- Email: [email protected]
Effect of memantine on the activity of the default mode network: A resting fMRI study
P38
Alzheimer’s Imaging Consortium IC-P: Poster Presentations
IC-P-084
There we no significant group differences by age, gender or education. Brain and WMH volumes were significantly different by diagnosis (p < 0.0001 and 0.0005 respectively) with 4% difference in brain and 15% in WMH volumes. The prevalence of MRI infarcts was increased in dementia versus normal and MCI (53%, 30% and 31%, respectively, p ¼ 0.025). Cortical infarcts were rare (5% prevalence) with no cortical infarcts identified in normals, and 5% and 9% of MCI and demented, respectively. The prevalence of subcortical infarcts also was increased in dementia versus normal and MCI (37%, 22%, 19% respectively; p ¼ 0.01). Finally, age, diagnosis and MRI infarcts were associated with WMH volumes (p <0.0006), whereas age, diagnosis and WMH volumes were significantly associated with brain volume (p ¼ 0.026). Conclusions: Evidence of cerebrovascular disease and brain atrophy was common in cognitively impaired subjects of the SCOBHI study. Moreover, MRI infarcts were associated with WMH volume and WMH volume was also significantly associated with brain volume, suggesting that the biology of cognitive impairment in SCOBHI likely reflects, in part, the effects of vascular brain injury. IC-P-083
AUTOMATED CLASSIFICATION OF PERIVENTRICULAR AND SUBCORTICAL WHITE MATTER LESIONS ON MRI
Benjamin F. J. Verhaaren, Fedde van der Lijn, Stefan Klein, Aad van der Lugt, Wiro J. Niessen, Monique M. B. Breteler, Erasmus University Medical Centre, Rotterdam, Netherlands. Contact e-mail: b.verhaaren@erasmusmc. nl Background: Age-related white matter lesions (WMLs) are often subdivided into periventricular and subcortical WMLs. We previously reported that periventricular lesions seem more relevant for cognitive decline and dementia. However, whether this differentiation is relevant remains debated. The interpretation of studies on the discrepancies in aetiology and clinical course is impeded by the use of different visual classification methods with limited reproducibility. We developed a fully automated method to classify periventricular and subcortical WMLs and validated this against the results from a visual rating. Methods: The automated classification method was developed and tested on 490 persons from the Rotterdam Scan Study, a population-based cohort study on diseases among the elderly. For each subject 3 different MR sequences, a WML segmentation obtained with an automated method, and a semi-quantitative lesion classification by two trained observers were available. For the automated WML classification, the lesions were classified based on their three-dimensional distance to the ventricles, which were segmented using an automated method. Maximizing the Pearson correlation coefficient between the automatically classified WML volumes and the rating assigned by the observers on a random subset of 100 subjects, suggested a distance of 7 mm as the optimal cut-off distance to distinguish periventricular from subcortical WMLs. This was validated in the remaining 390 persons by computing correlations between the automated and observerbased lesion scores. Subsequently, we assessed whether the automated classification replicated previous findings of a different effect of periventricular and subcortical lesion loads on the risk of dementia. Results: Correlation coefficients between automated and visual ratings were 0.71 (p-value < 0.001) for periventricular WMLs and 0.60 (p-value < 0.001) for subcortical WMLs. The hazard ratios of dementia per standard deviation increase, adjusted for sex and age, were 1.87 (95%-CI: 1.39-2.52) for periventricular lesions and 1.45 (95%-CI: 1.13-1.86) for subcortical lesions. Adjusted for each other, the hazard ratio slightly increased for periventricular WMLs (1.98 (95%CI: 1.26-3.13)), but attenuated for subcortical WMLs (0.93 (95%-CI: 0.60-1.44)). Conclusions: The automated WML classification is comparable to that of trained observers. The results support the notion that periventricular and subcortical WMLs bear different risks on the development of dementia.
POSITIVE EFFECTS OF A 6-MONTH STAGESPECIFIC COGNITIVE INTERVENTION PROGRAM ON BRAIN METABOLISM IN SUBJECTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT (AMCI) AND MILD ALZHEIMER’S DISEASE (AD)
Stefan Foerster1, Verena C. Buschert2, Hans G. Buchholz3, Stefan J. Teipel4, Christian Zach1, Harald Hampel5, Peter Bartenstein1, Katharina Buerger2, 1Department of Nuclear Medicine, Ludwig Maximilian University, Munich, Germany; 2Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig Maximilian University, Munich, Germany; 3 Department of Nuclear Medicine, Johannes Gutenberg University, Mainz, Germany; 4Department of Psychiatry, Rostock University, Rostock, Germany; 5Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging and Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland. Contact e-mail: [email protected] Background: Cognitive intervention has recently been found to be beneficial in patients with MCI and mild AD, but the effect of cognitive training on brain metabolism is unknown. We used F-18 fluoro-2-deoxy-glucose (FDG) positron emission tomography (PET) to measure the progression of declining cerebral glucose metabolism in aMCI/AD patients during six months, and to test effects of a newly-developed stage-specific cognitive intervention program on these reductions. Methods: In this randomised and controlled trial, 21 subjects with aMCI and 15 patients with mild AD (20 m, mean age 74 years) were assigned either to a cognitive intervention group (CIG), receiving weekly sessions of cognitive intervention, which was tailored to the stage of cognitive impairment, or to an active control group (CG), which met monthly and received only pencil and paper exercises for self-study. Groups were matched for age-, gender- and MMSE. All subjects underwent resting-state FDG PET scanning (Philips Allegro scanner) and also extensive neuropsychological testing at baseline, and again at six-month follow-up. PET images of FDG uptake were analyzed using SPM. Changes in regional glucose metabolism from baseline were determined in both groups (p < 0.001) and a ‘‘difference of differences’’ analysis between these in-group changes was performed (p < 0.005). Results: At six-month followup, the CG subjects showed widespread bilateral declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. In contrast, the CIG subjects showed only discrete declines in glucose metabolism, mainly in bilateral prefrontal cortex and left inferior temporal cortex. The ‘‘difference of differences’’ analysis revealed in the CIG a pattern of attenuated reduction in glucose metabolism, with significant clusters in the right parietal, temporal-, cingulate- and frontal cortices, and to a lesser degree in the left superior parietal- and frontal cortices. Conclusions: Pilot data in our group of aMCI and mild AD subjects show that participation for sixmonths in a stage-specific cognitive intervention program imparted cognitive benefits, which were linked the first time to a delayed progression of reduced glucose metabolism, notably in brain regions typically affected by AD. Based on these results, we are initiating an investigation in a larger population and over a longer observation period. IC-P-085
EFFECT OF MEMANTINE ON THE ACTIVITY OF THE DEFAULT MODE NETWORK: A RESTING FMRI STUDY
Marco Lorenzi1, Alberto Beltramello2, Giada Zoccatelli2, Francesca Benedetta Pizzini2, Franco Alessandrini2, Maria Cotelli3, Sandra Rosini3, Elisa Canu1, Daniela Costardi1, Giovanni Frisoni1, 1 LENITEM, IRCCS San Giovanni di Dio Fatebenefratelli., Brescia, Italy; 2 Service of Neuroradiology, Ospedale Maggiore, Borgo Trento, Verona, Italy; 3Cognitive Neuroscience Section, IRCCS San Giovanni di Dio Fatebenefratelli., Brescia, Italy. Contact e-mail: mlorenzi@ fatebenefratelli.it Background: Memantine is an approved symptomatic treatment for moderate to severe AD active on the excitotoxic effects of hyperactive glutamatergic transmission. The mechanism of the effect of memantine in living
Alzheimer’s Imaging Consortium IC-P: Poster Presentations patients is poorly known. The default mode network (DMN) is believed to monitor internal and external states and is hypofunctional in Alzheimer’s disease (AD). Methods: Within a phase IV double-blind controlled Trial, 15 moderate to severe AD patients, 7 (age 77þ/-7, MMSE 16þ/-4) treated with memantine and 8 treated with placebo (age 75þ/-6, MMSE 13þ/-4), underwent a resting state fMRI scan (Siemens, Allegra 3 T) at the baseline (T0) and after 6 months of treatment (T6). Images were spatially normalizated to an echo-planar template and resting state components were extracted with an independent component analysis on individual patients at baseline and follow-up. The consistency of the resulting components was assessed using ICASSO and the DMN was recognized through spatial correlation with a pre-defined template. SPM5 GLM voxel-based statistical analyses were then performed to study the change of DMN activity between the two groups. Results: The comparison of treated and untreated at T0 showed similar DMN activity except in the precuneus, where the treated showed slightly greater activity in a cluster of 15 voxels (two sample t-test, p < 0.05 corrected for false discovery rate). The prospective comparison between T0 and T6 in the treated showed increased DMN activation in in a cluster of 23 voxels mapping to the precuneus (paired t-test, p < 0.05 corrected), while the prospective comparison in the untreated did not show significant changes. The treatment x time interaction term was significant, with 3 clusters of 12, 5 and 2 voxels mapping to the precuneus (p < 0.05 corrected). Conclusions: Memantine treatment over 6 months enhances DMN activity in moderate to severe AD. IC-P-086
RATES OF REGIONAL BRAIN ATROPHY AND GAIN IN POWER FOR ASSESSMENT OF COGNITIVE DECLINE IN CLINICAL TRIALS
Norbert Schuff1, Sky Raptentsetsang2, Duygu Tosun2, Diana Truran2, Michael W. Weiner1, 1UCSF & VA Medical Center, San Francisco, CA, USA; 2VA Medical Center, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Clinical trials of Alzheimer’s disease (AD) are increasingly exploiting MRI measures of progressive brain tissue loss to assess if pharmacologic interventions have a disease modifying effect. However, there is an ongoing debate which brain regions provide the highest power. Moreover, the extent to which MRI can boost power in detecting a slowing in cognitive decline, the primary outcome in clinical trials, is not established. This study had two goals: First, to identify the brain regions that provide the highest sensitivity in measuring brain tissue loss and second to determine how much variance in cognitive decline each brain region explains. Methods: The study included age-matched groups of 79 patients with mild AD, 223 MCI patients and 135 cognitive normal subjects, who all had 3 consecutive clinical and MRI assessments within a year as part of the ADNI project. Ninety-six brain volumes were automatically segmented using Freesurfer software. Linear mixed effects statistics was used to estimate group rates and maximum likelihood tests were used to determine how much each brain region explains cognitive decline. Results: The volumes of hippocampus, followed by amygdale, lateral ventricles, parahippocampal gyrus and inferior/superior temporal cortex provided the highest sensitivity in measuring brain change. Taken all regions together showed that the entorhinal cortex [Likelihood ratio (LR): 8.6; p ¼ 0.01) explained most of the cognitive decline in AD whereas the middle temporal cortex (LR: 4.7; p ¼ 0.03) and parahippocampal gyrus (LR: 5.7, p ¼ 0.02) explained most cognitive decline in MCI and controls, respectively. Sample size estimations for a hypothetical trial (25% slowing of progression within Table 1 Sample sizes for a trial using as outcome measures MRI, ADASCog or ADASCog and MRI together Group
MRI
ADAS-Cog
ADAS-Cog & MRI
AD MCI Normal
98 158 350
800 7,500 9,100
610 (a) 4,600 (b) 4,200 (c)
addition of MRI (a) not significant; (b) p ¼ 0.001; (c) p ¼ 0.04.
P39
a year, 90% power, alpha ¼ 0.05) in which the primary outcome measures are either rates of brain atrophy (using MRI), cognitive decline (using ADAS-Cog) or cognitive decline conditioned for rates of brain atrophy are listed in the table. For example, 800 subjects/arm are required if the outcome measure is ADAS-Cog compared to only 98 subjects/arm if the outcome measure is MRI. Conclusions: Atrophy rates of temporal lobe structures and ventricular dilatation are the most sensitive brain alterations in AD, MCI and normal aging and also can increase power of clinical trials. IC-P-087
BASELINE SEMANTIC FLUENCY SCORES PREDICT CHEI RESPONSE AS RESTORATION OF NORMAL BRAIN ACTIVITY IN PATIENTS WITH ALZHEIMER’S DISEASE
William J. McGeown, Michael F. Shanks, Annalena Venneri, University of Hull, Hull, United Kingdom. Contact e-mail: [email protected] Background: Studies investigating the effects of cholinesterase inhibitor (ChEI) treatment in Alzheimer’s disease (AD) have reported only modest improvements. Most clinical studies have ignored the variance in response in this patient population and paid little attention to the subgroup of patients that show a substantial and prolonged response with cognitive stabilisation. There is no reliable clinical indicator which has been shown to predict ChEI response. This study investigated whether a cognitive measure, theoretically associated with those cholinergic regions affected early in the course of AD, might be able to predict normalisation of functional brain responses in fMRI activation tasks after treatment. Methods: Twenty-six patients were screened for AD and had clinical, neuropsychological (including semantic fluency) and structural MRI assessment. Their baseline activation patterns during a semantic association and a working memory fMRI task were recorded. The patients were then treated with a ChEI drug for twenty weeks and rescanned using the fMRI paradigms. Results: At retest activations in task relevant areas on the two fMRI tasks (both semantic association and the working memory) were negatively correlated with the baseline scores on the semantic fluency task. Retrospective classification of response using clinical measures (MMSE and CIBIC) showed that the patients classified as responders had lower semantic fluency scores at baseline. Conclusions: Baseline semantic fluency scores predicted degrees of normalisation of function in task relevant brain regions after ChEI treatment in mild AD. These tasks related effects were clearly distinguishable from the more general systemic increases in brain activity following cholinergic enhancement. IC-P-088
EFFECTS OF 12 MONTHS OF TREATMENT WITH THE PPARg AGONIST ROSIGLITAZONE ON BRAIN GLUCOSE METABOLISM IN ALZHEIMER’S DISEASE: A 18F-FDG PET STUDY
Eugenii A. Rabiner1, Sofia Tzimopoulou1, Vincent J. Cunningham1, Barbara Jeter2, Marina Zvartau-Hind1, Mary Castiglia2, Praful Mistry1, Nick P. Bird1, Julian Matthews3, Brandon Whitcher1, Thomas E. Nichols1, Robert Lai1, Narinder Lotay1, Ann Saunders2, Eric Reiman4, Kewei Chen4, Mike Gold2, Paul M. Matthews1, 1GlaxoSmithKline, London, United Kingdom; 2GlaxoSmithKline, Research Triangle Park, NC, USA; 3Manchester Molecular Imaging Centre, Manchester, United Kingdom; 4Banner Alzheimer’s Institute, Phoenix, AZ, USA. Contact e-mail: Eugenii_A_Rabiner@ gsk.com Background: Alzheimer’s Disease (AD) leads to a progressive reduction of brain metabolism, which correlates with disease severity and is detectable with 18F-FDG PET, Rosiglitazone was demonstrated to have a favorable effect on cognitive function in AD1, 2. We assessed the effects of rosiglitazone on brain metabolism over a 12-month period in a pilot double-blind, placebo controlled, randomized parallel group study. Methods: Eighty patients with mild-to-moderate AD (MMSE 16-23) were randomized in a 1:1 ratio to receive a daily dose of either rosiglitazone (8 mg extended release), or placebo, and underwent four 18F-FDG PET scans (baseline, 1, 6 and 12 months) and three T1 weighted structural MRI (baseline, 6 and 12 months). Commonly used clinical inventories (ADAS-Cog, CIBICþ), specific cognitive domain
Alzheimer’s Imaging Consortium IC-P: Poster Presentations
IC-P-084
There we no significant group differences by age, gender or education. Brain and WMH volumes were significantly different by diagnosis (p < 0.0001 and 0.0005 respectively) with 4% difference in brain and 15% in WMH volumes. The prevalence of MRI infarcts was increased in dementia versus normal and MCI (53%, 30% and 31%, respectively, p ¼ 0.025). Cortical infarcts were rare (5% prevalence) with no cortical infarcts identified in normals, and 5% and 9% of MCI and demented, respectively. The prevalence of subcortical infarcts also was increased in dementia versus normal and MCI (37%, 22%, 19% respectively; p ¼ 0.01). Finally, age, diagnosis and MRI infarcts were associated with WMH volumes (p <0.0006), whereas age, diagnosis and WMH volumes were significantly associated with brain volume (p ¼ 0.026). Conclusions: Evidence of cerebrovascular disease and brain atrophy was common in cognitively impaired subjects of the SCOBHI study. Moreover, MRI infarcts were associated with WMH volume and WMH volume was also significantly associated with brain volume, suggesting that the biology of cognitive impairment in SCOBHI likely reflects, in part, the effects of vascular brain injury. IC-P-083
AUTOMATED CLASSIFICATION OF PERIVENTRICULAR AND SUBCORTICAL WHITE MATTER LESIONS ON MRI
Benjamin F. J. Verhaaren, Fedde van der Lijn, Stefan Klein, Aad van der Lugt, Wiro J. Niessen, Monique M. B. Breteler, Erasmus University Medical Centre, Rotterdam, Netherlands. Contact e-mail: b.verhaaren@erasmusmc. nl Background: Age-related white matter lesions (WMLs) are often subdivided into periventricular and subcortical WMLs. We previously reported that periventricular lesions seem more relevant for cognitive decline and dementia. However, whether this differentiation is relevant remains debated. The interpretation of studies on the discrepancies in aetiology and clinical course is impeded by the use of different visual classification methods with limited reproducibility. We developed a fully automated method to classify periventricular and subcortical WMLs and validated this against the results from a visual rating. Methods: The automated classification method was developed and tested on 490 persons from the Rotterdam Scan Study, a population-based cohort study on diseases among the elderly. For each subject 3 different MR sequences, a WML segmentation obtained with an automated method, and a semi-quantitative lesion classification by two trained observers were available. For the automated WML classification, the lesions were classified based on their three-dimensional distance to the ventricles, which were segmented using an automated method. Maximizing the Pearson correlation coefficient between the automatically classified WML volumes and the rating assigned by the observers on a random subset of 100 subjects, suggested a distance of 7 mm as the optimal cut-off distance to distinguish periventricular from subcortical WMLs. This was validated in the remaining 390 persons by computing correlations between the automated and observerbased lesion scores. Subsequently, we assessed whether the automated classification replicated previous findings of a different effect of periventricular and subcortical lesion loads on the risk of dementia. Results: Correlation coefficients between automated and visual ratings were 0.71 (p-value < 0.001) for periventricular WMLs and 0.60 (p-value < 0.001) for subcortical WMLs. The hazard ratios of dementia per standard deviation increase, adjusted for sex and age, were 1.87 (95%-CI: 1.39-2.52) for periventricular lesions and 1.45 (95%-CI: 1.13-1.86) for subcortical lesions. Adjusted for each other, the hazard ratio slightly increased for periventricular WMLs (1.98 (95%CI: 1.26-3.13)), but attenuated for subcortical WMLs (0.93 (95%-CI: 0.60-1.44)). Conclusions: The automated WML classification is comparable to that of trained observers. The results support the notion that periventricular and subcortical WMLs bear different risks on the development of dementia.
POSITIVE EFFECTS OF A 6-MONTH STAGESPECIFIC COGNITIVE INTERVENTION PROGRAM ON BRAIN METABOLISM IN SUBJECTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT (AMCI) AND MILD ALZHEIMER’S DISEASE (AD)
Stefan Foerster1, Verena C. Buschert2, Hans G. Buchholz3, Stefan J. Teipel4, Christian Zach1, Harald Hampel5, Peter Bartenstein1, Katharina Buerger2, 1Department of Nuclear Medicine, Ludwig Maximilian University, Munich, Germany; 2Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig Maximilian University, Munich, Germany; 3 Department of Nuclear Medicine, Johannes Gutenberg University, Mainz, Germany; 4Department of Psychiatry, Rostock University, Rostock, Germany; 5Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging and Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland. Contact e-mail: [email protected] Background: Cognitive intervention has recently been found to be beneficial in patients with MCI and mild AD, but the effect of cognitive training on brain metabolism is unknown. We used F-18 fluoro-2-deoxy-glucose (FDG) positron emission tomography (PET) to measure the progression of declining cerebral glucose metabolism in aMCI/AD patients during six months, and to test effects of a newly-developed stage-specific cognitive intervention program on these reductions. Methods: In this randomised and controlled trial, 21 subjects with aMCI and 15 patients with mild AD (20 m, mean age 74 years) were assigned either to a cognitive intervention group (CIG), receiving weekly sessions of cognitive intervention, which was tailored to the stage of cognitive impairment, or to an active control group (CG), which met monthly and received only pencil and paper exercises for self-study. Groups were matched for age-, gender- and MMSE. All subjects underwent resting-state FDG PET scanning (Philips Allegro scanner) and also extensive neuropsychological testing at baseline, and again at six-month follow-up. PET images of FDG uptake were analyzed using SPM. Changes in regional glucose metabolism from baseline were determined in both groups (p < 0.001) and a ‘‘difference of differences’’ analysis between these in-group changes was performed (p < 0.005). Results: At six-month followup, the CG subjects showed widespread bilateral declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. In contrast, the CIG subjects showed only discrete declines in glucose metabolism, mainly in bilateral prefrontal cortex and left inferior temporal cortex. The ‘‘difference of differences’’ analysis revealed in the CIG a pattern of attenuated reduction in glucose metabolism, with significant clusters in the right parietal, temporal-, cingulate- and frontal cortices, and to a lesser degree in the left superior parietal- and frontal cortices. Conclusions: Pilot data in our group of aMCI and mild AD subjects show that participation for sixmonths in a stage-specific cognitive intervention program imparted cognitive benefits, which were linked the first time to a delayed progression of reduced glucose metabolism, notably in brain regions typically affected by AD. Based on these results, we are initiating an investigation in a larger population and over a longer observation period. IC-P-085
EFFECT OF MEMANTINE ON THE ACTIVITY OF THE DEFAULT MODE NETWORK: A RESTING FMRI STUDY
Marco Lorenzi1, Alberto Beltramello2, Giada Zoccatelli2, Francesca Benedetta Pizzini2, Franco Alessandrini2, Maria Cotelli3, Sandra Rosini3, Elisa Canu1, Daniela Costardi1, Giovanni Frisoni1, 1 LENITEM, IRCCS San Giovanni di Dio Fatebenefratelli., Brescia, Italy; 2 Service of Neuroradiology, Ospedale Maggiore, Borgo Trento, Verona, Italy; 3Cognitive Neuroscience Section, IRCCS San Giovanni di Dio Fatebenefratelli., Brescia, Italy. Contact e-mail: mlorenzi@ fatebenefratelli.it Background: Memantine is an approved symptomatic treatment for moderate to severe AD active on the excitotoxic effects of hyperactive glutamatergic transmission. The mechanism of the effect of memantine in living
Alzheimer’s Imaging Consortium IC-P: Poster Presentations patients is poorly known. The default mode network (DMN) is believed to monitor internal and external states and is hypofunctional in Alzheimer’s disease (AD). Methods: Within a phase IV double-blind controlled Trial, 15 moderate to severe AD patients, 7 (age 77þ/-7, MMSE 16þ/-4) treated with memantine and 8 treated with placebo (age 75þ/-6, MMSE 13þ/-4), underwent a resting state fMRI scan (Siemens, Allegra 3 T) at the baseline (T0) and after 6 months of treatment (T6). Images were spatially normalizated to an echo-planar template and resting state components were extracted with an independent component analysis on individual patients at baseline and follow-up. The consistency of the resulting components was assessed using ICASSO and the DMN was recognized through spatial correlation with a pre-defined template. SPM5 GLM voxel-based statistical analyses were then performed to study the change of DMN activity between the two groups. Results: The comparison of treated and untreated at T0 showed similar DMN activity except in the precuneus, where the treated showed slightly greater activity in a cluster of 15 voxels (two sample t-test, p < 0.05 corrected for false discovery rate). The prospective comparison between T0 and T6 in the treated showed increased DMN activation in in a cluster of 23 voxels mapping to the precuneus (paired t-test, p < 0.05 corrected), while the prospective comparison in the untreated did not show significant changes. The treatment x time interaction term was significant, with 3 clusters of 12, 5 and 2 voxels mapping to the precuneus (p < 0.05 corrected). Conclusions: Memantine treatment over 6 months enhances DMN activity in moderate to severe AD. IC-P-086
RATES OF REGIONAL BRAIN ATROPHY AND GAIN IN POWER FOR ASSESSMENT OF COGNITIVE DECLINE IN CLINICAL TRIALS
Norbert Schuff1, Sky Raptentsetsang2, Duygu Tosun2, Diana Truran2, Michael W. Weiner1, 1UCSF & VA Medical Center, San Francisco, CA, USA; 2VA Medical Center, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Clinical trials of Alzheimer’s disease (AD) are increasingly exploiting MRI measures of progressive brain tissue loss to assess if pharmacologic interventions have a disease modifying effect. However, there is an ongoing debate which brain regions provide the highest power. Moreover, the extent to which MRI can boost power in detecting a slowing in cognitive decline, the primary outcome in clinical trials, is not established. This study had two goals: First, to identify the brain regions that provide the highest sensitivity in measuring brain tissue loss and second to determine how much variance in cognitive decline each brain region explains. Methods: The study included age-matched groups of 79 patients with mild AD, 223 MCI patients and 135 cognitive normal subjects, who all had 3 consecutive clinical and MRI assessments within a year as part of the ADNI project. Ninety-six brain volumes were automatically segmented using Freesurfer software. Linear mixed effects statistics was used to estimate group rates and maximum likelihood tests were used to determine how much each brain region explains cognitive decline. Results: The volumes of hippocampus, followed by amygdale, lateral ventricles, parahippocampal gyrus and inferior/superior temporal cortex provided the highest sensitivity in measuring brain change. Taken all regions together showed that the entorhinal cortex [Likelihood ratio (LR): 8.6; p ¼ 0.01) explained most of the cognitive decline in AD whereas the middle temporal cortex (LR: 4.7; p ¼ 0.03) and parahippocampal gyrus (LR: 5.7, p ¼ 0.02) explained most cognitive decline in MCI and controls, respectively. Sample size estimations for a hypothetical trial (25% slowing of progression within Table 1 Sample sizes for a trial using as outcome measures MRI, ADASCog or ADASCog and MRI together Group
MRI
ADAS-Cog
ADAS-Cog & MRI
AD MCI Normal
98 158 350
800 7,500 9,100
610 (a) 4,600 (b) 4,200 (c)
addition of MRI (a) not significant; (b) p ¼ 0.001; (c) p ¼ 0.04.
P39
a year, 90% power, alpha ¼ 0.05) in which the primary outcome measures are either rates of brain atrophy (using MRI), cognitive decline (using ADAS-Cog) or cognitive decline conditioned for rates of brain atrophy are listed in the table. For example, 800 subjects/arm are required if the outcome measure is ADAS-Cog compared to only 98 subjects/arm if the outcome measure is MRI. Conclusions: Atrophy rates of temporal lobe structures and ventricular dilatation are the most sensitive brain alterations in AD, MCI and normal aging and also can increase power of clinical trials. IC-P-087
BASELINE SEMANTIC FLUENCY SCORES PREDICT CHEI RESPONSE AS RESTORATION OF NORMAL BRAIN ACTIVITY IN PATIENTS WITH ALZHEIMER’S DISEASE
William J. McGeown, Michael F. Shanks, Annalena Venneri, University of Hull, Hull, United Kingdom. Contact e-mail: [email protected] Background: Studies investigating the effects of cholinesterase inhibitor (ChEI) treatment in Alzheimer’s disease (AD) have reported only modest improvements. Most clinical studies have ignored the variance in response in this patient population and paid little attention to the subgroup of patients that show a substantial and prolonged response with cognitive stabilisation. There is no reliable clinical indicator which has been shown to predict ChEI response. This study investigated whether a cognitive measure, theoretically associated with those cholinergic regions affected early in the course of AD, might be able to predict normalisation of functional brain responses in fMRI activation tasks after treatment. Methods: Twenty-six patients were screened for AD and had clinical, neuropsychological (including semantic fluency) and structural MRI assessment. Their baseline activation patterns during a semantic association and a working memory fMRI task were recorded. The patients were then treated with a ChEI drug for twenty weeks and rescanned using the fMRI paradigms. Results: At retest activations in task relevant areas on the two fMRI tasks (both semantic association and the working memory) were negatively correlated with the baseline scores on the semantic fluency task. Retrospective classification of response using clinical measures (MMSE and CIBIC) showed that the patients classified as responders had lower semantic fluency scores at baseline. Conclusions: Baseline semantic fluency scores predicted degrees of normalisation of function in task relevant brain regions after ChEI treatment in mild AD. These tasks related effects were clearly distinguishable from the more general systemic increases in brain activity following cholinergic enhancement. IC-P-088
EFFECTS OF 12 MONTHS OF TREATMENT WITH THE PPARg AGONIST ROSIGLITAZONE ON BRAIN GLUCOSE METABOLISM IN ALZHEIMER’S DISEASE: A 18F-FDG PET STUDY
Eugenii A. Rabiner1, Sofia Tzimopoulou1, Vincent J. Cunningham1, Barbara Jeter2, Marina Zvartau-Hind1, Mary Castiglia2, Praful Mistry1, Nick P. Bird1, Julian Matthews3, Brandon Whitcher1, Thomas E. Nichols1, Robert Lai1, Narinder Lotay1, Ann Saunders2, Eric Reiman4, Kewei Chen4, Mike Gold2, Paul M. Matthews1, 1GlaxoSmithKline, London, United Kingdom; 2GlaxoSmithKline, Research Triangle Park, NC, USA; 3Manchester Molecular Imaging Centre, Manchester, United Kingdom; 4Banner Alzheimer’s Institute, Phoenix, AZ, USA. Contact e-mail: Eugenii_A_Rabiner@ gsk.com Background: Alzheimer’s Disease (AD) leads to a progressive reduction of brain metabolism, which correlates with disease severity and is detectable with 18F-FDG PET, Rosiglitazone was demonstrated to have a favorable effect on cognitive function in AD1, 2. We assessed the effects of rosiglitazone on brain metabolism over a 12-month period in a pilot double-blind, placebo controlled, randomized parallel group study. Methods: Eighty patients with mild-to-moderate AD (MMSE 16-23) were randomized in a 1:1 ratio to receive a daily dose of either rosiglitazone (8 mg extended release), or placebo, and underwent four 18F-FDG PET scans (baseline, 1, 6 and 12 months) and three T1 weighted structural MRI (baseline, 6 and 12 months). Commonly used clinical inventories (ADAS-Cog, CIBICþ), specific cognitive domain