- Email: [email protected]
The characterization of presenilin 1 with G206D mutation associated with familial Alzheimer's disease
P312
P2-151
Poster Presentations: P2
PICALM REGULATES Ab42 PRODUCTION BY MODULATION OF GAMMA-SECRETASE TRAFFICKING
Taisuke Tomita, Yuichi Morohashi, Kunihiko Kanatsu, Takeshi Iwatsubo, The University of Tokyo, Tokyo, Japan. Background: Alzheimer disease (AD) is the most common type of dementia worldwide. Several lines of evidence suggest that aberrant production, clearance and aggregation of amyloid-beta peptide (Ab) in human brain are linked to the etiology of AD. Recently, genome-wide association studies in late-onset AD patients have reported evidence that variation in phosphatidylinositol binding clathrin assembly protein (PICALM) gene confer genetic risk for AD. Methods: To investigate the role of PICALM in Ab generation, we analyzed the effects of knockdown or overexpression of PICALM in cultured cells on the processing of amyloid precursor protein (APP). We also monitored the trafficking of the gamma-secretase by monoclonal antibody A5226A, which recognizes the extracellular domain of mature Nicastrin on the cell surface (Hayashi et al., Oncogene 2011). Results: Depletion of PICALM caused a decrease in the production ratio of Ab42, the most aggregable Ab species. Moreover, PICALM RNAi altered the endocytic rate of gamma-secretase, while the endocytosis of transferrin, one of the typical cargo proteins for clathrin-mediated endocytosis, was not affected. In contrast, total Ab levels as well as Ab42 ratio were increased by the overexpression of PICALM. Conclusions: These results suggest PICALM modulates gamma-secretase activity by regulating its clathrin-mediated endocytosis. Alteration in endocytic rate of gamma-secretase by PICALM RNAi/overexpression may change its steady-state subcellular localization, leading to alteration in both the total Ab generation and the Ab42 ratio.
P2-152
PATTERN OF BETA-AMYLOID PRODUCTION BY MOUSE EMBRYONIC FIBROBLASTS OVEREXPRESSING PSEN1 WITH I143T MUTATION
Temu Qina1, Nobuo Sanjo2, Takumi Hori1, Paul Fraser3, Hidehiro Mizusawa1, 1Tokyo Medical and Dental University, Tokyo, Japan; 2 Tokyo Medical and Dental University, Tokyo, Japan; 3Centre for Research in Neurodegenerative Diseases, Toronto, Ontario, Canada. Background: Amyloid-b peptide (Ab) is produced by the sequential cleavage of amyloid-b precursor protein (bAPP) by b -secretase and g-secretase complex. Presenilins (PS1 and PS2) have been demonstrated to be the catalytic core of the g-secretase complex. Most cases of early onset familial Alzheimer disease (EOFAD) have been reportedly caused by m utations in the presenilin genes (PSEN1 and PSEN2). Recently, both Ab42 and Ab43 were reported to be present in plaque cores in the brain of patients with PSEN1 I143T mutation, which is one of the earliest onset causative genes of EOFAD (average age of onset is 34.0). Furthermore, Ab43 is reported to be amyloido g enic and pathogenic in PSEN1 R278I FAD. Methods: Wild-type and I143T mutant PSEN1 were subcloned into the retroviral vector pMXs-Puro, and these constructs were transfected to Platinum-E cells to package and produce retroviruses carrying either of these genes respectively. Next, PSEN1 and PSEN2 double knock out mouse embryonic fibroblasts (PSDKO/MEFs) overexpressing APP with Swedish mutation (SweAPP) were infected with retroviruses to transduce each PSEN1 gene for creating cell lines stably expressing each wild-type or I143T PS1. For measuring Ab production by each cell line, 83105 cells were plated into 6-well plates, and after 24-hour incubation, quantitative changes in Ab40, Ab42, and Ab43 levels in the cell culture medium were measured using ELISA. Conclusions: The ratio of Ab42 to Ab40 is possibly the most important factor in determining the age at onset of EOFAD I143T, despite the fact that both Ab42 and Ab43 proteins are deposited in the brains of I143T patients.
P2-153
MEMBRANE MICRODOMAIN LOCALIZATION OF APP C-TERMINAL FRAGMENTS REGULATED BY THE PHOSPHORYLATION AT CYTOPLASMIC THR668 RESIDUE
Takahide Matsushima1, Yuhki Saito1, Masaki Nishimura2, Nobuyuki Kimura3, Saori Hata1, Toshiharu Suzuki1, 1Hokkaido University, Sapporo, Japan; 2Shiga University of Medical Science, Shiga, Japan; 3 National Institute of Biological Innovation, Ibaraki, Japan. Background: APP is primarily cleaved by a - or b -secretase to generate the membrane-bound C-terminal fragments, CTFs, which are subject to a second intramembrane cleavage by g -secretase, which is active in the membrane microdomain. Mature APP (N- and O- glycosilated APP) is phosphorylated at the cytoplasmic residue Thr668 and the phosphorylation changes the overall conformation of the cytoplasmic domain of APP. Methods: Mouse brain APP CTFs are fractionated to quantify their contens. Phosphorylated CTFs are detected by immunoblotting with anti-pAPP Thr668 antibody. In vitro g-cleavage of CTFs was performed under the condition to prevent protein degradation and dephosphorylation. Detergent-resistant membrane (DRM) fractions were prepared in TNE buffer containing 1% (v/v) CHAPSO. Ab40 and Ab42 secreted into the medium were quantified by a sandwich ELISA. Results: We found that phosphorylated and nonphosphorylated CTFs exist equally in the brain and are equivalent as substrates for g -secretase, in vitro. Nevertheless, the in vivo level of the phosphorylated APP intracellular domain peptide (AICD) generated by g -cleavage of CTFs was very low when compared to the nonphosphorylated AICD. Phosphorylated CTFs (pCTFs), rather than nonphosphorylated CTFs (nCTFs), were preferentially located outside of detergent-resistant membrane microdomains. The APP cytoplasmic domain peptide with phosphoThr668 did not associate with liposomes composed of membrane lipids from mouse brain to which the nonphosphorylated-peptide preferentially bound. The pCTFs are relatively movable within the membrane while the nCTFs are susceptible to being anchored into the membrane, an interaction made available as a consequence of not being phosphorylated. Conclusions: By this mechanism, nCTFs can be preferentially captured and cleaved by g -secretase. Preservation of the phosphorylated state of APP-CTFs may be a potential treatment to lower the generation of A b in Alzheimer disease.
P2-154
THE CHARACTERIZATION OF PRESENILIN 1 WITH G206D MUTATION ASSOCIATED WITH FAMILIAL ALZHEIMER’S DISEASE
Yi-Fang Hsieh1, Ya-Ying Wu2, Irene Han-Juo Cheng1, 1Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 2Institute of Brain Science, Taipei, Taiwan. Background: One of the important pathological characteristics of Alzheimer’s disease (AD) in the brain is the deposition of amyloid beta peptide (Ab), which is generated from sequential cleavage of amyloid precursor protein (APP) by b- and g-secretases. g-Secretase is a multiple-subunit protein complex and is able to act on numerous substrates including APP and Notch. Mutation in presenilin 1 (PS1), the catalytic subunit of g-secretase, is the most common cause of familial Alzheimer’s disease (FAD). Previous clinical study found a pathological confirmed FAD family with G206D mutation in PS1. The mechanism of PS1 G206D mutant leading to FAD pathology is unknown. We aim to determine whether this mutant alters g-secretase complex activity, stability, assembly and subcellular localization. Methods: To test this hypothesis, we generated constructs expressing PS1 wt and PS1 G206D and transiently transfected into various cell lines. The levels of Ab and Notch intracellular domain (NICD), indicating g-secretase activity, are measured by ELISA and western blot. To identify PS1 stability, the degree of PS1 degradation with time is determined after treatment of cycloheximide, a protein synthesis inhibitor. The assembly and subcellular localization of g-secretase complex are examined by co-immunoprecipitation and immunocytochemistry. Results: We found that the level of Ab and the ratio of Ab 42 to Ab total were significantly higher in PS1 G206D than
Poster Presentations: P2 PS1 wt expressing cell lines. However, this mutation does not have influence on the production of NICD level. Conclusions: The results suggest that the mutant form of PS1 alter g-secretase activity toward APP but not Notch, producing more Ab 42, which are thought to be prone to aggregate and has higher neuro toxicity. Nevertheless, the precise mechanism needs further investigation. P2-155
ASSOCIATION OF DIABETES AND PREDIABETES WITH COGNITIVE IMPAIRMENT AND DEPRESSION AMONG CHINESE ELDERLY PEOPLE: THE CONFUCIUS HOMETOWN AGING PROJECT
Zhongrui Yan1, Chuanzhu Cai2, Haiqing Song3, Hui Jiang2, Binglun Sun2, Bo Bai3, Chengxuan Qiu4, 1Jining First People’s Hospital, Jining, China; 2 Xing Long Zhuang Coal Mine Hospital, Jining, China; 3Jining Medical University, Jining, China; 4Karolinska Institutet, Stockholm, Sweden. Background: Diabetes is frequently linked to cognitive impairment and depression in older adults, but few studies have been conducted among Chinese elderly people. We seek to investigate the association of diabetes and prediabetes with cognitive impairment and depression among Chinese elderly people. Methods: This cross-sectional study included 1528 participants (age 60 years, mean age 68.6; 59.2% women) of Chinese elderly people who were living in the community nearby the hometown of Confucius (Q€ ufu), Shandong, China. We assessed global cognitive function with Mini-Mental State Examination (MMSE) and depressive symptoms with the 15-item Geriatric Depression Scale (GDS). Diabetes and prediabetes were defined according to self-reported history of diabetes, blood glucose-lowering treatment, insulin injection, and fasting blood glucose test. Data were analyzed with logistic regression models controlling for demographic features and major cardiovascular risk factors. Results: Of the 1528 participants, cognitive impairment (MMSE score <24) was found in 377 (24.7%) and depression (GDS score 5) in 310 (20.3%) subjects. The multiple adjusted OR of cognitive impairment was 1.61 (95% CI 0.92-2.81) for prediabetes, 1.38 (0.97-1.96) for diabetes, and 1.43 (1.041.97) for having either prediabetes or diabetes; such associations did not vary by sex. Overall, there was no significant association of diabetes or prediabetes with depression. However, a statistical interaction of sex with diabetic status (P for interaction term 0.05) on depression was detected, such that men with prediabetes or diabetes had a marginally increased OR of 1.51 (0.98-2.32; P ¼ 0.06) for depression, whereas there was no association between diabetic status and depression among women. Conclusions: Having diabetes or prediabetes is associated with cognitive impairment and depression among Chinese elderly people living in the community. P2-156
ASSOCIATION OF INSTRUMENTAL ACTIVITIES OF DAILY LIVING WITH MCI DIAGNOSIS IN A LARGE, OLDER, COMMUNITY-BASED POPULATION
Emily Trittschuh1, Brenna Cholerton2, Eric Larson3, Paul Crane4, Susan McCurry4, Wayne McCormick5, James Bowen6, Matthew Arbuckle2, Laura Baker7, Suzanne Craft8, 1VA Puget Sound Health Care System/ University of Washington, Seattle, Washington, United States; 2VAPSHCS, Seattle, Washington, United States; 3GHRI, Seattle, Washington, United States; 4University of Washington, Seattle, Washington, United States; 5 UW/Harborview Medical Center, Seattle, Washington, United States; 6 Swedish Neuroscience Institute, Seattle, Washington, United States; 7 University of Washington School of Medicine, Seattle, Washington, United States; 8VA Puget Sound/University of Washington, Seattle, Washington, United States. Background: Loss of independence in activities of daily living (ADLs) is a criterion for dementia diagnosis. With objective evidence of cognitive deficits, the presence or absence of functional decline is often the fulcrum for diagnosis of dementia versus Mild Cognitive Impairment (MCI). At the same time, MCI diagnosis is a consistent risk factor for incident dementia. The Adult Changes in Thought (ACT) cohort provides a unique opportunity to examine whether subtle changes in ADLs might enhance early and accu-
P313
rate identification of MCI. Methods: Participants in a community-based, random sample of non-demented older adults are seen biennially and receive cognitive examinations which have included tests known to be sensitive to the early effects of cognitive decline. Diagnosis of MCI was determined based on published definitions and a cut-off of 1.5 sd below normative means. Instrumental ADLs were assessed during a phone conversation subsequent to biennial visits. Experienced raters completed the Activities of Daily Living Questionnaire (ADLQ), a 15-question, 45-point scale based on participant self-report. We used logistic regression to determine whether ADLQ scores were associated with MCI diagnosis. We adjusted models for age and education. Additional analyses considered MCI subtype and ADLQ items. Results: The ADLQ was completed for n ¼ 1144 participants (mean age ¼ 81.3, standard deviation ¼ 0.2). ADLQ scores were associated with MCI diagnosis in crude and adjusted models; each point of ADLQ was associated with a 16% reduced odds of MCI (OR ¼ 0.84; 95% confidence interval 12-20%, P <0.01, for the adjusted model). The association between ADLQ score and MCI diagnosis was stronger for amnestic than non-amnestic MCI. Preliminary analyses suggest that not all ADLQ items are equally useful. Conclusions: These findings suggest assessment of ADLs has a role beyond “ruling out” dementia. Questionnaires such as the ADLQ are easily administered, inexpensive, and well tolerated, and may add to the armamentarium designed to identify people who are more likely to go on to develop dementia. Perhaps more intriguing, is the possibility that these scores might assist in predicting those individuals likely to stay stable. P2-157
EFFECTS OF MULTICOMPONENT EXERCISE ON CEREBRAL HEMOGLOBIN OXYGENATION IN OLDER ADULTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT: FUNCTIONAL MONITORING USING NIR SPECTROSCOPY
Hyuntae Park1, Hiroyuki Shimada2, Hyuma Makizako3, Takehiko Doi3, Daisuke Yoshida3, Kota Tsutsumimoto4, Yuya Anan4, Kazuki Uemura4, Takao Suzuki4, 1National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; 2National Center for Geriatrics and Gerontology, Aichi, Japan; 3National Center for Geriatrics and Gerontology, Obu, Japan; 4 National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. Background: It has been suggested that moderate exercise and habitual physical activity may have a neuroprotective effects in those at risk for Alzheimer’s disease. A recent randomized controlled trials examining the effect of exercise has been proposed to be associated with varied cognitive benefits in older adults diagnosied with mild cognitive impairement. Moreover, a recent meta-analysis reported that physical activity or exercise may have neurogenic and angiogenic effects in human hippocampi. Near-infrared spectroscopy (NIRS) is a noninvasive neuroimaging tool for studying evoked cerebral hemodynamic changes, and has been used as a practical indicator of cerebral oxygenation and hemodynamic change. However, no quantitative analysis has been performed on the cumulative evidence from studies that used NIRS to measure brain hemodynamic responses before and after exercise intervention in MCI patients. Methods: Twenty subjects (9 men) with aMCI ranging in age from 65 to 86 years (mean age, 73 years) were divided arbitrarily into two groups. Subjects in the multicomponent exercise group (n ¼ 10) performed moderate exercise under the supervision of physiotherapists for 90 min/d, 2 d/wk, 80 times for 6 months. The exercise was included aerobic exercise, muscle strength training, and postural balance retraining which was conducted under multitask conditions to stimulate cognitive functions. The control group (n ¼ 10) attended three times education class during the same period of time. We used NIRS to measure cerebral oxygenation oxygenation changes during a verbal-fluency task before and after the intervention. Results: Compared to a baseline condition, we found a significant increase of delta HbO during the execution of the VFT over both hemispheres in intervention group. In the delta group activation maps from VFT using HRF models using NIRS-SPM (Ye et al. 2008), the t-statistic value and the activated regions from HbO signal during VFT significantly increased after 6 month exercise training in the left hemisphere areas and inferior frontal gyrus (all Ps < .05). Conclusions: The results of this study suggest that the 6-month multicomponent exercise intervention
P2-151
Poster Presentations: P2
PICALM REGULATES Ab42 PRODUCTION BY MODULATION OF GAMMA-SECRETASE TRAFFICKING
Taisuke Tomita, Yuichi Morohashi, Kunihiko Kanatsu, Takeshi Iwatsubo, The University of Tokyo, Tokyo, Japan. Background: Alzheimer disease (AD) is the most common type of dementia worldwide. Several lines of evidence suggest that aberrant production, clearance and aggregation of amyloid-beta peptide (Ab) in human brain are linked to the etiology of AD. Recently, genome-wide association studies in late-onset AD patients have reported evidence that variation in phosphatidylinositol binding clathrin assembly protein (PICALM) gene confer genetic risk for AD. Methods: To investigate the role of PICALM in Ab generation, we analyzed the effects of knockdown or overexpression of PICALM in cultured cells on the processing of amyloid precursor protein (APP). We also monitored the trafficking of the gamma-secretase by monoclonal antibody A5226A, which recognizes the extracellular domain of mature Nicastrin on the cell surface (Hayashi et al., Oncogene 2011). Results: Depletion of PICALM caused a decrease in the production ratio of Ab42, the most aggregable Ab species. Moreover, PICALM RNAi altered the endocytic rate of gamma-secretase, while the endocytosis of transferrin, one of the typical cargo proteins for clathrin-mediated endocytosis, was not affected. In contrast, total Ab levels as well as Ab42 ratio were increased by the overexpression of PICALM. Conclusions: These results suggest PICALM modulates gamma-secretase activity by regulating its clathrin-mediated endocytosis. Alteration in endocytic rate of gamma-secretase by PICALM RNAi/overexpression may change its steady-state subcellular localization, leading to alteration in both the total Ab generation and the Ab42 ratio.
P2-152
PATTERN OF BETA-AMYLOID PRODUCTION BY MOUSE EMBRYONIC FIBROBLASTS OVEREXPRESSING PSEN1 WITH I143T MUTATION
Temu Qina1, Nobuo Sanjo2, Takumi Hori1, Paul Fraser3, Hidehiro Mizusawa1, 1Tokyo Medical and Dental University, Tokyo, Japan; 2 Tokyo Medical and Dental University, Tokyo, Japan; 3Centre for Research in Neurodegenerative Diseases, Toronto, Ontario, Canada. Background: Amyloid-b peptide (Ab) is produced by the sequential cleavage of amyloid-b precursor protein (bAPP) by b -secretase and g-secretase complex. Presenilins (PS1 and PS2) have been demonstrated to be the catalytic core of the g-secretase complex. Most cases of early onset familial Alzheimer disease (EOFAD) have been reportedly caused by m utations in the presenilin genes (PSEN1 and PSEN2). Recently, both Ab42 and Ab43 were reported to be present in plaque cores in the brain of patients with PSEN1 I143T mutation, which is one of the earliest onset causative genes of EOFAD (average age of onset is 34.0). Furthermore, Ab43 is reported to be amyloido g enic and pathogenic in PSEN1 R278I FAD. Methods: Wild-type and I143T mutant PSEN1 were subcloned into the retroviral vector pMXs-Puro, and these constructs were transfected to Platinum-E cells to package and produce retroviruses carrying either of these genes respectively. Next, PSEN1 and PSEN2 double knock out mouse embryonic fibroblasts (PSDKO/MEFs) overexpressing APP with Swedish mutation (SweAPP) were infected with retroviruses to transduce each PSEN1 gene for creating cell lines stably expressing each wild-type or I143T PS1. For measuring Ab production by each cell line, 83105 cells were plated into 6-well plates, and after 24-hour incubation, quantitative changes in Ab40, Ab42, and Ab43 levels in the cell culture medium were measured using ELISA. Conclusions: The ratio of Ab42 to Ab40 is possibly the most important factor in determining the age at onset of EOFAD I143T, despite the fact that both Ab42 and Ab43 proteins are deposited in the brains of I143T patients.
P2-153
MEMBRANE MICRODOMAIN LOCALIZATION OF APP C-TERMINAL FRAGMENTS REGULATED BY THE PHOSPHORYLATION AT CYTOPLASMIC THR668 RESIDUE
Takahide Matsushima1, Yuhki Saito1, Masaki Nishimura2, Nobuyuki Kimura3, Saori Hata1, Toshiharu Suzuki1, 1Hokkaido University, Sapporo, Japan; 2Shiga University of Medical Science, Shiga, Japan; 3 National Institute of Biological Innovation, Ibaraki, Japan. Background: APP is primarily cleaved by a - or b -secretase to generate the membrane-bound C-terminal fragments, CTFs, which are subject to a second intramembrane cleavage by g -secretase, which is active in the membrane microdomain. Mature APP (N- and O- glycosilated APP) is phosphorylated at the cytoplasmic residue Thr668 and the phosphorylation changes the overall conformation of the cytoplasmic domain of APP. Methods: Mouse brain APP CTFs are fractionated to quantify their contens. Phosphorylated CTFs are detected by immunoblotting with anti-pAPP Thr668 antibody. In vitro g-cleavage of CTFs was performed under the condition to prevent protein degradation and dephosphorylation. Detergent-resistant membrane (DRM) fractions were prepared in TNE buffer containing 1% (v/v) CHAPSO. Ab40 and Ab42 secreted into the medium were quantified by a sandwich ELISA. Results: We found that phosphorylated and nonphosphorylated CTFs exist equally in the brain and are equivalent as substrates for g -secretase, in vitro. Nevertheless, the in vivo level of the phosphorylated APP intracellular domain peptide (AICD) generated by g -cleavage of CTFs was very low when compared to the nonphosphorylated AICD. Phosphorylated CTFs (pCTFs), rather than nonphosphorylated CTFs (nCTFs), were preferentially located outside of detergent-resistant membrane microdomains. The APP cytoplasmic domain peptide with phosphoThr668 did not associate with liposomes composed of membrane lipids from mouse brain to which the nonphosphorylated-peptide preferentially bound. The pCTFs are relatively movable within the membrane while the nCTFs are susceptible to being anchored into the membrane, an interaction made available as a consequence of not being phosphorylated. Conclusions: By this mechanism, nCTFs can be preferentially captured and cleaved by g -secretase. Preservation of the phosphorylated state of APP-CTFs may be a potential treatment to lower the generation of A b in Alzheimer disease.
P2-154
THE CHARACTERIZATION OF PRESENILIN 1 WITH G206D MUTATION ASSOCIATED WITH FAMILIAL ALZHEIMER’S DISEASE
Yi-Fang Hsieh1, Ya-Ying Wu2, Irene Han-Juo Cheng1, 1Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 2Institute of Brain Science, Taipei, Taiwan. Background: One of the important pathological characteristics of Alzheimer’s disease (AD) in the brain is the deposition of amyloid beta peptide (Ab), which is generated from sequential cleavage of amyloid precursor protein (APP) by b- and g-secretases. g-Secretase is a multiple-subunit protein complex and is able to act on numerous substrates including APP and Notch. Mutation in presenilin 1 (PS1), the catalytic subunit of g-secretase, is the most common cause of familial Alzheimer’s disease (FAD). Previous clinical study found a pathological confirmed FAD family with G206D mutation in PS1. The mechanism of PS1 G206D mutant leading to FAD pathology is unknown. We aim to determine whether this mutant alters g-secretase complex activity, stability, assembly and subcellular localization. Methods: To test this hypothesis, we generated constructs expressing PS1 wt and PS1 G206D and transiently transfected into various cell lines. The levels of Ab and Notch intracellular domain (NICD), indicating g-secretase activity, are measured by ELISA and western blot. To identify PS1 stability, the degree of PS1 degradation with time is determined after treatment of cycloheximide, a protein synthesis inhibitor. The assembly and subcellular localization of g-secretase complex are examined by co-immunoprecipitation and immunocytochemistry. Results: We found that the level of Ab and the ratio of Ab 42 to Ab total were significantly higher in PS1 G206D than
Poster Presentations: P2 PS1 wt expressing cell lines. However, this mutation does not have influence on the production of NICD level. Conclusions: The results suggest that the mutant form of PS1 alter g-secretase activity toward APP but not Notch, producing more Ab 42, which are thought to be prone to aggregate and has higher neuro toxicity. Nevertheless, the precise mechanism needs further investigation. P2-155
ASSOCIATION OF DIABETES AND PREDIABETES WITH COGNITIVE IMPAIRMENT AND DEPRESSION AMONG CHINESE ELDERLY PEOPLE: THE CONFUCIUS HOMETOWN AGING PROJECT
Zhongrui Yan1, Chuanzhu Cai2, Haiqing Song3, Hui Jiang2, Binglun Sun2, Bo Bai3, Chengxuan Qiu4, 1Jining First People’s Hospital, Jining, China; 2 Xing Long Zhuang Coal Mine Hospital, Jining, China; 3Jining Medical University, Jining, China; 4Karolinska Institutet, Stockholm, Sweden. Background: Diabetes is frequently linked to cognitive impairment and depression in older adults, but few studies have been conducted among Chinese elderly people. We seek to investigate the association of diabetes and prediabetes with cognitive impairment and depression among Chinese elderly people. Methods: This cross-sectional study included 1528 participants (age 60 years, mean age 68.6; 59.2% women) of Chinese elderly people who were living in the community nearby the hometown of Confucius (Q€ ufu), Shandong, China. We assessed global cognitive function with Mini-Mental State Examination (MMSE) and depressive symptoms with the 15-item Geriatric Depression Scale (GDS). Diabetes and prediabetes were defined according to self-reported history of diabetes, blood glucose-lowering treatment, insulin injection, and fasting blood glucose test. Data were analyzed with logistic regression models controlling for demographic features and major cardiovascular risk factors. Results: Of the 1528 participants, cognitive impairment (MMSE score <24) was found in 377 (24.7%) and depression (GDS score 5) in 310 (20.3%) subjects. The multiple adjusted OR of cognitive impairment was 1.61 (95% CI 0.92-2.81) for prediabetes, 1.38 (0.97-1.96) for diabetes, and 1.43 (1.041.97) for having either prediabetes or diabetes; such associations did not vary by sex. Overall, there was no significant association of diabetes or prediabetes with depression. However, a statistical interaction of sex with diabetic status (P for interaction term 0.05) on depression was detected, such that men with prediabetes or diabetes had a marginally increased OR of 1.51 (0.98-2.32; P ¼ 0.06) for depression, whereas there was no association between diabetic status and depression among women. Conclusions: Having diabetes or prediabetes is associated with cognitive impairment and depression among Chinese elderly people living in the community. P2-156
ASSOCIATION OF INSTRUMENTAL ACTIVITIES OF DAILY LIVING WITH MCI DIAGNOSIS IN A LARGE, OLDER, COMMUNITY-BASED POPULATION
Emily Trittschuh1, Brenna Cholerton2, Eric Larson3, Paul Crane4, Susan McCurry4, Wayne McCormick5, James Bowen6, Matthew Arbuckle2, Laura Baker7, Suzanne Craft8, 1VA Puget Sound Health Care System/ University of Washington, Seattle, Washington, United States; 2VAPSHCS, Seattle, Washington, United States; 3GHRI, Seattle, Washington, United States; 4University of Washington, Seattle, Washington, United States; 5 UW/Harborview Medical Center, Seattle, Washington, United States; 6 Swedish Neuroscience Institute, Seattle, Washington, United States; 7 University of Washington School of Medicine, Seattle, Washington, United States; 8VA Puget Sound/University of Washington, Seattle, Washington, United States. Background: Loss of independence in activities of daily living (ADLs) is a criterion for dementia diagnosis. With objective evidence of cognitive deficits, the presence or absence of functional decline is often the fulcrum for diagnosis of dementia versus Mild Cognitive Impairment (MCI). At the same time, MCI diagnosis is a consistent risk factor for incident dementia. The Adult Changes in Thought (ACT) cohort provides a unique opportunity to examine whether subtle changes in ADLs might enhance early and accu-
P313
rate identification of MCI. Methods: Participants in a community-based, random sample of non-demented older adults are seen biennially and receive cognitive examinations which have included tests known to be sensitive to the early effects of cognitive decline. Diagnosis of MCI was determined based on published definitions and a cut-off of 1.5 sd below normative means. Instrumental ADLs were assessed during a phone conversation subsequent to biennial visits. Experienced raters completed the Activities of Daily Living Questionnaire (ADLQ), a 15-question, 45-point scale based on participant self-report. We used logistic regression to determine whether ADLQ scores were associated with MCI diagnosis. We adjusted models for age and education. Additional analyses considered MCI subtype and ADLQ items. Results: The ADLQ was completed for n ¼ 1144 participants (mean age ¼ 81.3, standard deviation ¼ 0.2). ADLQ scores were associated with MCI diagnosis in crude and adjusted models; each point of ADLQ was associated with a 16% reduced odds of MCI (OR ¼ 0.84; 95% confidence interval 12-20%, P <0.01, for the adjusted model). The association between ADLQ score and MCI diagnosis was stronger for amnestic than non-amnestic MCI. Preliminary analyses suggest that not all ADLQ items are equally useful. Conclusions: These findings suggest assessment of ADLs has a role beyond “ruling out” dementia. Questionnaires such as the ADLQ are easily administered, inexpensive, and well tolerated, and may add to the armamentarium designed to identify people who are more likely to go on to develop dementia. Perhaps more intriguing, is the possibility that these scores might assist in predicting those individuals likely to stay stable. P2-157
EFFECTS OF MULTICOMPONENT EXERCISE ON CEREBRAL HEMOGLOBIN OXYGENATION IN OLDER ADULTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT: FUNCTIONAL MONITORING USING NIR SPECTROSCOPY
Hyuntae Park1, Hiroyuki Shimada2, Hyuma Makizako3, Takehiko Doi3, Daisuke Yoshida3, Kota Tsutsumimoto4, Yuya Anan4, Kazuki Uemura4, Takao Suzuki4, 1National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; 2National Center for Geriatrics and Gerontology, Aichi, Japan; 3National Center for Geriatrics and Gerontology, Obu, Japan; 4 National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. Background: It has been suggested that moderate exercise and habitual physical activity may have a neuroprotective effects in those at risk for Alzheimer’s disease. A recent randomized controlled trials examining the effect of exercise has been proposed to be associated with varied cognitive benefits in older adults diagnosied with mild cognitive impairement. Moreover, a recent meta-analysis reported that physical activity or exercise may have neurogenic and angiogenic effects in human hippocampi. Near-infrared spectroscopy (NIRS) is a noninvasive neuroimaging tool for studying evoked cerebral hemodynamic changes, and has been used as a practical indicator of cerebral oxygenation and hemodynamic change. However, no quantitative analysis has been performed on the cumulative evidence from studies that used NIRS to measure brain hemodynamic responses before and after exercise intervention in MCI patients. Methods: Twenty subjects (9 men) with aMCI ranging in age from 65 to 86 years (mean age, 73 years) were divided arbitrarily into two groups. Subjects in the multicomponent exercise group (n ¼ 10) performed moderate exercise under the supervision of physiotherapists for 90 min/d, 2 d/wk, 80 times for 6 months. The exercise was included aerobic exercise, muscle strength training, and postural balance retraining which was conducted under multitask conditions to stimulate cognitive functions. The control group (n ¼ 10) attended three times education class during the same period of time. We used NIRS to measure cerebral oxygenation oxygenation changes during a verbal-fluency task before and after the intervention. Results: Compared to a baseline condition, we found a significant increase of delta HbO during the execution of the VFT over both hemispheres in intervention group. In the delta group activation maps from VFT using HRF models using NIRS-SPM (Ye et al. 2008), the t-statistic value and the activated regions from HbO signal during VFT significantly increased after 6 month exercise training in the left hemisphere areas and inferior frontal gyrus (all Ps < .05). Conclusions: The results of this study suggest that the 6-month multicomponent exercise intervention