- Email: [email protected]
SMALL-VESSEL CEREBROVASCULAR PATHOLOGY IS ASSOCIATED WITH INCREASING ODDS OF POOR PHYSICAL PERFORMANCE IN THE OLDEST-OLD: THE 90+ STUDY
Oral Sessions: O4-08: Epidemiology: New Advances in Risk Factors
over several years could be clinically significant. As pesticides have become so ubiquitous, further study is needed to determine the effect on cognition of non-occupational exposures. O4-08-03
GENETIC RISK OF NEURODEGENERATIVE DISEASES IS ASSOCIATED WITH MILD COGNITIVE IMPAIRMENT AND CONVERSION TO DEMENTIA: THE ROTTERDAM STUDY
Hieab H.H. Adams1, Renee F.A.G. de Bruijn2, Albert Hofman3, Andre Uitterlinden1, Cornelia Van Duijn4, Meike Vernooij1, Peter Koudstaal3, Mohammad Arfan Ikram1, 1Erasmus MC, Rotterdam, Netherlands; 2Erasmus MC University Medical Center, Rotterdam, Netherlands; 3Erasmus Medical Center, Rotterdam, Netherlands; 4Erasmus University Medical Center, Rotterdam, Netherlands. Contact e-mail: h. [email protected] Background: Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored. We investigated whether genetic variants for Alzheimer’s disease (AD), Parkinson’s disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) associate with mild cognitive impairment (MCI) and subsequently lead to conversion to dementia. Methods: In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged 55 years were genotyped, screened for MCI in 2002-2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores were constructed from genetic variants for AD, PD and FTLD/ALS. Logistic regression models were used to examine associations between the risk scores and MCI status and Cox proportional hazard models to evaluate conversion of MCI to dementia. All analyses were adjusted for age and sex. Results: In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) amnestic and 213 (5.9%) non-amnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with non-amnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]). Conclusions: Genetic evidence supports the view that a common process leads to MCI, whereas subsequent conversion to dementia results from disease-specific mechanisms.
P267
between them remains unclear. We sought to investigate the association of frailty with the risk of incident mild cognitive impairment (MCI). Methods: We prospectively followed 2356 cognitively normal persons (aged 70 years upwards), enrolled in the population-based Mayo Clinic Study of Aging, for a median of 4.5 years to the outcome of incident MCI. Participants underwent comprehensive medical and cognitive assessments with follow-up every 15 months. Cognitive testing included tests of memory, executive function, language, and visuospatial skills. The diagnosis of MCI was made by an expert consensus panel. Frailty was measured using a 36-item Index of health deficits, including medical conditions, symptoms, functional impairments and psychological variables, based on a previously validated approach. Most deficits were binary, coded as 1¼ present, 0¼ absent. Variables with an intermediate response were coded as 0.5 for ’sometimes’ and 1 for ’all of the time’. Individual deficit scores were expressed as an Index ranging from 0¼no deficits to 1¼all 36 present. A cut-point of 0.25 (9 deficits) was used to denote someone as frail. The association of frailty with incident MCI was assessed using Cox proportional hazards models adjusted for age, male gender, education and ApoE4. Results: The mean (6standard deviation) age was 78.8 years (65.2) and 50.2% were male. The mean Frailty Index score was 0.18 (60.09). At baseline, 508 participants (21.6%) were classified as frail, tending to be older and male. Follow-up assessments were available for 2044 participants and 551 (27.0%) developed incident MCI. The number of deficits present predicted MCI. For each additional deficit added to the Index the hazard ratio (HR) for incident MCI was 1.12 (95% confidence interval (CI) ¼ 1.09-1.15). Being frail was associated with a significantly greater risk of incident MCI (HR ¼ 3.09; 95% CI ¼ 2.27-4.20). Conclusions: Baseline frailty, measured by a Frailty Index among cognitively normal older people, significantly increased the risk of incident MCI. This suggests that clinicians should consider frailty in the evaluation and management of older people at risk of MCI.
O4-08-05
SMALL-VESSEL CEREBROVASCULAR PATHOLOGY IS ASSOCIATED WITH INCREASING ODDS OF POOR PHYSICAL PERFORMANCE IN THE OLDEST-OLD: THE 90+ STUDY
Szofia S. Bullain, Shawna M. Perry, Claudia H. Kawas, Maria M. Corrada, University of California, Irvine, Irvine, California, United States. Contact e-mail: [email protected]
Table 1 Associations of genetic risk scores for neurodegenerative diseases with mild cognitive impairment Genetic risk score, per SD
OR for MCI
P value
OR for amnestic MCI
P value
OR for non-amnestic MCI
P value
Alzheimer disease Alzheimer disease without APOE Parkinson disease FTLD/ALS Combined risk score
1.15 (1.03 - 1.28) 1.19 (1.07 - 1.33) 1.09 (0.98 - 1.21) 1.09 (0.98 - 1.22) 1.20 (1.07 - 1.33)
0.011 0.002 0.132 0.130 0.001
1.16 (0.99 - 1.36) 1.11 (0.94 - 1.31) 1.00 (0.84 - 1.18) 0.97 (0.82 - 1.14) 1.11 (0.94 - 1.31)
0.062 0.223 0.954 0.680 0.211
1.14 (0.99 - 1.31) 1.25 (1.09 - 1.44) 1.15 (1.00 - 1.32) 1.19 (1.03 - 1.37) 1.26 (1.10 - 1.45)
0.063 0.002 0.044 0.019 0.001
Values are odds ratios with 95% confidence intervals per SD of genetic risk score, adjusted for age and sex. Abbreviations: OR ¼ odds ratio, SD ¼ standard deviation, MCI ¼ Mild cognitive impairment, FTLD/ALS ¼ Frontotemporal lobar degeneration/amyotrophic lateral sclerosis. O4-08-04
FRAILTY AND THE RISK OF INCIDENT MILD COGNITIVE IMPAIRMENT: THE MAYO CLINIC STUDY OF AGING
Mairead M. Bartley1, Teresa J.H. Christianson1, Vernon Pankratz1, Rosebud O. Roberts1, Yonas E. Geda2, Ronald Carl Petersen3, 1Mayo Clinic, Rochester, Minnesota, United States; 2Mayo Clinic College of Medicine. Rochester, Minnesota, and Scottsdale, Arizona, United States; 3Mayo Clinic Rochester, Rochester, Minnesota, United States. Contact e-mail: bartley. [email protected] Background: With the changing population demographics cognitive impairment and frailty are on an upward trajectory. The exact relationship
Background: We previously showed strong cross-sectional and prospective associations between poor physical performance and dementia in the oldestold, suggesting that poor physical performance might be a risk factor for lateage dementia. To further understand the association between cognitive and physical impairment, we sought to evaluate the relationship between underlying cerebrovascular pathology and physical performance in the oldest-old as cerebrovascular pathology had been previously linked to both physical and cognitive impairment in younger elderly. Methods: The 90+ Study is a population based investigation of dementia in people aged 90 years old and older. 141 participants with baseline physical performance measures and post-mortem neuropathological evaluation were included in this study. The outcome was physical performance (4-meter walk, 5 chair-stands, balance and
P268
Oral Sessions: O4-09: Molecular and Cell Biology: Neurodegeneration
handgrip strength tests) which was scored from 0-4 (0¼ unable to perform, 4¼ best performance) based on previously established sex specific quartiles. Performance was then re-categorized into unable to perform (score 0), low performance (scores 1, 2) and high performance (scores 3, 4). Here, we focused on small-vessel pathology defined as the presence of microinfarct or lacunar infarct (0¼absent, 1¼present). Odds ratios (OR) for poorer performance in relation to underlying small-vessel cerebrovascular pathology were estimated by using ordinal logistic regression after adjusting for age. Results: At baseline, participants were on average 93 years old (range: 90-103), and most were women (67%). On autopsy, 57% had small-vessel cerebrovascular pathology (53% microinfarcts and 17% lacunar infarcts). Presence of smallvessel cerebrovascular pathology was associated with increasing odds of poor performance in all measures; however, the associations were only significant in balance and 4-m walk (Table). Conclusions: We observed increasing odds of poor performance in all physical performance measures in the presence of small-vessel cerebrovascular pathology, although the association was greater in measures more dependent on coordination and proprioception than muscle strength. Our findings suggest that in the oldest-old the association between poor physical performance and dementia could be, at least partially, mediated by small-vessel cerebrovascular pathology. Future research is necessary to determine if small-vessel cerebrovascular pathology may be a target in preventing late-age cognitive and physical impairment. Table Odds of poor physical performance in the presence of small-vessel cerebrovascular pathology Physical Performance Measure
Odds Ratio (95% Confidence Interval)
p-value
Balance 4-meter walk Handgrip 5 chair-stands
2.27 (1.19 - 4.35) 1.98 (1.03 - 3.82) 1.67 (0.88 – 3.16) 1.61 (0.85 - 3.05)
0.01* 0.04* 0.12 0.14
*Significant at 0.05 level O4-08-06
SELF-REPORTED INDICATORS OF SLEEP APNEA ARE ASSOCIATED WITH WHITE MATTER HYPERINTENSITIES
Sara Rostanski1, Molly E. Zimmerman2, Nicole Schupf1, Jennifer Manly1, Andrew J. Westwood1, Richard Mayeux3, Adam M. Brickman1, Yian Gu1, 1 Columbia University Medical Center, New York, New York, United States; 2 Albert Einstein College of Medicine, Bronx, New York, United States; 3 Columbia University Medical Center, New York, New York, United States. Contact e-mail: [email protected] Background: Sleep-disordered breathing (SDB) has a well-established relationship with cardiovascular disease including stroke, although the exact pathophysiologic mechanisms are not known. While several large, population-based epidemiologic studies have shown relationships between self-reported sleep measures and cardiovascular outcomes, none have evaluated an association with leukoaraiosis. Some previous reports studying the association between leukoaraiosis and SDB have been mixed. We examined the association between several self-reported sleep variables and magnetic resonance imaging (MRI)-measured white matter hyperintensities volume (WMHV) in a community-based cohort of elders, 65 years and older. Methods: Participants in the study were from Washington Heights-Inwood Columbia Aging Project (WHICAP), a community-based, ethnically diverse, study of aging and dementia in New York City. Sleep problems over the prior four weeks were self-reported using the 12-item Medical Outcomes Study-Sleep Scale (MOS-SS). Nine questions that best measure six characteristics of sleep, including initiation, maintenance, adequacy, drowsiness, and respiratory impairments (including two SDB measures: shortness of breath and snoring) were used in the analysis. The six possible responses to each of the questions were dichotomized into high and low frequency. General linear regression models were used to assess the relationship between each MOS-SS response and total WMHV, controlling for age, gender, ethnicity, hypertension, APOE ε4 status, total intracranial volume, and body
mass index. Results: A total of 498 participants had both sleep and imaging data and were included in the study. Subjects who reported high frequencies of “waking short of breath or headache” (b¼1.98, p¼0.035) or “snoring” (b¼2.07, p¼0.005) had higher WMHV than those who reported low frequencies of each. Other measured sleep characteristics were not associated with WMHV.Results were similar when 64 dementia subjects were excluded from the analysis. Conclusions: Findings from the present cross-sectional study suggest that in this ethnically diverse, elderly population there is an association between WMHV and those sleep characteristics most associated with apnea. Sleep apnea could be associated with leukoaraiosis by inducing hypoperfusion as well as other altered cerebral hemodynamics. Further prospective studies with objective sleep data are needed. WEDNESDAY, JULY 16, 2014 ORAL SESSIONS O4-09 MOLECULAR AND CELL BIOLOGY: NEURODEGENERATION O4-09-01
SLEEP DEPRIVATION IMPAIRS MEMORY, TAU METABOLISM, AND SYNAPTIC INTEGRITY OF A MOUSE MODEL OF ALZHEIMER’S DISEASE
Antonio DiMeco1, Domenico Pratico1, Yash B. Joshi2, 1Temple University, Philadelphia, Pennsylvania, United States; 2Temple University School of Medicine, Philadelphia, Pennsylvania, United States. Contact e-mail: [email protected] Background: Several studies have highlighted the frequency of sleep disturbances in Alzheimer’s disease (AD). However, whether they are secondary to the disease or per se increase its risk remains to be fully investigated. Methods: The aim of the current investigation was to study the effect of sleep deprivation (SD) on the development of AD phenotype in a transgenic mouse model with plaques and tangles, the 3xTg mice. To this end, we evaluated the functional and biological consequences on 3xTg mice that underwent four hours sleep restrain per day for 8 weeks. Results: Compared with controls, behavioral assessment showed that SD-treated mice had a significant decline in their learning and memory. While no differences were detected in the levels of soluble Abeta peptides, the same animals displayed a decrease in tau phosphorylation, which associated with a significant increase in its insoluble fraction. In addition, we observed that SD resulted in lower levels of post-synaptic density protein 95 and increased glial fibrillary acidic protein levels. Finally, while total levels of the transcription factor CREB was unchanged, its phosphorylated form was significantly diminished in brains of sleep-deprived mice when compared with controls. Conclusions: Our study underlines the importance of SD as a chronic stressor, which by modulating biochemical processes influences the development of memory impairments and AD neuropathologies. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD in individuals bearing this risk factor. O4-09-02
PET IMAGING OF SYNERGISTIC, BUT MODALLY DISTINCT OBESITY- AND AB-TRIGGERED ABNORMALITIES IN CEREBRAL GLUCOSE METABOLISM AND GLIOSIS IN MICE
Anna M. Barron1, Masaki Tokunaga2, Bin Ji2, Tetsuya Suhara2, Makoto Higuchi2, 1National Institute of Radiological Sciences, Tokyo, Japan; 2National Institute of Radiological Sciences, Chiba, Japan. Contact e-mail: [email protected] Background: High sucrose, high saturated fat western diets are increasingly leading to health issues such as obesity, metabolic syndrome and diabetes. Growing evidence also suggests that the western diet, and resulting metabolic abnormalities such as chronic hyperglycemia and inflammation, may increase the risk of cognitive decline and Alzheimer’s disease (AD). The aim of this study was to assess changes in cerebral glucose metabolism and glial TSPO expression in response to obesity and intracerebroventricular Ab infusion in vivo using PET. Methods: Three month old C57BL/J6 mice were fed either a standard (non-obese group) or high fat diet (obese group) for 3 months, and intracerebroventricularly infused with vehicle or
over several years could be clinically significant. As pesticides have become so ubiquitous, further study is needed to determine the effect on cognition of non-occupational exposures. O4-08-03
GENETIC RISK OF NEURODEGENERATIVE DISEASES IS ASSOCIATED WITH MILD COGNITIVE IMPAIRMENT AND CONVERSION TO DEMENTIA: THE ROTTERDAM STUDY
Hieab H.H. Adams1, Renee F.A.G. de Bruijn2, Albert Hofman3, Andre Uitterlinden1, Cornelia Van Duijn4, Meike Vernooij1, Peter Koudstaal3, Mohammad Arfan Ikram1, 1Erasmus MC, Rotterdam, Netherlands; 2Erasmus MC University Medical Center, Rotterdam, Netherlands; 3Erasmus Medical Center, Rotterdam, Netherlands; 4Erasmus University Medical Center, Rotterdam, Netherlands. Contact e-mail: h. [email protected] Background: Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored. We investigated whether genetic variants for Alzheimer’s disease (AD), Parkinson’s disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) associate with mild cognitive impairment (MCI) and subsequently lead to conversion to dementia. Methods: In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged 55 years were genotyped, screened for MCI in 2002-2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores were constructed from genetic variants for AD, PD and FTLD/ALS. Logistic regression models were used to examine associations between the risk scores and MCI status and Cox proportional hazard models to evaluate conversion of MCI to dementia. All analyses were adjusted for age and sex. Results: In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) amnestic and 213 (5.9%) non-amnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with non-amnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]). Conclusions: Genetic evidence supports the view that a common process leads to MCI, whereas subsequent conversion to dementia results from disease-specific mechanisms.
P267
between them remains unclear. We sought to investigate the association of frailty with the risk of incident mild cognitive impairment (MCI). Methods: We prospectively followed 2356 cognitively normal persons (aged 70 years upwards), enrolled in the population-based Mayo Clinic Study of Aging, for a median of 4.5 years to the outcome of incident MCI. Participants underwent comprehensive medical and cognitive assessments with follow-up every 15 months. Cognitive testing included tests of memory, executive function, language, and visuospatial skills. The diagnosis of MCI was made by an expert consensus panel. Frailty was measured using a 36-item Index of health deficits, including medical conditions, symptoms, functional impairments and psychological variables, based on a previously validated approach. Most deficits were binary, coded as 1¼ present, 0¼ absent. Variables with an intermediate response were coded as 0.5 for ’sometimes’ and 1 for ’all of the time’. Individual deficit scores were expressed as an Index ranging from 0¼no deficits to 1¼all 36 present. A cut-point of 0.25 (9 deficits) was used to denote someone as frail. The association of frailty with incident MCI was assessed using Cox proportional hazards models adjusted for age, male gender, education and ApoE4. Results: The mean (6standard deviation) age was 78.8 years (65.2) and 50.2% were male. The mean Frailty Index score was 0.18 (60.09). At baseline, 508 participants (21.6%) were classified as frail, tending to be older and male. Follow-up assessments were available for 2044 participants and 551 (27.0%) developed incident MCI. The number of deficits present predicted MCI. For each additional deficit added to the Index the hazard ratio (HR) for incident MCI was 1.12 (95% confidence interval (CI) ¼ 1.09-1.15). Being frail was associated with a significantly greater risk of incident MCI (HR ¼ 3.09; 95% CI ¼ 2.27-4.20). Conclusions: Baseline frailty, measured by a Frailty Index among cognitively normal older people, significantly increased the risk of incident MCI. This suggests that clinicians should consider frailty in the evaluation and management of older people at risk of MCI.
O4-08-05
SMALL-VESSEL CEREBROVASCULAR PATHOLOGY IS ASSOCIATED WITH INCREASING ODDS OF POOR PHYSICAL PERFORMANCE IN THE OLDEST-OLD: THE 90+ STUDY
Szofia S. Bullain, Shawna M. Perry, Claudia H. Kawas, Maria M. Corrada, University of California, Irvine, Irvine, California, United States. Contact e-mail: [email protected]
Table 1 Associations of genetic risk scores for neurodegenerative diseases with mild cognitive impairment Genetic risk score, per SD
OR for MCI
P value
OR for amnestic MCI
P value
OR for non-amnestic MCI
P value
Alzheimer disease Alzheimer disease without APOE Parkinson disease FTLD/ALS Combined risk score
1.15 (1.03 - 1.28) 1.19 (1.07 - 1.33) 1.09 (0.98 - 1.21) 1.09 (0.98 - 1.22) 1.20 (1.07 - 1.33)
0.011 0.002 0.132 0.130 0.001
1.16 (0.99 - 1.36) 1.11 (0.94 - 1.31) 1.00 (0.84 - 1.18) 0.97 (0.82 - 1.14) 1.11 (0.94 - 1.31)
0.062 0.223 0.954 0.680 0.211
1.14 (0.99 - 1.31) 1.25 (1.09 - 1.44) 1.15 (1.00 - 1.32) 1.19 (1.03 - 1.37) 1.26 (1.10 - 1.45)
0.063 0.002 0.044 0.019 0.001
Values are odds ratios with 95% confidence intervals per SD of genetic risk score, adjusted for age and sex. Abbreviations: OR ¼ odds ratio, SD ¼ standard deviation, MCI ¼ Mild cognitive impairment, FTLD/ALS ¼ Frontotemporal lobar degeneration/amyotrophic lateral sclerosis. O4-08-04
FRAILTY AND THE RISK OF INCIDENT MILD COGNITIVE IMPAIRMENT: THE MAYO CLINIC STUDY OF AGING
Mairead M. Bartley1, Teresa J.H. Christianson1, Vernon Pankratz1, Rosebud O. Roberts1, Yonas E. Geda2, Ronald Carl Petersen3, 1Mayo Clinic, Rochester, Minnesota, United States; 2Mayo Clinic College of Medicine. Rochester, Minnesota, and Scottsdale, Arizona, United States; 3Mayo Clinic Rochester, Rochester, Minnesota, United States. Contact e-mail: bartley. [email protected] Background: With the changing population demographics cognitive impairment and frailty are on an upward trajectory. The exact relationship
Background: We previously showed strong cross-sectional and prospective associations between poor physical performance and dementia in the oldestold, suggesting that poor physical performance might be a risk factor for lateage dementia. To further understand the association between cognitive and physical impairment, we sought to evaluate the relationship between underlying cerebrovascular pathology and physical performance in the oldest-old as cerebrovascular pathology had been previously linked to both physical and cognitive impairment in younger elderly. Methods: The 90+ Study is a population based investigation of dementia in people aged 90 years old and older. 141 participants with baseline physical performance measures and post-mortem neuropathological evaluation were included in this study. The outcome was physical performance (4-meter walk, 5 chair-stands, balance and
P268
Oral Sessions: O4-09: Molecular and Cell Biology: Neurodegeneration
handgrip strength tests) which was scored from 0-4 (0¼ unable to perform, 4¼ best performance) based on previously established sex specific quartiles. Performance was then re-categorized into unable to perform (score 0), low performance (scores 1, 2) and high performance (scores 3, 4). Here, we focused on small-vessel pathology defined as the presence of microinfarct or lacunar infarct (0¼absent, 1¼present). Odds ratios (OR) for poorer performance in relation to underlying small-vessel cerebrovascular pathology were estimated by using ordinal logistic regression after adjusting for age. Results: At baseline, participants were on average 93 years old (range: 90-103), and most were women (67%). On autopsy, 57% had small-vessel cerebrovascular pathology (53% microinfarcts and 17% lacunar infarcts). Presence of smallvessel cerebrovascular pathology was associated with increasing odds of poor performance in all measures; however, the associations were only significant in balance and 4-m walk (Table). Conclusions: We observed increasing odds of poor performance in all physical performance measures in the presence of small-vessel cerebrovascular pathology, although the association was greater in measures more dependent on coordination and proprioception than muscle strength. Our findings suggest that in the oldest-old the association between poor physical performance and dementia could be, at least partially, mediated by small-vessel cerebrovascular pathology. Future research is necessary to determine if small-vessel cerebrovascular pathology may be a target in preventing late-age cognitive and physical impairment. Table Odds of poor physical performance in the presence of small-vessel cerebrovascular pathology Physical Performance Measure
Odds Ratio (95% Confidence Interval)
p-value
Balance 4-meter walk Handgrip 5 chair-stands
2.27 (1.19 - 4.35) 1.98 (1.03 - 3.82) 1.67 (0.88 – 3.16) 1.61 (0.85 - 3.05)
0.01* 0.04* 0.12 0.14
*Significant at 0.05 level O4-08-06
SELF-REPORTED INDICATORS OF SLEEP APNEA ARE ASSOCIATED WITH WHITE MATTER HYPERINTENSITIES
Sara Rostanski1, Molly E. Zimmerman2, Nicole Schupf1, Jennifer Manly1, Andrew J. Westwood1, Richard Mayeux3, Adam M. Brickman1, Yian Gu1, 1 Columbia University Medical Center, New York, New York, United States; 2 Albert Einstein College of Medicine, Bronx, New York, United States; 3 Columbia University Medical Center, New York, New York, United States. Contact e-mail: [email protected] Background: Sleep-disordered breathing (SDB) has a well-established relationship with cardiovascular disease including stroke, although the exact pathophysiologic mechanisms are not known. While several large, population-based epidemiologic studies have shown relationships between self-reported sleep measures and cardiovascular outcomes, none have evaluated an association with leukoaraiosis. Some previous reports studying the association between leukoaraiosis and SDB have been mixed. We examined the association between several self-reported sleep variables and magnetic resonance imaging (MRI)-measured white matter hyperintensities volume (WMHV) in a community-based cohort of elders, 65 years and older. Methods: Participants in the study were from Washington Heights-Inwood Columbia Aging Project (WHICAP), a community-based, ethnically diverse, study of aging and dementia in New York City. Sleep problems over the prior four weeks were self-reported using the 12-item Medical Outcomes Study-Sleep Scale (MOS-SS). Nine questions that best measure six characteristics of sleep, including initiation, maintenance, adequacy, drowsiness, and respiratory impairments (including two SDB measures: shortness of breath and snoring) were used in the analysis. The six possible responses to each of the questions were dichotomized into high and low frequency. General linear regression models were used to assess the relationship between each MOS-SS response and total WMHV, controlling for age, gender, ethnicity, hypertension, APOE ε4 status, total intracranial volume, and body
mass index. Results: A total of 498 participants had both sleep and imaging data and were included in the study. Subjects who reported high frequencies of “waking short of breath or headache” (b¼1.98, p¼0.035) or “snoring” (b¼2.07, p¼0.005) had higher WMHV than those who reported low frequencies of each. Other measured sleep characteristics were not associated with WMHV.Results were similar when 64 dementia subjects were excluded from the analysis. Conclusions: Findings from the present cross-sectional study suggest that in this ethnically diverse, elderly population there is an association between WMHV and those sleep characteristics most associated with apnea. Sleep apnea could be associated with leukoaraiosis by inducing hypoperfusion as well as other altered cerebral hemodynamics. Further prospective studies with objective sleep data are needed. WEDNESDAY, JULY 16, 2014 ORAL SESSIONS O4-09 MOLECULAR AND CELL BIOLOGY: NEURODEGENERATION O4-09-01
SLEEP DEPRIVATION IMPAIRS MEMORY, TAU METABOLISM, AND SYNAPTIC INTEGRITY OF A MOUSE MODEL OF ALZHEIMER’S DISEASE
Antonio DiMeco1, Domenico Pratico1, Yash B. Joshi2, 1Temple University, Philadelphia, Pennsylvania, United States; 2Temple University School of Medicine, Philadelphia, Pennsylvania, United States. Contact e-mail: [email protected] Background: Several studies have highlighted the frequency of sleep disturbances in Alzheimer’s disease (AD). However, whether they are secondary to the disease or per se increase its risk remains to be fully investigated. Methods: The aim of the current investigation was to study the effect of sleep deprivation (SD) on the development of AD phenotype in a transgenic mouse model with plaques and tangles, the 3xTg mice. To this end, we evaluated the functional and biological consequences on 3xTg mice that underwent four hours sleep restrain per day for 8 weeks. Results: Compared with controls, behavioral assessment showed that SD-treated mice had a significant decline in their learning and memory. While no differences were detected in the levels of soluble Abeta peptides, the same animals displayed a decrease in tau phosphorylation, which associated with a significant increase in its insoluble fraction. In addition, we observed that SD resulted in lower levels of post-synaptic density protein 95 and increased glial fibrillary acidic protein levels. Finally, while total levels of the transcription factor CREB was unchanged, its phosphorylated form was significantly diminished in brains of sleep-deprived mice when compared with controls. Conclusions: Our study underlines the importance of SD as a chronic stressor, which by modulating biochemical processes influences the development of memory impairments and AD neuropathologies. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD in individuals bearing this risk factor. O4-09-02
PET IMAGING OF SYNERGISTIC, BUT MODALLY DISTINCT OBESITY- AND AB-TRIGGERED ABNORMALITIES IN CEREBRAL GLUCOSE METABOLISM AND GLIOSIS IN MICE
Anna M. Barron1, Masaki Tokunaga2, Bin Ji2, Tetsuya Suhara2, Makoto Higuchi2, 1National Institute of Radiological Sciences, Tokyo, Japan; 2National Institute of Radiological Sciences, Chiba, Japan. Contact e-mail: [email protected] Background: High sucrose, high saturated fat western diets are increasingly leading to health issues such as obesity, metabolic syndrome and diabetes. Growing evidence also suggests that the western diet, and resulting metabolic abnormalities such as chronic hyperglycemia and inflammation, may increase the risk of cognitive decline and Alzheimer’s disease (AD). The aim of this study was to assess changes in cerebral glucose metabolism and glial TSPO expression in response to obesity and intracerebroventricular Ab infusion in vivo using PET. Methods: Three month old C57BL/J6 mice were fed either a standard (non-obese group) or high fat diet (obese group) for 3 months, and intracerebroventricularly infused with vehicle or