- Email: [email protected]
Neurofibrillary tangles and neuritic plaques in cognitively impaired nondemented and in cognitively normal elderly individuals: Evidence for early Alzheimer's disease
P298
P2-101
Poster Presentations: P2
BRAINS FOR DEMENTIA RESEARCH: PROVIDING HUMAN TISSUE FOR DEMENTIA RESEARCH TO PROMOTE UNDERSTANDING OF PATHOGENESIS AND AID DRUG DISCOVERY
Gillian Hayes, Richard Hudspith, Paul Francis, King’s College London, London, United Kingdom. Background: Brains for Dementia Research (BDR) is a network of six UK brain banks/collection centres that aims to address the shortage of highquality post-mortem brains from people with dementia and suitable control cases and provide researchers with the help they need to access the tissue. Post-mortem brains are critical to our understanding of neurodegenerative processes in dementia and the underlying causes of the symptoms observed. With increasing research sophistication the availability of tissue from individuals treated with dementia medication confirms the impact of treatment on pathology, which can inform future therapeutic research. Thus the need for quality post mortem brain tissue and the requirement for greater standardisation between brain tissue banks collaboratively providing samples remains high. Methods: Brain tissue from a range of dementias and healthy controls that have significant clinical, neuropathological and psychometric assessment information is available through BDR. Researchers worldwide can contact us or use an online tissue database to find tissue (www. brainsfordementiaresearch.org.uk) and complete a single tissue application form across all participating banks. Researchers can informally discuss requirements in terms of cases and tissue format prior to applying for tissue. Ongoing recruitment of potential donors occurs through self refer or contact through clinics and existing cohorts. Results: Brain tissue available: over 500 well characterised, high quality cases from a range of dementias and controls are available for researchers. Potential brain donors: more than 1200 clinically assessed participants aged 65 and over, 70% of which are healthy controls, projected to expand to 2500. Tissue distributed: since January 2010 we have processed approximately 30 tissue requests which could not be met by individual tissue banks, including contributing to a large GWAS study. What is welcome is that about 10% of tissue applications are from researchers who have not previously used human brain tissue. Conclusions: This initiative of the Alzheimer’s Society and Alzheimer’s Research Trust has been welcomed by those affected by dementia and their families. BDR is an easy route for researchers to access tissue needed for their studies, and in particular will help those researchers not working within neuropathology departments.
P2-102
ARTERIOSCLEROSIS AND ALZHEIMER’S DISEASE: A CASE-CONTROL PATHOLOGIC STUDY
James Noble1, Min-Suk Kang2, Lawrence Honig2, 1Taub Institute, Columbia University Medical Center, New York, New York, United States; 2 Columbia University, New York, New York, United States. Background: Vascular risk factors, such as hypertension and diabetes, are associated with dementia including Alzheimer disease (AD). In pathological studies, atherosclerosis and infarcts have had reported associations with AD, but evidence of an association with arteriosclerosis has been unclear. Hyalinization of small vessels has generally been assessed semiquantitatively. Here we use quantitative histological measurements to study the relationship with AD. Methods: Cases with autopsy-proven definite Alzheimer disease and matched controls without pathology were obtained from the Columbia Alzheimer’s Disease Research Center Brain Bank. Arteriolar changes were assessed in basal ganglia, superior frontal, parietal, temporal, and occipital regions in paraffin-sections stained with Mallory trichrome. Parenchymal vessels of <100 mm diameter (>12 for each section; > 60 per brain) were photomicrographed. Internal and external vessel diameters were measured along minor and major oval axes. Geometric mean diameters were used to calculate the sclerotic measure of Furuta (100 x [1internal diameter/external diameter] ; i.e. 100% is occlusion). Analyses used linear and logistic regressions to assess the relationship between vessel
sclerosis (S) and AD. Results: Age and gender were not significantly different in the 17 cases (33% male, mean age 82.8 yr 6 9.6 (SD), range 60-95) and 7 controls (43% male, 74.9 6 11, range 57-87). Averaged over all brain regions, AD brains had lower sclerotic change (38.5 6 8.2) compared to controls (44.6 6 8.6; P<0.05), most prominently within parietal subcortex (37.6 6 6.2 vs. 45.3 6 8.6; P <0.01). Differences were most pronounced in smaller vessels. Linear regression models including age and sex confirmed that brains with AD had overall lower sclerosis than the control subjects (average brain 7.1% lower, 95%CI : -11.9, -2.4, parietal cortex: 9.4% lower, 95%CI: -18.6, -0.3). Logistic regression analyses controlling for age and sex also showed lower sclerosis was associated with AD; each 1% increase in sclerotic proportion was associated with 10% lower odds of having Alzheimer pathology (O.R. ¼ 0.90, 95%CI: 0.84, 0.96, parietal cortex 0.80, 95%CI: 0.64, 1.01). Conclusions: Arteriosclerotic disease appeared to be inversely correlated with pathological Alzheimer disease in this detailed quantitative study of small vessel hyalinization. However, the study is limited by the case-control method, and small numbers of brains, despite large numbers of vessels measured.
P2-103
AGE-DEPENDENT INCREASE IN Aß DEPOSITION IN THE NASAL CAVITY OF A TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
Naoko Kameshima1, Toshifumi Nanjo2, Takaomi Fukuhara3, Seiji Sogabe4, Daijiro Yanagisawa5, Ikuo Tooyama5, 1Panasonic Healthcare Co., Ltd., Ehime-ken, Japan; 2Panasonic Healthcare Co., Ltd., Toon, Ehime, Japan; 3Panasonic Healthcare Co., Ltd., Ehime, Japan; 4 Panasonic Healthcare Co., Ltd., Ehime, Japan; 5Shiga University of Medical Science, Otsu, Japan. Background: The deposition of amyloid- b (Aß) is commonly reported in the nasal cavity of Alzheimer’s disease (AD) patients, although the pathological significance of this finding is unknown. We previously demonstrated that nasal Aß was transported from the brain via a non-blood pathway when 125 I-labeled Aß40 was injected into the ventricles of rats and the deposition of Aß in the nasal cavity of Tg2576 transgenic mice, which are a mouse model of AD. The present study used Tg2576 mice to investigate the age -dependent changes in deposition of Aß in the nasal cavity and brain. Methods: Immunohistochemistry Tg2576 mice (10-, 18-, and 28-monthold) and C57BL/6 control mice (15- and 30-month-old) were used. The nasal sections were pretreated with 70% formic acid (FA) and both nasal and brain sections were stained with anti-human Aß antibody. Results: No immunoreactivity for Aß deposits was detected in the nasal cavity of 10- and 18-month-old Tg2576 mice. Immunoreactivity for Aß was detectable in the olfactory and respiratory epithelia in 28-month-old mice, but no positive staining was observed in control mice. The 18-month-old mice had Aß deposits partially in the forebrain and the olfactory bulb, which then spread to the whole of the forebrain and the olfactory bulb in 28-month-old mice. Conclusions: The present study used Tg2576 mice to demonstrate age -dependent changes in deposition of Aß in the nasal cavity and brain. These data suggest that the Aß content of the nasal cavity may be a useful tool for diagnosing AD progression.
P2-104
NEUROFIBRILLARY TANGLES AND NEURITIC PLAQUES IN COGNITIVELY IMPAIRED NONDEMENTED AND IN COGNITIVELY NORMAL ELDERLY INDIVIDUALS: EVIDENCE FOR EARLY ALZHEIMER’S DISEASE
Renata Leite1, Mariana Molina2, Lea Grinberg3, Claudia Suemoto2, Renata Ferretti4, Jose Farfel2, Edilaine Tampellini2, Ana Alho2, Carlos Pasqualucci2, Wilson Jacob-Filho2, Ricardo Nitrini2, Brazilian Aging Brain Study Group2, 1University of S~ao Paulo Medical School, S~ao Paulo, Brazil; 2University of S~ao Paulo Medical School, Sao Paulo, United States; 3UCSF, San Francisco, California, United States; 4University of S~ao Paulo Medical School, S~ao Paulo, Brazil.
Poster Presentations: P2 Background: Neurofibrillary tangles (NFTs) and amyloid plaques are diagnostic markers for Alzheimer disease (AD). Whether a progressive distribution of these neuropathological markers exists in normal cognitive aging, cognitive impairment no dementia (CIND) and AD remains unknown. The relevance of vascular brain lesions for the occurrence of CIND is still unsettled. To address this question, we compared the burden of AD neuropathologic markers and vascular brain lesions in autopsied individuals with CIND and cognitive normal aging. Methods: Charts of deceased individuals older than 50 years of age whose brains had been donated to the Brain Bank of the Brazilian Aging Brain Study Group were examined. The clinical diagnosis was established through a postmortem interview with an informant including the Cognitive Dementia Rating (CDR). Only individuals with a global CDR score of 0 (control group, n ¼ 185) and 0.5 (CIND group, n ¼ 40) were included. To be included as CDR 0.5, besides the overall rating of 0.5, individuals should have a score of 0.5 or 1 in the memory domain and a score of 0 or 0.5 in the domains of judgment and problem solving, community affairs, home and hobbies, and personal care (in order to exclude individuals with significant functional impairment). All the individuals with severe visual and auditory impairment and active alcoholics were excluded from the study. Neuropathological examinations were carried out based on accepted criteria, using immunohistochemistry. Groups were compared using non-parametric tests followed by adjustment for confounding factors with multivariate logistic regression. Results: NFTs and neuritic plaques were higher (P ¼ 0.03 and 0.006, respectively) in the CIND group compared to controls. Both associations remained significant after multivariate logistic regression, adjusting for age, gender and years of education (P ¼ 0.006 and 0.002, respectively). Percentage of lacunar infarction was higher in the CIND group (P ¼ 0.02), however after multivariate analysis this association disappeared (P ¼ 0.12). Percentage of widespread hyaline arteriolosclerosis and cerebral amyloid angiopathy was similar between groups (P ¼ 0.07 and 0.80, respectively). Conclusions: CIND showed a higher burden of AD changes than controls, whereas no significant changes were found for vascular related lesions. From a neuropathologic perspective, CIND is best interpreted as a stage between normal cognitive aging and AD.
P2-105
DENDRITIC AND SPINAL PATHOLOGY IN THE VISUAL CORTEX IN ALZHEIMER’S DISEASE
Stavros Baloyannis, Aristotelian University, Thessaloniki, Greece. Background: Alzheimer’s disease is an age associated neurodegenerative disorder, causing progressive decline in mental faculties, loss of professional skills and decline in social performance. Various unstable neurological phenomena plot the clinical profile of the disease. The morphological hallmarks of the disease consist in accumulation of Ab peptide, neurofibrillary degeneration, synaptic loss, dendritic alteration and substantial mitochondrial pathology. In the present study we attempt to describe the morphological and morphometric alterations of the dendrites in the visual cortex in early cases of Alzheimer’s disease. Methods: We studied twenty brains derived from patients who suffered from Alzheimer’s disease, aged 77 to 82 years. Samples from the visual cortex were prepared for silver impregnation technique and electron microscopy. Results: Neuronal loss was prominent in the visual cortex. An impressive abbreviation of the neuronal arborization in the majority of neurons was seen. Loss of tertiary dendritic branches was prominent. Loss of large number of dendritic spines was noticed. Large number of spines demonstrated alterations of the shape and size as well as of the interior structure. Mitochondrial alterations were extensively seen in the dendrites associated with the pathology of the dendritic spines Conclusions: In Alzheimer’s disease the dendritic and spinal pathology associated with the alterations of the dendritic mitochondria play an important role in plotting the pathological profile of the disease and a definite role in the clinical phenomenology of the disease.
P2-106
P299 RELATIONSHIPS OF CEREBROVASCULAR ATHEROSCLEROSIS WITH AMYLOID, TAU, a-SYNUCLEIN AND TDP-43 PATHOLOGIES IN NEURODEGENERATIVE DISEASE DEMENTIAS
Steven Arnold, Mark Yarchoan, Sharon Xie, Mitchel Kling, Juan Toledo, David Wolk, Edward Lee, Vivianna Van Deerlin, Virginia Lee, John Trojanowski, Steven Arnold, University of Pennsylvania, Philadelphia Pennsylvania, United States. Background: Accumulating epidemiological data link atherosclerosis with Alzheimer’s disease (AD) and possibly other neurodegenerative diseases. Risk factors that are common among these include age, APOE E4 polymorphism, smoking, inflammation, obesity and the metabolic syndrome. Yet the nature and specificity of atherosclerotic vascular contributions to AD or other neurodegenerative diseases remain unclear. To address this, we investigated the frequency and grades of atherosclerotic plaques in the circle of Willis in AD and multiple other neurodegenerative diseases and we correlated severity ratings with the molecular pathological lesions of these diseases. Methods: Semi-quantitative data from gross and microscopic neuropathological exams in 1000 cases from the University of Pennsylvania’s Alzheimer’s Disease Center and Center for Neurodegenerative Disease Research were analyzed, including 410 with a primary diagnosis of AD, 230 with synucleinopathies (Parkinson’s disease with and without dementia, dementia with Lewy bodies, multiple system atrophies), 157 with TDP-43 proteinopathies (frontotemporal dementias, amyotrophic lateral sclerosis), 144 with tauopathies (Pick’s disease, progressive supranclear palsy, corticobasal degeneration and others), and 59 with normal aging. ANOVA, logistic and linear regression models assessed the relationships of circle of Willis atherosclerosis ratings with diagnoses and histological ratings of neurodegenerative disease lesions labeled with thioflavin-S and antibodies directed at PHFtau, a -synuclein and TDP-43 in multiple cortical and subcortical brain regions. Results: Over 77% of AD subjects had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43-67%). Age and sex adjusted atherosclerosis ratings were highly correlated with neuritic plaque (P <0.0001) and PHFtau neurofibrillary tangle (P <0.0001) ratings in the whole sample and within individual groups. We found no such associations between atherosclerosis ratings and a-synuclein or TDP-43 lesion ratings either in the whole sample or in individual disease categories. Conclusions: These results provide further confirmation that atherosclerotic vascular disease in the circle of Willis and AD are interrelated. We also find that this association is relatively specific to AD and is not observed with other major neurodegenerative diseases or disease lesions. Our findings are consistent with a hypothesis that common etiologic or reciprocally synergistic pathophysiological mechanisms promote both atherosclerotic vascular pathology and plaque and tangle pathology. P2-108
DIFFERENT ACTIVATED MICROGLIAL RESPONSE IN HUMAN HIPPOCAMPUS DURING ALZHEIMER’S DISEASE PROGRESSION
Antonia Gutierrez1, Victoria Navarro2, Elisabeth Sanchez-Mejias3, Laura Trujillo-Estrada4, Raquel Sanchez-Varo5, Sebastian Jimenez2, Marisa Vizuete2, Jose Carlos Davila5, Diego Ruano2, Joan Comella6, Javier Vitorica7, 1University of Malaga/CIBERNED, Malaga, Spain; 2 University of Seville/CIBERNED/IBIS, Seville, Spain; 3Universidad de Malaga/CIBERNED, Malaga, Spain; 4Universidad de Malaga/CIBERNED, Malaga, Spain; 5University of Malaga/CIBERNED, Malaga, Spain; 6Vall d’Hebron-Institut de Recerca /CIBERNED, Barcelona, Spain; 7University of Seville/CIBERNED /IBIS, Seville, Spain. Background: Inflammation has long been proposed as having a role in Alzheimer’s disease (AD), although it remains unclear whether inflammation represents a cause or consequence of AD. Microglia, the resident immune and phagocytic cells of the brain, may act as a double-edged sword being either detrimental or protective depending on their activation state. We have previously shown in the hippocampus of a PS1/APP transgenic
P2-101
Poster Presentations: P2
BRAINS FOR DEMENTIA RESEARCH: PROVIDING HUMAN TISSUE FOR DEMENTIA RESEARCH TO PROMOTE UNDERSTANDING OF PATHOGENESIS AND AID DRUG DISCOVERY
Gillian Hayes, Richard Hudspith, Paul Francis, King’s College London, London, United Kingdom. Background: Brains for Dementia Research (BDR) is a network of six UK brain banks/collection centres that aims to address the shortage of highquality post-mortem brains from people with dementia and suitable control cases and provide researchers with the help they need to access the tissue. Post-mortem brains are critical to our understanding of neurodegenerative processes in dementia and the underlying causes of the symptoms observed. With increasing research sophistication the availability of tissue from individuals treated with dementia medication confirms the impact of treatment on pathology, which can inform future therapeutic research. Thus the need for quality post mortem brain tissue and the requirement for greater standardisation between brain tissue banks collaboratively providing samples remains high. Methods: Brain tissue from a range of dementias and healthy controls that have significant clinical, neuropathological and psychometric assessment information is available through BDR. Researchers worldwide can contact us or use an online tissue database to find tissue (www. brainsfordementiaresearch.org.uk) and complete a single tissue application form across all participating banks. Researchers can informally discuss requirements in terms of cases and tissue format prior to applying for tissue. Ongoing recruitment of potential donors occurs through self refer or contact through clinics and existing cohorts. Results: Brain tissue available: over 500 well characterised, high quality cases from a range of dementias and controls are available for researchers. Potential brain donors: more than 1200 clinically assessed participants aged 65 and over, 70% of which are healthy controls, projected to expand to 2500. Tissue distributed: since January 2010 we have processed approximately 30 tissue requests which could not be met by individual tissue banks, including contributing to a large GWAS study. What is welcome is that about 10% of tissue applications are from researchers who have not previously used human brain tissue. Conclusions: This initiative of the Alzheimer’s Society and Alzheimer’s Research Trust has been welcomed by those affected by dementia and their families. BDR is an easy route for researchers to access tissue needed for their studies, and in particular will help those researchers not working within neuropathology departments.
P2-102
ARTERIOSCLEROSIS AND ALZHEIMER’S DISEASE: A CASE-CONTROL PATHOLOGIC STUDY
James Noble1, Min-Suk Kang2, Lawrence Honig2, 1Taub Institute, Columbia University Medical Center, New York, New York, United States; 2 Columbia University, New York, New York, United States. Background: Vascular risk factors, such as hypertension and diabetes, are associated with dementia including Alzheimer disease (AD). In pathological studies, atherosclerosis and infarcts have had reported associations with AD, but evidence of an association with arteriosclerosis has been unclear. Hyalinization of small vessels has generally been assessed semiquantitatively. Here we use quantitative histological measurements to study the relationship with AD. Methods: Cases with autopsy-proven definite Alzheimer disease and matched controls without pathology were obtained from the Columbia Alzheimer’s Disease Research Center Brain Bank. Arteriolar changes were assessed in basal ganglia, superior frontal, parietal, temporal, and occipital regions in paraffin-sections stained with Mallory trichrome. Parenchymal vessels of <100 mm diameter (>12 for each section; > 60 per brain) were photomicrographed. Internal and external vessel diameters were measured along minor and major oval axes. Geometric mean diameters were used to calculate the sclerotic measure of Furuta (100 x [1internal diameter/external diameter] ; i.e. 100% is occlusion). Analyses used linear and logistic regressions to assess the relationship between vessel
sclerosis (S) and AD. Results: Age and gender were not significantly different in the 17 cases (33% male, mean age 82.8 yr 6 9.6 (SD), range 60-95) and 7 controls (43% male, 74.9 6 11, range 57-87). Averaged over all brain regions, AD brains had lower sclerotic change (38.5 6 8.2) compared to controls (44.6 6 8.6; P<0.05), most prominently within parietal subcortex (37.6 6 6.2 vs. 45.3 6 8.6; P <0.01). Differences were most pronounced in smaller vessels. Linear regression models including age and sex confirmed that brains with AD had overall lower sclerosis than the control subjects (average brain 7.1% lower, 95%CI : -11.9, -2.4, parietal cortex: 9.4% lower, 95%CI: -18.6, -0.3). Logistic regression analyses controlling for age and sex also showed lower sclerosis was associated with AD; each 1% increase in sclerotic proportion was associated with 10% lower odds of having Alzheimer pathology (O.R. ¼ 0.90, 95%CI: 0.84, 0.96, parietal cortex 0.80, 95%CI: 0.64, 1.01). Conclusions: Arteriosclerotic disease appeared to be inversely correlated with pathological Alzheimer disease in this detailed quantitative study of small vessel hyalinization. However, the study is limited by the case-control method, and small numbers of brains, despite large numbers of vessels measured.
P2-103
AGE-DEPENDENT INCREASE IN Aß DEPOSITION IN THE NASAL CAVITY OF A TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
Naoko Kameshima1, Toshifumi Nanjo2, Takaomi Fukuhara3, Seiji Sogabe4, Daijiro Yanagisawa5, Ikuo Tooyama5, 1Panasonic Healthcare Co., Ltd., Ehime-ken, Japan; 2Panasonic Healthcare Co., Ltd., Toon, Ehime, Japan; 3Panasonic Healthcare Co., Ltd., Ehime, Japan; 4 Panasonic Healthcare Co., Ltd., Ehime, Japan; 5Shiga University of Medical Science, Otsu, Japan. Background: The deposition of amyloid- b (Aß) is commonly reported in the nasal cavity of Alzheimer’s disease (AD) patients, although the pathological significance of this finding is unknown. We previously demonstrated that nasal Aß was transported from the brain via a non-blood pathway when 125 I-labeled Aß40 was injected into the ventricles of rats and the deposition of Aß in the nasal cavity of Tg2576 transgenic mice, which are a mouse model of AD. The present study used Tg2576 mice to investigate the age -dependent changes in deposition of Aß in the nasal cavity and brain. Methods: Immunohistochemistry Tg2576 mice (10-, 18-, and 28-monthold) and C57BL/6 control mice (15- and 30-month-old) were used. The nasal sections were pretreated with 70% formic acid (FA) and both nasal and brain sections were stained with anti-human Aß antibody. Results: No immunoreactivity for Aß deposits was detected in the nasal cavity of 10- and 18-month-old Tg2576 mice. Immunoreactivity for Aß was detectable in the olfactory and respiratory epithelia in 28-month-old mice, but no positive staining was observed in control mice. The 18-month-old mice had Aß deposits partially in the forebrain and the olfactory bulb, which then spread to the whole of the forebrain and the olfactory bulb in 28-month-old mice. Conclusions: The present study used Tg2576 mice to demonstrate age -dependent changes in deposition of Aß in the nasal cavity and brain. These data suggest that the Aß content of the nasal cavity may be a useful tool for diagnosing AD progression.
P2-104
NEUROFIBRILLARY TANGLES AND NEURITIC PLAQUES IN COGNITIVELY IMPAIRED NONDEMENTED AND IN COGNITIVELY NORMAL ELDERLY INDIVIDUALS: EVIDENCE FOR EARLY ALZHEIMER’S DISEASE
Renata Leite1, Mariana Molina2, Lea Grinberg3, Claudia Suemoto2, Renata Ferretti4, Jose Farfel2, Edilaine Tampellini2, Ana Alho2, Carlos Pasqualucci2, Wilson Jacob-Filho2, Ricardo Nitrini2, Brazilian Aging Brain Study Group2, 1University of S~ao Paulo Medical School, S~ao Paulo, Brazil; 2University of S~ao Paulo Medical School, Sao Paulo, United States; 3UCSF, San Francisco, California, United States; 4University of S~ao Paulo Medical School, S~ao Paulo, Brazil.
Poster Presentations: P2 Background: Neurofibrillary tangles (NFTs) and amyloid plaques are diagnostic markers for Alzheimer disease (AD). Whether a progressive distribution of these neuropathological markers exists in normal cognitive aging, cognitive impairment no dementia (CIND) and AD remains unknown. The relevance of vascular brain lesions for the occurrence of CIND is still unsettled. To address this question, we compared the burden of AD neuropathologic markers and vascular brain lesions in autopsied individuals with CIND and cognitive normal aging. Methods: Charts of deceased individuals older than 50 years of age whose brains had been donated to the Brain Bank of the Brazilian Aging Brain Study Group were examined. The clinical diagnosis was established through a postmortem interview with an informant including the Cognitive Dementia Rating (CDR). Only individuals with a global CDR score of 0 (control group, n ¼ 185) and 0.5 (CIND group, n ¼ 40) were included. To be included as CDR 0.5, besides the overall rating of 0.5, individuals should have a score of 0.5 or 1 in the memory domain and a score of 0 or 0.5 in the domains of judgment and problem solving, community affairs, home and hobbies, and personal care (in order to exclude individuals with significant functional impairment). All the individuals with severe visual and auditory impairment and active alcoholics were excluded from the study. Neuropathological examinations were carried out based on accepted criteria, using immunohistochemistry. Groups were compared using non-parametric tests followed by adjustment for confounding factors with multivariate logistic regression. Results: NFTs and neuritic plaques were higher (P ¼ 0.03 and 0.006, respectively) in the CIND group compared to controls. Both associations remained significant after multivariate logistic regression, adjusting for age, gender and years of education (P ¼ 0.006 and 0.002, respectively). Percentage of lacunar infarction was higher in the CIND group (P ¼ 0.02), however after multivariate analysis this association disappeared (P ¼ 0.12). Percentage of widespread hyaline arteriolosclerosis and cerebral amyloid angiopathy was similar between groups (P ¼ 0.07 and 0.80, respectively). Conclusions: CIND showed a higher burden of AD changes than controls, whereas no significant changes were found for vascular related lesions. From a neuropathologic perspective, CIND is best interpreted as a stage between normal cognitive aging and AD.
P2-105
DENDRITIC AND SPINAL PATHOLOGY IN THE VISUAL CORTEX IN ALZHEIMER’S DISEASE
Stavros Baloyannis, Aristotelian University, Thessaloniki, Greece. Background: Alzheimer’s disease is an age associated neurodegenerative disorder, causing progressive decline in mental faculties, loss of professional skills and decline in social performance. Various unstable neurological phenomena plot the clinical profile of the disease. The morphological hallmarks of the disease consist in accumulation of Ab peptide, neurofibrillary degeneration, synaptic loss, dendritic alteration and substantial mitochondrial pathology. In the present study we attempt to describe the morphological and morphometric alterations of the dendrites in the visual cortex in early cases of Alzheimer’s disease. Methods: We studied twenty brains derived from patients who suffered from Alzheimer’s disease, aged 77 to 82 years. Samples from the visual cortex were prepared for silver impregnation technique and electron microscopy. Results: Neuronal loss was prominent in the visual cortex. An impressive abbreviation of the neuronal arborization in the majority of neurons was seen. Loss of tertiary dendritic branches was prominent. Loss of large number of dendritic spines was noticed. Large number of spines demonstrated alterations of the shape and size as well as of the interior structure. Mitochondrial alterations were extensively seen in the dendrites associated with the pathology of the dendritic spines Conclusions: In Alzheimer’s disease the dendritic and spinal pathology associated with the alterations of the dendritic mitochondria play an important role in plotting the pathological profile of the disease and a definite role in the clinical phenomenology of the disease.
P2-106
P299 RELATIONSHIPS OF CEREBROVASCULAR ATHEROSCLEROSIS WITH AMYLOID, TAU, a-SYNUCLEIN AND TDP-43 PATHOLOGIES IN NEURODEGENERATIVE DISEASE DEMENTIAS
Steven Arnold, Mark Yarchoan, Sharon Xie, Mitchel Kling, Juan Toledo, David Wolk, Edward Lee, Vivianna Van Deerlin, Virginia Lee, John Trojanowski, Steven Arnold, University of Pennsylvania, Philadelphia Pennsylvania, United States. Background: Accumulating epidemiological data link atherosclerosis with Alzheimer’s disease (AD) and possibly other neurodegenerative diseases. Risk factors that are common among these include age, APOE E4 polymorphism, smoking, inflammation, obesity and the metabolic syndrome. Yet the nature and specificity of atherosclerotic vascular contributions to AD or other neurodegenerative diseases remain unclear. To address this, we investigated the frequency and grades of atherosclerotic plaques in the circle of Willis in AD and multiple other neurodegenerative diseases and we correlated severity ratings with the molecular pathological lesions of these diseases. Methods: Semi-quantitative data from gross and microscopic neuropathological exams in 1000 cases from the University of Pennsylvania’s Alzheimer’s Disease Center and Center for Neurodegenerative Disease Research were analyzed, including 410 with a primary diagnosis of AD, 230 with synucleinopathies (Parkinson’s disease with and without dementia, dementia with Lewy bodies, multiple system atrophies), 157 with TDP-43 proteinopathies (frontotemporal dementias, amyotrophic lateral sclerosis), 144 with tauopathies (Pick’s disease, progressive supranclear palsy, corticobasal degeneration and others), and 59 with normal aging. ANOVA, logistic and linear regression models assessed the relationships of circle of Willis atherosclerosis ratings with diagnoses and histological ratings of neurodegenerative disease lesions labeled with thioflavin-S and antibodies directed at PHFtau, a -synuclein and TDP-43 in multiple cortical and subcortical brain regions. Results: Over 77% of AD subjects had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43-67%). Age and sex adjusted atherosclerosis ratings were highly correlated with neuritic plaque (P <0.0001) and PHFtau neurofibrillary tangle (P <0.0001) ratings in the whole sample and within individual groups. We found no such associations between atherosclerosis ratings and a-synuclein or TDP-43 lesion ratings either in the whole sample or in individual disease categories. Conclusions: These results provide further confirmation that atherosclerotic vascular disease in the circle of Willis and AD are interrelated. We also find that this association is relatively specific to AD and is not observed with other major neurodegenerative diseases or disease lesions. Our findings are consistent with a hypothesis that common etiologic or reciprocally synergistic pathophysiological mechanisms promote both atherosclerotic vascular pathology and plaque and tangle pathology. P2-108
DIFFERENT ACTIVATED MICROGLIAL RESPONSE IN HUMAN HIPPOCAMPUS DURING ALZHEIMER’S DISEASE PROGRESSION
Antonia Gutierrez1, Victoria Navarro2, Elisabeth Sanchez-Mejias3, Laura Trujillo-Estrada4, Raquel Sanchez-Varo5, Sebastian Jimenez2, Marisa Vizuete2, Jose Carlos Davila5, Diego Ruano2, Joan Comella6, Javier Vitorica7, 1University of Malaga/CIBERNED, Malaga, Spain; 2 University of Seville/CIBERNED/IBIS, Seville, Spain; 3Universidad de Malaga/CIBERNED, Malaga, Spain; 4Universidad de Malaga/CIBERNED, Malaga, Spain; 5University of Malaga/CIBERNED, Malaga, Spain; 6Vall d’Hebron-Institut de Recerca /CIBERNED, Barcelona, Spain; 7University of Seville/CIBERNED /IBIS, Seville, Spain. Background: Inflammation has long been proposed as having a role in Alzheimer’s disease (AD), although it remains unclear whether inflammation represents a cause or consequence of AD. Microglia, the resident immune and phagocytic cells of the brain, may act as a double-edged sword being either detrimental or protective depending on their activation state. We have previously shown in the hippocampus of a PS1/APP transgenic