- Email: [email protected]
Amyloid deposition, glucose metabolism, hippocampal volume, and cognitive decline in mild cognitive impairment: A longitudinal PET study
P532
Poster Presentations: P2
SUVr 1.17, and 53.9% vs. 46.1% had a CDR of 0 vs. 0.5, respectively. We found a significant association between gait speed and brain Ab in the posterior and anterior putamen, the occipital cortex, precuneus and anterior cingulate. Ab burden explained up to 10% of the variance in gait speed, and significantly improved regression models already containing demographic variables and BMI. Conclusions: This study showed an association between brain Ab amyloid and slow gait speed in a population of elderly subjects ranging from healthy to MCI. More research is needed to elucidate the neural mechanisms underlying this association and its potential implications for the early detection of AD.
Figure 1. Standardised regression coefficients of regional amyloid ([1SF] AV45 SUV) on gait speed
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MICCAI 2012;15(Pt2):262–70; Diedrichsen et al., NeuroImage 2009;46:39–46). Cerebellar lobules were grouped into four regions, and volumes were corrected for total intracranial volumes (Figure). Results: When compared with controls, C9orf72 carriers showed a 10% reduction in the whole cerebellar volume (p¼0.009, MannWhitney U test), mainly located in the superior-posterior portion and specifically in the crus I bilaterally and in the left lobule VI (-18% p¼0.027 and -10% p¼0.047, respectively). The vermis and the interposed nuclei were also atrophic (-11% p¼0.033 and -15% p¼0.012, respectively). MAPT carriers compared with controls showed a significant reduction in the vermis IX and in the lobule IX bilaterally (-13% p¼0.015 and -17% p¼0.005, respectively). Comparing FTD subgroups, C9orf72 carriers showed lower volumes in the crus I bilaterally and in the superior-posterior portion in general, when compared with MAPT carriers (-19% p<0.05 and -14% p¼0.012). Conclusions: C9orf72 FTD patients showed atrophy in the crus I region which seems to be functionally connected via the thalamus to the dorsolateral prefrontal cortex and involved in cognitive function. Atrophy in MAPT carriers was found in cerebellar regions related to the regulation of balance, posture and eye movements, and its relevance remains unclear.
Figure. Segmentation of the cerebellar lobules (left side) mapped on a 3T Tl-weighted MR image of a control subject. Classification was made according to Bogovic et al., Neurolmage 2013;64:616-629 and Pierson et al., Neurolmage 2002;17:61-76.
VOLUMETRY OF THE CEREBELLUM AND ITS SUBREGIONS IN GENETIC FRONTOTEMPORAL DEMENTIA
Martina Bocchetta1,2,3, M. Jorge Cardoso1, David M. Cash1, Martin N. Rossor4, Giovanni Battista Frisoni2,5, Sebastien Ourselin6, Jonathan D. Rohrer4, 1University College London, London, United Kingdom; 2IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; 3University of Brescia, Brescia, Italy; 4UCL Institute of Neurology, London, United Kingdom; 5H^opitaux Universitaires de Geneve et Universite de Geneve, Geneva, Switzerland; 6Centre for Medical Image Computing, University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Frontotemporal dementia (FTD) is a neurodegenerative disorder normally presenting with cognitive and neuropsychiatric features. About 20% of people with FTD have a mutation in one of three genes: MAPT, GRN and C9orf72. The cerebellum is involved in sensory-motor coordination and learning, but has also been shown to take part in the processing of cognition and emotion. Its role in FTD remains unclear. Methods: We investigated the volumetry of cerebellar subregions in a sample of 15 genetic FTD patients (9 MAPT mutation carriers and 6 C9orf72 expansion carriers) compared with 18 cognitively-normal controls, to determine whether specific cerebellar regions are associated with genetic mutations in bvFTD. All participants were scanned on a 3T Siemens Trio and matched for age, sex and education. We used an atlas propagation and label fusion strategy of the Diedrichsen cerebellar atlas to automatically extract 33 regions, including the cerebellar lobules, the vermis and the deep nuclei (Cardoso et al.,
P2-128
AMYLOID DEPOSITION, GLUCOSE METABOLISM, HIPPOCAMPAL VOLUME, AND COGNITIVE DECLINE IN MILD COGNITIVE IMPAIRMENT: A LONGITUDINAL PET STUDY
Grazia Daniela Femminella, Zhen Fan, Ewa Wietlicka, Paul Edison, Imperial College London, London, United Kingdom. Contact e-mail: paul. [email protected] Background: Around 50-60% of mild cognitive impairment (MCI) subjects have high amyloid load, while the rest of them are amyloid negative. It is suggested that amyloid positive (Ab+) subjects have accelerated cognitive decline compared to the amyloid negative (Ab-). It is also unclear about the time course of the neuropathological changes in the Ab-. Intervention studies evaluating amyloid clearing agents, screen patients for amyloid positivity. However, it is shown that Ab- subjects could also deteriorate, and indeed neurofibrillary tangles could be the underlying pathology in these subjects. Here we evaluated the role of hippocampal atrophy and glucose metabolism in cognitive deterioration in Ab- subjects. Methods: All images and clinical information of participants were collected from ADNI database. We selected 95 MCI subjects who had neuropsychological assessment, MRI, [18F]AV45 PET, [18F]FDG PET between 2010 and 2011. 10 Normal control subjects were also included in the study. MCI were classified as Ab+ if the mean [18F] AV45 retention in selected brain regions was 2SD than mean
Poster Presentations: P2
of controls (n¼39), otherwise they were classified as Ab- (n¼56). We selected age and cognitively matched subjects with two years follow up data. Results: At baseline, Ab+MCI and Ab-MCI had comparable MMSE, CDR and ADAS-Cog11 scores; Ab+MCI had higher prevalence of ApoEε4 carriers (66.7% vs 28.6%). There were no significant differences in brain glucose metabolism between the two groups in all the predefined regions, as well as in hippocampal volume. At 2-years follow-up, Ab+MCI had a significant reduction in ADAS-Cog11 scores, in hippocampal volume and glucose uptake compared to baseline. However, Ab-MCI only showed a significant decrease in hippocampal volume compared to baseline. Regression analysis has shown that cognitive decline measured by ADAS-Cog11 was associated with APOEε4 carrier status in Ab+MCI, but not with age and gender; in Ab-MCI, ADAS-Cog11 change was associated with baseline hippocampal FDG uptake. Conclusions: This data suggests that ApoE4 is a significant predictor of cognitive decline in amyloid positive MCI subjects, while hippocampal glucose metabolism is a better predictor of cognitive deterioration in amyloid negative MCI subjects. This will have significant impact on the selection of biomarkers to evaluate therapeutic intervention studies.
P2-129
ABNORMAL CSF BETA-AMYLOID LEVELS ARE ASSOCIATED WITH A SPECIFIC PATTERN OF CEREBRAL WHITE MATTER INJURY IN INDIVIDUALS WITH MILD COGNITIVE IMPAIRMENT ENROLLED TO THE ADNI STUDY
Michael Marnane, Osama Aljawadi, Shervin A. Mortazavi, Kathleen Pogorzelec, Bing-Wei Wang, Howard Feldman, Ging-Yuek Robin Hsiung, University of British Columbia, Vancouver, BC, Canada. Contact e-mail: [email protected] Background: Previous studies comparing cerebrospinal fluid (CSF) levels of Alzheimer Disease (AD) biomarkers and white matter lesion (WML) burden have shown conflicting results. Recent DTI MRI data suggests that abnormal AD CSF biomarker levels are associated with changes in specific white matter tracts early in disease course. In a large well-characterised cohort, we evaluated the topographic distribution of WMLs in those with low CSF beta-amyloid (<192pg/ml, Ab-positive) suggestive of AD compared to those with normal levels. Methods: We identified patients with mild cognitive impairment (MCI) from the Alzheimer Disease Neuroimaging Initiative (ADNI) study in whom cerebral MRI, CSF Ab and ApoE genotype were available. Images were rated independently by trained investigators blinded to CSF data based on a validated visual rating scale (Schelten scale) which semiquantitatively grades burden of WMLs in lobar subcortical and periventricular areas, basal ganglia and brainstem. Receiver operating characteristic (ROC) analysis was performed to assess test precision. Results: 196 patients were identified. CSF Ab-positivity was significantly associated with increased periventricular WML burden in frontal (Schelten score >1 vs. 1, 47.44% [65/ 137] vs. 32% [19/59], p¼0.048), parietal (70.8% [97/137] vs. 44.1% [26/59], p<0.001) and occipital (73.7% [101/137] vs. 55.9% [33/59], p¼0.014) areas. No association was found between CSF Ab-positivity and WML burden in lobar subcortical, basal ganglia or brainstem areas. CSF Ab-positivity was identified with moderate precision using periventricular WML measurement (taking frontal, parietal and occipital measurements into account, ROC AUC¼0.66) and apoE4 status (ROC AUC¼0.73). Combining peri-
P533
ventricular WML measurements and apoE4 status significantly improved accuracy (ROC AUC¼ 0.81, p for difference <0.001). Inter-rater reliability using Scheltens scale was good (kappa >0.61 for all). Conclusions: CSF Ab-positivity is associated with periventricular WMLs in the parieto-occipital and to lesser extent frontal lobes. This suggests that AD pathology may be associated with a specific pattern of predominantly periventricular white matter injury. The pathophysiologic basis of this remains to be investigated. Periventricular WML measurements can be easily and reproducibly obtained from standard MRI images. Using these in conjunction with other risk markers such as apoE4 status could improve patient selection for future disease-modifying therapeutic trials in AD.
P2-130
AMYLOID IMAGING AND CEREBROSPINAL FLUID BIOMARKERS PREDICT DRIVING PERFORMANCE IN PRECLINICAL ALZHEIMER’S DISEASE
Catherine M. Roe1, Peggy P. Barco1, Denise M. Head2, Nupur Ghoshal1, Natalie Selsor1, Ganesh M. Babulal1, Rebecca Fierberg1, Elizabeth Kathleen Vernon1, Neal Shulman3, Ann Johnson1, M. Scott Fague1, Chengjie Xiong2, Elizabeth Grant1, Angela Campbell1, David M. Holtzman1, Tammie Lee Smith Benzinger1, Anne Fagan1, David B. Carr1, John C. Morris2, 1Washington University School of Medicine, St. Louis, MO, USA; 2Washington University School of Medicine, St. Louis, MO, USA; 3Arizona State University, Tempe, AZ, USA. Contact e-mail: [email protected] Background: The number of older adults in the U.S. is expected to double within the next 40 years, with a dramatic increase in the number of older adult drivers. During the long preclinical stage of Alzheimer disease (AD), AD pathology is present without notable cognitive or functional impairment, although whether there are subtle deficits that may impair complex behaviors such as driving has not been well-studied. The purpose of this study was to examine whether AD biomarker levels (amyloid imaging, cerebrospinal fluid) are associated with driving performance in cognitively normal older adults. Methods: We recruited 134 participants with normal cognition (Clinical Dementia Rating 0), aged 65 years and older. Participants took part in an on-the-road driving test, clinical and psychometric assessments, Pittsburgh compound B (PIB) amyloid brain imaging, and cerebrospinal fluid (CSF) collection. We examined whether higher and lower values of each of our biomarker variables (mean cortical binding potential [MCBP] for PIB, and CSF Ab42, tau, ptau181, tau/Ab42, ptau181/Ab42) were associated with the total number of errors made on the driving test. For each variable, a median split was used to assign participants to either a “lower” or “higher” group based on the measured biomarker value. General linear models (adjusted for age, education, and gender) were used to test whether the number of total driving errors differed for each of the dichotomous biomarker variables. The analyses were repeated treating the biomarker variables as continuous. Results: Of the first (N¼121) participants who had PIB (N¼116) and CSF (N¼82) data available for analysis, 52.1% were women and 9.1% were African American. Their mean age and education were 72.6 (SD¼5.1) and 16.1 (SD¼2.6) years respectively. Participants in the groups with higher MCBP for PIB and higher CSF tau/Ab42 and ptau181/Ab42 values made approximately 2.5 more driving errors, on average, than those in the groups with lower values (Table 1). In the analyses treating the biomarkers continuously, only the effect of MCBP for PIB
Poster Presentations: P2
SUVr 1.17, and 53.9% vs. 46.1% had a CDR of 0 vs. 0.5, respectively. We found a significant association between gait speed and brain Ab in the posterior and anterior putamen, the occipital cortex, precuneus and anterior cingulate. Ab burden explained up to 10% of the variance in gait speed, and significantly improved regression models already containing demographic variables and BMI. Conclusions: This study showed an association between brain Ab amyloid and slow gait speed in a population of elderly subjects ranging from healthy to MCI. More research is needed to elucidate the neural mechanisms underlying this association and its potential implications for the early detection of AD.
Figure 1. Standardised regression coefficients of regional amyloid ([1SF] AV45 SUV) on gait speed
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MICCAI 2012;15(Pt2):262–70; Diedrichsen et al., NeuroImage 2009;46:39–46). Cerebellar lobules were grouped into four regions, and volumes were corrected for total intracranial volumes (Figure). Results: When compared with controls, C9orf72 carriers showed a 10% reduction in the whole cerebellar volume (p¼0.009, MannWhitney U test), mainly located in the superior-posterior portion and specifically in the crus I bilaterally and in the left lobule VI (-18% p¼0.027 and -10% p¼0.047, respectively). The vermis and the interposed nuclei were also atrophic (-11% p¼0.033 and -15% p¼0.012, respectively). MAPT carriers compared with controls showed a significant reduction in the vermis IX and in the lobule IX bilaterally (-13% p¼0.015 and -17% p¼0.005, respectively). Comparing FTD subgroups, C9orf72 carriers showed lower volumes in the crus I bilaterally and in the superior-posterior portion in general, when compared with MAPT carriers (-19% p<0.05 and -14% p¼0.012). Conclusions: C9orf72 FTD patients showed atrophy in the crus I region which seems to be functionally connected via the thalamus to the dorsolateral prefrontal cortex and involved in cognitive function. Atrophy in MAPT carriers was found in cerebellar regions related to the regulation of balance, posture and eye movements, and its relevance remains unclear.
Figure. Segmentation of the cerebellar lobules (left side) mapped on a 3T Tl-weighted MR image of a control subject. Classification was made according to Bogovic et al., Neurolmage 2013;64:616-629 and Pierson et al., Neurolmage 2002;17:61-76.
VOLUMETRY OF THE CEREBELLUM AND ITS SUBREGIONS IN GENETIC FRONTOTEMPORAL DEMENTIA
Martina Bocchetta1,2,3, M. Jorge Cardoso1, David M. Cash1, Martin N. Rossor4, Giovanni Battista Frisoni2,5, Sebastien Ourselin6, Jonathan D. Rohrer4, 1University College London, London, United Kingdom; 2IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; 3University of Brescia, Brescia, Italy; 4UCL Institute of Neurology, London, United Kingdom; 5H^opitaux Universitaires de Geneve et Universite de Geneve, Geneva, Switzerland; 6Centre for Medical Image Computing, University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Frontotemporal dementia (FTD) is a neurodegenerative disorder normally presenting with cognitive and neuropsychiatric features. About 20% of people with FTD have a mutation in one of three genes: MAPT, GRN and C9orf72. The cerebellum is involved in sensory-motor coordination and learning, but has also been shown to take part in the processing of cognition and emotion. Its role in FTD remains unclear. Methods: We investigated the volumetry of cerebellar subregions in a sample of 15 genetic FTD patients (9 MAPT mutation carriers and 6 C9orf72 expansion carriers) compared with 18 cognitively-normal controls, to determine whether specific cerebellar regions are associated with genetic mutations in bvFTD. All participants were scanned on a 3T Siemens Trio and matched for age, sex and education. We used an atlas propagation and label fusion strategy of the Diedrichsen cerebellar atlas to automatically extract 33 regions, including the cerebellar lobules, the vermis and the deep nuclei (Cardoso et al.,
P2-128
AMYLOID DEPOSITION, GLUCOSE METABOLISM, HIPPOCAMPAL VOLUME, AND COGNITIVE DECLINE IN MILD COGNITIVE IMPAIRMENT: A LONGITUDINAL PET STUDY
Grazia Daniela Femminella, Zhen Fan, Ewa Wietlicka, Paul Edison, Imperial College London, London, United Kingdom. Contact e-mail: paul. [email protected] Background: Around 50-60% of mild cognitive impairment (MCI) subjects have high amyloid load, while the rest of them are amyloid negative. It is suggested that amyloid positive (Ab+) subjects have accelerated cognitive decline compared to the amyloid negative (Ab-). It is also unclear about the time course of the neuropathological changes in the Ab-. Intervention studies evaluating amyloid clearing agents, screen patients for amyloid positivity. However, it is shown that Ab- subjects could also deteriorate, and indeed neurofibrillary tangles could be the underlying pathology in these subjects. Here we evaluated the role of hippocampal atrophy and glucose metabolism in cognitive deterioration in Ab- subjects. Methods: All images and clinical information of participants were collected from ADNI database. We selected 95 MCI subjects who had neuropsychological assessment, MRI, [18F]AV45 PET, [18F]FDG PET between 2010 and 2011. 10 Normal control subjects were also included in the study. MCI were classified as Ab+ if the mean [18F] AV45 retention in selected brain regions was 2SD than mean
Poster Presentations: P2
of controls (n¼39), otherwise they were classified as Ab- (n¼56). We selected age and cognitively matched subjects with two years follow up data. Results: At baseline, Ab+MCI and Ab-MCI had comparable MMSE, CDR and ADAS-Cog11 scores; Ab+MCI had higher prevalence of ApoEε4 carriers (66.7% vs 28.6%). There were no significant differences in brain glucose metabolism between the two groups in all the predefined regions, as well as in hippocampal volume. At 2-years follow-up, Ab+MCI had a significant reduction in ADAS-Cog11 scores, in hippocampal volume and glucose uptake compared to baseline. However, Ab-MCI only showed a significant decrease in hippocampal volume compared to baseline. Regression analysis has shown that cognitive decline measured by ADAS-Cog11 was associated with APOEε4 carrier status in Ab+MCI, but not with age and gender; in Ab-MCI, ADAS-Cog11 change was associated with baseline hippocampal FDG uptake. Conclusions: This data suggests that ApoE4 is a significant predictor of cognitive decline in amyloid positive MCI subjects, while hippocampal glucose metabolism is a better predictor of cognitive deterioration in amyloid negative MCI subjects. This will have significant impact on the selection of biomarkers to evaluate therapeutic intervention studies.
P2-129
ABNORMAL CSF BETA-AMYLOID LEVELS ARE ASSOCIATED WITH A SPECIFIC PATTERN OF CEREBRAL WHITE MATTER INJURY IN INDIVIDUALS WITH MILD COGNITIVE IMPAIRMENT ENROLLED TO THE ADNI STUDY
Michael Marnane, Osama Aljawadi, Shervin A. Mortazavi, Kathleen Pogorzelec, Bing-Wei Wang, Howard Feldman, Ging-Yuek Robin Hsiung, University of British Columbia, Vancouver, BC, Canada. Contact e-mail: [email protected] Background: Previous studies comparing cerebrospinal fluid (CSF) levels of Alzheimer Disease (AD) biomarkers and white matter lesion (WML) burden have shown conflicting results. Recent DTI MRI data suggests that abnormal AD CSF biomarker levels are associated with changes in specific white matter tracts early in disease course. In a large well-characterised cohort, we evaluated the topographic distribution of WMLs in those with low CSF beta-amyloid (<192pg/ml, Ab-positive) suggestive of AD compared to those with normal levels. Methods: We identified patients with mild cognitive impairment (MCI) from the Alzheimer Disease Neuroimaging Initiative (ADNI) study in whom cerebral MRI, CSF Ab and ApoE genotype were available. Images were rated independently by trained investigators blinded to CSF data based on a validated visual rating scale (Schelten scale) which semiquantitatively grades burden of WMLs in lobar subcortical and periventricular areas, basal ganglia and brainstem. Receiver operating characteristic (ROC) analysis was performed to assess test precision. Results: 196 patients were identified. CSF Ab-positivity was significantly associated with increased periventricular WML burden in frontal (Schelten score >1 vs. 1, 47.44% [65/ 137] vs. 32% [19/59], p¼0.048), parietal (70.8% [97/137] vs. 44.1% [26/59], p<0.001) and occipital (73.7% [101/137] vs. 55.9% [33/59], p¼0.014) areas. No association was found between CSF Ab-positivity and WML burden in lobar subcortical, basal ganglia or brainstem areas. CSF Ab-positivity was identified with moderate precision using periventricular WML measurement (taking frontal, parietal and occipital measurements into account, ROC AUC¼0.66) and apoE4 status (ROC AUC¼0.73). Combining peri-
P533
ventricular WML measurements and apoE4 status significantly improved accuracy (ROC AUC¼ 0.81, p for difference <0.001). Inter-rater reliability using Scheltens scale was good (kappa >0.61 for all). Conclusions: CSF Ab-positivity is associated with periventricular WMLs in the parieto-occipital and to lesser extent frontal lobes. This suggests that AD pathology may be associated with a specific pattern of predominantly periventricular white matter injury. The pathophysiologic basis of this remains to be investigated. Periventricular WML measurements can be easily and reproducibly obtained from standard MRI images. Using these in conjunction with other risk markers such as apoE4 status could improve patient selection for future disease-modifying therapeutic trials in AD.
P2-130
AMYLOID IMAGING AND CEREBROSPINAL FLUID BIOMARKERS PREDICT DRIVING PERFORMANCE IN PRECLINICAL ALZHEIMER’S DISEASE
Catherine M. Roe1, Peggy P. Barco1, Denise M. Head2, Nupur Ghoshal1, Natalie Selsor1, Ganesh M. Babulal1, Rebecca Fierberg1, Elizabeth Kathleen Vernon1, Neal Shulman3, Ann Johnson1, M. Scott Fague1, Chengjie Xiong2, Elizabeth Grant1, Angela Campbell1, David M. Holtzman1, Tammie Lee Smith Benzinger1, Anne Fagan1, David B. Carr1, John C. Morris2, 1Washington University School of Medicine, St. Louis, MO, USA; 2Washington University School of Medicine, St. Louis, MO, USA; 3Arizona State University, Tempe, AZ, USA. Contact e-mail: [email protected] Background: The number of older adults in the U.S. is expected to double within the next 40 years, with a dramatic increase in the number of older adult drivers. During the long preclinical stage of Alzheimer disease (AD), AD pathology is present without notable cognitive or functional impairment, although whether there are subtle deficits that may impair complex behaviors such as driving has not been well-studied. The purpose of this study was to examine whether AD biomarker levels (amyloid imaging, cerebrospinal fluid) are associated with driving performance in cognitively normal older adults. Methods: We recruited 134 participants with normal cognition (Clinical Dementia Rating 0), aged 65 years and older. Participants took part in an on-the-road driving test, clinical and psychometric assessments, Pittsburgh compound B (PIB) amyloid brain imaging, and cerebrospinal fluid (CSF) collection. We examined whether higher and lower values of each of our biomarker variables (mean cortical binding potential [MCBP] for PIB, and CSF Ab42, tau, ptau181, tau/Ab42, ptau181/Ab42) were associated with the total number of errors made on the driving test. For each variable, a median split was used to assign participants to either a “lower” or “higher” group based on the measured biomarker value. General linear models (adjusted for age, education, and gender) were used to test whether the number of total driving errors differed for each of the dichotomous biomarker variables. The analyses were repeated treating the biomarker variables as continuous. Results: Of the first (N¼121) participants who had PIB (N¼116) and CSF (N¼82) data available for analysis, 52.1% were women and 9.1% were African American. Their mean age and education were 72.6 (SD¼5.1) and 16.1 (SD¼2.6) years respectively. Participants in the groups with higher MCBP for PIB and higher CSF tau/Ab42 and ptau181/Ab42 values made approximately 2.5 more driving errors, on average, than those in the groups with lower values (Table 1). In the analyses treating the biomarkers continuously, only the effect of MCBP for PIB