- Email: [email protected]
BLOOD PRESSURE AND BLOOD GLUCOSE ARE ASSOCIATED WITH MYELIN VULNERABILITY IN AN ETHNICALLY DIVERSE SAMPLE OF OLDER ADULTS
P780
Poster Presentations: Monday, July 17, 2017
underwent complete neuropsychological assessment and MR imaging to measure hippocampus and basal forebrain (Ch4 subregion) volumes. Regional nicotinic acetylcholinergic receptor (nAChR) binding (VT/fp) was measured in vivo using 2-18F-fluoro-3-(2(S)azetidinylmethoxy) pyridine PET imaging. Results: nAChR binding was different across the three groups in voxel clusters that included the thalamus, medial and inferior temporal cortex, anterior cingulate, insula, and brainstem. Binding was lower in AD than OA; binding in the MCI group was generally between that of OA and AD, with evidence of preserved binding in medial temporal cortex. In the OA group, older age was highly correlated with lower nAChR binding. In the AD group, there was no significant relationship between nAChR binding and DRS total score or memory composite score. In a subsample of 62 participants that excluded those with advanced AD (30 OA, 24 MCI, and 8 very mild AD), lower DRS total score was associated with lower nAChR binding in multiple regions, with the highest correlations in hippocampus (right r¼.59, p<.001; left r¼.58, p<.001). There were also relationships between memory score and hippocampal binding, and between Trails A score and both thalamus and anterior cingulate binding. Memory score was associated with Ch4 (r¼.39, p<.001) and hippocampal (r¼.41, p<.001) volume. In a stepwise regression model, hippocampal nAChR binding (b¼.35, p¼.005) and Ch4 volume (b ¼.31, p¼.01), but not hippocampal volume, were each independently associated with memory score. Conclusions: Decline in nAChR binding occurs over the course of normal aging and more substantially in AD. Lower binding in key structures, including hippocampus, is associated with memory impairment, beyond the effect of basal forebrain or hippocampal atrophy. nAChR binding is a useful biomarker for cholinergic receptor tone and a potential treatment target in aging and AD.
P2-393
GRADIENT ECHO PLURAL CONTRAST MRI PROVIDES NEW SURROGATE MARKERS OF BRAIN PATHOLOGY IN ALZHEIMER’S DISEASE
Dmitriy A. Yablonskiy1, Yue Zhao1, Nigel J. Cairns1,2, Jason Hassenstab1,2, Tammie L. S. Benzinger1,2, Serguei V. Astafiev1, Jie Wen1, Marcus E. Raichle1,2, John C. Morris1,2, 1Washington University in St. Louis, St. Louis, MO, USA; 2Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA. Contact e-mail: [email protected] Background: One of the important directions in AD research is devel-
oping widely accessible surrogate markers that could detect AD brain pathology at the clinically silent preclinical stages. Our approach relies on the MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides in vivo quantitative high resolution 3D measurements of several brain-tissue-specific relaxation properties (GEPCI metrics) of the gradient recalled echo (GRE) MRI signal. Since GEPCI metrics depend on the molecular constituents present in the brain they can serve as surrogate markers of tissue alterations that reflect the integrity of brain cellular structure and disease-related tissue damage. Methods: 34 participants (ranging from normal, to preclinical, to mild AD) selected from the studies of aging and dementia at the Knight Alzheimer’s Disease Research Center at Washington University underwent GEPCI MRI (Siemens 3T) and a collection of cognitive performance tests. PET PiB data were available for 19 participants. Results: Our data show that AD brain pathology can be characterized by two GEPCI metrics: total (R2*) relaxation rate constant, sensitive to amyloid-b (Ab) accumulation, and tissue specific (R2t*) relaxation rate constant, sensitive to alterations in tissue cellular structure. We found that (i) The accumulation of Ab leads to increased R2* values and this increase can be used as a surrogate measure of Ab that strongly corre-
Figure 1. An 81 year old male study participant with a clinical diagnosis of AD dementia (CDR 1) who underwent MRI 11 months prior to expiration. (A) MPRAGE image, (B) GEPCI R2t* map. GEPCI R2t* in the hippocampus (outlined in yellow, segmented based on FreeSurfer) shows hypointense lesions (reduced R2t* values) consistent with the loss of cellular integrity even in the remaining part of hippocampus, thus suggesting higher sensitivity of GEPCI R2t* measurements to tissue neuronal loss as compared to standard volumetric measurements. This is confirmed by direct neuropathological examination shown in panel C (hippocampal area), obtained from the postmortem studies from this participant. Severe neuronal loss (hematoxylin and eosin stain) is indicated by the only present neuron on this image (indicated by the arrow). Also shown (panel D) is an example from hippocampus of a 79-year-old female with Alzheimer disease showing preservation of many neurons. Scale bars are 0.1 mm.
Figure 2. Correlation between cognition and hippocampal R2t* (upper panel). Cognitive measures included Free and Cued Selective Reminding Test (Srtfree), Animal Naming (ANIMALS), and Trail making Test Part A completion time (Tma). Note that higher scores on Tma indicate worse performance. Correlations with hippocampal volume are also presented for comparison (lower panel). Each point represents a single participant (n ¼ 34). Shaded areas represent 95% confidence intervals of linear fits (solid lines). Pearson correlation coefficients (r) and p values are shown in the left upper corners.
lates with PET measurements (e.g. r¼ 0.61,0.68, 0.84 in precuneus, paracentral and parahippocampal cortices); (ii) The neuronal loss leads to decreased GEPCI R2t* values and the magnitude of this decrease can be used as a surrogate measure of neuronal loss (Fig.1); (iii) Decreased GEPCI R2t* in the hippocampus demonstrated much stronger correlations with psychometric tests than hippocampal atrophy (Fig.2) suggesting higher GEPCI R2t* sensitivity to tissue neuronal loss as compared to volumetric measurements. (iv) GEPCI metrics demonstrated significant differences between normal and preclinical, normal and mild AD, and preclinical and mild AD groups. Conclusions:GEPCI in vivo measurements obtained on a clinical MRI provide information on brain AD-related pathology in human participants. Since MRI is a widely-available technology, the GEPCI technique has great potential for widespread use in tracking early brain pathology and evaluation of new disease-modifying therapies. P2-394
BLOOD PRESSURE AND BLOOD GLUCOSE ARE ASSOCIATED WITH MYELIN VULNERABILITY IN AN ETHNICALLY DIVERSE SAMPLE OF OLDER ADULTS
Elizabeth A. Boots1,2, Douglas C. Dean, III3, Olusola Ajilore1, Xiaohong Zhou1, Sean Deoni4, Melissa Lamar1,2, 1University of Illinois at Chicago, Chicago, IL, USA; 2Rush Alzheimer’s Disease Center, Chicago, IL, USA; 3Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, USA; 4University of Colorado Denver, Denver, CO, USA. Contact e-mail: [email protected]
Poster Presentations: Monday, July 17, 2017
P781
Figure 1. Age-adjusted associates of myelin water fraction with systolic blood pressure (red) and fasting blood glucose (blue) fully corrected for multiple comparisons: Threshold-Free Cluster Enhancement p<.05 in 46 adults (a) and 15 Hispanics (b). Background: Hypertension and Type 2 diabetes are cardiovascular disease risk factors (CVD-RFs) associated with pathological aging, including Alzheimer’s disease (AD) and vascular dementia. Mid-life hypertension and diabetes predict late-life white matter alterations including white matter hyperintensities (WMH) associated with dementia. Further, evidence suggests that these CVD-RFs may exert their impact as early as the third or fourth decade of life in affected individuals. Hypertension and diabetes are two of the most prevalent CVDRFs in minority populations, and rates of treatment-related control in these populations lag behind those of non-Hispanic Whites. Work is needed to detect white matter vulnerability associated with CVDRFs before overt damage occurs. Given that myelin degradation is thought to contribute to white matter damage, we focused this study on multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) as it relates to CVD-RFs in an ethnically diverse sample of older adults. Methods: Forty-six non-demented/ non-depressed participants (mean age¼66.4 years; 56% female; equal % Black/Hispanic/non-Hispanic White) underwent 3T MRI. mcDESPOT quantified ‘restricted’ water trapped within the lipid bilayers of myelin sheath, providing a measure of myelin water fraction (MWF). Regardless of medication status, systolic blood pressure (SBP) was determined via two readings separated by 5-minute intervals; blood glucose was measured by fasting levels of hemoglobin A1c. Separate age-adjusted linear regressions investigated the associations between SBP and A1c on whole-brain MWF. Analyses were fully corrected for multiple comparisons and utilized threshold-free cluster enhancement. Results: Higher SBP was associated with lower MWF within deep white matter and parietal regions (p<.05), whereas greater A1c was associated with lower MWF in deep white matter and more temporal regions (p<.05; see Figure 1a). Similar associations were noted in a subset of fifteen Hispanics at increased risk for uncontrolled CVD-RFs (see Figure 1b). Conclusions: Higher levels of SBP and A1c are associated with decreased myelin integrity in a sample of older, ethnically diverse adults. These results suggest that mcDESPOT may be a useful tool to detect the adverse effects of CVD-RFs on white matter integrity in and around areas of WMH in older non-demented/nondepressed adults.
P2-395
DECREASED SYNAPTIC DENSITY IN EARLY ALZHEIMER’S DISEASE ASSESSED WITH [18F]UCB-H-PET
Eric Salmon, Mohamed Ali Bahri, Marine Manard, Alain Plenevaux, Guillaume Becker, Alain Seret, Christine Mella, Joel Aerts, Fabrice Giacomelli, Andre Luxen, Christine Bastin, GIGA-CRC, University of Liege, Liege, Belgium. Contact e-mail: [email protected]
Background: Along with neurofibrillary tangles and amyloid pla-
ques, an early pathological feature of Alzheimer’s disease (AD) is the loss of brain synapses. Synaptic loss can be measured with PET and radiotracers of synaptic vesicle 2A. Methods: Nineteen MCI-AD and early AD patients with positive [18F]flutemetamol amyloid-PET were compared to 13 healthy controls. Brain accumulation of [18F]UCB-H (a SV2A radiotracer) was modeled using carotid activity on dynamic PET acquisitions. SPM12 was used for statistical group comparisons of [18F]UCB-H regional brain distribution volume. Grey matter density extracted from anatomical MRI was also compared between groups. Results: In AD patients, significant decrease of synaptic density was observed in medial temporal structures, centered on the entorhinal cortex, extending to amygdala and basal forebrain structures (Figure 1). Atrophy was also present in entorhinal cortex and amygdala, but not in the basal forebrain. Conclusions: [18F]UCB-H-PET allows to detect synaptic loss in brain structures known to be the initial sites of AD pathology, i.e. entorhinal cortex and amygdala. Interestingly, synaptic PET tracer might be particularly sensitive to basal forebrain pathology. Besides markers of amyloid and tau pathology, [18F]UCB-H-PET is thus a promising biomarker of early AD. P2-396
HOW AMYLOID PET CHANGES COGNITIVE CARE: A BROADER VIEW
Norman L. Foster1, Rorie DuPrey1, Richard D. King1, John M. Hoffman2, Jeffrey T. Yap3, Satoshi Minoshima1, Kevin Horn2, Yue Zhang1, 1University of Utah, Salt Lake City, UT, USA; 2Huntsman Cancer Institute, Salt Lake City, UT, USA; 3 Hunstman Cancer Institute, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: Amyloid PET imaging is a reliable biomarker of Alz-
heimer’s disease pathology and could prove valuable in clinical care. A standard formulation is that diagnostic testing should be performed only if it modifies drug or surgical treatment. There are, however, many additional reasons for knowing the cause of the cognitive impairment with greater certainty. Although some recommendations are relevant irrespective of diagnosis, others
Poster Presentations: Monday, July 17, 2017
underwent complete neuropsychological assessment and MR imaging to measure hippocampus and basal forebrain (Ch4 subregion) volumes. Regional nicotinic acetylcholinergic receptor (nAChR) binding (VT/fp) was measured in vivo using 2-18F-fluoro-3-(2(S)azetidinylmethoxy) pyridine PET imaging. Results: nAChR binding was different across the three groups in voxel clusters that included the thalamus, medial and inferior temporal cortex, anterior cingulate, insula, and brainstem. Binding was lower in AD than OA; binding in the MCI group was generally between that of OA and AD, with evidence of preserved binding in medial temporal cortex. In the OA group, older age was highly correlated with lower nAChR binding. In the AD group, there was no significant relationship between nAChR binding and DRS total score or memory composite score. In a subsample of 62 participants that excluded those with advanced AD (30 OA, 24 MCI, and 8 very mild AD), lower DRS total score was associated with lower nAChR binding in multiple regions, with the highest correlations in hippocampus (right r¼.59, p<.001; left r¼.58, p<.001). There were also relationships between memory score and hippocampal binding, and between Trails A score and both thalamus and anterior cingulate binding. Memory score was associated with Ch4 (r¼.39, p<.001) and hippocampal (r¼.41, p<.001) volume. In a stepwise regression model, hippocampal nAChR binding (b¼.35, p¼.005) and Ch4 volume (b ¼.31, p¼.01), but not hippocampal volume, were each independently associated with memory score. Conclusions: Decline in nAChR binding occurs over the course of normal aging and more substantially in AD. Lower binding in key structures, including hippocampus, is associated with memory impairment, beyond the effect of basal forebrain or hippocampal atrophy. nAChR binding is a useful biomarker for cholinergic receptor tone and a potential treatment target in aging and AD.
P2-393
GRADIENT ECHO PLURAL CONTRAST MRI PROVIDES NEW SURROGATE MARKERS OF BRAIN PATHOLOGY IN ALZHEIMER’S DISEASE
Dmitriy A. Yablonskiy1, Yue Zhao1, Nigel J. Cairns1,2, Jason Hassenstab1,2, Tammie L. S. Benzinger1,2, Serguei V. Astafiev1, Jie Wen1, Marcus E. Raichle1,2, John C. Morris1,2, 1Washington University in St. Louis, St. Louis, MO, USA; 2Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA. Contact e-mail: [email protected] Background: One of the important directions in AD research is devel-
oping widely accessible surrogate markers that could detect AD brain pathology at the clinically silent preclinical stages. Our approach relies on the MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides in vivo quantitative high resolution 3D measurements of several brain-tissue-specific relaxation properties (GEPCI metrics) of the gradient recalled echo (GRE) MRI signal. Since GEPCI metrics depend on the molecular constituents present in the brain they can serve as surrogate markers of tissue alterations that reflect the integrity of brain cellular structure and disease-related tissue damage. Methods: 34 participants (ranging from normal, to preclinical, to mild AD) selected from the studies of aging and dementia at the Knight Alzheimer’s Disease Research Center at Washington University underwent GEPCI MRI (Siemens 3T) and a collection of cognitive performance tests. PET PiB data were available for 19 participants. Results: Our data show that AD brain pathology can be characterized by two GEPCI metrics: total (R2*) relaxation rate constant, sensitive to amyloid-b (Ab) accumulation, and tissue specific (R2t*) relaxation rate constant, sensitive to alterations in tissue cellular structure. We found that (i) The accumulation of Ab leads to increased R2* values and this increase can be used as a surrogate measure of Ab that strongly corre-
Figure 1. An 81 year old male study participant with a clinical diagnosis of AD dementia (CDR 1) who underwent MRI 11 months prior to expiration. (A) MPRAGE image, (B) GEPCI R2t* map. GEPCI R2t* in the hippocampus (outlined in yellow, segmented based on FreeSurfer) shows hypointense lesions (reduced R2t* values) consistent with the loss of cellular integrity even in the remaining part of hippocampus, thus suggesting higher sensitivity of GEPCI R2t* measurements to tissue neuronal loss as compared to standard volumetric measurements. This is confirmed by direct neuropathological examination shown in panel C (hippocampal area), obtained from the postmortem studies from this participant. Severe neuronal loss (hematoxylin and eosin stain) is indicated by the only present neuron on this image (indicated by the arrow). Also shown (panel D) is an example from hippocampus of a 79-year-old female with Alzheimer disease showing preservation of many neurons. Scale bars are 0.1 mm.
Figure 2. Correlation between cognition and hippocampal R2t* (upper panel). Cognitive measures included Free and Cued Selective Reminding Test (Srtfree), Animal Naming (ANIMALS), and Trail making Test Part A completion time (Tma). Note that higher scores on Tma indicate worse performance. Correlations with hippocampal volume are also presented for comparison (lower panel). Each point represents a single participant (n ¼ 34). Shaded areas represent 95% confidence intervals of linear fits (solid lines). Pearson correlation coefficients (r) and p values are shown in the left upper corners.
lates with PET measurements (e.g. r¼ 0.61,0.68, 0.84 in precuneus, paracentral and parahippocampal cortices); (ii) The neuronal loss leads to decreased GEPCI R2t* values and the magnitude of this decrease can be used as a surrogate measure of neuronal loss (Fig.1); (iii) Decreased GEPCI R2t* in the hippocampus demonstrated much stronger correlations with psychometric tests than hippocampal atrophy (Fig.2) suggesting higher GEPCI R2t* sensitivity to tissue neuronal loss as compared to volumetric measurements. (iv) GEPCI metrics demonstrated significant differences between normal and preclinical, normal and mild AD, and preclinical and mild AD groups. Conclusions:GEPCI in vivo measurements obtained on a clinical MRI provide information on brain AD-related pathology in human participants. Since MRI is a widely-available technology, the GEPCI technique has great potential for widespread use in tracking early brain pathology and evaluation of new disease-modifying therapies. P2-394
BLOOD PRESSURE AND BLOOD GLUCOSE ARE ASSOCIATED WITH MYELIN VULNERABILITY IN AN ETHNICALLY DIVERSE SAMPLE OF OLDER ADULTS
Elizabeth A. Boots1,2, Douglas C. Dean, III3, Olusola Ajilore1, Xiaohong Zhou1, Sean Deoni4, Melissa Lamar1,2, 1University of Illinois at Chicago, Chicago, IL, USA; 2Rush Alzheimer’s Disease Center, Chicago, IL, USA; 3Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, USA; 4University of Colorado Denver, Denver, CO, USA. Contact e-mail: [email protected]
Poster Presentations: Monday, July 17, 2017
P781
Figure 1. Age-adjusted associates of myelin water fraction with systolic blood pressure (red) and fasting blood glucose (blue) fully corrected for multiple comparisons: Threshold-Free Cluster Enhancement p<.05 in 46 adults (a) and 15 Hispanics (b). Background: Hypertension and Type 2 diabetes are cardiovascular disease risk factors (CVD-RFs) associated with pathological aging, including Alzheimer’s disease (AD) and vascular dementia. Mid-life hypertension and diabetes predict late-life white matter alterations including white matter hyperintensities (WMH) associated with dementia. Further, evidence suggests that these CVD-RFs may exert their impact as early as the third or fourth decade of life in affected individuals. Hypertension and diabetes are two of the most prevalent CVDRFs in minority populations, and rates of treatment-related control in these populations lag behind those of non-Hispanic Whites. Work is needed to detect white matter vulnerability associated with CVDRFs before overt damage occurs. Given that myelin degradation is thought to contribute to white matter damage, we focused this study on multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) as it relates to CVD-RFs in an ethnically diverse sample of older adults. Methods: Forty-six non-demented/ non-depressed participants (mean age¼66.4 years; 56% female; equal % Black/Hispanic/non-Hispanic White) underwent 3T MRI. mcDESPOT quantified ‘restricted’ water trapped within the lipid bilayers of myelin sheath, providing a measure of myelin water fraction (MWF). Regardless of medication status, systolic blood pressure (SBP) was determined via two readings separated by 5-minute intervals; blood glucose was measured by fasting levels of hemoglobin A1c. Separate age-adjusted linear regressions investigated the associations between SBP and A1c on whole-brain MWF. Analyses were fully corrected for multiple comparisons and utilized threshold-free cluster enhancement. Results: Higher SBP was associated with lower MWF within deep white matter and parietal regions (p<.05), whereas greater A1c was associated with lower MWF in deep white matter and more temporal regions (p<.05; see Figure 1a). Similar associations were noted in a subset of fifteen Hispanics at increased risk for uncontrolled CVD-RFs (see Figure 1b). Conclusions: Higher levels of SBP and A1c are associated with decreased myelin integrity in a sample of older, ethnically diverse adults. These results suggest that mcDESPOT may be a useful tool to detect the adverse effects of CVD-RFs on white matter integrity in and around areas of WMH in older non-demented/nondepressed adults.
P2-395
DECREASED SYNAPTIC DENSITY IN EARLY ALZHEIMER’S DISEASE ASSESSED WITH [18F]UCB-H-PET
Eric Salmon, Mohamed Ali Bahri, Marine Manard, Alain Plenevaux, Guillaume Becker, Alain Seret, Christine Mella, Joel Aerts, Fabrice Giacomelli, Andre Luxen, Christine Bastin, GIGA-CRC, University of Liege, Liege, Belgium. Contact e-mail: [email protected]
Background: Along with neurofibrillary tangles and amyloid pla-
ques, an early pathological feature of Alzheimer’s disease (AD) is the loss of brain synapses. Synaptic loss can be measured with PET and radiotracers of synaptic vesicle 2A. Methods: Nineteen MCI-AD and early AD patients with positive [18F]flutemetamol amyloid-PET were compared to 13 healthy controls. Brain accumulation of [18F]UCB-H (a SV2A radiotracer) was modeled using carotid activity on dynamic PET acquisitions. SPM12 was used for statistical group comparisons of [18F]UCB-H regional brain distribution volume. Grey matter density extracted from anatomical MRI was also compared between groups. Results: In AD patients, significant decrease of synaptic density was observed in medial temporal structures, centered on the entorhinal cortex, extending to amygdala and basal forebrain structures (Figure 1). Atrophy was also present in entorhinal cortex and amygdala, but not in the basal forebrain. Conclusions: [18F]UCB-H-PET allows to detect synaptic loss in brain structures known to be the initial sites of AD pathology, i.e. entorhinal cortex and amygdala. Interestingly, synaptic PET tracer might be particularly sensitive to basal forebrain pathology. Besides markers of amyloid and tau pathology, [18F]UCB-H-PET is thus a promising biomarker of early AD. P2-396
HOW AMYLOID PET CHANGES COGNITIVE CARE: A BROADER VIEW
Norman L. Foster1, Rorie DuPrey1, Richard D. King1, John M. Hoffman2, Jeffrey T. Yap3, Satoshi Minoshima1, Kevin Horn2, Yue Zhang1, 1University of Utah, Salt Lake City, UT, USA; 2Huntsman Cancer Institute, Salt Lake City, UT, USA; 3 Hunstman Cancer Institute, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: Amyloid PET imaging is a reliable biomarker of Alz-
heimer’s disease pathology and could prove valuable in clinical care. A standard formulation is that diagnostic testing should be performed only if it modifies drug or surgical treatment. There are, however, many additional reasons for knowing the cause of the cognitive impairment with greater certainty. Although some recommendations are relevant irrespective of diagnosis, others