- Email: [email protected]
O4-04-07: The efficacy of exogenous estrogen on cognitive functioning in men with mild cognitive impairment
T192
Oral O4-04: Therapeutic Strategies 2
littermates on a mtau KO background (n⫽10). The mice (3-4 months) received the first 3 injections every 2 weeks and then at monthly intervals. At 7-8 months, the mice went through extensive behavioral testing to determine treatment efficacy and were then killed at 8-9 months for analysis. Results: The immunogen elicited an IgM/IgG response and the therapy prevented cognitive decline in three different tests: Radial Arm Maze (p 0.01-0.001); Closed Field Symmetrical Maze (p 0.01-0.001), and; Object Recognition Test (p 0.01). The groups performed equally well in motor tests indicating that motor deficits were not a confounding variable, which further strengthens our results. Tau/tangle aggregates were reduced by 56% in the pyriform cortex (p 0.01) in the immunized mice. Analysis is underway of other brain regions as well as of levels of soluble and insoluble tau protein. Importantly, the cognitive improvements correlated well with reduction of tau aggregates. In the Radial Arm Maze, correlation was observed in days 4-9 as the mice improve at navigating the maze (p 0.05-0.001). Likewise, in the Closed Field Symmetrical Maze, correlation was only observed in the most complex maze (Maze C, p⫽0.01), and not in the Object Recognition Test, which is a simpler task. Conclusions: Overall, our findings support the feasibility of immunotherapy targeting pathological tau as a potential treatment for Alzheimer’s disease. Supported by: AG20197. O4-04-05
ACCELARATION OF FAMILIAL ALZHEIMER’S DISEASE BY HOMOCYSTEIC ACID AND RECOVERY FROM NEUROPATHOLOGY BY ANTI-HOMOCYSTEIC ACID ANTIBODY
Tohru Hasegawa, Saga Woman Junior College, Saga, Japan. Contact e-mail: [email protected] Background: Intracellular amyloid 42 (A42) is increasingly recognized as an early pathological trigger that can lead to amyloid plaques and even induce neurofibrillary tangles. We previously found that HA induces intracellular accumulation of A42. Methods: In this study, we observed that the anti-homocysteic acid (HA) polyclonal antibody inhibited the disease process in 3xTg-AD model mice. 3xTg-AD hemizygous mice (3xTg-AD-h) at 5 months and 7months of age were fed with vitamin B6-deficient food for 3 weeks using a ventricular cannula. The control group was administrated 5 l of physiological saline every 3 days into the ventricular space (VS) through the ventricular cannula , and the experimental group was administrated 5 l anti-HA antibody* into the VS every three days through the cannula. Results: While the control mice showed a strong, abnormal anxiety reaction, the experimental group did not show any anxiety reactions. After three weeks of deficient food feeding, Moris water maze task was performed for memory measurement (short- and long-term memory). Non Tg mice fed with B6-deficient food showed good memory performance in both measurements, but Tg control showed strong memory impairment in both measurements. On the other hand, Tg experimental group showed good memory performance and even better longterm memory than non-Tg. In addition, 3xTg-AD-h (5 months of age) fed with normal food did not show memory impairment. 7 month old mice showed very serious neuropathology, but anti-HA antibody induced strong recovery process in pathological change of 7 months old mice. Conclusions: We conclude that vitamin B6-deficient food accelerated Alzheimer’s cognitive impairment of 3xTg-AD-h, since 3xTg-AD-h fed with normal food and non-Tg fed with vitamin B6-deficient good did not show memory impairment. We also found that HA accelerated Alzheimer’s cognitive impairment of 3xTg-AD-h, because anti-HA antibody inhibited memory impairment of 3xTg-AD-h fed with vitamin B6-deficient food. Amyloid beta accumulated in neurons in the amygdale, hippocampus and cortex of the 3xTg-AD-h control group, but the 3xTg-AD-h experimental group did not show any accumulation of amyloid beta. Also anti-HA antibody induced the strong recovery process (very few accumulation of amyloid of 7 months old mice).
O4-04-06
HUPERZINE A FOR ALZHEIMER’S DISEASE 1
Hongmei Wu , Jun Li1, RongLe Zhou1, Guanjian Liu2, Birong Dong1, 1 Department of Geriatrics, West China Hospital/West China Medical School, Sichun University, Chengdu, Sichuan, China; 2Chinese Cochrane Center, West China Hospital/West China Medical School, Sichun University, Chengdu, Sichuan, China. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) has become a major public health problem around the world due to its increasing prevalence, caregiver burden and high financial cost of care. The degeneration of acetylcholinecontaining neurons in the basal forebrain has been implicated in the symptoms of AD. Cholinesterase inhibitors may block the degradation of acetylcholine, thus increasing the efficacy of the remaining cholinergic neurons. Huperzine A is a reversible inhibitor of acetyl cholinesterase. This systematic review is to assess the efficacy and safety of Huperzine A for AD. Methods: We performed a sensitive electronic search of multiple reference databases in the early 2006, including the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group which contains records from databases (MEDLINE, EMBASE, PsycINFO, CINAHL, SIGLE, ISTP, INSIDE, LILACS), CBM and AMED. We included all randomized clinical trials among patients with AD, which compared huperzine A with either placebo or routine treatment. Results: Six trials including a total of 454 patients met our inclusion criteria. The methodological quality of most included trials was not high. It was shown that compared to placebo, Huperzine A had beneficial effects on the improvement of general cognitive function measured by MMSE (WMD 2.81; 95%CI 1.87 to 3.76) and ADAS-Cog (WMD 2.51; 95% CI 1.74 to 3.28), global clinical assessment measured by CIBIC-plus (OR 4.32,95%CI 2.37 to7.90), behavioral disturbance measured by ADAS-non Cog (WMD -1.52, 95%CI-2.39 to -0.65), and functional performance measured by ADL (WMD ⫽ -7.17; 95%CI -9.13 to -5.22). No data were available on allcause mortality, quality of life and caregiver burden. The adverse events of Huperzine A were mild and there were no significant differences between Huperzine A groups and control groups. Conclusions: Huperzine A seems to have some beneficial effects on improvement of general cognitive function, global clinical status, behavioral disturbance and functional performance, with no obvious serious adverse events for patients with AD, but the small trials with limited numbers of patients and their low methodological quality has resulted in cautious assessment of the results. Rigorous design, randomized, multi-centre, large-sample trials of Huperzine A for AD are needed to further assess the effects. O4-04-07
THE EFFICACY OF EXOGENOUS ESTROGEN ON COGNITIVE FUNCTIONING IN MEN WITH MILD COGNITIVE IMPAIRMENT
Howard M. Chertkow1, Barbara B. Sherwin2, Ziad Nasreddine3, Victor Whitehead4, Hyman Schipper1, 1Department of Neurology and Neurosurgery and Department of Medicine (Geriatrics), McGill University, Montreal, QC, Canada; 2Department of Psychology, McGill University, Montreal, QC, Canada; 3Department of Neurology and Neurosurgery, University of Sherbrooke, Sherbrooke, QC, Canada; 4 Bloomfied Centre for Research in Aging, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada. Contact e-mail: [email protected] Background: There is evidence that administration of estrogen to postmenopausal women specifically enhances verbal memory. E2 is likely responsible for maintaining verbal memory in older men as in women. In view of the fact that there are currently no approved treatments for Mild Cognitive Impairment (MCI), we hypothesized that the administration of E2 to men with MCI would improve their performance on tests of verbal memory, might improve global cognition, but would not affect performance in cognitive domains in which men typically excel such as visuospatial ability. Methods: This hypothesis was tested using a double-blind,
Oral O4-05: Epidemiology and Risk Factors 2 randomized, cross-over design. Subjects who met the MCI inclusion criteria were randomized to receive treatment with either 1 mg micronized E2 (Estrace, Shire Biochem Inc., Quebec, Canada) or placebo for 12 weeks following which they were crossed-over to the other treatment for an additional 12 weeks. All subjects thus received both micronized E2 and placebo. The Buschke Serial Reminding task , the Logical Memory 1 & 2 paragraph recall test of the Wechsler Memory Scale-Revised, and the Paired Associates Learning subtest of the WMS-R were used to assess short and long term verbal memory. The Visual Reproduction subtest of the WMS-R was used to assess visual memory. The Mini-Mental Status exam (MMSE) and the Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used to assess global cognitive function. Results: Men who received 12 weeks of treatment with E2 following 12 weeks of treatment with placebo had significantly higher total score on the Buschke Serial Reminding Task total score (p⬍.05), and on three subscales of that test, namely, the Long Term Recall score (p⬍.05), on the Continuous Long Term Recall score (p .05) and on the Delayed Recall score (p⬍.05) compared to their performance at baseline and following 12 weeks of treatment with placebo. Non-verbal memory and global measures showed no significant difference between placebo and estrogen. Conclusions: A beneficial effect of E2 on verbal memory in MCI individuals was confirmed. The hypothesis that estrogen-treatment would improve scores on measures of global cognitive functioning in these male MCI subjects was not supported. O4-04-08
IMPROVEMENT OF COGNITION WITH A NEUROGENIC/NEUROTROPHIC PEPTIDE
Inge Grundke-Iqbal, M. Omar Chohan, Bin Li, Julie Blanchard, Khalid Iqbal, NYS Institute for Basic Research, Staten Island, NY, USA. Contact e-mail: [email protected] Background: Alzheimer disease (AD) is multifactorial, heterogeneous, and probably involves several different etiopathogenic mechanisms. Prevention and treatment of this disease will most likely require multiple approaches. Two major therapeutic approaches are (1) inhibition of neurodegeneration and (2) stimulation of regeneration of the affected areas of the brain. In AD, the hippocampus is the area of the brain affected earliest and most severely by neurodegeneration. Although the AD brain responds by attempting to form new neurons in the dentate gyrus, these newborn cells apparently do not develop into mature functional cells. We postulate that the regeneration of the hippocampus in AD is compromised, and that neurogenic and neurotrophic activities and, consequently, cognition can be enhanced by treatment with active peptides of neurotrophic factors. Methods: Peptides were designed based on biologically active regions of human Ciliary Neurotrophic Factor (CNTF), and were tested in vitro in rat adult hippocampal progenitor cultures and in vivo in 8-10-month old adult female mice. Results: We have found that levels of the adult dendritic marker microtubule associated protein (MAP) 2 and its mRNA are dramatically decreased in dentate gyrus. In contrast, levels of MAP2c, a marker for immature neurons, seem to be only minimally decreased. This inability of the AD hippocampus to regenerate itself, in part, is probably due to the dysregulation of the neurotrophic factors which serve as cues for neurogenic and neurotrophic activity. We have developed a novel 11-mer peptide based on ciliary neurotrophic factor (CNTF), which increases proliferation and survival of adult hippocampal progenitors, both in vitro and in normal adult mice. This peptide, CNTF6, also induces early neuronal fate commitment and neuronal maturation in newly divided progenitors, along with a general neurotrophic effect on the dentate gyrus. CNTF6 significantly enhances hippocampal-dependent spatial memory in normal adult mice. Conclusions: Regeneration of the hippocampus in AD is compromised. Pharmacological enhancement of dentate gyrus neurogenic/ neurotrophic activity and associated learning and memory is a promising therapeutic approach for AD and related disorders.
T193
WEDNESDAY, JULY 30, 2008 ORAL O4-05 EPIDEMIOLOGY AND RISK FACTORS 2 O4-05-01
LONGITUDINAL ANALYSIS OF THE ASSOCIATION BETWEEN DEPRESSIVE SYMPTOMS AND DEMENTIA: THE THREE-CITY (3C) STUDY
Hermine Lenoir1, Ophelia Godin2, Jean-Marc Lacombe2, Carole Dufouil2, Karen Ritchie3, Jean-Franc¸ois Dartigues4, Annick Alperovitch5, Christophe Tzourio5, 1INSERM U780 & Broca Hospital, Paris, France; 2INSERM U780, PARIS, France; 3INSERM U888, Montpellier, France; 4INSERM U593, Bordeaux, France; 5 INSERM U780, Paris, France. Contact e-mail: [email protected] Background: Clinical studies indicate that depression or depressive symptoms are associated with dementia, however, their temporal relationships are controversial. Our study aimed to explore whether DS is predictive of developing dementia in elderly subjects. Methods: Longitudinal analysis in a survey of 9294 non-demented non-institutionalized elderly aged 65 years and over, followed-up for 4 years, in 3 French cities. We performed logistic regression analyses of the relation between the level of depressive symptoms assessed by the Center for Epidemiological Studies Depression (CES-D) scale, considered dichotomously, at baseline and at 2-year followup, and the incidence of dementia adjusting for sex, age, education, history of cardiovascular events, the Mini-Mental State Examination score at baseline, and use of antidepressant agents. Results: Our working sample had a mean age (SD) of 73.7 (5.0) years, included 60.7% of women and 12% of subjects with high level of depressive symptoms at baseline. The incidence rate of dementia was 3%. A high level of depressive symptoms at baseline was predictive of incident dementia (adjusted OR CES-D high vs CES-D low 1.6, 95% CI 1.1-2.4). The risk of dementia increased statistically significantly with decreasing time interval between the last time high levels of depressive symptoms was achieved and the incidence of dementia. Moreover, the risk of new onset dementia increased with the recurrence of high level of depressive symptoms over the period of followup. Conclusions: We found a close temporal association between high level of depressive symptoms and new-onset dementia in elderly subjects. Depressive symptoms seem to be less a risk factor for than a prodromal noncognitive manifestation of dementia. O4-05-02
NO RELATIONSHIP OF CARDIOVASCULAR DISEASE RISK FACTORS TO THE PROGRESSION OF ALZHEIMER’S DISEASE
Gabor Abellan van Kan1, Yves Rolland2, Fati Nourhashemi2, Christelle Cantet2, Sandrine Andrieu2, Bruno Vellas2, 1Department of Geriatric Medicine. University Hospital Toulouse, Toulouse, France; 2 University Hospital Toulouse, Toulouse, France. Contact e-mail: [email protected] Background: Although the importance of cardiovascular disease risk factors, CVDRF, as risk factors for cognitive decline has been well demonstrated in many epidemiological studies, none of these have evaluated progression of cognitive decline in the presence of these risk factors once diagnosis of AD is established.The aim of our study was to evaluate if three cardiovascular disease risk factors (CVDRF; hypertension, diabetes and hypercholesterolemia), alone or in association, were predictive factors for a worse evolution in cognitive decline in Alzheimer’s disease (AD) patients. Methods: The Reseau de la maladie d’Alzheimer.France (REAL.FR) study is a prospective multicentre cohort which has recruited 686 community dwelling patients presenting mild to moderate AD (Mini-Mental State Examination, MMSE, scores between 10 and 26). At inclusion and every 6 months, for a duration of 2 years, a standardised assessment was performed in an outpatient consultation. The presence of self-reported
Oral O4-04: Therapeutic Strategies 2
littermates on a mtau KO background (n⫽10). The mice (3-4 months) received the first 3 injections every 2 weeks and then at monthly intervals. At 7-8 months, the mice went through extensive behavioral testing to determine treatment efficacy and were then killed at 8-9 months for analysis. Results: The immunogen elicited an IgM/IgG response and the therapy prevented cognitive decline in three different tests: Radial Arm Maze (p 0.01-0.001); Closed Field Symmetrical Maze (p 0.01-0.001), and; Object Recognition Test (p 0.01). The groups performed equally well in motor tests indicating that motor deficits were not a confounding variable, which further strengthens our results. Tau/tangle aggregates were reduced by 56% in the pyriform cortex (p 0.01) in the immunized mice. Analysis is underway of other brain regions as well as of levels of soluble and insoluble tau protein. Importantly, the cognitive improvements correlated well with reduction of tau aggregates. In the Radial Arm Maze, correlation was observed in days 4-9 as the mice improve at navigating the maze (p 0.05-0.001). Likewise, in the Closed Field Symmetrical Maze, correlation was only observed in the most complex maze (Maze C, p⫽0.01), and not in the Object Recognition Test, which is a simpler task. Conclusions: Overall, our findings support the feasibility of immunotherapy targeting pathological tau as a potential treatment for Alzheimer’s disease. Supported by: AG20197. O4-04-05
ACCELARATION OF FAMILIAL ALZHEIMER’S DISEASE BY HOMOCYSTEIC ACID AND RECOVERY FROM NEUROPATHOLOGY BY ANTI-HOMOCYSTEIC ACID ANTIBODY
Tohru Hasegawa, Saga Woman Junior College, Saga, Japan. Contact e-mail: [email protected] Background: Intracellular amyloid 42 (A42) is increasingly recognized as an early pathological trigger that can lead to amyloid plaques and even induce neurofibrillary tangles. We previously found that HA induces intracellular accumulation of A42. Methods: In this study, we observed that the anti-homocysteic acid (HA) polyclonal antibody inhibited the disease process in 3xTg-AD model mice. 3xTg-AD hemizygous mice (3xTg-AD-h) at 5 months and 7months of age were fed with vitamin B6-deficient food for 3 weeks using a ventricular cannula. The control group was administrated 5 l of physiological saline every 3 days into the ventricular space (VS) through the ventricular cannula , and the experimental group was administrated 5 l anti-HA antibody* into the VS every three days through the cannula. Results: While the control mice showed a strong, abnormal anxiety reaction, the experimental group did not show any anxiety reactions. After three weeks of deficient food feeding, Moris water maze task was performed for memory measurement (short- and long-term memory). Non Tg mice fed with B6-deficient food showed good memory performance in both measurements, but Tg control showed strong memory impairment in both measurements. On the other hand, Tg experimental group showed good memory performance and even better longterm memory than non-Tg. In addition, 3xTg-AD-h (5 months of age) fed with normal food did not show memory impairment. 7 month old mice showed very serious neuropathology, but anti-HA antibody induced strong recovery process in pathological change of 7 months old mice. Conclusions: We conclude that vitamin B6-deficient food accelerated Alzheimer’s cognitive impairment of 3xTg-AD-h, since 3xTg-AD-h fed with normal food and non-Tg fed with vitamin B6-deficient good did not show memory impairment. We also found that HA accelerated Alzheimer’s cognitive impairment of 3xTg-AD-h, because anti-HA antibody inhibited memory impairment of 3xTg-AD-h fed with vitamin B6-deficient food. Amyloid beta accumulated in neurons in the amygdale, hippocampus and cortex of the 3xTg-AD-h control group, but the 3xTg-AD-h experimental group did not show any accumulation of amyloid beta. Also anti-HA antibody induced the strong recovery process (very few accumulation of amyloid of 7 months old mice).
O4-04-06
HUPERZINE A FOR ALZHEIMER’S DISEASE 1
Hongmei Wu , Jun Li1, RongLe Zhou1, Guanjian Liu2, Birong Dong1, 1 Department of Geriatrics, West China Hospital/West China Medical School, Sichun University, Chengdu, Sichuan, China; 2Chinese Cochrane Center, West China Hospital/West China Medical School, Sichun University, Chengdu, Sichuan, China. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) has become a major public health problem around the world due to its increasing prevalence, caregiver burden and high financial cost of care. The degeneration of acetylcholinecontaining neurons in the basal forebrain has been implicated in the symptoms of AD. Cholinesterase inhibitors may block the degradation of acetylcholine, thus increasing the efficacy of the remaining cholinergic neurons. Huperzine A is a reversible inhibitor of acetyl cholinesterase. This systematic review is to assess the efficacy and safety of Huperzine A for AD. Methods: We performed a sensitive electronic search of multiple reference databases in the early 2006, including the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group which contains records from databases (MEDLINE, EMBASE, PsycINFO, CINAHL, SIGLE, ISTP, INSIDE, LILACS), CBM and AMED. We included all randomized clinical trials among patients with AD, which compared huperzine A with either placebo or routine treatment. Results: Six trials including a total of 454 patients met our inclusion criteria. The methodological quality of most included trials was not high. It was shown that compared to placebo, Huperzine A had beneficial effects on the improvement of general cognitive function measured by MMSE (WMD 2.81; 95%CI 1.87 to 3.76) and ADAS-Cog (WMD 2.51; 95% CI 1.74 to 3.28), global clinical assessment measured by CIBIC-plus (OR 4.32,95%CI 2.37 to7.90), behavioral disturbance measured by ADAS-non Cog (WMD -1.52, 95%CI-2.39 to -0.65), and functional performance measured by ADL (WMD ⫽ -7.17; 95%CI -9.13 to -5.22). No data were available on allcause mortality, quality of life and caregiver burden. The adverse events of Huperzine A were mild and there were no significant differences between Huperzine A groups and control groups. Conclusions: Huperzine A seems to have some beneficial effects on improvement of general cognitive function, global clinical status, behavioral disturbance and functional performance, with no obvious serious adverse events for patients with AD, but the small trials with limited numbers of patients and their low methodological quality has resulted in cautious assessment of the results. Rigorous design, randomized, multi-centre, large-sample trials of Huperzine A for AD are needed to further assess the effects. O4-04-07
THE EFFICACY OF EXOGENOUS ESTROGEN ON COGNITIVE FUNCTIONING IN MEN WITH MILD COGNITIVE IMPAIRMENT
Howard M. Chertkow1, Barbara B. Sherwin2, Ziad Nasreddine3, Victor Whitehead4, Hyman Schipper1, 1Department of Neurology and Neurosurgery and Department of Medicine (Geriatrics), McGill University, Montreal, QC, Canada; 2Department of Psychology, McGill University, Montreal, QC, Canada; 3Department of Neurology and Neurosurgery, University of Sherbrooke, Sherbrooke, QC, Canada; 4 Bloomfied Centre for Research in Aging, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada. Contact e-mail: [email protected] Background: There is evidence that administration of estrogen to postmenopausal women specifically enhances verbal memory. E2 is likely responsible for maintaining verbal memory in older men as in women. In view of the fact that there are currently no approved treatments for Mild Cognitive Impairment (MCI), we hypothesized that the administration of E2 to men with MCI would improve their performance on tests of verbal memory, might improve global cognition, but would not affect performance in cognitive domains in which men typically excel such as visuospatial ability. Methods: This hypothesis was tested using a double-blind,
Oral O4-05: Epidemiology and Risk Factors 2 randomized, cross-over design. Subjects who met the MCI inclusion criteria were randomized to receive treatment with either 1 mg micronized E2 (Estrace, Shire Biochem Inc., Quebec, Canada) or placebo for 12 weeks following which they were crossed-over to the other treatment for an additional 12 weeks. All subjects thus received both micronized E2 and placebo. The Buschke Serial Reminding task , the Logical Memory 1 & 2 paragraph recall test of the Wechsler Memory Scale-Revised, and the Paired Associates Learning subtest of the WMS-R were used to assess short and long term verbal memory. The Visual Reproduction subtest of the WMS-R was used to assess visual memory. The Mini-Mental Status exam (MMSE) and the Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used to assess global cognitive function. Results: Men who received 12 weeks of treatment with E2 following 12 weeks of treatment with placebo had significantly higher total score on the Buschke Serial Reminding Task total score (p⬍.05), and on three subscales of that test, namely, the Long Term Recall score (p⬍.05), on the Continuous Long Term Recall score (p .05) and on the Delayed Recall score (p⬍.05) compared to their performance at baseline and following 12 weeks of treatment with placebo. Non-verbal memory and global measures showed no significant difference between placebo and estrogen. Conclusions: A beneficial effect of E2 on verbal memory in MCI individuals was confirmed. The hypothesis that estrogen-treatment would improve scores on measures of global cognitive functioning in these male MCI subjects was not supported. O4-04-08
IMPROVEMENT OF COGNITION WITH A NEUROGENIC/NEUROTROPHIC PEPTIDE
Inge Grundke-Iqbal, M. Omar Chohan, Bin Li, Julie Blanchard, Khalid Iqbal, NYS Institute for Basic Research, Staten Island, NY, USA. Contact e-mail: [email protected] Background: Alzheimer disease (AD) is multifactorial, heterogeneous, and probably involves several different etiopathogenic mechanisms. Prevention and treatment of this disease will most likely require multiple approaches. Two major therapeutic approaches are (1) inhibition of neurodegeneration and (2) stimulation of regeneration of the affected areas of the brain. In AD, the hippocampus is the area of the brain affected earliest and most severely by neurodegeneration. Although the AD brain responds by attempting to form new neurons in the dentate gyrus, these newborn cells apparently do not develop into mature functional cells. We postulate that the regeneration of the hippocampus in AD is compromised, and that neurogenic and neurotrophic activities and, consequently, cognition can be enhanced by treatment with active peptides of neurotrophic factors. Methods: Peptides were designed based on biologically active regions of human Ciliary Neurotrophic Factor (CNTF), and were tested in vitro in rat adult hippocampal progenitor cultures and in vivo in 8-10-month old adult female mice. Results: We have found that levels of the adult dendritic marker microtubule associated protein (MAP) 2 and its mRNA are dramatically decreased in dentate gyrus. In contrast, levels of MAP2c, a marker for immature neurons, seem to be only minimally decreased. This inability of the AD hippocampus to regenerate itself, in part, is probably due to the dysregulation of the neurotrophic factors which serve as cues for neurogenic and neurotrophic activity. We have developed a novel 11-mer peptide based on ciliary neurotrophic factor (CNTF), which increases proliferation and survival of adult hippocampal progenitors, both in vitro and in normal adult mice. This peptide, CNTF6, also induces early neuronal fate commitment and neuronal maturation in newly divided progenitors, along with a general neurotrophic effect on the dentate gyrus. CNTF6 significantly enhances hippocampal-dependent spatial memory in normal adult mice. Conclusions: Regeneration of the hippocampus in AD is compromised. Pharmacological enhancement of dentate gyrus neurogenic/ neurotrophic activity and associated learning and memory is a promising therapeutic approach for AD and related disorders.
T193
WEDNESDAY, JULY 30, 2008 ORAL O4-05 EPIDEMIOLOGY AND RISK FACTORS 2 O4-05-01
LONGITUDINAL ANALYSIS OF THE ASSOCIATION BETWEEN DEPRESSIVE SYMPTOMS AND DEMENTIA: THE THREE-CITY (3C) STUDY
Hermine Lenoir1, Ophelia Godin2, Jean-Marc Lacombe2, Carole Dufouil2, Karen Ritchie3, Jean-Franc¸ois Dartigues4, Annick Alperovitch5, Christophe Tzourio5, 1INSERM U780 & Broca Hospital, Paris, France; 2INSERM U780, PARIS, France; 3INSERM U888, Montpellier, France; 4INSERM U593, Bordeaux, France; 5 INSERM U780, Paris, France. Contact e-mail: [email protected] Background: Clinical studies indicate that depression or depressive symptoms are associated with dementia, however, their temporal relationships are controversial. Our study aimed to explore whether DS is predictive of developing dementia in elderly subjects. Methods: Longitudinal analysis in a survey of 9294 non-demented non-institutionalized elderly aged 65 years and over, followed-up for 4 years, in 3 French cities. We performed logistic regression analyses of the relation between the level of depressive symptoms assessed by the Center for Epidemiological Studies Depression (CES-D) scale, considered dichotomously, at baseline and at 2-year followup, and the incidence of dementia adjusting for sex, age, education, history of cardiovascular events, the Mini-Mental State Examination score at baseline, and use of antidepressant agents. Results: Our working sample had a mean age (SD) of 73.7 (5.0) years, included 60.7% of women and 12% of subjects with high level of depressive symptoms at baseline. The incidence rate of dementia was 3%. A high level of depressive symptoms at baseline was predictive of incident dementia (adjusted OR CES-D high vs CES-D low 1.6, 95% CI 1.1-2.4). The risk of dementia increased statistically significantly with decreasing time interval between the last time high levels of depressive symptoms was achieved and the incidence of dementia. Moreover, the risk of new onset dementia increased with the recurrence of high level of depressive symptoms over the period of followup. Conclusions: We found a close temporal association between high level of depressive symptoms and new-onset dementia in elderly subjects. Depressive symptoms seem to be less a risk factor for than a prodromal noncognitive manifestation of dementia. O4-05-02
NO RELATIONSHIP OF CARDIOVASCULAR DISEASE RISK FACTORS TO THE PROGRESSION OF ALZHEIMER’S DISEASE
Gabor Abellan van Kan1, Yves Rolland2, Fati Nourhashemi2, Christelle Cantet2, Sandrine Andrieu2, Bruno Vellas2, 1Department of Geriatric Medicine. University Hospital Toulouse, Toulouse, France; 2 University Hospital Toulouse, Toulouse, France. Contact e-mail: [email protected] Background: Although the importance of cardiovascular disease risk factors, CVDRF, as risk factors for cognitive decline has been well demonstrated in many epidemiological studies, none of these have evaluated progression of cognitive decline in the presence of these risk factors once diagnosis of AD is established.The aim of our study was to evaluate if three cardiovascular disease risk factors (CVDRF; hypertension, diabetes and hypercholesterolemia), alone or in association, were predictive factors for a worse evolution in cognitive decline in Alzheimer’s disease (AD) patients. Methods: The Reseau de la maladie d’Alzheimer.France (REAL.FR) study is a prospective multicentre cohort which has recruited 686 community dwelling patients presenting mild to moderate AD (Mini-Mental State Examination, MMSE, scores between 10 and 26). At inclusion and every 6 months, for a duration of 2 years, a standardised assessment was performed in an outpatient consultation. The presence of self-reported