- Email: [email protected]
APATHY AND CORTICAL THICKNESS IN THE ALZHEIMER'S DISEASE SPECTRUM: THE ARGENTINA-ADNI EXPERIENCE
Poster Presentations: Sunday, July 24, 2016
b-amyloid loadings and FDG, particularly in the angular gyrus and posterior cingulate cortex (Figure 2A). For comparison, no significant regions were observed using a whole cortex average of b-amyloid burden (Figure 2B). Conclusions: Multivariate, cross-correlation analyses can uncover complex brain patterns not found with univariate statistical analysis approaches. These results support the notion that it is the spatially distributed, rather than focal, accumulation of b-amyloid that is associated with metabolic dysfunction. Future work will expand this analysis to identify the pattern of b-amyloid maximally related to metabolic connectivity. P1-267
AMYLOID BURDEN DOES NOT DIFFERENTIATE COGNITIVE STATUS AMONGST THE OLDEST OLD: THE 90+ STUDY
Charles DeCarli1, Llana J. Bennett2, Evan Fletcher3, Dana Greenia2, Maria M. Corrada4, Claudia H. Kawas4, 1University of California Davis, Davis, CA, USA; 2University of California at Irvine, Irvine, CA, USA; 3 University of California, Davis, Davis, CA, USA; 4University of California, Irvine, Irvine, CA, USA. Contact e-mail: [email protected] Background: Accruing evidence suggests that the etiology of
dementia is multi-factorial, even among individuals with clinical presentations classic for Alzheimer’s disease (AD). This is particularly true amongst the oldest old where the prevalence of substantial amyloid burden reaches 30% among cognitively normal individuals. Pathological studies confirm that multiple etiologies are involved with dementia severity amongst the oldest old. Here, we tested the degree to which in vivo measures of amyloid burden and atrophy predict clinical diagnosis of cognitively normal (NL), cognitive impairment, not demented (CIND) and demented (DEM) among the oldest-old. Methods: Participants were 132 individuals (95 +3 years, 73% female) from The 90 + Study, a populationbased longitudinal study of aging and dementia among people aged 90 years. Regular clinical evaluations diagnosed participants as 64% NL, 30% CIND and 6% DEM. We acquired Amyvid PET to quantify amyloid burden as measured by standard uptake value ratios (SUVRs) calculated as the ratio to whole cerebellum mean uptake. A global brain SUVR index was determined from previously described frontal, parietal and temporal regions commonly involved in AD. MRI quantification included volumes of brain, cortical gray, hippocampus, and white matter hyperintensity (WMH). Results: Multiple linear regression models adjusting for age, gender and head size (for MRI measures) were used to assess the relationship between each imaging metric and clinical diagnosis (NL, CIND and DEM). Results revealed significant differences in hippocampal (5.6, 5.4 and 5.1 cc, p¼0.03), lateral ventricle (46, 54
P517
and 57 cc, p¼0.04) and third ventricle (1.8, 2.0 and 2.4, p¼0.005) volumes, but not global brain SUVR index (see table for details). A logistic regression model found that third ventricle volume was the only significant discriminator of clinical diagnosis when the significant MRI findings from the prior linear regression models were included in a single model. Third ventricle volume remained a significant discriminator in a logistic regression model that combined PET and MRI measures. Conclusions: Cognitive impairment among the oldest old has complex determinants that appear to be more strongly related to measures of degeneration than to amyloidosis when using in vivo neuroimaging methods. Further work is needed to identify premorbid causes of dementia amongst these individuals. P1-268
APATHY AND CORTICAL THICKNESS IN THE ALZHEIMER’S DISEASE SPECTRUM: THE ARGENTINA-ADNI EXPERIENCE
Ismael Luis Calandri, Pablo Bagnati, Juan Pablo Garcia Lombardi, Silvia Vazquez, Fernando Ventrice, Jorge Campos, Gustavo Sevlever, Allegri Ricardo, FLENI, Buenos Aires, Argentina. Contact e-mail: [email protected] Background: Apathy is a predominant behavioral symptom in
Alzheimer’s Disease with severe consequences in every day function. Physicopathological aspects, clinical features, and differential diagnosis in depression still remain controversial. The finding of biological markers of apathy could be a useful diagnostic tool, and atrophy identification trough MRI could represent this option. Our aim is to study possible correlation between neuropsychiatric behavior focused in apathy and localized cortical atrophy in AD spectrum. Methods: 22 patients (dementia¼8 and mild cognitive impairment¼13) from the Argentina-ADNI cohort with a positive amyloid biomarker (Ab42 in CSF or PiB-PET) were selected. Apathy and depression were measured with Neuropsychiatric Inventory apathy sub score (NPI-AS) and Geriatric Depression Scale (GDS) respectively. Patient underwent a 3T MRI scanning and the cortical images were analyzed using Freesurfer. Two statistical analysis were performed, a multiple lineal regression using SPSS and a voxel-based surface group analysis using Qdec tool of freesurfer. Results: An age related lineal regression model showed correlation between cortical thickness with apathy (aR2¼0.70, p<0.01). A decrease in 1mm in left anterior-medial region of cingulum gyrus explained 6 points increase in NPIAS(p<0.001), in left occipitotemporal lateral fusiform gyrus 3 points increase in NPI-AS (p<0.05) and in right frontal superior gyrus 3.8 points decrease in the NPI-AS (p<0.05). White matter
Table Parameter estimates and significance of MRI measures based on linear regression models with MRI measure as dependent variable. Diagnostic comparisons are post-hoc adjusted least squared contrasts of differences in mean volumes summarized in the text. Parameter
Hippocampus
Lateral Ventricle
Third Ventricle
Global Index SUVR
Intercept Age Gender Head size NL v CIND NL v Dementia
3.16 6 1.9 -0.018 6 0.017 -0.23 6 0.12 0.003 6 0.0005 *** 0.23 6 0.12 0.43 6 0.19*
-183 6 59 1.05 6 0.53 5.1 6 4.8 0.093 6 0.016*** -8.3 6 4.0* -11.0 6 5.9
-2.36 6 1.95 0.020 6 0.017 -0.05 6 0.16 0.002 6 0.0005*** -0.23 6 0.13 -0.61 6 0.19**
0.98 6 0.65 0.002 6 0.007 -0.05 6 0.05 N/A -0.05 6 0.05 0.01 6 0.09
P < *0.05, ** 0.01, ***0.001
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Poster Presentations: Sunday, July 24, 2016
lesions showed no-significant impact in the model and there was not founded correlation between GDS and cortical atrophy. In parallel surface group analysis show similar regional differences between apathetic and non-apathetic patients and could show more specific boundaries of the related local atrophy. Conclusions: The compromise of cortical structures such as cingular cortex and its high correlation with apathy confirm his role in motivation circuits in AD spectrum. White matter lesions don’t correlate in this AD-apathy model, maybe their relevance has to be confine to another neurological diseases. The relevance of right superior frontal gyrus in this model suggest new queries about the complexity of the motivation network involved in AD, further research could be perform to accurate his role. P1-269
APPLICATION OF BRAIN ATROPHY LESION INDEX (BALI) TO COMMON CLINICAL MRI SEQUENCES: EVALUATION OF WHOLE BRAIN STRUCTURAL CHANGES IN AGING AND DEMENTIA
Xiaowei Song1,2, Hui Guo1,3, Ryan C. N. D’Arcy1,2, William Siu1, John Diggle1, Yunting Zhang3, 1Fraser Health Authority, Surrey, BC, Canada; 2Simon Fraser University, Surrey, BC, Canada; 3Tianjin Medical University General Hospital, Tianjin, China. Contact e-mail: xiaowei. [email protected] Background: Aging is associated with multiple structural brain
changes, which occur heterogeneously in older adults and, combined, can affect general cognitive functioning. The MRI-based Brain Atrophy and Lesion Index (BALI) assesses age-related common brain changes, and has been validated to
evaluate whole brain structural health in aging and dementia. Previous BALI research has shown significant sensitivity across both T1 and T2 weighted whole brain images. The present study expands this investigation to the use of BALI on additional routine clinical MRI examinations (e.g., T2-FLAIR and T2*GRE). Methods: We evaluated anatomical MRI data from three independent studies: The Alzheimer’s Disease Neuroimaging Initiative (n¼950; women¼47.9%; age¼72.767.4 yrs) consisted of participants with normal cognition, mild cognitive impairment, and Alzheimer disease; the National Alzheimer’s Coordinating Centre (n¼829; women¼56.0%; age¼70.0612.9 yrs) contained multiple clinical and research protocols of the Alzheimer’s Disease Centres on patients with different dementia subtypes; the Tianjin Medical University General Hospital dataset (n¼142; women¼43.7%; age¼74.066.6 yrs) involved older outpatients who were diagnosed with no cognitive disorders. Brain images with T1WI, T2WI, T2-FLAIR, and T2*GRE were examined following BALI scheme. Results: Atrophic and lesion based changes were detected using each of the four sequences (Figure 1). A greater number of cases with cavernous malformation, patchy or lacunar malacia, meningioma, and normal pressure hydrocephalus were found in the clinical samples than in the research samples (p<0.05). Increased sensitivity from T2FLAIR revealed lesions in the white matter, but missed identifying dilated perivascular spaces in subcortical, deep white matter, basal ganglia and surrounding regions, and cerebral peduncle. Lacunar malacia and dilated perivascular spaces were more clearly differentiated using T2-FLAIR. Microhaemorrhage and malacia lesion with hemosiderin deposition and calcification were more frequently seen in the clinical samples (p<0.05), which were sensitively detected using T2*GRE. Conclusions: BALI was successfully applied to several routine clinical MRI sequences for the evaluation of whole brain structural health in aging and dementia. The T1WI and T2WI based evaluation appeared to consistently capture common brain changes in the various BALI categories. Inclusion of T2-FLAIR and T2*GRE may increase BALI sensitivity.
P1-270
AV-1451 TAU-PET IN CLINICAL VARIANTS OF PROGRESSIVE SUPRANUCLEAR PALSY
Keith A. Josephs, Jennifer L. Whitwell, Nirubol Tosakulwong, Stephen D. Weigand, Matthew L. Senjem, Ronald C. Petersen, Clifford R. Jack, Jr. Val J. Lowe, Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Different clinical variants of progressive supranu-
clear palsy (PSP) have been described, the most common of which is Richardson’s syndrome. The relationship between these clinical variants and pathology is heterogeneous, with all variants associated with tau pathology but with varying patterns of tau deposition within, and across, brain regions. TauPET imaging using AV-1451 demonstrates striking uptake in Alzheimer’s disease (AD), although it is unclear whether uptake is observed in the different variants of PSP. Methods: Six subjects representing four clinical variants of PSP (Richardson’s syndrome n¼3, pure akinesia with gait freezing (PAGF) n¼1, primary progressive apraxia of speech (PPAOS) n¼1, and post-surgical PSP n¼1) underwent tau-PET imaging with AV-1451. These subjects were compared to 101 age-matched CN subjects and 19 subjects with AD. Regional tau-PET uptake
b-amyloid loadings and FDG, particularly in the angular gyrus and posterior cingulate cortex (Figure 2A). For comparison, no significant regions were observed using a whole cortex average of b-amyloid burden (Figure 2B). Conclusions: Multivariate, cross-correlation analyses can uncover complex brain patterns not found with univariate statistical analysis approaches. These results support the notion that it is the spatially distributed, rather than focal, accumulation of b-amyloid that is associated with metabolic dysfunction. Future work will expand this analysis to identify the pattern of b-amyloid maximally related to metabolic connectivity. P1-267
AMYLOID BURDEN DOES NOT DIFFERENTIATE COGNITIVE STATUS AMONGST THE OLDEST OLD: THE 90+ STUDY
Charles DeCarli1, Llana J. Bennett2, Evan Fletcher3, Dana Greenia2, Maria M. Corrada4, Claudia H. Kawas4, 1University of California Davis, Davis, CA, USA; 2University of California at Irvine, Irvine, CA, USA; 3 University of California, Davis, Davis, CA, USA; 4University of California, Irvine, Irvine, CA, USA. Contact e-mail: [email protected] Background: Accruing evidence suggests that the etiology of
dementia is multi-factorial, even among individuals with clinical presentations classic for Alzheimer’s disease (AD). This is particularly true amongst the oldest old where the prevalence of substantial amyloid burden reaches 30% among cognitively normal individuals. Pathological studies confirm that multiple etiologies are involved with dementia severity amongst the oldest old. Here, we tested the degree to which in vivo measures of amyloid burden and atrophy predict clinical diagnosis of cognitively normal (NL), cognitive impairment, not demented (CIND) and demented (DEM) among the oldest-old. Methods: Participants were 132 individuals (95 +3 years, 73% female) from The 90 + Study, a populationbased longitudinal study of aging and dementia among people aged 90 years. Regular clinical evaluations diagnosed participants as 64% NL, 30% CIND and 6% DEM. We acquired Amyvid PET to quantify amyloid burden as measured by standard uptake value ratios (SUVRs) calculated as the ratio to whole cerebellum mean uptake. A global brain SUVR index was determined from previously described frontal, parietal and temporal regions commonly involved in AD. MRI quantification included volumes of brain, cortical gray, hippocampus, and white matter hyperintensity (WMH). Results: Multiple linear regression models adjusting for age, gender and head size (for MRI measures) were used to assess the relationship between each imaging metric and clinical diagnosis (NL, CIND and DEM). Results revealed significant differences in hippocampal (5.6, 5.4 and 5.1 cc, p¼0.03), lateral ventricle (46, 54
P517
and 57 cc, p¼0.04) and third ventricle (1.8, 2.0 and 2.4, p¼0.005) volumes, but not global brain SUVR index (see table for details). A logistic regression model found that third ventricle volume was the only significant discriminator of clinical diagnosis when the significant MRI findings from the prior linear regression models were included in a single model. Third ventricle volume remained a significant discriminator in a logistic regression model that combined PET and MRI measures. Conclusions: Cognitive impairment among the oldest old has complex determinants that appear to be more strongly related to measures of degeneration than to amyloidosis when using in vivo neuroimaging methods. Further work is needed to identify premorbid causes of dementia amongst these individuals. P1-268
APATHY AND CORTICAL THICKNESS IN THE ALZHEIMER’S DISEASE SPECTRUM: THE ARGENTINA-ADNI EXPERIENCE
Ismael Luis Calandri, Pablo Bagnati, Juan Pablo Garcia Lombardi, Silvia Vazquez, Fernando Ventrice, Jorge Campos, Gustavo Sevlever, Allegri Ricardo, FLENI, Buenos Aires, Argentina. Contact e-mail: [email protected] Background: Apathy is a predominant behavioral symptom in
Alzheimer’s Disease with severe consequences in every day function. Physicopathological aspects, clinical features, and differential diagnosis in depression still remain controversial. The finding of biological markers of apathy could be a useful diagnostic tool, and atrophy identification trough MRI could represent this option. Our aim is to study possible correlation between neuropsychiatric behavior focused in apathy and localized cortical atrophy in AD spectrum. Methods: 22 patients (dementia¼8 and mild cognitive impairment¼13) from the Argentina-ADNI cohort with a positive amyloid biomarker (Ab42 in CSF or PiB-PET) were selected. Apathy and depression were measured with Neuropsychiatric Inventory apathy sub score (NPI-AS) and Geriatric Depression Scale (GDS) respectively. Patient underwent a 3T MRI scanning and the cortical images were analyzed using Freesurfer. Two statistical analysis were performed, a multiple lineal regression using SPSS and a voxel-based surface group analysis using Qdec tool of freesurfer. Results: An age related lineal regression model showed correlation between cortical thickness with apathy (aR2¼0.70, p<0.01). A decrease in 1mm in left anterior-medial region of cingulum gyrus explained 6 points increase in NPIAS(p<0.001), in left occipitotemporal lateral fusiform gyrus 3 points increase in NPI-AS (p<0.05) and in right frontal superior gyrus 3.8 points decrease in the NPI-AS (p<0.05). White matter
Table Parameter estimates and significance of MRI measures based on linear regression models with MRI measure as dependent variable. Diagnostic comparisons are post-hoc adjusted least squared contrasts of differences in mean volumes summarized in the text. Parameter
Hippocampus
Lateral Ventricle
Third Ventricle
Global Index SUVR
Intercept Age Gender Head size NL v CIND NL v Dementia
3.16 6 1.9 -0.018 6 0.017 -0.23 6 0.12 0.003 6 0.0005 *** 0.23 6 0.12 0.43 6 0.19*
-183 6 59 1.05 6 0.53 5.1 6 4.8 0.093 6 0.016*** -8.3 6 4.0* -11.0 6 5.9
-2.36 6 1.95 0.020 6 0.017 -0.05 6 0.16 0.002 6 0.0005*** -0.23 6 0.13 -0.61 6 0.19**
0.98 6 0.65 0.002 6 0.007 -0.05 6 0.05 N/A -0.05 6 0.05 0.01 6 0.09
P < *0.05, ** 0.01, ***0.001
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Poster Presentations: Sunday, July 24, 2016
lesions showed no-significant impact in the model and there was not founded correlation between GDS and cortical atrophy. In parallel surface group analysis show similar regional differences between apathetic and non-apathetic patients and could show more specific boundaries of the related local atrophy. Conclusions: The compromise of cortical structures such as cingular cortex and its high correlation with apathy confirm his role in motivation circuits in AD spectrum. White matter lesions don’t correlate in this AD-apathy model, maybe their relevance has to be confine to another neurological diseases. The relevance of right superior frontal gyrus in this model suggest new queries about the complexity of the motivation network involved in AD, further research could be perform to accurate his role. P1-269
APPLICATION OF BRAIN ATROPHY LESION INDEX (BALI) TO COMMON CLINICAL MRI SEQUENCES: EVALUATION OF WHOLE BRAIN STRUCTURAL CHANGES IN AGING AND DEMENTIA
Xiaowei Song1,2, Hui Guo1,3, Ryan C. N. D’Arcy1,2, William Siu1, John Diggle1, Yunting Zhang3, 1Fraser Health Authority, Surrey, BC, Canada; 2Simon Fraser University, Surrey, BC, Canada; 3Tianjin Medical University General Hospital, Tianjin, China. Contact e-mail: xiaowei. [email protected] Background: Aging is associated with multiple structural brain
changes, which occur heterogeneously in older adults and, combined, can affect general cognitive functioning. The MRI-based Brain Atrophy and Lesion Index (BALI) assesses age-related common brain changes, and has been validated to
evaluate whole brain structural health in aging and dementia. Previous BALI research has shown significant sensitivity across both T1 and T2 weighted whole brain images. The present study expands this investigation to the use of BALI on additional routine clinical MRI examinations (e.g., T2-FLAIR and T2*GRE). Methods: We evaluated anatomical MRI data from three independent studies: The Alzheimer’s Disease Neuroimaging Initiative (n¼950; women¼47.9%; age¼72.767.4 yrs) consisted of participants with normal cognition, mild cognitive impairment, and Alzheimer disease; the National Alzheimer’s Coordinating Centre (n¼829; women¼56.0%; age¼70.0612.9 yrs) contained multiple clinical and research protocols of the Alzheimer’s Disease Centres on patients with different dementia subtypes; the Tianjin Medical University General Hospital dataset (n¼142; women¼43.7%; age¼74.066.6 yrs) involved older outpatients who were diagnosed with no cognitive disorders. Brain images with T1WI, T2WI, T2-FLAIR, and T2*GRE were examined following BALI scheme. Results: Atrophic and lesion based changes were detected using each of the four sequences (Figure 1). A greater number of cases with cavernous malformation, patchy or lacunar malacia, meningioma, and normal pressure hydrocephalus were found in the clinical samples than in the research samples (p<0.05). Increased sensitivity from T2FLAIR revealed lesions in the white matter, but missed identifying dilated perivascular spaces in subcortical, deep white matter, basal ganglia and surrounding regions, and cerebral peduncle. Lacunar malacia and dilated perivascular spaces were more clearly differentiated using T2-FLAIR. Microhaemorrhage and malacia lesion with hemosiderin deposition and calcification were more frequently seen in the clinical samples (p<0.05), which were sensitively detected using T2*GRE. Conclusions: BALI was successfully applied to several routine clinical MRI sequences for the evaluation of whole brain structural health in aging and dementia. The T1WI and T2WI based evaluation appeared to consistently capture common brain changes in the various BALI categories. Inclusion of T2-FLAIR and T2*GRE may increase BALI sensitivity.
P1-270
AV-1451 TAU-PET IN CLINICAL VARIANTS OF PROGRESSIVE SUPRANUCLEAR PALSY
Keith A. Josephs, Jennifer L. Whitwell, Nirubol Tosakulwong, Stephen D. Weigand, Matthew L. Senjem, Ronald C. Petersen, Clifford R. Jack, Jr. Val J. Lowe, Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Different clinical variants of progressive supranu-
clear palsy (PSP) have been described, the most common of which is Richardson’s syndrome. The relationship between these clinical variants and pathology is heterogeneous, with all variants associated with tau pathology but with varying patterns of tau deposition within, and across, brain regions. TauPET imaging using AV-1451 demonstrates striking uptake in Alzheimer’s disease (AD), although it is unclear whether uptake is observed in the different variants of PSP. Methods: Six subjects representing four clinical variants of PSP (Richardson’s syndrome n¼3, pure akinesia with gait freezing (PAGF) n¼1, primary progressive apraxia of speech (PPAOS) n¼1, and post-surgical PSP n¼1) underwent tau-PET imaging with AV-1451. These subjects were compared to 101 age-matched CN subjects and 19 subjects with AD. Regional tau-PET uptake