- Email: [email protected]
CEREBROSPINAL FLUID TAU, BUT NOT AMYLOID, TRACKS ATROPHY IN ALZHEIMER-VULNERABLE HIPPOCAMPAL SUBFIELDS
Poster Presentations: IC-P IC-P-166
CEREBROSPINAL FLUID TAU, BUT NOT AMYLOID, TRACKS ATROPHY IN ALZHEIMERVULNERABLE HIPPOCAMPAL SUBFIELDS
Geoffrey A. Kerchner1, Eva Czirr2, Jeffrey D. Bernstein1, Tony WyssCoray1, Brian K. Rutt1, 1Stanford University, Stanford, California, United States; 2Stanford University, Santa Clara, California, United States. Contact e-mail: [email protected] Background: Hippocampal atrophy begins quite focally in Alzheimer’s disease (AD). We have used high-resolution 7.0-Tesla MRI to visualize hippocampal subfields and strata, including the CA1 stratum radiatum / lacunosum-moleculare (CA1-SRLM, a site of key synapses for learning and memory), and showed that CA1-SRLM atrophy is evident in AD, is exacerbated by the ApoE4 gene, and correlates with memory performance (Kerchner et al., 2010, 2012, 2013, 2014). Autopsy studies have suggested that the hippocampus is one of the first brain structures to exhibit neurofibrillary tau pathology but one of the last to develop amyloid plaques. We postulated that CA1-SRLM atrophy would correlate with cerebrospinal fluid (CSF) measures of tau but not Ab42. Methods: We recruited older adults across a cognitive spectrum, including healthy controls (n¼12) and patients with Subjective Cognitive Impairment (n¼3), amnestic Mild Cognitive Impairment (n¼10), and mild AD dementia (n¼5). Each subject underwent lumbar puncture for CSF collection, and we determined CSF Ab42, total tau, and phospho-tau levels using standard enzyme-linked immunosorbent assays. Each subject also underwent 7T MRI for hippocampal microstructural analysis at an in-plane resolution of 220 mm, allowing direct visual identification of subfields. Results: Between diagnostic groups, the Ab42:tau ratio varied significantly (one-way ANOVA, p¼0.0002). While Ab42 concentrations were not different between groups, tau concentrations were (p¼0.004). Across pooled subjects, CA1-SRLM width correlated with CSF concentrations of total tau (r¼-0.48; p¼0.006) and phospho-tau (r¼-0.41; p¼0.036). CA1 stratum pyramidale and entorhinal cortex, other sites of tau pathology, showed similar correlations. By contrast, the dentate gyrus and CA3 area did not correlate with CSF total tau or phospho-tau. Importantly, CSF Ab42 concentrations did not correlate with any medial temporal lobe structural metric. Finally, among these subjects, episodic memory performance correlated with CA1-SRLM width (r¼0.58, p¼0.003), CSF total tau (r¼-0.51, p¼0.013), and CSF phospho-tau (r¼-0.53, p¼0.007), but not CSF Ab42. Conclusions: CSF total tau and phospho-tau levels reflect atrophy in CA1-SRLM and other specific medial temporal lobe structures known to be selectively vulnerable to tau pathology. These data raise the possibility that CSF tau levels may go beyond representing nonspecific effects of neurodegeneration and may reflect the actual focal burden of tau pathology. IC-P-167
P93
task with 15 sequential trials of a 15-turn route through an animated landscape, and performance was quantified as the number of correct turns on trials 2-15. Results: Navigational performance correlated with the widths of the entorhinal cortex (r¼0.46, p¼0.026) and CA1 stratum radiatum / lacunosum-moleculare (CA1-SRLM, a key synapse-containing layer of the hippocampus) (r¼0.53, p¼0.004). Performance did not correlate with other hippocampal subfields, including CA1 stratum pyramidale and dentate gyrus / CA3. Finally, navigational performance correlated with scores on a range of executive and working memory tasks, as well as delayed recall, despite the absence of any objective impairment on these tasks. Conclusions: Navigational performance on a computerized, routelearning task correlated with the morphology of the entorhinal cortex and CA1-SRLM, but not other hippocampal subfields, among cognitively normal older adults. This may point to a specific role of entorhinal cortex and CA1-SRLM for egocentric route-learning. Perhaps not by coincidence, these same two areas exhibit selective, age-related atrophy (Kerchner et al., 2013) and are known to be among the first brain areas to develop neurofibrillary tau pathology. These data point to the possibility that poor navigational skill may be an early indicator of preclinical AD. IC-P-168
INVOLVEMENT OF ANTERIOR AND POSTERIOR MTL NETWORKS IN EARLY ALZHEIMER’S DISEASE
Sandhitsu Das, John Pluta, Lauren Mancuso, Dasha Kliot, Paul Yushkevich, David A. Wolk, University of Pennsylvania, Philadelphia, Pennsylvania, United States. Contact e-mail: [email protected] Background: We present cortical thickness data in amnestic Mild Cognitive Impairment (a-MCI) patients showing atrophyin both anterior and posterior medial temporal lobe (MTL) networks and their correlations with molecular biomarkers.Recent work has described two dissociable networks associated with MTL structures: (1) a ’posterior MTL network’ including posterior MTL regions [hippocampal tail, parahippocampus(PHC)], posterior cingulate/precuneus, and posterior lateral parietal regions and (2) an ‘anterior MTL network’ comprising anterior MTL regions [hippocampal head and perirhinal cortex (PRC)], ventral and polar temporal lobe, and lateral orbitofrontal cortices (Nat Rev Neurosci 13:716-726, 2012). Alzheimer’s Disease (AD) is often described as a neurodegenerative disease that, at a network level, most early and significantly affects the posterior default mode network (DMN), which is essentially the posterior MTL network. However, earliest appearance of neurofibrillary tangles in anterior MTL regions, such as PRC, suggests potential early involvement of the anterior MTL network. Here we study cortical atrophy in both networks and
ALZHEIMER-VULNERABLE HIPPOCAMPAL SUBFIELDS PREDICT NAVIGATIONAL PERFORMANCE IN OLDER ADULTS
Geoffrey A. Kerchner1, Michelle C. Fenesy1, Erica Johnson2, Jeffrey Bernstein1, Brian K. Rutt1, Katherine L. Possin2, 1Stanford University, Stanford, California, United States; 2UCSF, San Francisco, California, United States. Contact e-mail: [email protected] Background: The medial temporal lobe (MTL) facilitates navigation in rodents. Limited evidence suggests the same in humans, but the contributions of specific MTL components, including hippocampal subfields, are unclear. Given that cognitively-healthy older adults are at risk of harboring a potentially substantial burden of preclinical AD-related pathology, such adults are likely to exhibit a range of structural changes within AD-vulnerable hippocampal subfields. If those subfields contribute to navigation, then we hypothesized that there would be a correlation between subfield size and navigational performance. Methods: We recruited 23 cognitively-healthy older adults from the community, who all scored normally on a standardized neuropsychological testing battery. Each underwent 7T MRI for MTL microstructural analysis at an in-plane resolution of 220 mm, allowing direct visual identification of subfields (Kerchner et al., 2012, 2013, 2014). Each also completed a computerized, egocentric navigational
Figure 1. Cortical regions belonging to anterior and posterior MTL networks defined in a separate cohort of OHC subjects. Magenta shows over lap of networks defined by both seeds.
CEREBROSPINAL FLUID TAU, BUT NOT AMYLOID, TRACKS ATROPHY IN ALZHEIMERVULNERABLE HIPPOCAMPAL SUBFIELDS
Geoffrey A. Kerchner1, Eva Czirr2, Jeffrey D. Bernstein1, Tony WyssCoray1, Brian K. Rutt1, 1Stanford University, Stanford, California, United States; 2Stanford University, Santa Clara, California, United States. Contact e-mail: [email protected] Background: Hippocampal atrophy begins quite focally in Alzheimer’s disease (AD). We have used high-resolution 7.0-Tesla MRI to visualize hippocampal subfields and strata, including the CA1 stratum radiatum / lacunosum-moleculare (CA1-SRLM, a site of key synapses for learning and memory), and showed that CA1-SRLM atrophy is evident in AD, is exacerbated by the ApoE4 gene, and correlates with memory performance (Kerchner et al., 2010, 2012, 2013, 2014). Autopsy studies have suggested that the hippocampus is one of the first brain structures to exhibit neurofibrillary tau pathology but one of the last to develop amyloid plaques. We postulated that CA1-SRLM atrophy would correlate with cerebrospinal fluid (CSF) measures of tau but not Ab42. Methods: We recruited older adults across a cognitive spectrum, including healthy controls (n¼12) and patients with Subjective Cognitive Impairment (n¼3), amnestic Mild Cognitive Impairment (n¼10), and mild AD dementia (n¼5). Each subject underwent lumbar puncture for CSF collection, and we determined CSF Ab42, total tau, and phospho-tau levels using standard enzyme-linked immunosorbent assays. Each subject also underwent 7T MRI for hippocampal microstructural analysis at an in-plane resolution of 220 mm, allowing direct visual identification of subfields. Results: Between diagnostic groups, the Ab42:tau ratio varied significantly (one-way ANOVA, p¼0.0002). While Ab42 concentrations were not different between groups, tau concentrations were (p¼0.004). Across pooled subjects, CA1-SRLM width correlated with CSF concentrations of total tau (r¼-0.48; p¼0.006) and phospho-tau (r¼-0.41; p¼0.036). CA1 stratum pyramidale and entorhinal cortex, other sites of tau pathology, showed similar correlations. By contrast, the dentate gyrus and CA3 area did not correlate with CSF total tau or phospho-tau. Importantly, CSF Ab42 concentrations did not correlate with any medial temporal lobe structural metric. Finally, among these subjects, episodic memory performance correlated with CA1-SRLM width (r¼0.58, p¼0.003), CSF total tau (r¼-0.51, p¼0.013), and CSF phospho-tau (r¼-0.53, p¼0.007), but not CSF Ab42. Conclusions: CSF total tau and phospho-tau levels reflect atrophy in CA1-SRLM and other specific medial temporal lobe structures known to be selectively vulnerable to tau pathology. These data raise the possibility that CSF tau levels may go beyond representing nonspecific effects of neurodegeneration and may reflect the actual focal burden of tau pathology. IC-P-167
P93
task with 15 sequential trials of a 15-turn route through an animated landscape, and performance was quantified as the number of correct turns on trials 2-15. Results: Navigational performance correlated with the widths of the entorhinal cortex (r¼0.46, p¼0.026) and CA1 stratum radiatum / lacunosum-moleculare (CA1-SRLM, a key synapse-containing layer of the hippocampus) (r¼0.53, p¼0.004). Performance did not correlate with other hippocampal subfields, including CA1 stratum pyramidale and dentate gyrus / CA3. Finally, navigational performance correlated with scores on a range of executive and working memory tasks, as well as delayed recall, despite the absence of any objective impairment on these tasks. Conclusions: Navigational performance on a computerized, routelearning task correlated with the morphology of the entorhinal cortex and CA1-SRLM, but not other hippocampal subfields, among cognitively normal older adults. This may point to a specific role of entorhinal cortex and CA1-SRLM for egocentric route-learning. Perhaps not by coincidence, these same two areas exhibit selective, age-related atrophy (Kerchner et al., 2013) and are known to be among the first brain areas to develop neurofibrillary tau pathology. These data point to the possibility that poor navigational skill may be an early indicator of preclinical AD. IC-P-168
INVOLVEMENT OF ANTERIOR AND POSTERIOR MTL NETWORKS IN EARLY ALZHEIMER’S DISEASE
Sandhitsu Das, John Pluta, Lauren Mancuso, Dasha Kliot, Paul Yushkevich, David A. Wolk, University of Pennsylvania, Philadelphia, Pennsylvania, United States. Contact e-mail: [email protected] Background: We present cortical thickness data in amnestic Mild Cognitive Impairment (a-MCI) patients showing atrophyin both anterior and posterior medial temporal lobe (MTL) networks and their correlations with molecular biomarkers.Recent work has described two dissociable networks associated with MTL structures: (1) a ’posterior MTL network’ including posterior MTL regions [hippocampal tail, parahippocampus(PHC)], posterior cingulate/precuneus, and posterior lateral parietal regions and (2) an ‘anterior MTL network’ comprising anterior MTL regions [hippocampal head and perirhinal cortex (PRC)], ventral and polar temporal lobe, and lateral orbitofrontal cortices (Nat Rev Neurosci 13:716-726, 2012). Alzheimer’s Disease (AD) is often described as a neurodegenerative disease that, at a network level, most early and significantly affects the posterior default mode network (DMN), which is essentially the posterior MTL network. However, earliest appearance of neurofibrillary tangles in anterior MTL regions, such as PRC, suggests potential early involvement of the anterior MTL network. Here we study cortical atrophy in both networks and
ALZHEIMER-VULNERABLE HIPPOCAMPAL SUBFIELDS PREDICT NAVIGATIONAL PERFORMANCE IN OLDER ADULTS
Geoffrey A. Kerchner1, Michelle C. Fenesy1, Erica Johnson2, Jeffrey Bernstein1, Brian K. Rutt1, Katherine L. Possin2, 1Stanford University, Stanford, California, United States; 2UCSF, San Francisco, California, United States. Contact e-mail: [email protected] Background: The medial temporal lobe (MTL) facilitates navigation in rodents. Limited evidence suggests the same in humans, but the contributions of specific MTL components, including hippocampal subfields, are unclear. Given that cognitively-healthy older adults are at risk of harboring a potentially substantial burden of preclinical AD-related pathology, such adults are likely to exhibit a range of structural changes within AD-vulnerable hippocampal subfields. If those subfields contribute to navigation, then we hypothesized that there would be a correlation between subfield size and navigational performance. Methods: We recruited 23 cognitively-healthy older adults from the community, who all scored normally on a standardized neuropsychological testing battery. Each underwent 7T MRI for MTL microstructural analysis at an in-plane resolution of 220 mm, allowing direct visual identification of subfields (Kerchner et al., 2012, 2013, 2014). Each also completed a computerized, egocentric navigational
Figure 1. Cortical regions belonging to anterior and posterior MTL networks defined in a separate cohort of OHC subjects. Magenta shows over lap of networks defined by both seeds.