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Amyloid imaging in members of a family harbouring the Arctic APP mutation
Oral O2-07: Histopathology hippocampal volumes were associated with higher Braak NFT stage in this cohort of normal, LBD, mixed AD/LBD and AD cases (r ¼ 0.59; p < 0.001). Hippocampal volumes distinguished cases with low likelihood of AD from intermediate or high likelihood of AD with an area under the curve of 0.84 independent of the presence of LBD pathology. Conclusions: Hippocampal atrophy on MRI is associated with a high likelihood of AD and higher Braak NFT stage independent of LBD pathology. Patients with LBD who have a low likelihood of AD pathology typically have normal hippocampal volumes.
O2-06-08
AMYLOID IMAGING IN MEMBERS OF A FAMILY HARBOURING THE ARCTIC APP MUTATION
Michael Sch€ oll, Ove Almkvist, Caroline Graff, Agneta Nordberg, Karolinska Institutet, Stockholm, Sweden. Background: A small percentage of Alzheimer’s disease (AD) cases are caused by early-onset familial Alzheimer’s disease (eoFAD) mutations in the presenilin 1 and 2 and the amyloid precursor protein (APP) genes. These mutations are commonly associated with complete penetrance, leading in virtually all cases to AD. Despite their rareness, eoFAD mutations have hence become the underlying basis for many AD animal models. The Arctic APP mutation is the only mutation located within the beta-amyloid sequence to cause clinically typical AD. With the introduction of 11C-Pittsburgh compound B positron emission tomography (PIB-PET), in vivo imaging of fibrillar beta-amyloid pathology typical for AD has become possible. Methods: One AD patient carrying the Arctic APP mutation (ArcAPP-1, 65 y, MMSE ¼ 11), her cognitively normal twin sibling (ArcAPP-2, 65 y, MMSE ¼ 28), and two additional siblings from the same family (ArcAPP-3, 38 y, MMSE ¼ 30; ArcAPP-4,71 y, MMSE ¼ 27) underwent PET scanning with PIB and 18F-Fluorodeoxyglucose (FDG) and neuropsychological testing. Results: The symptomatic mutation carrier ArcAPP-1 showed no cortical PIB retention, while the FDG uptake pattern and neuropsychological test results were clearly pathological and typical for AD. The examined siblings showed normal PIB and FDG-PET scans as well as neuropsychological test scores. Conclusions: The absence of PIB retention in the symptomatic mutation carrier suggests that the Arctic APP mutation alters amyloid processing in a different way than other eoFAD mutations or the sporadic variant of AD, leading to an absence of fibrillar beta-amyloid pathology as visualized by PIB-PET with an otherwise typical clinical picture of AD in mutation carriers. This underlines the need for new amyloid tracers for the in vivo detection of non-fibrillar forms of beta-amyloid.
S303 MONDAY, JULY 18, 2011 ORAL O2-07 HISTOPATHOLOGY
O2-07-01
NEUROPATHOLOGY OF PRECLINICAL AND INCIPIENT ALZHEIMER’S DEMENTIA
Lisa Taylor-Reinwald, Elizabeth Grant, Alison Goate, John Morris, Nigel Cairns, Washington University School of Medicine, Saint Louis, Mo., United States. Background: The concept of ‘preclinical Alzheimer’s disease’ (AD) postulates that the pathology of AD, beta-amyloid plaques and tangles, accumulates in the brain for years, or decades, before signs of cognitive impairment occur. To test this hypothesis, we undertook a comprehensive study of the neuropathology of cognitively normal individuals and those with very mild dementia who came to autopsy. Specifically, we determined the presence, burden and distribution of the molecular pathologies in our cohort of cognitively normal and very mildly demented participants aging brain. Methods: Brains from 94 participants, including 50 cognitively normal participants with a Clinical Dementia Rating (CDR) of zero and 44 participants with ‘incipient’ or very mild Alzheimer’s dementia (CDR 0.5), were obtained at autopsy. All were APOE genotyped but none had a known pathogenic mutation. The CDR of each case was determined by clinicians in the Memory and Aging Project of the Washington University Knight Alzheimer’s Disease Research Center, and is based on clinical interviews with the participant and an informant without regard for psychometric testing or neuropathological findings. Brains were processed according to an established protocol. Briefly, the left hemibrain was fixed in 10% neutral buffered formalin, coronally sliced, and regions of interest were sampled and embedded in paraffin. In addition to standard stains (hematoxylin and eosin and a modified Bielschowsky silver impregnation), the molecular pathology present in each brain was determined by immunohistochemistry using anti-b-amyloid (10D5), anti-tau (PHF-1), anti-a-synuclein, and anti-TDP-43 antibodies. AD-type changes and Lewy body pathology were assessed using established criteria, where they exist. Stereological methods were used to determine unbiased estimates of cortical b-amyloid burden (Stereo Investigator, Micro Bright Field Inc., Williston, VT). Data analysis included ANOVA for covariates including: age, APOE genotype, Braak tangle stage, and cortical and global b-amyloid burden. Results: Both tau and cortical b-amyloid burden in mildly demented individuals (CDR 0.5) were increased when compared to cognitively normal individuals. In addition, TDP-43 proteinopathy was increased in 10/44 (22.7%) mildly demented participants compared to 7/50 (14%) of cognitively normal individuals. Conclusions: The pre-clinical stage of AD is distinguished from incipient Alzheimer’s dementia, not by the type of lesions present, but by the burden of molecular pathology. O2-07-02
MODELING THE TEMPORAL EVOLUTION OF ALZHEIMER’S PATHOLOGY WITH AUTOPSY DATA
Donald Royall1, Raymond Palmer1, Lon White2, 1University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States; 2 John A Burns School of Medicine, University of Hawaii at manoa, Honolulu, Hawaii, United States. Background: Recent longitudinal clinical and imaging studies suggest that Alzheimer’s disease (AD) pathology begins before clinical symptoms can be diagnosed, and evolves non-linearly. However, the association between longitudinal changes and autopsy findings cannot be easily determined because autopsy data are available only after death. In this study, we combine autopsy data with latent growth curve (LGC) models of in vivo cognitive change in formal and arguably causal mediation models of the temporal development of AD neuropathology. Methods: Autopsy data from 435 participants in the Honolulu-Asia Aging Study (HAAS) were combined into latent factor measures of neuritic plaque (NP) and neurofibrillary tangle (NFT) counts. These were associated with latent intercept and slope parameters from a LGC model of 10-year change in cognitive test performance. Figure
O2-06-08
AMYLOID IMAGING IN MEMBERS OF A FAMILY HARBOURING THE ARCTIC APP MUTATION
Michael Sch€ oll, Ove Almkvist, Caroline Graff, Agneta Nordberg, Karolinska Institutet, Stockholm, Sweden. Background: A small percentage of Alzheimer’s disease (AD) cases are caused by early-onset familial Alzheimer’s disease (eoFAD) mutations in the presenilin 1 and 2 and the amyloid precursor protein (APP) genes. These mutations are commonly associated with complete penetrance, leading in virtually all cases to AD. Despite their rareness, eoFAD mutations have hence become the underlying basis for many AD animal models. The Arctic APP mutation is the only mutation located within the beta-amyloid sequence to cause clinically typical AD. With the introduction of 11C-Pittsburgh compound B positron emission tomography (PIB-PET), in vivo imaging of fibrillar beta-amyloid pathology typical for AD has become possible. Methods: One AD patient carrying the Arctic APP mutation (ArcAPP-1, 65 y, MMSE ¼ 11), her cognitively normal twin sibling (ArcAPP-2, 65 y, MMSE ¼ 28), and two additional siblings from the same family (ArcAPP-3, 38 y, MMSE ¼ 30; ArcAPP-4,71 y, MMSE ¼ 27) underwent PET scanning with PIB and 18F-Fluorodeoxyglucose (FDG) and neuropsychological testing. Results: The symptomatic mutation carrier ArcAPP-1 showed no cortical PIB retention, while the FDG uptake pattern and neuropsychological test results were clearly pathological and typical for AD. The examined siblings showed normal PIB and FDG-PET scans as well as neuropsychological test scores. Conclusions: The absence of PIB retention in the symptomatic mutation carrier suggests that the Arctic APP mutation alters amyloid processing in a different way than other eoFAD mutations or the sporadic variant of AD, leading to an absence of fibrillar beta-amyloid pathology as visualized by PIB-PET with an otherwise typical clinical picture of AD in mutation carriers. This underlines the need for new amyloid tracers for the in vivo detection of non-fibrillar forms of beta-amyloid.
S303 MONDAY, JULY 18, 2011 ORAL O2-07 HISTOPATHOLOGY
O2-07-01
NEUROPATHOLOGY OF PRECLINICAL AND INCIPIENT ALZHEIMER’S DEMENTIA
Lisa Taylor-Reinwald, Elizabeth Grant, Alison Goate, John Morris, Nigel Cairns, Washington University School of Medicine, Saint Louis, Mo., United States. Background: The concept of ‘preclinical Alzheimer’s disease’ (AD) postulates that the pathology of AD, beta-amyloid plaques and tangles, accumulates in the brain for years, or decades, before signs of cognitive impairment occur. To test this hypothesis, we undertook a comprehensive study of the neuropathology of cognitively normal individuals and those with very mild dementia who came to autopsy. Specifically, we determined the presence, burden and distribution of the molecular pathologies in our cohort of cognitively normal and very mildly demented participants aging brain. Methods: Brains from 94 participants, including 50 cognitively normal participants with a Clinical Dementia Rating (CDR) of zero and 44 participants with ‘incipient’ or very mild Alzheimer’s dementia (CDR 0.5), were obtained at autopsy. All were APOE genotyped but none had a known pathogenic mutation. The CDR of each case was determined by clinicians in the Memory and Aging Project of the Washington University Knight Alzheimer’s Disease Research Center, and is based on clinical interviews with the participant and an informant without regard for psychometric testing or neuropathological findings. Brains were processed according to an established protocol. Briefly, the left hemibrain was fixed in 10% neutral buffered formalin, coronally sliced, and regions of interest were sampled and embedded in paraffin. In addition to standard stains (hematoxylin and eosin and a modified Bielschowsky silver impregnation), the molecular pathology present in each brain was determined by immunohistochemistry using anti-b-amyloid (10D5), anti-tau (PHF-1), anti-a-synuclein, and anti-TDP-43 antibodies. AD-type changes and Lewy body pathology were assessed using established criteria, where they exist. Stereological methods were used to determine unbiased estimates of cortical b-amyloid burden (Stereo Investigator, Micro Bright Field Inc., Williston, VT). Data analysis included ANOVA for covariates including: age, APOE genotype, Braak tangle stage, and cortical and global b-amyloid burden. Results: Both tau and cortical b-amyloid burden in mildly demented individuals (CDR 0.5) were increased when compared to cognitively normal individuals. In addition, TDP-43 proteinopathy was increased in 10/44 (22.7%) mildly demented participants compared to 7/50 (14%) of cognitively normal individuals. Conclusions: The pre-clinical stage of AD is distinguished from incipient Alzheimer’s dementia, not by the type of lesions present, but by the burden of molecular pathology. O2-07-02
MODELING THE TEMPORAL EVOLUTION OF ALZHEIMER’S PATHOLOGY WITH AUTOPSY DATA
Donald Royall1, Raymond Palmer1, Lon White2, 1University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States; 2 John A Burns School of Medicine, University of Hawaii at manoa, Honolulu, Hawaii, United States. Background: Recent longitudinal clinical and imaging studies suggest that Alzheimer’s disease (AD) pathology begins before clinical symptoms can be diagnosed, and evolves non-linearly. However, the association between longitudinal changes and autopsy findings cannot be easily determined because autopsy data are available only after death. In this study, we combine autopsy data with latent growth curve (LGC) models of in vivo cognitive change in formal and arguably causal mediation models of the temporal development of AD neuropathology. Methods: Autopsy data from 435 participants in the Honolulu-Asia Aging Study (HAAS) were combined into latent factor measures of neuritic plaque (NP) and neurofibrillary tangle (NFT) counts. These were associated with latent intercept and slope parameters from a LGC model of 10-year change in cognitive test performance. Figure