- Email: [email protected]
NEUROFIBRILLARY TANGLE PREDOMINANT DEMENTIA: CLINICAL AND PATHOLOGICAL DESCRIPTION IN A CASE SERIES
Poster Presentations: Sunday, July 24, 2016
dysfunction (Dubois, 2014). There is an association between non-amnestic symptoms and the severity of NFT pathology in the parietal cortex (Tang Wai, 2004). We hypothesize that next to NFT the occurrence of phosphorylated tau, amyloid beta and microglia differ in cortical distribution between amnestic (AAD) and non-amnestic AD (NAAD) patients. Methods: AAD cases (n¼10; mean age¼85) were defined as having memory dysfunction as presenting symptom and a NFT distribution typical according to Braak staging. NAAD cases (n¼10; mean age¼63) were defined as having non-amnestic symptomatology as presenting symptom and a predominance of NFT in the parietal cortex compared with the temporal cortex. In the temporal and parietal cortex the presence of amyloid (A)beta (n-terminus), phosphorylated (p)Tau (pSer202+Thr205), and microglia (HLA-DP, DQ, DR) was assessed by immunohistochemistry and analyzed for optical density using the ImageJ analysis programme. Results: In NAAD cases levels of pTau were similar in the parietal and temporal cortex, while AAD cases showed 20% higher level of pTau in the temporal cortex. Compared with the AAD cases, NAAD cases had 15% higher levels of pTau in the parietal cortex (p<0.05). Remarkably, no differences in Abeta levels were found, neither between groups nor regions. In the parietal cortex, the NAAD group had twice the amount of microglia compared with their temporal cortex, whereas the AAD group had twice the amount of microglia in their temporal cortex. The NAAD group had a three times higher load of microglia in the parietal cortex than the AAD group (p<0.05). pTau and microglia levels did not differ in the temporal cortex between groups. Conclusions: Our data are in line with previous findings illustrating different distribution patterns of pathological hallmarks in variants of AD. The increased presence of pTau and microglia in the parietal cortex of NAAD compared with AAD suggests a different un-
P559
derlying neuropathological mechanism and disease progression in AD variants. P1-340
FRAILTY IMPACTS THE RELATIONSHIP BETWEEN NEUROPATHOLOGY AND DEMENTIA DISEASE EXPRESSION
Joshua J. Armstrong1,2, Judith Godin2,3, Lindsay MK. Wallace1,2, Melissa K. Andrew1,2, Kenneth Rockwood1,2, 1Dalhousie University, Halifax, NS, Canada; 2Canadian Consortium on Neurodegeneration in Aging, Halifax, NS, Canada; 3Nova Scotia Health Authority, Halifax, NS, Canada. Contact e-mail: [email protected] Background: Although a number of studies have linked frailty
with cognitive impairment, fewer studies have examined these constructs together in relation to brain health. Examining the relationships between neuropathological lesions, frailty and late-life cognitive function may provide insight into why some individuals can tolerate more neuropathological lesions than others. Here, we examine the National Alzheimer’s Coordinating Center (NACC) database to evaluate the variance in clinical outcomes explained by frailty, after accounting for neuropathology. Methods: Health assessment data from the last visit prior to death was linked to neuropathology information collected at autopsy in the NACC. An accumulation of health deficits frailty index (FI) was developed using 30 assessment variables. Hierarchical multiple regression models were developed to evaluate the separate impact of control variables (age, sex, education), neuropathology, and frailty on clinical outcome measures. Results: After accounting for the control variables, seven neuropathological markers accounted for a significant amount of variation in both the Mini-Mental State Exam (MMSE; R2 change ¼ 0.24) and Clinical Dementia rating (CDR; R2 change ¼ 0.21) scores. When the FI was added to these models, the FI accounted for a significant amount of additional variation in both the MMSE (R2 change ¼ 0.07) and CDR (R2 change ¼ 0.14) scores. Conclusions: Consideration of frailty reduced the explanatory power of neuropathology on clinical outcomes, suggesting that frailty has an important impact on the relationship between neuropathology and disease expression. Additional analyses using the NACC may provide further insights into the relationships between frailty, aging, neuropathology, and cognition in older adults. P1-341
NEUROFIBRILLARY TANGLE PREDOMINANT DEMENTIA: CLINICAL AND PATHOLOGICAL DESCRIPTION IN A CASE SERIES
Morgan Schwarz1, Geidy E. Serrano1, Thomas G. Beach1, Michael Malek Ahmadi1, Lucia Sue1, Kathryn Davis1, Marwan N. Sabbagh2, 1Banner Sun Health Research Institute, Sun City, AZ, USA; 2Barrow Neurological Institute, Phoenix, AZ, USA. Contact e-mail: [email protected]
Fig. 1. The mean phosphorylated tau (AT8), amyloid beta (Abeta), and microglia (CR3/43) immunoreactivity per region in amnestic and non-amnestic Alzheimer’s disease (AD) cases. + ¼ significant region effect * ¼ significant region per group effect
Background: The aim of this study is to contribute to an understanding of the clinical presentation and pathological features of neurofibrillary tangle predominant dementia (NFTPD) that will assist with the eventual development of methods for its ante-mortem identification. Methods: We contrast eight NFTPD cases identified in the Banner Sun Health Research Institute Brain and Body Donation Program (SHRI-BBDP) database to 114 Alzheimer’s disease (AD) subjects, in terms of their
P560
Poster Presentations: Sunday, July 24, 2016
demographics, clinical features, and pathological features. Results: When NFTPD subjects were compared to AD subjects, they were found to have a later onset of symptoms, an older age at death, less impairment prior to death, and less frequent appearance of the Apolipoprotein E ε4 variant. None of the eight NFTPD subjects met the clinical criteria for probable AD. They possessed a diverse range of diagnoses including possible AD, mixed vascular dementia (VAD), dementia NOS, and dementia with Lewy bodies (DLB). AD-related pathology, for both amyloid plaques and neurofibrillary tangles, was less severe in NFTPD subjects than in AD subjects. All eight NFTPD subjects were classified as neurofibrillary tangle Braak stage IV and therefore had fewer tangles in the neocortex when compared to AD subjects with mean Braak stage V (range II – VI). Conclusions: NFTPD subjects have dementia despite a lower pathological burden when compared to AD subjects. In this small sample, the ante-mortem presentation is such that NFTPD subjects are not diagnosed with probable AD. The cognitive and non-cognitive clinical features (delusions, depression, parkinsonism, and hallucinations) of NFTPD and AD are very similar and do not serve as indicators for a diagnosis, but older age (> 80), lack of an ApoE ε4 allele and less severe cognitive impairment should further inform the differential diagnosis of NFTPD from AD.
AGD subjects had lower socioeconomic status (p¼ 0.011). Subjects with AGD were older than normal controls (AGD: 76.469.8 years; controls: 65.9610.5, p<0.0001). AGD rarely occurred as an isolated pathological finding (9.3%). Higher frequency of neurofibrillary pathology was observed in AGD subjects compared to controls (p<0.001); however the frequency of neuritic plaques was similar between groups. Some degree of neuropsychiatric symptoms (NPS) were found in 55 of 86 (64%) AGD subjects, and AGD had higher odds of NPS than controls even after adjustment for age, sex, and education (OR¼2.50, 95%CI¼1.43-4.36, p¼0.001). Specifically, participants with AGD had higher odds of depression than controls (OR¼4.32, (95%CI¼2.06-9.08,p<0.0001), apathy (OR¼2.75, 95%CI¼1.12-6.74, p¼0.03), appetite and eating abnormalities (OR¼3.12, 95%CI¼1.71-5.72, p<0.0001), and nighttime behaviors (OR¼2.60, 95%CI¼1.29-5.25, p¼0.008) in multivariate analyses. Conclusions: AGD patients present a significant higher presence of depression, appetite and eating abnormalities than controls. Studies investigating in details the features of these changes are necessary to identify an antemortem diagnostic marker to AGD. Longitudinal follow up in AGD patients potentially will clarify the clinical significance of such a frequent finding in postmortem brains. P1-343
P1-342
NEUROPSYCHIATRIC SYMPTOMS IN ARGYROPHILIC BRAIN DISEASE: EARLY CLINICAL SYMPTOMS?
Roberta Diehl Rodriguez1, Claudia K. Suemoto1, Mariana Molina2, Renata Elaine Paraizo Leite1, Renata Eloah de Lucena Ferretti-Rebustini3, Jose M. Farfel1, Helmut Heinsen4,5, Ricardo Nitrini4, Carlos Augusto Pasquallucci1, Wilson Jacob-Filho1, Lea Tenenholz Grinberg6, 1University of S~ao Paulo Medical School, S~ao Paulo, Brazil; 2University of Sao Paulo Medical School, Sao Paulo, Brazil; 3 University of S~ ao Paulo, School of Nursing, S~ao Paulo, Brazil; 4University of S~ ao Paulo, S~ ao Paulo, Brazil; 5Universiy of W€uerzburg, W€uerzburg, ao Paulo School of Medicine, S~ao Paulo, Brazil. Germany; 6University of S~ Contact e-mail: [email protected] Background: Argyrophilic grain disease (AGD) is age-related
tauopathy. Despite its high prevalence, AGD clinical significance is still controversial. Examining AGD clinical impact is curbed by a lack of an antemortem diagnosis marker. We aimed to identify possible distinctive AGD antemortem markers comparing cognitive and neuropsychiatric scores in cognitive normal subject with AGD pathology and controls. Methods: A total of 351 brains from 265 cognitively normal controls and 86 subjects with a neuropathological diagnosis of pure AGD were investigated. Normal control subjects were defined as having: 1) no cognitive impairment according the clinical dementia rating scale (CDR¼0), 2) no limitations on basic and instrumental activities of daily living, and 3) no neuropathological changes. In addition, AGD subjects were characterized as “pure” if they did not fulfill criteria for another neurodegenerative disease. Demographic and clinico-functional data were collected via a knowledgeable informant and included the informant questionnaire on cognitive decline in the elderly, CDR, and neuropsychiatric inventory. Comprehensive neuropathological diagnosis followed internationally accepted criteria. Results:
PATHOLOGICAL CORRELATES ASSOCIATED WITH ANTE-MORTEM NEUROPSYCHOLOGICAL PERFORMANCE IN ALZHEIMER’S DISEASE
Brandy L. Callahan1,2,3,4, Simon Duchesne5,6,7, Sandra E. Black2,3,8,9,10, 1 Faculty of Medicine, University Laval, Quebec, QC, Canada; 2Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 3LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 4 Centre de Recherche de l’Institut Universitaire en Sante Mentale de Quebec, Quebec, Canada; 5Departement de Radiologie et Medecine Nucleaire, Universite Laval, Quebec, QC, Canada; 6Institut Universitaire en Sante Mentale de Quebec, Quebec, Canada; 7Faculty of Medicine, University Laval, Quebec, QC, Canada; 8Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 9Sunnybrook Research Institute, Toronto, ON, Canada; 10Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Autopsy evidence has revealed that Alzheimer’s
disease (AD) pathology is often accompanied by co-morbid vasculopathy. Our aims were to determine which specific pathologies tend to co-occur post-mortem in clinical AD patients, and to describe the cognitive characteristics associated with these different pathological clusters. Methods: We conducted an exploratory factor analysis on autopsy data from 1,370 participants of the National Alzheimer Coordination Centre (NACC) database. We performed confirmatory analyses on 237 participants of the Rush Memory and Aging Program (MAP). All participants had an ante mortem clinical diagnosis of AD and complete autopsy data. We further analyzed longitudinal cognitive characteristics (executive; memory; attention; language; up to seven years pre-mortem) of NACC participants, clustered along each factor, using ANOVA, and determined the nature and strength of the association between cognition and pathology using logistic regression. Results: Two latent pathological factors were identified from the NACC sample and
dysfunction (Dubois, 2014). There is an association between non-amnestic symptoms and the severity of NFT pathology in the parietal cortex (Tang Wai, 2004). We hypothesize that next to NFT the occurrence of phosphorylated tau, amyloid beta and microglia differ in cortical distribution between amnestic (AAD) and non-amnestic AD (NAAD) patients. Methods: AAD cases (n¼10; mean age¼85) were defined as having memory dysfunction as presenting symptom and a NFT distribution typical according to Braak staging. NAAD cases (n¼10; mean age¼63) were defined as having non-amnestic symptomatology as presenting symptom and a predominance of NFT in the parietal cortex compared with the temporal cortex. In the temporal and parietal cortex the presence of amyloid (A)beta (n-terminus), phosphorylated (p)Tau (pSer202+Thr205), and microglia (HLA-DP, DQ, DR) was assessed by immunohistochemistry and analyzed for optical density using the ImageJ analysis programme. Results: In NAAD cases levels of pTau were similar in the parietal and temporal cortex, while AAD cases showed 20% higher level of pTau in the temporal cortex. Compared with the AAD cases, NAAD cases had 15% higher levels of pTau in the parietal cortex (p<0.05). Remarkably, no differences in Abeta levels were found, neither between groups nor regions. In the parietal cortex, the NAAD group had twice the amount of microglia compared with their temporal cortex, whereas the AAD group had twice the amount of microglia in their temporal cortex. The NAAD group had a three times higher load of microglia in the parietal cortex than the AAD group (p<0.05). pTau and microglia levels did not differ in the temporal cortex between groups. Conclusions: Our data are in line with previous findings illustrating different distribution patterns of pathological hallmarks in variants of AD. The increased presence of pTau and microglia in the parietal cortex of NAAD compared with AAD suggests a different un-
P559
derlying neuropathological mechanism and disease progression in AD variants. P1-340
FRAILTY IMPACTS THE RELATIONSHIP BETWEEN NEUROPATHOLOGY AND DEMENTIA DISEASE EXPRESSION
Joshua J. Armstrong1,2, Judith Godin2,3, Lindsay MK. Wallace1,2, Melissa K. Andrew1,2, Kenneth Rockwood1,2, 1Dalhousie University, Halifax, NS, Canada; 2Canadian Consortium on Neurodegeneration in Aging, Halifax, NS, Canada; 3Nova Scotia Health Authority, Halifax, NS, Canada. Contact e-mail: [email protected] Background: Although a number of studies have linked frailty
with cognitive impairment, fewer studies have examined these constructs together in relation to brain health. Examining the relationships between neuropathological lesions, frailty and late-life cognitive function may provide insight into why some individuals can tolerate more neuropathological lesions than others. Here, we examine the National Alzheimer’s Coordinating Center (NACC) database to evaluate the variance in clinical outcomes explained by frailty, after accounting for neuropathology. Methods: Health assessment data from the last visit prior to death was linked to neuropathology information collected at autopsy in the NACC. An accumulation of health deficits frailty index (FI) was developed using 30 assessment variables. Hierarchical multiple regression models were developed to evaluate the separate impact of control variables (age, sex, education), neuropathology, and frailty on clinical outcome measures. Results: After accounting for the control variables, seven neuropathological markers accounted for a significant amount of variation in both the Mini-Mental State Exam (MMSE; R2 change ¼ 0.24) and Clinical Dementia rating (CDR; R2 change ¼ 0.21) scores. When the FI was added to these models, the FI accounted for a significant amount of additional variation in both the MMSE (R2 change ¼ 0.07) and CDR (R2 change ¼ 0.14) scores. Conclusions: Consideration of frailty reduced the explanatory power of neuropathology on clinical outcomes, suggesting that frailty has an important impact on the relationship between neuropathology and disease expression. Additional analyses using the NACC may provide further insights into the relationships between frailty, aging, neuropathology, and cognition in older adults. P1-341
NEUROFIBRILLARY TANGLE PREDOMINANT DEMENTIA: CLINICAL AND PATHOLOGICAL DESCRIPTION IN A CASE SERIES
Morgan Schwarz1, Geidy E. Serrano1, Thomas G. Beach1, Michael Malek Ahmadi1, Lucia Sue1, Kathryn Davis1, Marwan N. Sabbagh2, 1Banner Sun Health Research Institute, Sun City, AZ, USA; 2Barrow Neurological Institute, Phoenix, AZ, USA. Contact e-mail: [email protected]
Fig. 1. The mean phosphorylated tau (AT8), amyloid beta (Abeta), and microglia (CR3/43) immunoreactivity per region in amnestic and non-amnestic Alzheimer’s disease (AD) cases. + ¼ significant region effect * ¼ significant region per group effect
Background: The aim of this study is to contribute to an understanding of the clinical presentation and pathological features of neurofibrillary tangle predominant dementia (NFTPD) that will assist with the eventual development of methods for its ante-mortem identification. Methods: We contrast eight NFTPD cases identified in the Banner Sun Health Research Institute Brain and Body Donation Program (SHRI-BBDP) database to 114 Alzheimer’s disease (AD) subjects, in terms of their
P560
Poster Presentations: Sunday, July 24, 2016
demographics, clinical features, and pathological features. Results: When NFTPD subjects were compared to AD subjects, they were found to have a later onset of symptoms, an older age at death, less impairment prior to death, and less frequent appearance of the Apolipoprotein E ε4 variant. None of the eight NFTPD subjects met the clinical criteria for probable AD. They possessed a diverse range of diagnoses including possible AD, mixed vascular dementia (VAD), dementia NOS, and dementia with Lewy bodies (DLB). AD-related pathology, for both amyloid plaques and neurofibrillary tangles, was less severe in NFTPD subjects than in AD subjects. All eight NFTPD subjects were classified as neurofibrillary tangle Braak stage IV and therefore had fewer tangles in the neocortex when compared to AD subjects with mean Braak stage V (range II – VI). Conclusions: NFTPD subjects have dementia despite a lower pathological burden when compared to AD subjects. In this small sample, the ante-mortem presentation is such that NFTPD subjects are not diagnosed with probable AD. The cognitive and non-cognitive clinical features (delusions, depression, parkinsonism, and hallucinations) of NFTPD and AD are very similar and do not serve as indicators for a diagnosis, but older age (> 80), lack of an ApoE ε4 allele and less severe cognitive impairment should further inform the differential diagnosis of NFTPD from AD.
AGD subjects had lower socioeconomic status (p¼ 0.011). Subjects with AGD were older than normal controls (AGD: 76.469.8 years; controls: 65.9610.5, p<0.0001). AGD rarely occurred as an isolated pathological finding (9.3%). Higher frequency of neurofibrillary pathology was observed in AGD subjects compared to controls (p<0.001); however the frequency of neuritic plaques was similar between groups. Some degree of neuropsychiatric symptoms (NPS) were found in 55 of 86 (64%) AGD subjects, and AGD had higher odds of NPS than controls even after adjustment for age, sex, and education (OR¼2.50, 95%CI¼1.43-4.36, p¼0.001). Specifically, participants with AGD had higher odds of depression than controls (OR¼4.32, (95%CI¼2.06-9.08,p<0.0001), apathy (OR¼2.75, 95%CI¼1.12-6.74, p¼0.03), appetite and eating abnormalities (OR¼3.12, 95%CI¼1.71-5.72, p<0.0001), and nighttime behaviors (OR¼2.60, 95%CI¼1.29-5.25, p¼0.008) in multivariate analyses. Conclusions: AGD patients present a significant higher presence of depression, appetite and eating abnormalities than controls. Studies investigating in details the features of these changes are necessary to identify an antemortem diagnostic marker to AGD. Longitudinal follow up in AGD patients potentially will clarify the clinical significance of such a frequent finding in postmortem brains. P1-343
P1-342
NEUROPSYCHIATRIC SYMPTOMS IN ARGYROPHILIC BRAIN DISEASE: EARLY CLINICAL SYMPTOMS?
Roberta Diehl Rodriguez1, Claudia K. Suemoto1, Mariana Molina2, Renata Elaine Paraizo Leite1, Renata Eloah de Lucena Ferretti-Rebustini3, Jose M. Farfel1, Helmut Heinsen4,5, Ricardo Nitrini4, Carlos Augusto Pasquallucci1, Wilson Jacob-Filho1, Lea Tenenholz Grinberg6, 1University of S~ao Paulo Medical School, S~ao Paulo, Brazil; 2University of Sao Paulo Medical School, Sao Paulo, Brazil; 3 University of S~ ao Paulo, School of Nursing, S~ao Paulo, Brazil; 4University of S~ ao Paulo, S~ ao Paulo, Brazil; 5Universiy of W€uerzburg, W€uerzburg, ao Paulo School of Medicine, S~ao Paulo, Brazil. Germany; 6University of S~ Contact e-mail: [email protected] Background: Argyrophilic grain disease (AGD) is age-related
tauopathy. Despite its high prevalence, AGD clinical significance is still controversial. Examining AGD clinical impact is curbed by a lack of an antemortem diagnosis marker. We aimed to identify possible distinctive AGD antemortem markers comparing cognitive and neuropsychiatric scores in cognitive normal subject with AGD pathology and controls. Methods: A total of 351 brains from 265 cognitively normal controls and 86 subjects with a neuropathological diagnosis of pure AGD were investigated. Normal control subjects were defined as having: 1) no cognitive impairment according the clinical dementia rating scale (CDR¼0), 2) no limitations on basic and instrumental activities of daily living, and 3) no neuropathological changes. In addition, AGD subjects were characterized as “pure” if they did not fulfill criteria for another neurodegenerative disease. Demographic and clinico-functional data were collected via a knowledgeable informant and included the informant questionnaire on cognitive decline in the elderly, CDR, and neuropsychiatric inventory. Comprehensive neuropathological diagnosis followed internationally accepted criteria. Results:
PATHOLOGICAL CORRELATES ASSOCIATED WITH ANTE-MORTEM NEUROPSYCHOLOGICAL PERFORMANCE IN ALZHEIMER’S DISEASE
Brandy L. Callahan1,2,3,4, Simon Duchesne5,6,7, Sandra E. Black2,3,8,9,10, 1 Faculty of Medicine, University Laval, Quebec, QC, Canada; 2Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 3LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 4 Centre de Recherche de l’Institut Universitaire en Sante Mentale de Quebec, Quebec, Canada; 5Departement de Radiologie et Medecine Nucleaire, Universite Laval, Quebec, QC, Canada; 6Institut Universitaire en Sante Mentale de Quebec, Quebec, Canada; 7Faculty of Medicine, University Laval, Quebec, QC, Canada; 8Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 9Sunnybrook Research Institute, Toronto, ON, Canada; 10Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Autopsy evidence has revealed that Alzheimer’s
disease (AD) pathology is often accompanied by co-morbid vasculopathy. Our aims were to determine which specific pathologies tend to co-occur post-mortem in clinical AD patients, and to describe the cognitive characteristics associated with these different pathological clusters. Methods: We conducted an exploratory factor analysis on autopsy data from 1,370 participants of the National Alzheimer Coordination Centre (NACC) database. We performed confirmatory analyses on 237 participants of the Rush Memory and Aging Program (MAP). All participants had an ante mortem clinical diagnosis of AD and complete autopsy data. We further analyzed longitudinal cognitive characteristics (executive; memory; attention; language; up to seven years pre-mortem) of NACC participants, clustered along each factor, using ANOVA, and determined the nature and strength of the association between cognition and pathology using logistic regression. Results: Two latent pathological factors were identified from the NACC sample and