- Email: [email protected]
FRONTO-SUBCORTICAL HYPOPERFUSION IN PRESYMPTOMATIC FTD IS ASSOCIATED WITH BEHAVIORAL MEASURES, BUT NOT COGNITIVE DEFICITS: THE GENFI STUDY
Podium Presentations: Monday, July 17, 2017
Subscale scores on the Wide Range Achievement Test IV, and scores on a questionnaire measuring intellectual, social, and physical activities. Participants completed a 60-minute, in-traffic (12 mile), road test along a predetermined route annually, and were followed up to 4 years. Cox proportional hazards models using the stepwise selection method were employed to test the association of each of the biomarkers, the cognitive reserve variables, age and gender, with time to a Marginal or Fail rating on the road test. A significance level to enter and retain variables of .10 was used. Results: Participants (N¼121) had a mean age of 72.4 years, and had a mean follow-up time of 2.2 years. For all analyses, the biomarker and education variables, but no others, entered the model. As expected, abnormality of CSF and amyloid imaging biomarkers was associated with a faster time to a Marginal/Fail rating. Greater education was also associated with a faster time to receiving a Marginal/Fail rating in each model (e.g., HR¼1.33, 95%CI¼1.09-1.61, p¼.004). Conclusions: Unlike the effect of education and preclinical AD on cognition, higher education is associated with worse driving performance over time. Others have reported that higher education is associated with greater numbers of driving errors, and greater numbers of moving violations. Several possible reasons for this finding were explored.
O2-01-06
FRONTO-SUBCORTICAL HYPOPERFUSION IN PRESYMPTOMATIC FTD IS ASSOCIATED WITH BEHAVIORAL MEASURES, BUT NOT COGNITIVE DEFICITS: THE GENFI STUDY
Saira S. Mirza1,2, Henri J. M. M. Mutsaerts3, David M. Cash4,5, Martina Bocchetta5, David L. Thomas6, Katrina M. Dick4,5, John C. van Swieten7, Barbara Borroni8, Daniela Galimberti9, Maria Carmela Tartaglia1, James B. Rowe10, Caroline Graff11, Fabrizio Tagliavini12, Giovanni B. Frisoni13, Robert Laforce Jr.14, Elizabeth Finger15, Alexandre Mendonca16, Sandro Sorbi17, Martin N. Rossor4, Sebastien Ourselin6, Jonathan D. Rohrer6, Bradley J. Macintosh18, Mario Masellis1,19, 1University of Toronto, Toronto, ON, Canada; 2Sunnybrook Health Sciences Center, Toronto, ON, Canada; 3 Sunnybrook Research Institute, Toronto, ON, Canada; 4Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom; 5UCL Institute of Neurology, London, United Kingdom; 6 University College London, London, United Kingdom; 7Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 8University of Brescia, Brescia, Italy; 9University of Milan, Milan, Italy; 10University of Cambridge, Cambridge, United Kingdom; 11Karolinska Institutet, Stockholm, Sweden; 12Fondazione IRCSS Istituto Neurologico Carlo Besta, Milano, Italy; 13Lab Alzheimer’s Neuroimaging & Epidemiology, IRCCS Fatebenefratelli, Brescia, Italy; 14Universite Laval, Faculte de Medecine, Quebec, QC, Canada; 15University of Western Ontario, London, ON, Canada; 16University of Lisbon, Lisbon, Portugal; 17University of Florence, Florence, Italy; 18Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 19Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Frontotemporal dementia (FTD) is a highly heritable
neurodegenerative condition. Genetic mutations in the three genes account for the majority of genetic FTD: Chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT). We hypothesize that in pre-symptomatic mutation carriers, regional hypoperfusion in frontal regions will associate with behavioral and cognitive measures. Methods: In the large multi-centre pre-symptomatic genetic FTD study(GENFI), we previously identified “regions of interest (ROIs) of cerebral hypoperfusion” using a voxel-based analysis (VBA) of Arterial Spin Labeling MRI data from presymptomatic mutation carriers (n¼95; C9orf72¼30,
P551
GRN¼48, MAPT¼17) vs. non-carrier controls (n¼100). These hypoperfusion ROIs were then associated with cognitive and behavioural measures using multiple linear regression. Specifically, in these models, the dependent variables included: global cognition (MiniMental State Examination), executive function (Trail making test A and B), language (Boston naming and verbal fluency), logical memory (immediate and delayed recall), working memory (forward and backward digit span), and behavioural measures (Cambridge Behavior Inventory-Revised [CBI-R] and FTD rating scale). Analyses were repeated after stratifying on mutation, and all models were adjusted for age, sex, and education. Results: The hypoperfusion ROIs in carriers identified from the VBA included: paracingulate, orbitofrontal/ insula, frontal pole (right), putamen, frontal pole (bilateral), and middle frontal gyrus/inferior frontal gyrus/superior frontal gyrus (MFG, IFG, SFG). No associations were observed between ROIs and cognitive domains in carriers or non-carriers. In the ROI-behavior analyses using CBI-R score, significant interactions were observed between cerebral perfusion and carrier-status across the ROIs. In carriers only, hypoperfusion in the paracingulate region [b 0.16 (95% CI:0.23,0.04) p <0.001, p-interaction <0.001], frontal pole (right) [b 0.14 (95% CI:0.06,0.22) p<0.001, p-interaction 0.01], putamen [b 0.20 (95% CI:0.06,0.34) p¼ 0.006, p-interaction ¼0.01], frontal pole (bilateral) [b 0.14 (95% CI:0.06,0.22) p <0.001, p-interaction 0.008], and MFG/IFG/SFG [b 0.13 (95% CI: 0.06,0.21) p <0.001, p-interaction 0.01] was strongly associated with behaviour features. No ROI-behavior associations were observed in non-carriers. In subsequent mutation stratified analyses, we found that observed associations were driven by MAPT carriers. Conclusions: Cerebral hypoperfusion within frontal-subcortical regions in presymptomatic FTD is associated with early behavioral changes but not with cognitive deficits. MONDAY, JULY 17, 2017 ORAL SESSION O2-02 MOLECULAR AND CELL BIOLOGY: METABOLIC AND OTHER CELLULAR PROCESSES IN NEURODEGENERATION O2-02-01
PRELIMINARY FINDINGS FROM AN ONGOING LONGITUDINAL METABOLOME-WIDE ASSOCIATION STUDY OF COGNITIVE DECLINE IN HEALTHY ADULTS WITH INCREASED RISK FOR ALZHEIMER’S DISEASE
Burcu F. Darst1,2, Matthew J. P. Rush1,3,4, Paul D. Hutchins1,3,4, Thiruchelvi Rajagobal Reddy5, Jason D. Russell1,3,5, Ronald Gangnon1,2,6, Rebecca L. Koscik1,7, Sanjay Asthana1,7,8,9, Sterling C. Johnson1,7,10,11, Kirk J. Hogan1,7,12, Joshua J. Coon1,3,4,5,13, Corinne D. Engelman1,2,7,9, 1 University of Wisconsin, Madison, Madison, WI, USA; 2Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 3Genome Center of Wisconsin, University of Wisconsin, Madison, Madison, WI, USA; 4Chemistry, University of Wisconsin, Madison, Madison, WI, USA; 5Morgridge Institute for Research, Madison, WI, USA; 6Biostatistics and Medical Informatics, University of Wisconsin, Madison, Madison, WI, USA; 7Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 8 Geriatric Research Education and Clinical Center, W.S. Middleton Memorial Veterans Hospital, Madison, WI, USA; 9Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 10Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; 11Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison,
Subscale scores on the Wide Range Achievement Test IV, and scores on a questionnaire measuring intellectual, social, and physical activities. Participants completed a 60-minute, in-traffic (12 mile), road test along a predetermined route annually, and were followed up to 4 years. Cox proportional hazards models using the stepwise selection method were employed to test the association of each of the biomarkers, the cognitive reserve variables, age and gender, with time to a Marginal or Fail rating on the road test. A significance level to enter and retain variables of .10 was used. Results: Participants (N¼121) had a mean age of 72.4 years, and had a mean follow-up time of 2.2 years. For all analyses, the biomarker and education variables, but no others, entered the model. As expected, abnormality of CSF and amyloid imaging biomarkers was associated with a faster time to a Marginal/Fail rating. Greater education was also associated with a faster time to receiving a Marginal/Fail rating in each model (e.g., HR¼1.33, 95%CI¼1.09-1.61, p¼.004). Conclusions: Unlike the effect of education and preclinical AD on cognition, higher education is associated with worse driving performance over time. Others have reported that higher education is associated with greater numbers of driving errors, and greater numbers of moving violations. Several possible reasons for this finding were explored.
O2-01-06
FRONTO-SUBCORTICAL HYPOPERFUSION IN PRESYMPTOMATIC FTD IS ASSOCIATED WITH BEHAVIORAL MEASURES, BUT NOT COGNITIVE DEFICITS: THE GENFI STUDY
Saira S. Mirza1,2, Henri J. M. M. Mutsaerts3, David M. Cash4,5, Martina Bocchetta5, David L. Thomas6, Katrina M. Dick4,5, John C. van Swieten7, Barbara Borroni8, Daniela Galimberti9, Maria Carmela Tartaglia1, James B. Rowe10, Caroline Graff11, Fabrizio Tagliavini12, Giovanni B. Frisoni13, Robert Laforce Jr.14, Elizabeth Finger15, Alexandre Mendonca16, Sandro Sorbi17, Martin N. Rossor4, Sebastien Ourselin6, Jonathan D. Rohrer6, Bradley J. Macintosh18, Mario Masellis1,19, 1University of Toronto, Toronto, ON, Canada; 2Sunnybrook Health Sciences Center, Toronto, ON, Canada; 3 Sunnybrook Research Institute, Toronto, ON, Canada; 4Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom; 5UCL Institute of Neurology, London, United Kingdom; 6 University College London, London, United Kingdom; 7Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 8University of Brescia, Brescia, Italy; 9University of Milan, Milan, Italy; 10University of Cambridge, Cambridge, United Kingdom; 11Karolinska Institutet, Stockholm, Sweden; 12Fondazione IRCSS Istituto Neurologico Carlo Besta, Milano, Italy; 13Lab Alzheimer’s Neuroimaging & Epidemiology, IRCCS Fatebenefratelli, Brescia, Italy; 14Universite Laval, Faculte de Medecine, Quebec, QC, Canada; 15University of Western Ontario, London, ON, Canada; 16University of Lisbon, Lisbon, Portugal; 17University of Florence, Florence, Italy; 18Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 19Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Frontotemporal dementia (FTD) is a highly heritable
neurodegenerative condition. Genetic mutations in the three genes account for the majority of genetic FTD: Chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT). We hypothesize that in pre-symptomatic mutation carriers, regional hypoperfusion in frontal regions will associate with behavioral and cognitive measures. Methods: In the large multi-centre pre-symptomatic genetic FTD study(GENFI), we previously identified “regions of interest (ROIs) of cerebral hypoperfusion” using a voxel-based analysis (VBA) of Arterial Spin Labeling MRI data from presymptomatic mutation carriers (n¼95; C9orf72¼30,
P551
GRN¼48, MAPT¼17) vs. non-carrier controls (n¼100). These hypoperfusion ROIs were then associated with cognitive and behavioural measures using multiple linear regression. Specifically, in these models, the dependent variables included: global cognition (MiniMental State Examination), executive function (Trail making test A and B), language (Boston naming and verbal fluency), logical memory (immediate and delayed recall), working memory (forward and backward digit span), and behavioural measures (Cambridge Behavior Inventory-Revised [CBI-R] and FTD rating scale). Analyses were repeated after stratifying on mutation, and all models were adjusted for age, sex, and education. Results: The hypoperfusion ROIs in carriers identified from the VBA included: paracingulate, orbitofrontal/ insula, frontal pole (right), putamen, frontal pole (bilateral), and middle frontal gyrus/inferior frontal gyrus/superior frontal gyrus (MFG, IFG, SFG). No associations were observed between ROIs and cognitive domains in carriers or non-carriers. In the ROI-behavior analyses using CBI-R score, significant interactions were observed between cerebral perfusion and carrier-status across the ROIs. In carriers only, hypoperfusion in the paracingulate region [b 0.16 (95% CI:0.23,0.04) p <0.001, p-interaction <0.001], frontal pole (right) [b 0.14 (95% CI:0.06,0.22) p<0.001, p-interaction 0.01], putamen [b 0.20 (95% CI:0.06,0.34) p¼ 0.006, p-interaction ¼0.01], frontal pole (bilateral) [b 0.14 (95% CI:0.06,0.22) p <0.001, p-interaction 0.008], and MFG/IFG/SFG [b 0.13 (95% CI: 0.06,0.21) p <0.001, p-interaction 0.01] was strongly associated with behaviour features. No ROI-behavior associations were observed in non-carriers. In subsequent mutation stratified analyses, we found that observed associations were driven by MAPT carriers. Conclusions: Cerebral hypoperfusion within frontal-subcortical regions in presymptomatic FTD is associated with early behavioral changes but not with cognitive deficits. MONDAY, JULY 17, 2017 ORAL SESSION O2-02 MOLECULAR AND CELL BIOLOGY: METABOLIC AND OTHER CELLULAR PROCESSES IN NEURODEGENERATION O2-02-01
PRELIMINARY FINDINGS FROM AN ONGOING LONGITUDINAL METABOLOME-WIDE ASSOCIATION STUDY OF COGNITIVE DECLINE IN HEALTHY ADULTS WITH INCREASED RISK FOR ALZHEIMER’S DISEASE
Burcu F. Darst1,2, Matthew J. P. Rush1,3,4, Paul D. Hutchins1,3,4, Thiruchelvi Rajagobal Reddy5, Jason D. Russell1,3,5, Ronald Gangnon1,2,6, Rebecca L. Koscik1,7, Sanjay Asthana1,7,8,9, Sterling C. Johnson1,7,10,11, Kirk J. Hogan1,7,12, Joshua J. Coon1,3,4,5,13, Corinne D. Engelman1,2,7,9, 1 University of Wisconsin, Madison, Madison, WI, USA; 2Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 3Genome Center of Wisconsin, University of Wisconsin, Madison, Madison, WI, USA; 4Chemistry, University of Wisconsin, Madison, Madison, WI, USA; 5Morgridge Institute for Research, Madison, WI, USA; 6Biostatistics and Medical Informatics, University of Wisconsin, Madison, Madison, WI, USA; 7Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 8 Geriatric Research Education and Clinical Center, W.S. Middleton Memorial Veterans Hospital, Madison, WI, USA; 9Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 10Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; 11Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison,