- Email: [email protected]
Calorie restriction improves brain health in aging rhesus macaques
P302
Podium Presentations: Thursday, July 23, 2015
analysis highlighted major changes in phosphatidylcholines (PC), ethanolamine plasmalogens (PlsEtn), and the sphingolipidome (SL) pointing to major changes in membrane structure and function. We will share key findings from ADNI I study. Conclusions: Metabolomics/lipidomics data and its integration with genomics and imaging data provides a systems approach and steps to enable precision medicine for the study of AD and its subtypes.
THURSDAY, JULY 23, 2015 SYMPOSIA S5-01 NOVEL DEVELOPMENTS IN FLUID BIOMARKERS S5-01-01
NOVEL CSF BIOMARKERS OF SYNAPTIC DYSFUNCTION
Anne M. Fagan, Washington University School of Medicine, St. Louis, MO, USA, Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA, Hope Center for Neurological Disorders, St. Louis, MO, USA. Contact e-mail: [email protected] Background: Neuropathological studies have shown that synapse
loss occurs early in Alzheimer’s disease (AD) and is more strongly correlated with cognitive decline than are plaques or tangles. Therefore, quantifiable biomarker measures of synaptic dysfunction and/ or loss may be particularly useful for identifying neuronal pathology during early stages of the disease and for predicting future cognitive decline. Methods: Novel biomarker assays have recently been developed that measure the synapse-related proteins, Neurogranin (NGRN, post-synaptic) and synaptosomal-associated protein 25 (SNAP-25, pre-synaptic), in human CSF. Results: Recent studies have demonstrated that levels of both of these proteins are elevated in individuals with AD dementia compared to cognitively normal controls, likely reflecting AD-associated synaptic degeneration. Levels of synaptic markers are also higher in amyloid-positive individuals diagnosed with mild cognitive impairment (MCI) and are associated with a faster rate of cognitive decline and predict progression to dementia. Although levels of NGRN and SNAP-25 are highly correlated with levels of CSF tau and ptau181 (markers of tangles and/or neuronal cell death), longitudinal, within-person comparisons of changes among these biomarkers are needed to determine their more precise temporal ordering with disease progression. Conclusions: Biomarkers of synaptic dysfunction may ultimately be useful for early disease diagnosis, predicting and monitoring cognitive decline during disease progression and for identifying drug effects on synaptic dysfunction and degeneration in clinical trials.
S5-01-02
BLOOD BIOMARKER ASSAYS
Sid O’Bryant, University of North Texas Health Science Center, Fort Worth, TX, USA. Contact e-mail: [email protected] Background: The search for blood-based biomarkers of relevance in
Alzheimer’s disease has grown rapidly. The first-ever consensusbased guidelines for pre-analytic processing were recently published; however, little work has been undertaken to examine the consistency of putative biomarkers across blood fractions and assay platforms. The current study therefore sought to investigate comparison of potential AD biomarkers across blood fractions and assay platform. Methods: Non-fasting serum and plasma samples were analyzed from 300 research participants (AD n¼150, control n¼150) from the Texas Alzheimer’s Research & Care Consortium. Proteomic markers were assayed via multi-plex platforms using
electrochemiluminescence (Meso Scale Discovery) or luminex (Myriad Rules Based Medicine). Results: On the MSD platform, 10 out of the 21markers shared >50% of the variance across blood fraction (SAA R2¼0.99, IL10 R2¼0.95, FABP R2¼0.94, I309 R2¼0.94, IL5 R2¼0.94, IL6 R2¼0.94, Eotaxin3 R2¼0.91, IL18 R2¼0.87, sTNFR1 R2¼0.85, PPY R2¼0.81). When examining the variable importance in detecting AD, only three (IL5, IL6 and IL7) were common among the top 10 markers for the serum versus plasma-based algorithm. Finally, when examining protein concentrations across platforms, only five markers shared >50% of the variance (b2M R2¼0.92, IL18 R2¼0.80, FVII R2¼0.78, CRP R2¼0.74, FABP R2¼0.70). Conclusions: The current findings highlight the importance of considering blood fraction and assay platform when searching for AD biomarkers. Additionally, comparing results across blood fraction and/or platforms likely explains much of the inconsistencies found in the current literature. However, the current findings also point to an underlying logic for the consistency of FABP and CRP across multiple cohorts, assay platforms as well as blood fraction. Additional work is needed to understand these differences in order for the field to progress forward and be able to make interpretable comparisons across studies. S5-01-03
CSF BIOMARKERS VERSUS PET BIOMARKERS
Niklas Mattsson, Lund University, Lund, Sweden. Contact e-mail: niklas. [email protected]
Abstract not available. S5-01-04
ALZBIOMARKER DATABASE ON ESTABLISHED AND NOVEL CSF AND PLASMA BIOMARKERS FOR ALZHEIMER’S DISEASE 1 1 € , Bob Olsson , Ronald Lautner1, Ulf Andreasson1, Annika Ohrfelt Erik Portelius1, Maria Bjerke1, Mikko H€oltt€a1, Christoffer Rosen1, Kelly Dakin2, Elisabeth Wu2, Caroline Olsson3, Max Petzold3, olndal, Kaj Blennow1, Henrik Zetterberg1, 1University of Gothenburg, M€ Sweden; 2Alzforum, Boston, MA, USA; 3University of Gothenburg, Gothenburg, Sweden. Contact e-mail: [email protected]
Abstract not available.
THURSDAY, JULY 23, 2015 FEATURED RESEARCH SESSIONS F5-01 BRAIN CORRELATES OF MODIFIABLE LIFESTYLE RISK FACTORS FOR ALZHEIMER’S DISEASE: FROM ANIMAL RESEARCH TO INTERVENTION TRIALS F5-01-01
CALORIE RESTRICTION IMPROVES BRAIN HEALTH IN AGING RHESUS MACAQUES
Sterling C. Johnson, Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA; Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Contact e-mail: [email protected] Background: Calorie restriction (CR) without malnutrition slows the
aging and disease process, prolonging median and maximum lifespan in yeast, worms, fish, flies, and rodents. Studies of CR in non-human primates (Macaca mulatta) indicate a protective effect of CR against aging-related diseases and a salutary effect on brain health. Methods: Our group has studied the specific effects of CR on the non-human primate brain using neuroimaging, behavioral, and post-mortem histological techniques and this talk will provide an
Podium Presentations: Thursday, July 23, 2015
overview of these findings. Animals in this study were part of the longitudinal “Dietary Restriction and Aging Study” at the Wisconsin National Primate Research Center (WNPRC). Animals were either fed a normal diet or maintained on a moderately restricted diet (approximately 30% reduced intake from baseline), with both groups receiving comparable diet supplements. Results: Using volumetric imaging we demonstrated that CR preserves gray matter cortex in limbic and heteromodal association areas, indicating a positive effect of CR against age-related brain atrophy. Diffusion tensor imaging showed preservation of white matter integrity in the corpus callosum and fronto-occipital fasciculus, superior longitudinal fasciculus, external capsule, and brainstem. CR also attenuated age-related iron accumulation in the basal ganglia, red nucleus, and parietal, temporal, and perirhinal cortex. Decreased iron accumulation was in turn associated with faster performance on fine motor function tests, signifying a protective effect against motor slowness that results during aging. CR moderated the effect of important plasma-based inflammatory markers (e.g. IL-6) on gray and white matter changes in several brain areas, including the parietal and temporal gray matter regions that are sensitive to aging. CR improved glucoregulatory profiles and positively influenced gray matter volume in the hippocampus. Histopathology studies reveal that CR monkeys express significantly lower (w30%) levels of microglial activation in the hippocampus. Energy metabolism in the hippocampus as indexed by PGC1alpha and GSK3B was preserved in CR. Number of MTL amyloid plaques was however equivalent between groups. Conclusions: Overall, these results recapitulate the neuroprotective effects of CR from lower animal models. Taken together, these findings point to an overall beneficial effect of CR on the brain in this non-human primate model of aging.
F5-01-02
IMPACT OF CALORIC RESTRICTION AND CALORIC RESTRICTION-MIMETICS ON BRAIN STRUCTURE AND FUNCTION IN OLDER ADULTS AND PATIENTS WITH MILD COGNITIVE IMPAIRMENT
Agnes Fl€ oel1, Veronica A. Witte2, 1NeuroCure Clinical Research Center, Charite – Universit€ atsmedizin Berlin, Berlin, Germany; 2Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. Contact e-mail: [email protected] Background: In a series of randomized controlled trials, we aim to
elucidate whether caloric restriction (CR) and CR-mimetics exert a beneficial impact on glucose control, memory performance, and brain structure and connectivity in healthy older adults (HO) and patients with mild cognitive impairment (MCI). Methods: 102 HO were assessed for fasting glucose, HbA1c and memory. In the group receiving resveratrol, we additionally conducted MRI scans to determine volume, microstructure, and functional connectivity (FC) of the hippocampus. 50 subjects participated in the CR trial, and were stratified into 3 groups: caloric restriction, increased intake of unsaturated fatty acids, or control; for 3 months. 52 subjects participated in the resveratrol trial and were stratified into 2 groups: 200 mg/d resveratrol or placebo; for 6 months. Baseline parameters were again assessed after 3 and 6 months, respectively. 40 patients with MCI have now (11/2014) completed their intervention (200 mg resveratrol vs placebo) for 6 months. Results: In HV, we found a decrease in fasting insulin and HbA1c levels and an improvement of verbal memory performance (all p < 0.05; [1, 2]). Moreover, MRI revealed increases in hippocampal FC [1]; see Fig. 1. Increases in FC between the left posterior hippocampus
P303
and the medial prefrontal cortex correlated with increases in retention scores and with decreases in HbA1c (all p < 0.05). Analysis of data from the MCI group is still ongoing. Conclusions: Our findings offer the basis for novel strategies to maintain brain health during aging, using not only CR or resveratrol but also lifestyle interventions known to improve glucose control [3]. The study just completed in MCI will demonstrate if these findings extend to the diseased brain. References: 1. Witte, A.V., et al., Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci, 2014. 34(23): p. 7862-70. 2. Witte, A.V., et al., Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A, 2009. 106(4): p. 1255-60. 3. Erickson, K.I., et al., Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A, 2011. 108(7): p. 3017-22.
Figure. In the group receiving resveratrol, decreases in HbA1ccorrelated significantly with increases in FC (r¼0.4, p¼0.04). Triangles show median changes in functional connectivity within a significant cluster in the left medial prefrontal cortex (mPFC) (outlined in red, see inset) using the left posterior hippocampus as seed in relation to changes in HbA1c. Line indicates regression fit.
F5-01-03
BETTER INTELLECTUAL LIFESTYLE TO KEEP COGNITIVE IMPAIRMENT AWAY
Prashanthi Vemuri1, Timothy G. Lesnick1, Scott A. Przybelski1, Mary M. Machulda1, David S. Knopman1, Michelle Mielke1, Rosebud Roberts1, Val J. Lowe1, Walter Rocca1, Yonas E. Geda2, Ronald C. Petersen1, Clifford R. Jack, Jr.1, 1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic, Scottsdale, AZ, USA. Contact e-mail: Vemuri. [email protected] Background: Intellectual lifestyle enrichment throughout life is
increasingly viewed as a protective strategy against cognitive decline in the elderly. Numerous studies demonstrate that all components of intellectual enrichment – higher lifetime non-leisure learning components such as education and primary occupation as well as cognitively stimulating activities are protective against cognitive decline and dementia. The objective of this abstract was to combine data from our earlier published studies with some new data shown here to investigate the influence of lifestyle on the AD biomarker-cognition trajectories. Methods: In two recent studies, we found that 1) high lifetime intellectual enrichment (75th percentile of both education/occupation and mid/late-life cognitive activity) delayed the onset of cognitive impairment by at least 8
Podium Presentations: Thursday, July 23, 2015
analysis highlighted major changes in phosphatidylcholines (PC), ethanolamine plasmalogens (PlsEtn), and the sphingolipidome (SL) pointing to major changes in membrane structure and function. We will share key findings from ADNI I study. Conclusions: Metabolomics/lipidomics data and its integration with genomics and imaging data provides a systems approach and steps to enable precision medicine for the study of AD and its subtypes.
THURSDAY, JULY 23, 2015 SYMPOSIA S5-01 NOVEL DEVELOPMENTS IN FLUID BIOMARKERS S5-01-01
NOVEL CSF BIOMARKERS OF SYNAPTIC DYSFUNCTION
Anne M. Fagan, Washington University School of Medicine, St. Louis, MO, USA, Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA, Hope Center for Neurological Disorders, St. Louis, MO, USA. Contact e-mail: [email protected] Background: Neuropathological studies have shown that synapse
loss occurs early in Alzheimer’s disease (AD) and is more strongly correlated with cognitive decline than are plaques or tangles. Therefore, quantifiable biomarker measures of synaptic dysfunction and/ or loss may be particularly useful for identifying neuronal pathology during early stages of the disease and for predicting future cognitive decline. Methods: Novel biomarker assays have recently been developed that measure the synapse-related proteins, Neurogranin (NGRN, post-synaptic) and synaptosomal-associated protein 25 (SNAP-25, pre-synaptic), in human CSF. Results: Recent studies have demonstrated that levels of both of these proteins are elevated in individuals with AD dementia compared to cognitively normal controls, likely reflecting AD-associated synaptic degeneration. Levels of synaptic markers are also higher in amyloid-positive individuals diagnosed with mild cognitive impairment (MCI) and are associated with a faster rate of cognitive decline and predict progression to dementia. Although levels of NGRN and SNAP-25 are highly correlated with levels of CSF tau and ptau181 (markers of tangles and/or neuronal cell death), longitudinal, within-person comparisons of changes among these biomarkers are needed to determine their more precise temporal ordering with disease progression. Conclusions: Biomarkers of synaptic dysfunction may ultimately be useful for early disease diagnosis, predicting and monitoring cognitive decline during disease progression and for identifying drug effects on synaptic dysfunction and degeneration in clinical trials.
S5-01-02
BLOOD BIOMARKER ASSAYS
Sid O’Bryant, University of North Texas Health Science Center, Fort Worth, TX, USA. Contact e-mail: [email protected] Background: The search for blood-based biomarkers of relevance in
Alzheimer’s disease has grown rapidly. The first-ever consensusbased guidelines for pre-analytic processing were recently published; however, little work has been undertaken to examine the consistency of putative biomarkers across blood fractions and assay platforms. The current study therefore sought to investigate comparison of potential AD biomarkers across blood fractions and assay platform. Methods: Non-fasting serum and plasma samples were analyzed from 300 research participants (AD n¼150, control n¼150) from the Texas Alzheimer’s Research & Care Consortium. Proteomic markers were assayed via multi-plex platforms using
electrochemiluminescence (Meso Scale Discovery) or luminex (Myriad Rules Based Medicine). Results: On the MSD platform, 10 out of the 21markers shared >50% of the variance across blood fraction (SAA R2¼0.99, IL10 R2¼0.95, FABP R2¼0.94, I309 R2¼0.94, IL5 R2¼0.94, IL6 R2¼0.94, Eotaxin3 R2¼0.91, IL18 R2¼0.87, sTNFR1 R2¼0.85, PPY R2¼0.81). When examining the variable importance in detecting AD, only three (IL5, IL6 and IL7) were common among the top 10 markers for the serum versus plasma-based algorithm. Finally, when examining protein concentrations across platforms, only five markers shared >50% of the variance (b2M R2¼0.92, IL18 R2¼0.80, FVII R2¼0.78, CRP R2¼0.74, FABP R2¼0.70). Conclusions: The current findings highlight the importance of considering blood fraction and assay platform when searching for AD biomarkers. Additionally, comparing results across blood fraction and/or platforms likely explains much of the inconsistencies found in the current literature. However, the current findings also point to an underlying logic for the consistency of FABP and CRP across multiple cohorts, assay platforms as well as blood fraction. Additional work is needed to understand these differences in order for the field to progress forward and be able to make interpretable comparisons across studies. S5-01-03
CSF BIOMARKERS VERSUS PET BIOMARKERS
Niklas Mattsson, Lund University, Lund, Sweden. Contact e-mail: niklas. [email protected]
Abstract not available. S5-01-04
ALZBIOMARKER DATABASE ON ESTABLISHED AND NOVEL CSF AND PLASMA BIOMARKERS FOR ALZHEIMER’S DISEASE 1 1 € , Bob Olsson , Ronald Lautner1, Ulf Andreasson1, Annika Ohrfelt Erik Portelius1, Maria Bjerke1, Mikko H€oltt€a1, Christoffer Rosen1, Kelly Dakin2, Elisabeth Wu2, Caroline Olsson3, Max Petzold3, olndal, Kaj Blennow1, Henrik Zetterberg1, 1University of Gothenburg, M€ Sweden; 2Alzforum, Boston, MA, USA; 3University of Gothenburg, Gothenburg, Sweden. Contact e-mail: [email protected]
Abstract not available.
THURSDAY, JULY 23, 2015 FEATURED RESEARCH SESSIONS F5-01 BRAIN CORRELATES OF MODIFIABLE LIFESTYLE RISK FACTORS FOR ALZHEIMER’S DISEASE: FROM ANIMAL RESEARCH TO INTERVENTION TRIALS F5-01-01
CALORIE RESTRICTION IMPROVES BRAIN HEALTH IN AGING RHESUS MACAQUES
Sterling C. Johnson, Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA; Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Contact e-mail: [email protected] Background: Calorie restriction (CR) without malnutrition slows the
aging and disease process, prolonging median and maximum lifespan in yeast, worms, fish, flies, and rodents. Studies of CR in non-human primates (Macaca mulatta) indicate a protective effect of CR against aging-related diseases and a salutary effect on brain health. Methods: Our group has studied the specific effects of CR on the non-human primate brain using neuroimaging, behavioral, and post-mortem histological techniques and this talk will provide an
Podium Presentations: Thursday, July 23, 2015
overview of these findings. Animals in this study were part of the longitudinal “Dietary Restriction and Aging Study” at the Wisconsin National Primate Research Center (WNPRC). Animals were either fed a normal diet or maintained on a moderately restricted diet (approximately 30% reduced intake from baseline), with both groups receiving comparable diet supplements. Results: Using volumetric imaging we demonstrated that CR preserves gray matter cortex in limbic and heteromodal association areas, indicating a positive effect of CR against age-related brain atrophy. Diffusion tensor imaging showed preservation of white matter integrity in the corpus callosum and fronto-occipital fasciculus, superior longitudinal fasciculus, external capsule, and brainstem. CR also attenuated age-related iron accumulation in the basal ganglia, red nucleus, and parietal, temporal, and perirhinal cortex. Decreased iron accumulation was in turn associated with faster performance on fine motor function tests, signifying a protective effect against motor slowness that results during aging. CR moderated the effect of important plasma-based inflammatory markers (e.g. IL-6) on gray and white matter changes in several brain areas, including the parietal and temporal gray matter regions that are sensitive to aging. CR improved glucoregulatory profiles and positively influenced gray matter volume in the hippocampus. Histopathology studies reveal that CR monkeys express significantly lower (w30%) levels of microglial activation in the hippocampus. Energy metabolism in the hippocampus as indexed by PGC1alpha and GSK3B was preserved in CR. Number of MTL amyloid plaques was however equivalent between groups. Conclusions: Overall, these results recapitulate the neuroprotective effects of CR from lower animal models. Taken together, these findings point to an overall beneficial effect of CR on the brain in this non-human primate model of aging.
F5-01-02
IMPACT OF CALORIC RESTRICTION AND CALORIC RESTRICTION-MIMETICS ON BRAIN STRUCTURE AND FUNCTION IN OLDER ADULTS AND PATIENTS WITH MILD COGNITIVE IMPAIRMENT
Agnes Fl€ oel1, Veronica A. Witte2, 1NeuroCure Clinical Research Center, Charite – Universit€ atsmedizin Berlin, Berlin, Germany; 2Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. Contact e-mail: [email protected] Background: In a series of randomized controlled trials, we aim to
elucidate whether caloric restriction (CR) and CR-mimetics exert a beneficial impact on glucose control, memory performance, and brain structure and connectivity in healthy older adults (HO) and patients with mild cognitive impairment (MCI). Methods: 102 HO were assessed for fasting glucose, HbA1c and memory. In the group receiving resveratrol, we additionally conducted MRI scans to determine volume, microstructure, and functional connectivity (FC) of the hippocampus. 50 subjects participated in the CR trial, and were stratified into 3 groups: caloric restriction, increased intake of unsaturated fatty acids, or control; for 3 months. 52 subjects participated in the resveratrol trial and were stratified into 2 groups: 200 mg/d resveratrol or placebo; for 6 months. Baseline parameters were again assessed after 3 and 6 months, respectively. 40 patients with MCI have now (11/2014) completed their intervention (200 mg resveratrol vs placebo) for 6 months. Results: In HV, we found a decrease in fasting insulin and HbA1c levels and an improvement of verbal memory performance (all p < 0.05; [1, 2]). Moreover, MRI revealed increases in hippocampal FC [1]; see Fig. 1. Increases in FC between the left posterior hippocampus
P303
and the medial prefrontal cortex correlated with increases in retention scores and with decreases in HbA1c (all p < 0.05). Analysis of data from the MCI group is still ongoing. Conclusions: Our findings offer the basis for novel strategies to maintain brain health during aging, using not only CR or resveratrol but also lifestyle interventions known to improve glucose control [3]. The study just completed in MCI will demonstrate if these findings extend to the diseased brain. References: 1. Witte, A.V., et al., Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci, 2014. 34(23): p. 7862-70. 2. Witte, A.V., et al., Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A, 2009. 106(4): p. 1255-60. 3. Erickson, K.I., et al., Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A, 2011. 108(7): p. 3017-22.
Figure. In the group receiving resveratrol, decreases in HbA1ccorrelated significantly with increases in FC (r¼0.4, p¼0.04). Triangles show median changes in functional connectivity within a significant cluster in the left medial prefrontal cortex (mPFC) (outlined in red, see inset) using the left posterior hippocampus as seed in relation to changes in HbA1c. Line indicates regression fit.
F5-01-03
BETTER INTELLECTUAL LIFESTYLE TO KEEP COGNITIVE IMPAIRMENT AWAY
Prashanthi Vemuri1, Timothy G. Lesnick1, Scott A. Przybelski1, Mary M. Machulda1, David S. Knopman1, Michelle Mielke1, Rosebud Roberts1, Val J. Lowe1, Walter Rocca1, Yonas E. Geda2, Ronald C. Petersen1, Clifford R. Jack, Jr.1, 1Mayo Clinic, Rochester, MN, USA; 2Mayo Clinic, Scottsdale, AZ, USA. Contact e-mail: Vemuri. [email protected] Background: Intellectual lifestyle enrichment throughout life is
increasingly viewed as a protective strategy against cognitive decline in the elderly. Numerous studies demonstrate that all components of intellectual enrichment – higher lifetime non-leisure learning components such as education and primary occupation as well as cognitively stimulating activities are protective against cognitive decline and dementia. The objective of this abstract was to combine data from our earlier published studies with some new data shown here to investigate the influence of lifestyle on the AD biomarker-cognition trajectories. Methods: In two recent studies, we found that 1) high lifetime intellectual enrichment (75th percentile of both education/occupation and mid/late-life cognitive activity) delayed the onset of cognitive impairment by at least 8