- Email: [email protected]
Plasma ceramides predict age-related differences in white matter microstructure
Poster Presentations: P2
P555
those with suspected mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Although many studies have described atrophy using structural neuroimaging, most have used matched cohorts of limited size with manual or automated segmentation techniques not readily available, reducing the possibility for reproducibility and comparability. Our objective was to produce norms for volumetric estimates of brain structures from MRI using a large sample of cognitively healthy adults and a free, widely available segmentation technique. Methods: We merged T1-weighted MRI data on 2018 healthy adults (1035 women) aged 18 to 90 year old from fifteen datasets (Table 1). Images were acquired using various 3D protocols and scanners but identically processed using FreeSurfer (version 5.3.0) to produce volume or thickness estimates for 25 subcortical and 62 cortical brain subdivisions. We generated general linear models for each subdivision with age, sex, total intracranial volume (TIV), and magnetic field strength as predictors as well as interactions between predictors and quadratic and cubic terms for age and intracranial volume. Final models only included significant predictors (p<.05). Formulas to predict expected volumes/thicknesses according to an individual’s characteristics will be provided. Results: We present results for the hippocampi as an example, given its high relevance to AD. The models explained 46% and 44% of the variance for the left and right hippocampi, respectively (Figure 1). Both models included a cubic term for
age (p<.001) and the interactions TIV X magnetic field strength (p<.001) and age X TIV (p<.001). Sex was also included in the left hippocampus model (p¼.006). The use of these equations is illustrated using controls (n ¼ 200), MCI (n ¼ 402) and AD (n¼189) individuals. As expected, hippocampi volume Z scores generated by the normative models differed significantly between each group (Figure 2; p<.0001). Conclusions: By using these structural neuroimaging normative data and brain volumes generated by FreeSurfer, researchers can easily measure the magnitude of potential brain atrophy according to an individual’s age and sex. P2-170
PLASMA CERAMIDES PREDICT AGE-RELATED DIFFERENCES IN WHITE MATTER MICROSTRUCTURE
Christopher E. Gonzalez1, Vijay K. Venkatraman1, Yang An1, Bennett Landman2, Veera Venkata Ratnam Bandaru3, Norman J. Haughey3, Luigi Ferrucci1, Michelle Mielke4, Susan M. Resnick1, 1National Institute on Aging, Baltimore, MD, USA; 2Vanderbilt University, Nashville, TN, USA; 3 Johns Hopkins University, Baltimore, MD, USA; 4Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: White matter changes measured with diffusion tensor imaging (DTI) are associated with conversion from
P556
Poster Presentations: P2
normal to amnestic mild cognitive impairment (Zhuang et al, 2012). Elevated levels of peripheral sphingolipids predict incident cognitive impairment in cognitively normal individuals (Mielke et al, 2010). Therefore, we investigated whether elevated levels of plasma ceramides predict age-related white matter differences, defined as decreased fractional anisotropy (FA) and increased mean diffusivity (MD), in a group of cognitively normal participants from the Baltimore Longitudinal Study of Aging (BLSA). Methods: BLSA participants (n ¼ 150; baseline age, 67.2 (6 6.7) yrs; 68 males) had fasting plasma samples drawn an average of 10 years before a 3.0 Tesla DTI scan (Philips Achieva). Ceramide concentrations were determined using a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. DTI processing followed standard procedures for motion correction, tensor fitting, and quality assessment (Lauzon et al, 2013). We used linear regression to determine if the plasma ceramide concentrations of different chain lengths and saturation were associated with FA and MD in 17 white matter ROIs from the EVE atlas (a priori p-value p< 0.05). All models adjusted for age, sex, BMI, the interval between peripheral measure and DTI, scanner, diabetes status, and ratio of white matter lesions to intracranial volume. Results: Elevated C20:0 and C22:0 were associated with decreased FA in several regions, including total cerebral white matter, cingulum of cingulate gyrus, and the anterior corona radiata. Elevated C22:1 was associated with decreased FA in the cingulum of the hippocampus and C24:1 with decreased FA and increased MD in the anterior corona radiata. Results for C22:0 and C24:1 remained significant after controlling for total cholesterol and triglycerides. While these results were not adjusted for multiple comparisons, there were no findings at the p<0.05 level indicating high ceramides were associated with higher FA or lower MD. Conclusions: Elevated ceramides were associated with FA and MD an average of 10 years later in several white matter regions. These findings may implicate ceramides as early predictors of age-related changes in white matter integrity, and may be relevant to neurodegenerative diseases such as Alzheimer’s disease.
P2-171
TESTOSTERONE AND SEX-HORMONE BINDING GLOBULIN LEVELS AND BRAIN REGIONS ASSOCIATED WITH COGNITIVE DISORDERS IN MIDDLE-AGE MEN
Martine Elbejjani1, Pamela Schreiner2, R. Nick Bryan3, David Siscovick4, Lenore J. Launer1, 1National Institute on Aging, Bethesda, MD, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3University of Pennsylvania Health System, Philadelphia, PA, USA; 4University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Prior research suggests an association between declining testosterone levels and decreasing cognitive performance and increased risk for neurocognitive disorders in older men. These findings are supported by animal and experimental studies reporting that testosterone has protective effects on the brain and that it is involved in several cognitive-related mechanisms. However, little is known on the direct links between sex-hormone levels and morphological characteristics of candidate brain regions for cognitive functioning in middle-age. Methods: This study examined the relationships of testosterone and sex hormone-binding globulin
(SHBG) levels with volumes of brain regions associated with cognitive functioning in a community-based sample of middleage men. Data come from the Coronary Artery Risk Development in Young Adults CARDIA-brain magnetic resonance (MRI) substudy (n¼267): gray matter (GM) volumes of the prefrontal cortex, medial-temporal lobe, and parietal lobe were collected at the average age of 50 years; data on total testosterone, bioavailable testosterone, and SHBG levels were obtained 10 to 15 years prior to the brain measurements. Results: Adjusted for potential confounders, total and bioavailable testosterone levels were not related to GM volumes in the prefrontal cortex, medial-temporal lobe, or parietal lobe. One z-score increase in SHBG concentration was associated with a -0.8 cm3 decrease in parietal lobe GM (95% Confidence interval (CI)¼ -1.50, -0.13; p¼0.02)). This association was unchanged after adjusting for testosterone levels and additional covariates. We found no associations between sex-hormone levels and GM volumes in specific structures (hippocampus, amygdala, and enthorinal cortex). Conclusions: The parietal lobe has been shown to have distinct characteristics and development in males and has been linked to sex-hormones levels in boys and elderly men. Our results complement these findings and present a relationship between SHBG levels and parietal GM volume in middle-age men. Future studies integrating additional data on estrogen can help improve our understanding of the role of SHBG and its regulatory properties in relation to brain and neurocognitive outcomes. P2-172
THE IMPACT OF MAINTAINING PHYSICAL ACTIVITY IN LATE LIFE ON SUBSEQUENT CHANGE IN BRAIN MICRO- AND MACROSTRUCTURE: FINDINGS FROM THE HEALTH, AGING, AND BODY COMPOSITION STUDY
John R. Best1,2, Caterina Rosano3, Robert M. Boudreau3, Hilsa N. Ayonayon4, Suzanne Satterfield5, Eleanor M. Simonsick6, Stephanie Studenski6, Kristine Yaffe7, Anne B. Newman3, Teresa LiuAmbrose1,2, 1University of British Columbia, Vancouver, BC, Canada; 2 Djavad Mowafaghian Centre for Brain Health, Vancouver, BC, Canada; 3 University of Pittsburgh, Pittsburgh, PA, USA; 4University of California San Francisco, San Francisco, CA, USA; 5University of Tennessee Health Science Center, Memphis, TN, USA; 6National Institutes of Health, Baltimore, MD, USA; 7University of California, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: The effects of maintaining physical activity over an extended period of time on future change in older adults’ brain structure are unknown. This study examined self-reported time spent walking (an index of physical activity) over a ten-year period on future change in brain macro- and microstructure. Methods: 313 older adults (mean age ¼ 72.9 years at year 1) from the Health ABC Study participated in a neuroimaging substudy. Time spent walking (mins/week) was reported annually from years 1 to 10. Magnetic resonance imaging with diffusion tensor was undertaken at years 10 and 13. Neuroimaging measures of interest were macrostructure (gray matter [GM] and white matter [WM] hyper-intensity volume) and microstructure (GM mean diffusivity and WM fractional anisotropy). Structural equation modeling examined whether change in walking over the 10year period predicted brain structure at year 10 and/or change in brain structure from year 10 to year 13 (see Figure). Covariates included cohort, age, education, race, BMI, sex, smoking and drinking status, prevalent diabetes, cerebrovascular and cardiovascular disease, and
P555
those with suspected mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Although many studies have described atrophy using structural neuroimaging, most have used matched cohorts of limited size with manual or automated segmentation techniques not readily available, reducing the possibility for reproducibility and comparability. Our objective was to produce norms for volumetric estimates of brain structures from MRI using a large sample of cognitively healthy adults and a free, widely available segmentation technique. Methods: We merged T1-weighted MRI data on 2018 healthy adults (1035 women) aged 18 to 90 year old from fifteen datasets (Table 1). Images were acquired using various 3D protocols and scanners but identically processed using FreeSurfer (version 5.3.0) to produce volume or thickness estimates for 25 subcortical and 62 cortical brain subdivisions. We generated general linear models for each subdivision with age, sex, total intracranial volume (TIV), and magnetic field strength as predictors as well as interactions between predictors and quadratic and cubic terms for age and intracranial volume. Final models only included significant predictors (p<.05). Formulas to predict expected volumes/thicknesses according to an individual’s characteristics will be provided. Results: We present results for the hippocampi as an example, given its high relevance to AD. The models explained 46% and 44% of the variance for the left and right hippocampi, respectively (Figure 1). Both models included a cubic term for
age (p<.001) and the interactions TIV X magnetic field strength (p<.001) and age X TIV (p<.001). Sex was also included in the left hippocampus model (p¼.006). The use of these equations is illustrated using controls (n ¼ 200), MCI (n ¼ 402) and AD (n¼189) individuals. As expected, hippocampi volume Z scores generated by the normative models differed significantly between each group (Figure 2; p<.0001). Conclusions: By using these structural neuroimaging normative data and brain volumes generated by FreeSurfer, researchers can easily measure the magnitude of potential brain atrophy according to an individual’s age and sex. P2-170
PLASMA CERAMIDES PREDICT AGE-RELATED DIFFERENCES IN WHITE MATTER MICROSTRUCTURE
Christopher E. Gonzalez1, Vijay K. Venkatraman1, Yang An1, Bennett Landman2, Veera Venkata Ratnam Bandaru3, Norman J. Haughey3, Luigi Ferrucci1, Michelle Mielke4, Susan M. Resnick1, 1National Institute on Aging, Baltimore, MD, USA; 2Vanderbilt University, Nashville, TN, USA; 3 Johns Hopkins University, Baltimore, MD, USA; 4Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: White matter changes measured with diffusion tensor imaging (DTI) are associated with conversion from
P556
Poster Presentations: P2
normal to amnestic mild cognitive impairment (Zhuang et al, 2012). Elevated levels of peripheral sphingolipids predict incident cognitive impairment in cognitively normal individuals (Mielke et al, 2010). Therefore, we investigated whether elevated levels of plasma ceramides predict age-related white matter differences, defined as decreased fractional anisotropy (FA) and increased mean diffusivity (MD), in a group of cognitively normal participants from the Baltimore Longitudinal Study of Aging (BLSA). Methods: BLSA participants (n ¼ 150; baseline age, 67.2 (6 6.7) yrs; 68 males) had fasting plasma samples drawn an average of 10 years before a 3.0 Tesla DTI scan (Philips Achieva). Ceramide concentrations were determined using a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. DTI processing followed standard procedures for motion correction, tensor fitting, and quality assessment (Lauzon et al, 2013). We used linear regression to determine if the plasma ceramide concentrations of different chain lengths and saturation were associated with FA and MD in 17 white matter ROIs from the EVE atlas (a priori p-value p< 0.05). All models adjusted for age, sex, BMI, the interval between peripheral measure and DTI, scanner, diabetes status, and ratio of white matter lesions to intracranial volume. Results: Elevated C20:0 and C22:0 were associated with decreased FA in several regions, including total cerebral white matter, cingulum of cingulate gyrus, and the anterior corona radiata. Elevated C22:1 was associated with decreased FA in the cingulum of the hippocampus and C24:1 with decreased FA and increased MD in the anterior corona radiata. Results for C22:0 and C24:1 remained significant after controlling for total cholesterol and triglycerides. While these results were not adjusted for multiple comparisons, there were no findings at the p<0.05 level indicating high ceramides were associated with higher FA or lower MD. Conclusions: Elevated ceramides were associated with FA and MD an average of 10 years later in several white matter regions. These findings may implicate ceramides as early predictors of age-related changes in white matter integrity, and may be relevant to neurodegenerative diseases such as Alzheimer’s disease.
P2-171
TESTOSTERONE AND SEX-HORMONE BINDING GLOBULIN LEVELS AND BRAIN REGIONS ASSOCIATED WITH COGNITIVE DISORDERS IN MIDDLE-AGE MEN
Martine Elbejjani1, Pamela Schreiner2, R. Nick Bryan3, David Siscovick4, Lenore J. Launer1, 1National Institute on Aging, Bethesda, MD, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3University of Pennsylvania Health System, Philadelphia, PA, USA; 4University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Prior research suggests an association between declining testosterone levels and decreasing cognitive performance and increased risk for neurocognitive disorders in older men. These findings are supported by animal and experimental studies reporting that testosterone has protective effects on the brain and that it is involved in several cognitive-related mechanisms. However, little is known on the direct links between sex-hormone levels and morphological characteristics of candidate brain regions for cognitive functioning in middle-age. Methods: This study examined the relationships of testosterone and sex hormone-binding globulin
(SHBG) levels with volumes of brain regions associated with cognitive functioning in a community-based sample of middleage men. Data come from the Coronary Artery Risk Development in Young Adults CARDIA-brain magnetic resonance (MRI) substudy (n¼267): gray matter (GM) volumes of the prefrontal cortex, medial-temporal lobe, and parietal lobe were collected at the average age of 50 years; data on total testosterone, bioavailable testosterone, and SHBG levels were obtained 10 to 15 years prior to the brain measurements. Results: Adjusted for potential confounders, total and bioavailable testosterone levels were not related to GM volumes in the prefrontal cortex, medial-temporal lobe, or parietal lobe. One z-score increase in SHBG concentration was associated with a -0.8 cm3 decrease in parietal lobe GM (95% Confidence interval (CI)¼ -1.50, -0.13; p¼0.02)). This association was unchanged after adjusting for testosterone levels and additional covariates. We found no associations between sex-hormone levels and GM volumes in specific structures (hippocampus, amygdala, and enthorinal cortex). Conclusions: The parietal lobe has been shown to have distinct characteristics and development in males and has been linked to sex-hormones levels in boys and elderly men. Our results complement these findings and present a relationship between SHBG levels and parietal GM volume in middle-age men. Future studies integrating additional data on estrogen can help improve our understanding of the role of SHBG and its regulatory properties in relation to brain and neurocognitive outcomes. P2-172
THE IMPACT OF MAINTAINING PHYSICAL ACTIVITY IN LATE LIFE ON SUBSEQUENT CHANGE IN BRAIN MICRO- AND MACROSTRUCTURE: FINDINGS FROM THE HEALTH, AGING, AND BODY COMPOSITION STUDY
John R. Best1,2, Caterina Rosano3, Robert M. Boudreau3, Hilsa N. Ayonayon4, Suzanne Satterfield5, Eleanor M. Simonsick6, Stephanie Studenski6, Kristine Yaffe7, Anne B. Newman3, Teresa LiuAmbrose1,2, 1University of British Columbia, Vancouver, BC, Canada; 2 Djavad Mowafaghian Centre for Brain Health, Vancouver, BC, Canada; 3 University of Pittsburgh, Pittsburgh, PA, USA; 4University of California San Francisco, San Francisco, CA, USA; 5University of Tennessee Health Science Center, Memphis, TN, USA; 6National Institutes of Health, Baltimore, MD, USA; 7University of California, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: The effects of maintaining physical activity over an extended period of time on future change in older adults’ brain structure are unknown. This study examined self-reported time spent walking (an index of physical activity) over a ten-year period on future change in brain macro- and microstructure. Methods: 313 older adults (mean age ¼ 72.9 years at year 1) from the Health ABC Study participated in a neuroimaging substudy. Time spent walking (mins/week) was reported annually from years 1 to 10. Magnetic resonance imaging with diffusion tensor was undertaken at years 10 and 13. Neuroimaging measures of interest were macrostructure (gray matter [GM] and white matter [WM] hyper-intensity volume) and microstructure (GM mean diffusivity and WM fractional anisotropy). Structural equation modeling examined whether change in walking over the 10year period predicted brain structure at year 10 and/or change in brain structure from year 10 to year 13 (see Figure). Covariates included cohort, age, education, race, BMI, sex, smoking and drinking status, prevalent diabetes, cerebrovascular and cardiovascular disease, and