- Email: [email protected]
The relationship of diet to neurocognitive health: A systematic review
P472
P1-301
Poster Presentations: P1
THE RELATIONSHIP OF DIET TO NEUROCOGNITIVE HEALTH: A SYSTEMATIC REVIEW
Xi Sophie Chen1, Henry Brodaty2, Fiona Oleary3, 1University of New South Wales, Sydney, Australia; 2Dementia Collaborative Research Centre – Assessment and Better Care (DCRC-ABC), School of Psychiatry, UNSW Medicine, UNSW Australia, Sydney, Australia; 3Sydney University, Sydney, Australia. Contact e-mail: [email protected] Background: Diet and nutrition may play an important role in neurocognitive health. Whether and how effective can single nutrients, or diet patterns be protective against neurocognitive decline, remains controversial. In this paper we review data from cohort studies, case-control studies and RCT relating either signal nutrients or dietary pattern to the risk of cognitive decline and dementia. We focus on the following six groups: caloric restriction, alcohol, vitamin B, antioxidants, fatty acids, and dietary patterns. Methods: We systematically reviewed selected modifiable dietary
factors including calorie, alcohol, vitamin B, antioxidants, fatty acids, and dietary patterns that were studied in relation to neurocognitive health, including incident dementia. We searched MEDLINE, EMBASE and SCOPUS for published literature, excluding cross-sectional studies and laboratory trials. Analysis compared study finding consistency across factors, study designs e.g. population size, dosage of supplementation, age group and study-level characteristics. Results: In total, 90 studies were retrieved for systematic review. Research findings are mostly inconsistent even for those mostly studied compound such as vitamin B and antioxidant. Studies indicating daily energy deficit not significantly related to change in cognitive function except for DASH diet combined with a weight reduction program, however limited due to small sample size. A few RCT and cohort studies suggested no significant association between unsaturated fatty acids intake and incident dementia while others provide evidence of the opposite. Most studies found low to moderate alcohol intake lower risk of dementia. Dietary Patterns which is characterized by higher intake of fruits, vegetables, fish, nuts and legumes, and lower intake of meats and butter seemed to be associated with reduced risk of dementia. Conclusions: Conflicting data is found due to methodology issues. Further studies need focus on specific age group, adequate sample size and follow up years, subjects whose diet is assessed and monitored at an earlier stage and adequate dosage of supplementation on nutrient of interest. P1-302
5-HT6 ANTAGONIST SUVN-502 POTENTIATES THE PROCOGNITIVE AND NEUROCHEMICAL EFFECTS OF DONEPEZIL AND MEMANTINE
Pradeep Jayarajan, Renny Abraham, Gopinadh Bhyrapuneni, Vijay S. Benade, Ganesh Ayyanki, Rajesh Babu Medapati, Ravirala Venkateshwarlu, Nageswararao Muddana, Ranjith Kumar Ponnamaneni, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: Deficits in the cholinergic neurotransmission have
been implicated in the Alzheimer’s disease. Memantine and donepezil are approved for the symptomatic treatment of cognitive deficits associated with Alzheimer’s disease (AD). Memantine added to stable donepezil in AD patients is associated with significant benefits in reducing decline in cognition, function and global status. SUVN-502 is a potent and selective 5-HT6 antagonist being developed for the symptomatic treatment of Alzheimer’s disease. 5-HT6 antagonist may potentiate the therapeutic effects of memantine and donepezil. Methods: The effect of SUVN-502 alone and in combination with memantine and donepezil was evaluated in object
recognition task. The effect of the above combinations on the cholinergic neurotransmission was evaluated in the hippocampus of freely moving male Wistar rats using brain microdialysis. Results: Co-treatment of SUVN-502 with memantine and donepezil significantly potentiated the procognitive effects when compared with memantine and donepezil treatment group. These effects were seen even after repeated treatment for 14 days. Similarly co-treatment of SUVN-502 with memantine and donepezil significantly enhanced the acetylcholine levels in the hippocampus. Conclusions: The enhanced procognitive effects seen in the group co-treated with SUVN-502, memantine and donepezil can be attributed to the augmentation of the cholinergic neurotransmission in the brain. Thus, combination of SUVN-502 with memantine and donepezil may offer a novel therapeutic strategy for the symptomatic treatment of Alzheimer’s disease. P1-303
ALLOPREGNANOLONE CHRONIC EXPOSURE USING REGENERATIVE TREATMENT REGIMEN: PRECLINICAL IND ENABLING TOXICOLOGY INDICATING SAFETY
Ronald W. Irwin1, Kyuri Kim2, Carol E. Green2, Christine M. Solinsky1, Gerhard Bauer3, Michael A. Rogawski3, Kathleen E. Rodgers1, Roberta Diaz Brinton1, 1University of Southern California, Los Angeles, CA, USA; 2 SRI International, Menlo Park, CA, USA; 3University of California, Davis, Sacramento, CA, USA. Contact e-mail: [email protected] Background: To develop Allopregnanolone (Allo) as the first regenerative therapeutic for Alzheimer’s disease, standard toxicology was conducted to identify target organs of toxicity and to estimate the no observed adverse effect level (NOAEL) of Allo after 24 weeks of once-per-week dosing to adult male and female Sprague Dawley rats. Methods: Rats were administered Allo 0, 1, 4, and 8mg/kg bolus intramuscularly once-per-week for 24 weeks. Necropsies were on Day163 (Main group) and on Day191 (Recovery group). Endpoints were clinical observations, body weight, food consumption, functional observational battery (FOB), ophthalmologic examination, plasma drug levels and toxicokinetics, clinical pathology, urinalysis, organ weight, and macroscopic and microscopic tissue examination. Results: No toxicologically relevant changes were found in body weight, food consumption, ophthalmology, gross necropsy, organ weight, urinalysis parameters, or clinical pathology. Acute sedative effects were observed in highdose groups determined by FOB parameters (home cage, handling, and reflex and physiology measurements) primarily in high-dose males and females on Day1 and 162. Sedative effects for the high-dose groups were more enhanced in males than females. The incidence of epithelial hyperplasia in the non-glandular stomach was increased in highest dose Main group males but was not found in Recovery group. Drug concentrations were similar between males and females on Day1 at all doses, and trended higher in males compared to females on Day162 in the mid- and high-dose groups. Day162 exposures trended higher than Day1 at all doses, suggesting slight accumulation of Allo. The terminal phase halflife values were less than 1hr in all groups except high-dose males on Day162. Conclusions: All animals survived to the end of the study. At 4 and 8mg/kg dose levels, toxicological threshold of sedation was achieved based on behavioral observations related to sedation. The high-dose group males exhibited histopathological changes to the nonglandular stomach, an anatomical feature not present in humans. Based on these findings, the MTD for Allo is w4mg/kg, and the NOAEL is w1mg/kg. Clinical dose-escalating studies with Allo are warranted to determine safety and tolerability
P1-301
Poster Presentations: P1
THE RELATIONSHIP OF DIET TO NEUROCOGNITIVE HEALTH: A SYSTEMATIC REVIEW
Xi Sophie Chen1, Henry Brodaty2, Fiona Oleary3, 1University of New South Wales, Sydney, Australia; 2Dementia Collaborative Research Centre – Assessment and Better Care (DCRC-ABC), School of Psychiatry, UNSW Medicine, UNSW Australia, Sydney, Australia; 3Sydney University, Sydney, Australia. Contact e-mail: [email protected] Background: Diet and nutrition may play an important role in neurocognitive health. Whether and how effective can single nutrients, or diet patterns be protective against neurocognitive decline, remains controversial. In this paper we review data from cohort studies, case-control studies and RCT relating either signal nutrients or dietary pattern to the risk of cognitive decline and dementia. We focus on the following six groups: caloric restriction, alcohol, vitamin B, antioxidants, fatty acids, and dietary patterns. Methods: We systematically reviewed selected modifiable dietary
factors including calorie, alcohol, vitamin B, antioxidants, fatty acids, and dietary patterns that were studied in relation to neurocognitive health, including incident dementia. We searched MEDLINE, EMBASE and SCOPUS for published literature, excluding cross-sectional studies and laboratory trials. Analysis compared study finding consistency across factors, study designs e.g. population size, dosage of supplementation, age group and study-level characteristics. Results: In total, 90 studies were retrieved for systematic review. Research findings are mostly inconsistent even for those mostly studied compound such as vitamin B and antioxidant. Studies indicating daily energy deficit not significantly related to change in cognitive function except for DASH diet combined with a weight reduction program, however limited due to small sample size. A few RCT and cohort studies suggested no significant association between unsaturated fatty acids intake and incident dementia while others provide evidence of the opposite. Most studies found low to moderate alcohol intake lower risk of dementia. Dietary Patterns which is characterized by higher intake of fruits, vegetables, fish, nuts and legumes, and lower intake of meats and butter seemed to be associated with reduced risk of dementia. Conclusions: Conflicting data is found due to methodology issues. Further studies need focus on specific age group, adequate sample size and follow up years, subjects whose diet is assessed and monitored at an earlier stage and adequate dosage of supplementation on nutrient of interest. P1-302
5-HT6 ANTAGONIST SUVN-502 POTENTIATES THE PROCOGNITIVE AND NEUROCHEMICAL EFFECTS OF DONEPEZIL AND MEMANTINE
Pradeep Jayarajan, Renny Abraham, Gopinadh Bhyrapuneni, Vijay S. Benade, Ganesh Ayyanki, Rajesh Babu Medapati, Ravirala Venkateshwarlu, Nageswararao Muddana, Ranjith Kumar Ponnamaneni, Ramakrishna Nirogi, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: Deficits in the cholinergic neurotransmission have
been implicated in the Alzheimer’s disease. Memantine and donepezil are approved for the symptomatic treatment of cognitive deficits associated with Alzheimer’s disease (AD). Memantine added to stable donepezil in AD patients is associated with significant benefits in reducing decline in cognition, function and global status. SUVN-502 is a potent and selective 5-HT6 antagonist being developed for the symptomatic treatment of Alzheimer’s disease. 5-HT6 antagonist may potentiate the therapeutic effects of memantine and donepezil. Methods: The effect of SUVN-502 alone and in combination with memantine and donepezil was evaluated in object
recognition task. The effect of the above combinations on the cholinergic neurotransmission was evaluated in the hippocampus of freely moving male Wistar rats using brain microdialysis. Results: Co-treatment of SUVN-502 with memantine and donepezil significantly potentiated the procognitive effects when compared with memantine and donepezil treatment group. These effects were seen even after repeated treatment for 14 days. Similarly co-treatment of SUVN-502 with memantine and donepezil significantly enhanced the acetylcholine levels in the hippocampus. Conclusions: The enhanced procognitive effects seen in the group co-treated with SUVN-502, memantine and donepezil can be attributed to the augmentation of the cholinergic neurotransmission in the brain. Thus, combination of SUVN-502 with memantine and donepezil may offer a novel therapeutic strategy for the symptomatic treatment of Alzheimer’s disease. P1-303
ALLOPREGNANOLONE CHRONIC EXPOSURE USING REGENERATIVE TREATMENT REGIMEN: PRECLINICAL IND ENABLING TOXICOLOGY INDICATING SAFETY
Ronald W. Irwin1, Kyuri Kim2, Carol E. Green2, Christine M. Solinsky1, Gerhard Bauer3, Michael A. Rogawski3, Kathleen E. Rodgers1, Roberta Diaz Brinton1, 1University of Southern California, Los Angeles, CA, USA; 2 SRI International, Menlo Park, CA, USA; 3University of California, Davis, Sacramento, CA, USA. Contact e-mail: [email protected] Background: To develop Allopregnanolone (Allo) as the first regenerative therapeutic for Alzheimer’s disease, standard toxicology was conducted to identify target organs of toxicity and to estimate the no observed adverse effect level (NOAEL) of Allo after 24 weeks of once-per-week dosing to adult male and female Sprague Dawley rats. Methods: Rats were administered Allo 0, 1, 4, and 8mg/kg bolus intramuscularly once-per-week for 24 weeks. Necropsies were on Day163 (Main group) and on Day191 (Recovery group). Endpoints were clinical observations, body weight, food consumption, functional observational battery (FOB), ophthalmologic examination, plasma drug levels and toxicokinetics, clinical pathology, urinalysis, organ weight, and macroscopic and microscopic tissue examination. Results: No toxicologically relevant changes were found in body weight, food consumption, ophthalmology, gross necropsy, organ weight, urinalysis parameters, or clinical pathology. Acute sedative effects were observed in highdose groups determined by FOB parameters (home cage, handling, and reflex and physiology measurements) primarily in high-dose males and females on Day1 and 162. Sedative effects for the high-dose groups were more enhanced in males than females. The incidence of epithelial hyperplasia in the non-glandular stomach was increased in highest dose Main group males but was not found in Recovery group. Drug concentrations were similar between males and females on Day1 at all doses, and trended higher in males compared to females on Day162 in the mid- and high-dose groups. Day162 exposures trended higher than Day1 at all doses, suggesting slight accumulation of Allo. The terminal phase halflife values were less than 1hr in all groups except high-dose males on Day162. Conclusions: All animals survived to the end of the study. At 4 and 8mg/kg dose levels, toxicological threshold of sedation was achieved based on behavioral observations related to sedation. The high-dose group males exhibited histopathological changes to the nonglandular stomach, an anatomical feature not present in humans. Based on these findings, the MTD for Allo is w4mg/kg, and the NOAEL is w1mg/kg. Clinical dose-escalating studies with Allo are warranted to determine safety and tolerability