Stage I. Sections of cortex were stained with antibodies against smooth muscle actin (SMA) and amyloid (BA4) and evaluated by image analysis. Secondly, we abstracted 51 pathological and clinical features from complete autopsy records for 77 demented subjects and 67 non-demented controls for information on organ weights, cardiovascular disease, renal, liver disease and cancer. These 51 features were jointly investigated using grade-of-membership analysis. Five groups labeled "Controls, cancer"; "Controls, extensive atherosclerosis"; "Dementia, Early-onset"; "Dementia, Late-onset male"; "Dementia, Lateonset female" represented the data defined by probabilities of responses for features. Results: There was significantly lower vascular (SMA) density in AD arteries than in Controls. There was less SMA in ApoE4,4 AD than in ApoE3,3 AD arteries. We found more 13A4 in arteries of ApoE4,4 AD than in ApoE3,3 AD subjects or controls. The autopsy data analysis revealed ApoE3,3 females had more severe eerebrovascular atherosclerosis The late-onset dementia groups, had frequent ApoE 4. They also had lower body mass index, lower organ weights, thyroid atrophy, and less coronary atherosclerosis than the control groups. Unexpectedly, there was more aortic and myocardial valve dilation and evidence of ischemic injury to the left ventricular myocardium in the late onset dementia groups than in the control groups. Conclusions: Vascular abnormalities are common in AD. There is less SMA and more amyloid. This difference is accentuated in subjects with ApoE 4. Patients with dementia also have evidence of cardiovascular compromise. These observations would suggest that vascular processes other than atherosclerosis, possibly mediated by APOE, operate in parallel or causally in the evolution of dementia. Supported by NIA AG05128, AG11380, NIMH MH60451
~ - ]
R E L A T I V E D E C R E A S E O F CAPILLARY DENSITY DURING HUMAN BRAIN AGING
Dan Xu*, Luning Wang, Mingwei Zhu, Yazhuo Hu, Qiuping Gui, Honghong Zhang. Chinese PLA General Hospital, Beijing, China. Contact
e-mail: xudan3Ol @sina.com
Background: Capillary and neuron density changes with brain aging have been long investigated. However, the method of capillary/neuron ratio assessment, which greatly diminishes the influence of volume changes on density accounting, has never been applied in the research of brain aging and Alzheimer's diseaes (AD). As the importance of vascular factors in the pathogenesis of AD is widely considered, it is necessary to reveal the relative changes of capillary density with human brain aging compared to
$402
Numerous CWP, PLA, NFT and leukoencephalopathy were characteristic in this patient, suggesting dense deposition of A[3 in the cerebral parenchyma and blood vessels may have caused both AD changes and Binswanger type leukoencephalopathy. CWP occur in dementias other than familial AD of presenilin- 1 gene mutation.
~ L O S S O F PERINEURONAL NETS IN ALZHEIMER'S DISEASE IS NOT RELATED TO TAU PATHOLOGY Shabnam M. Baig*, Seth Love, Gordon K. Wilcock. University of Bristol,
Bristol, United Kingdom. Contact e-mail: Shabnam.Baig @bristol, ac. uk Background: The perineuronal net (PN) is a speciafised region of extracellular matrix (ECM) that surrounds neuronal cell bodies and dendrites. It is thought to be involved in regulating the microenvironment around neurones, in buffering of ions and maintenance of synapses. Molecules such as tenascin and hyahironan are expressed in ECM throughout the brain, whereas chondroitin sulphate proteoglycans (CSPGs) are largely confined to the PNs. Regions of cortex with high levels of CSPGs have been reported to have reduced susceptibility to neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). Objectives: To determine (i) whether there is a loss of PNs in AD, and (ii) whether the distribution of any PN loss is related to the distribution of NFTs and other tan pathology. Methods: Paraffin sections of frontal lobe from 72 cases with a pathologically confirmed diagnosis of AD and 45 normal controls were used. Perineuronal nets were labelled with lectin histochemistry for Wisteria floribunda agglutinin, which binds to the N-acetylgalactosamine residue of CSPGs. Tan was immunostained with AT8 in AD cases that showed marked variation in PN preservation between different areas in the same section. The numbers of intact PNs were counted in 10 randomly selected areas of cortex. Computer-assisted image analysis was used to measure the fraction of each area that was immunopositive for tan. Results: Significantly fewer intact PNs were present in sections from patients with AD compared to control sections (p = 0.001). AD brains also showed more marked variation in the preservation of PNs between different areas in the same section. However, there was no significant difference between the levels of tan in areas with and without intact PNs. Conclusions: There is loss of PNs in AD but this is not related to the severity of tan pathology.
•
HIGHER EXPRESSION OF ALPHA7 NICOTINIC RECEPTOR ON ASTROCYTES IN ALZHEIMER PATIENTS WITH SWEDISH APP 670/671MUTATION COMPARED TO SPORADIC ALZHEIMER'S DISEASE
Wenfeng Yu*, Zhizhong Guan, Nenad Bogdanovic, Agneta Nordberg.
Karolinska Instituter, Stockholm, Sweden. Contact e-mail: wenfeng, [email protected] Background: The nicotinic acetylcholine receptors (nAChRs) in brain is suggested to play an important role in memory processes as well as neuroprotective mechanisms. Significant losses in nAChRs especially for the alpha 4 subunit has been found in sporadic AD as well as Familiar AD carrying the Swedish amyloid precursor protein (APP) 670/671 mutation (APPswe) brains. An increase in alpha 7 nicotinic receptor has been observed in APPswe transgenic mice brains. Objective(s): In this study, we investigated the expression of nAChR subunits in astrocytes and neurons in the hippocampus and temporal cortex of APPswe, sporadic AD, and control brain and the possible correlation between changes of nAChR subunit expression and neuropathological changes in AD brains. Results: The a7 nAChR subunit, but not the ct4, c~3 or [32 subunits, was found to be express in astrocytes, while all four subunits were detected in neurons. A significant loss in the number of alpha 7 nAchR binding sites as measured by [lZSI]0t-BTX binding in the temporal cortex of APPswe brain compared to control while no significant change was observed in sporadic AD compared to control. An increased expression of ct7 nAChR was measured on astrocytes and a significant decrease of ct7 and ct4 nAChRs in neuron in the hippocampus and temporal cortex of both APPswe and sporadic
AD brains as compared to control. A significant higher expression of a7 nAChR was detected in astrocytes in the hippocampus and upper layer of the temporal cortex, as well as a larger decrease of ct7 and cx4 rlAChR subunits in neurons in the hippocampus and temporal cortex in APPswe brains compared to sporadic AD. The increased expression of a7 nAChR on astrocytes was found to correlate with the extent of neuropathological changes in the AD brains. There was a strong association between c~7 nAChR positive astrocytes and amyloid plaques cortical and hippocampus of AD brains. Conclusions: The up-regulation of c~7 nAChR in astrocytes might be involved in the A[3 cascade and formation of amyloid plaque and as such might play an important role in the pathogenesis of AD.
•
VASCULAR PATHOLOGY IN PATIENTS WITH DEMENTIA
Christine M. Hulette*, John E Ervin, Yvette Edmonds, Marl H. Szymansld, Donald E. Schmechel, Elizabeth H. Corder. Duke University Medical
Center, Durham, NC, USA. Contact e-mail: [email protected] Background: The lipid transport molecule, ApoE4, is associated with increased risk of Alzheimer's Disease (AD), vascular amyloid and coronary atherosclerosis. Objective(s): In this autopsy study, we investigated cerebrovascular and cardiovascular disease in AD patients mad Controls. Methods: First, we analyzed microvascular changes in the brains of 10 ApoFA,4 and 10 ApoE3,3 AD subjects, matched for age, sex and duration of dementia, and 20 coguitively normal controls. 10 controls exhibited Possible AD, Braak Stage less than IIL 10 were normal, Braak Stage I. Sections of cortex were stained with antibodies against smooth muscle actin (SMA) and amyloid (BA4) and evaluated by image analysis. Secondly, we abstracted 51 pathological and clinical features from complete autopsy records for 77 demented subjects and 67 non-demented controls for information on organ weights, cardiovascular disease, renal, liver disease and cancer. These 51 features were jointly investigated using grade-of-membership analysis. Five groups labeled "Controls, cancer"; "Controls, extensive atherosclerosis"; "Dementia, Early-onset"; "Dementia, Late-onset male"; "Dementia, Lateonset female" represented the data defined by probabilities of responses for features. Results: There was significantly lower vascular (SMA) density in AD arteries than in Controls. There was less SMA in ApoE4,4 AD than in ApoE3,3 AD arteries. We found more 13A4 in arteries of ApoE4,4 AD than in ApoE3,3 AD subjects or controls. The autopsy data analysis revealed ApoE3,3 females had more severe eerebrovascular atherosclerosis The late-onset dementia groups, had frequent ApoE 4. They also had lower body mass index, lower organ weights, thyroid atrophy, and less coronary atherosclerosis than the control groups. Unexpectedly, there was more aortic and myocardial valve dilation and evidence of ischemic injury to the left ventricular myocardium in the late onset dementia groups than in the control groups. Conclusions: Vascular abnormalities are common in AD. There is less SMA and more amyloid. This difference is accentuated in subjects with ApoE 4. Patients with dementia also have evidence of cardiovascular compromise. These observations would suggest that vascular processes other than atherosclerosis, possibly mediated by APOE, operate in parallel or causally in the evolution of dementia. Supported by NIA AG05128, AG11380, NIMH MH60451
~ - ]
R E L A T I V E D E C R E A S E O F CAPILLARY DENSITY DURING HUMAN BRAIN AGING
Dan Xu*, Luning Wang, Mingwei Zhu, Yazhuo Hu, Qiuping Gui, Honghong Zhang. Chinese PLA General Hospital, Beijing, China. Contact
e-mail: xudan3Ol @sina.com
Background: Capillary and neuron density changes with brain aging have been long investigated. However, the method of capillary/neuron ratio assessment, which greatly diminishes the influence of volume changes on density accounting, has never been applied in the research of brain aging and Alzheimer's diseaes (AD). As the importance of vascular factors in the pathogenesis of AD is widely considered, it is necessary to reveal the relative changes of capillary density with human brain aging compared to