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P.1.j.017 Effects of chronic etanercept, a TNF-α inhibitor, on cognitive dysfunction in cafeteria diet-fed rats
S342
P.1.j. Basic and clinical neuroscience − Cognitive neuroscience
P.1.j.016 Impact of smoking on cognitive functions S. Kim1 ° , K.W. Kim2 1 YangSan Hospital, Psychiatry, YangSan city, South-Korea; 2 Seoul National University Hospital, Neuropsychiatry, Seoul, South-Korea Smoking is increasingly recognized as a risk factor for dementia in elderly individuals [1]. There is also evidence to suggest that its impact on adverse cognitive outcomes, including dementia, may have been underestimated owing to selection effects as a result of greater mortality among smokers [2]. The extent to which smoking increases the cognitive decline remains unclear. The goals of this study were to investigate the impact of smoking on cognitive functions in the elderly Koreans. 1,118 Koreans were randomly sampled from the residents aged 65 years or older living in Seongnam, Korea, at phase 1 in 2006. Phase 2 assessment was conducted in 2013. Structured face-to-face interviews were conducted on the 714 respondent subjects using the Korean version of Mini International Neuropsychiatric Interview (MINI) [3]. Memory, vocabulary, executive function were assessed with the Korean version of CERAD(Consortium to Establish a Registry for Alzheimer disease) neuropsychological assessment battery(CERAD-K) [4], Digit span forward and backward test, Korean version of Frontal Assessment Battery(FAB-K). Of the 714 participants at phase 1, 77 had died and 252 had dropped out from the study before the second data collection in 2013. Of the 385 remaining individuals, 258 individuals who had cognitive diseases including all kinds of dementias, mild cognitive disorder, stroke at phase 1 and women who had extremely lower smoking rate compared to men(21.3%(men): 1%(women) in 2006) were excluded from the study. Finally, 127 men were included in data analyses of cognitive changes between phase 1 and phase 2. A current-smoker was defined as a person who had been smoking at least one cigarette per day for one year, and a past-smoker as a person who used to smoke but had not smoked in the past one year. Linear mixed models were used to assess the association between smoking history and cognitive decline for 7 years. Additionally Cox proportional hazard model was used to calculate the hazard rate and 95% confidence intervals of three smoking groups after adjusting age, education years, diabetes, hypertension and alcohol use disorders. Mean age was 69.9±4.2 for the whole sample and 70.2±4.5, 70.2±4.6 and 68.6±2.2 for never-smokers, past-smokers and current-smokers respectively at the first assessment. No faster cognitive decline on all tests was observed among current and past smokers compared with never smokers. On the contrary, a significantly slower cognitive declines were observed on MMSE(MiniMental State Examination) in past-smokers and current smokers than never smokers [mean difference in 7-year decline: neversmokers = reference, past-smokers = 0.88 (95% CI, 0.23 to 1.54), current-smokers = 0.91 (95% CI, 0.09 to 1.72)]. The hazard ratio (95% confidence interval) of mortality was 0.37 (0.09–1.55) for past-smokers and 3.01 (0.34–26.56) for current-smokers, but this outcome was not statistically significant. In conclusion, current-smokers and past-smokers did not show faster cognitive declines compared to never-smokers in the elderly Koreans. References [1] Anstey, K.J., von Sanden, C., Salim, A., O’Kearney, R., 2007. Smoking as a risk factor fordementia and cognitive decline: a meta-analysis of prospective studies. Am JEpidemiol 166(4), 367–378.
[2] Hern´an, M.A., Alonso, A., Logroscino, G., 2008. Cigarette smoking and dementia: potentialselection bias in the elderly. Epidemiology 19(3), 448–450. [3] Youu, S.W., Namkoong, K., Kim, S.J., 2006. Validity of Korean Version of the mini-international neuropsychiatric interview. Anxiety Mood 2, 50−55. [4] Lee, J.H., Lee, K.U., Lee, D.Y., Kim, K.W., Jhoo, J.H., Kim, J.H., Woo, J.I., 2002. Development of the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries. Research Support, Non-U.S. Gov’t Validation Studies. J Gerontol. B: Psychol. Sci. Soc. 57(1), 47−53.
P.1.j.017 Effects of chronic etanercept, a TNF-a inhibitor, on cognitive dysfunction in cafeteria diet-fed rats T. Demirtas1 ° , T. Utkan1 , S.S. Gocmez2 , A. Karson3 1 Kocaeli University Medical Faculty, Pharmacology, Kocaeli, Turkey; 2 Namik Kemal University Medical Faculty, Pharmacology, Tekirdag, Turkey; 3 Kocaeli University Medical Faculty, Physiology, Kocaeli, Turkey Purpose of the study: Obesity-associated systemic inflammation was identified some time ago. The suggestion that obesity can also result in central inflammation, however is a relatively recent one. Several studies showed also high fat diet elevates the expression of pro-inflammatory cytokines such as TNF-a and IL-6 in the hypothalamus. Moreover, evidence indicated that obesity is linked with cognitive dysfunction including learning and memory. In this study we aimed to investigate the development of obesityassociated cognitive dysfunction by assessing emotional and spatial memory after chronic etanercept treatment in cafeteria diet (CD)-fed rats. Methods: Male weanling Wistar Albino rats (50−70 g, 30 days after birth) were divided into three groups (n = 10−13): First group of rats (control) was fed a standard pelleted diet. The second group of animals (obese) was fed on CD which is a high-fat diet in order to generate a diet-induced obesity model as reported previously [1]. This diet was composed by a mixture of pate, bacon, chips, cookies, chocolate and chow with proportions of 2:1:1:1:1:1, respectively, and was given to each rat daily. The third group (etanercept-treated) was also fed on CD and treated with etanercept (0.8 mg/kg/weekly/subcutaneously) during 12 weeks. The body weights of animals were measured weekly. The memory functions were examined by passive avoidance test (PAT) and Morris Water Maze test (MWMT). Total locomotor activity (TLA) was also measured. One-way and two-way ANOVA and Tukey’s post hoc test used for statistical analysis. Results: After 12 weeks, the body weight of obese group was higher than control (p < 0.0001) and etanercept-treated group was lower than both control and obese group (p < 0.0001). There was no significant difference between three groups in terms of TLA (F(2,30) = 2.767, p = 0.0789). In the PAT, there was no significant difference between the first day latency of animals (F(2,30) = 0.1044, p = 0.9012). Second day, obese group showed a significantly lower latency compared to control group during the retention test (p < 0.0001), which indicated impaired retention of emotional memory in this task. However, there was no difference between etanercept-treated group and control group (p > 0.05). In the MWMT, the escape latency significantly increased in acquisition sessions in all groups and the time spent in escape platforms’s quadrant in the probe trial significantly decreased in obese group compared to control group (p < 0.0001), etanercept
P.1.j. Basic and clinical neuroscience − Cognitive neuroscience treatment significantly reversed the diminished retention latency (p < 0.0001). Conclusions: The results of our study confirm that obesity causes cognitive dysfunction. Etanercept prevented the impairment of emotional and spatial memory induced by obesity, indicating that inflammation process has an important role on memory deficits in obesity. Thus, a role for inflammation in mediating memory dysfunction presents an important avenue for the development of therapies to treat memory deficits in obesity. Additionally, anti-inflammatory treatment may be a new approach to treatment of obesity. References [1] Garcia-Diaz, D.F., Campion, J., Milagro, F.I., Lomba, A., Marzo, F., Martinez, J.A., 2007. Chronic mild stress induces variations in locomotor behavior and metabolic rates in high fat fed rats. J Physiol Biochem 63(4), 337–346.
P.1.j.018 A comparative study of cognitive impairment in patients at different stages of schizophrenia
S343
those in the other groups. The study revealed no statistically significant difference in reduction of clinical symptoms or in cognitive functioning in patients taking different antipsychotic drugs. Conclusions: No significant violations of visual-spatial and visual-constructive abilities were revealed (figures correspond to “medium” or “low normal”). Saved General pattern of loss of information was similar to healthy people (no more than 30%). Regardless of disease duration reduced volume and accuracy of the stored information was reduced. Chronic patients’ perfomance is characterized by the largest decline in the accuracy of the stored information and other qualitative parameters of neuropsychological functioning. Primary patients revealed a direct correlation between the severity of cognitive impairment and positive symptoms. The nature of antipsychotic treatment did not affect cognitive dysfunction. Thus, the severity of cognitive deficits and the degree of influence of positive and negative symptoms on cognitive functions of patients at different stages of schizophrenia varies, and that can be used for optimization of pharmacotherapy and rehabilitation measures.
M. Dorofeikova1 ° , N. Petrova1 , E. Voinkova1 1 St-Petersburg State University, Medical faculty, St-Petersburg, Russia Cognitive functioning of patients with a first psychotic episode is particularly important, because their social functioning, success of rehabilitation activities and achieving compliance are largely depending on it. The aim of the study was to analyze cognitive functioning of schizophrenic patients with different duration of the disease and psychotropic treatment. Methods: Present study was conducted in 45 patients with paranoid schizophrenia: 15 patients first admitted to a psychiatric institution (24.3±5.0 years old), 15 patients who also met criteria of the first episode psychosis, but were re-hospitalized (27.3±5.5 years old), and 15 patients with a history of more than three hospitalizations (disease duration of 8.3±3.9 years, mean age 27.5±6.3 years). PANSS was used to assess the severity of psychopathological symptoms upon admission and on the formation of remission stage. Neurocognitive functioning was assessed using ReyOsterich Complex Figure (ROCF). Data were processed with Statistica for Windows 8.0, StatPlus 2009 Professional 5.8.4. Results: The initial severity of symptoms was not significantly different. At the remission stage total score in both groups of patients with a first psychotic episode was significantly lower than in the chronic patients’ group. Visuospatial abilities and constructive praxis were average for the 2nd and 3rd groups’ patients, but were on the lower limit of normal range for patients hospitalized for the first time. Short-term visuospatial memory composite score was significantly lower in patients with chronic schizophrenia. It was significantly correlated with the severity of negative symptoms (r = 0.63, p < 0.05). Also a significant correlation between constructive praxis and thought disorganization scale of PANSS was found (r = 0.55, p < 0.05). Chronic patients demonstrated a trend toward reduction of the size of the figure and confabulations. The former may be a consequence of druginduced parkinsonism. Planning score were at the average level for all groups. A significant correlation of volume of the stored information with the reduction of positive symptoms (r = 0,62, p < 0.05) and total score on the PANSS scale (r = 0,65, p < 0.05) was found in patients with first episode. In newly hospitalized patients accuracy score was significantly lower compared with
P.1.j.020 Functioning of the posterior cingulate cortex predicts development of insight into one’s illness in patients with first-episode psychosis T.T. Raij1,2 ° , T. M¨antyl¨a2,3 , J. Suvisaari3 1 Helsinki University Hospital, Department of psychiatry, Helsinki, Finland; 2 Aalto University School of Science, department of Neuroscience and Biomedical engineering and Advanced Magnetic Imaging Centre, Espoo, Finland; 3 National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland Purpose of the study: Lack of insight into one’s symptoms is integral for the definition of psychosis, and many patients remain permanently unaware of their illness and its consequences, which constitutes a major obstacle for treatment and rehabilitation. Recent neuroimaging samples in chronic patients have shown an association between poor insight and functioning of the selfreflection-related cortical midline structures (CMS), anchored in the posterior cingulate cortex [1−3]. These studies cannot tell, however, about possible causal relationship between poor insight and CMS functioning. Methods: To address relationship between CMS functioning and future change in insight, we measured metacognition- and insight-related brain activation at baseline with fMRI. We presented statements from general metacognition scales (e.g. “I know how my mind functions when I solve a problem”) and from clinical insight scales (e.g. “Some of my experiences result from psychosis”) in blocks alternated with 30-s resting periods. Participants were asked to rate these statements on a visual analog scale ranging from “I fully disagree” to “I fully agree” during scanning. Clinical insight was measured also a few days before and 2 months after scanning with Schedule for the Assessment of Insight − Expanded (SAI-E [4]). Due to planned scanner change, we analyzed separately two samples, consisting of 15 patients and 12 control subjects each. The data were preprocessed and analyzed with general linear model in SPM8. Results: In the contrast ”metacognition > rest”, patients had stronger activation (or less deactivation) than control subjects in
P.1.j. Basic and clinical neuroscience − Cognitive neuroscience
P.1.j.016 Impact of smoking on cognitive functions S. Kim1 ° , K.W. Kim2 1 YangSan Hospital, Psychiatry, YangSan city, South-Korea; 2 Seoul National University Hospital, Neuropsychiatry, Seoul, South-Korea Smoking is increasingly recognized as a risk factor for dementia in elderly individuals [1]. There is also evidence to suggest that its impact on adverse cognitive outcomes, including dementia, may have been underestimated owing to selection effects as a result of greater mortality among smokers [2]. The extent to which smoking increases the cognitive decline remains unclear. The goals of this study were to investigate the impact of smoking on cognitive functions in the elderly Koreans. 1,118 Koreans were randomly sampled from the residents aged 65 years or older living in Seongnam, Korea, at phase 1 in 2006. Phase 2 assessment was conducted in 2013. Structured face-to-face interviews were conducted on the 714 respondent subjects using the Korean version of Mini International Neuropsychiatric Interview (MINI) [3]. Memory, vocabulary, executive function were assessed with the Korean version of CERAD(Consortium to Establish a Registry for Alzheimer disease) neuropsychological assessment battery(CERAD-K) [4], Digit span forward and backward test, Korean version of Frontal Assessment Battery(FAB-K). Of the 714 participants at phase 1, 77 had died and 252 had dropped out from the study before the second data collection in 2013. Of the 385 remaining individuals, 258 individuals who had cognitive diseases including all kinds of dementias, mild cognitive disorder, stroke at phase 1 and women who had extremely lower smoking rate compared to men(21.3%(men): 1%(women) in 2006) were excluded from the study. Finally, 127 men were included in data analyses of cognitive changes between phase 1 and phase 2. A current-smoker was defined as a person who had been smoking at least one cigarette per day for one year, and a past-smoker as a person who used to smoke but had not smoked in the past one year. Linear mixed models were used to assess the association between smoking history and cognitive decline for 7 years. Additionally Cox proportional hazard model was used to calculate the hazard rate and 95% confidence intervals of three smoking groups after adjusting age, education years, diabetes, hypertension and alcohol use disorders. Mean age was 69.9±4.2 for the whole sample and 70.2±4.5, 70.2±4.6 and 68.6±2.2 for never-smokers, past-smokers and current-smokers respectively at the first assessment. No faster cognitive decline on all tests was observed among current and past smokers compared with never smokers. On the contrary, a significantly slower cognitive declines were observed on MMSE(MiniMental State Examination) in past-smokers and current smokers than never smokers [mean difference in 7-year decline: neversmokers = reference, past-smokers = 0.88 (95% CI, 0.23 to 1.54), current-smokers = 0.91 (95% CI, 0.09 to 1.72)]. The hazard ratio (95% confidence interval) of mortality was 0.37 (0.09–1.55) for past-smokers and 3.01 (0.34–26.56) for current-smokers, but this outcome was not statistically significant. In conclusion, current-smokers and past-smokers did not show faster cognitive declines compared to never-smokers in the elderly Koreans. References [1] Anstey, K.J., von Sanden, C., Salim, A., O’Kearney, R., 2007. Smoking as a risk factor fordementia and cognitive decline: a meta-analysis of prospective studies. Am JEpidemiol 166(4), 367–378.
[2] Hern´an, M.A., Alonso, A., Logroscino, G., 2008. Cigarette smoking and dementia: potentialselection bias in the elderly. Epidemiology 19(3), 448–450. [3] Youu, S.W., Namkoong, K., Kim, S.J., 2006. Validity of Korean Version of the mini-international neuropsychiatric interview. Anxiety Mood 2, 50−55. [4] Lee, J.H., Lee, K.U., Lee, D.Y., Kim, K.W., Jhoo, J.H., Kim, J.H., Woo, J.I., 2002. Development of the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries. Research Support, Non-U.S. Gov’t Validation Studies. J Gerontol. B: Psychol. Sci. Soc. 57(1), 47−53.
P.1.j.017 Effects of chronic etanercept, a TNF-a inhibitor, on cognitive dysfunction in cafeteria diet-fed rats T. Demirtas1 ° , T. Utkan1 , S.S. Gocmez2 , A. Karson3 1 Kocaeli University Medical Faculty, Pharmacology, Kocaeli, Turkey; 2 Namik Kemal University Medical Faculty, Pharmacology, Tekirdag, Turkey; 3 Kocaeli University Medical Faculty, Physiology, Kocaeli, Turkey Purpose of the study: Obesity-associated systemic inflammation was identified some time ago. The suggestion that obesity can also result in central inflammation, however is a relatively recent one. Several studies showed also high fat diet elevates the expression of pro-inflammatory cytokines such as TNF-a and IL-6 in the hypothalamus. Moreover, evidence indicated that obesity is linked with cognitive dysfunction including learning and memory. In this study we aimed to investigate the development of obesityassociated cognitive dysfunction by assessing emotional and spatial memory after chronic etanercept treatment in cafeteria diet (CD)-fed rats. Methods: Male weanling Wistar Albino rats (50−70 g, 30 days after birth) were divided into three groups (n = 10−13): First group of rats (control) was fed a standard pelleted diet. The second group of animals (obese) was fed on CD which is a high-fat diet in order to generate a diet-induced obesity model as reported previously [1]. This diet was composed by a mixture of pate, bacon, chips, cookies, chocolate and chow with proportions of 2:1:1:1:1:1, respectively, and was given to each rat daily. The third group (etanercept-treated) was also fed on CD and treated with etanercept (0.8 mg/kg/weekly/subcutaneously) during 12 weeks. The body weights of animals were measured weekly. The memory functions were examined by passive avoidance test (PAT) and Morris Water Maze test (MWMT). Total locomotor activity (TLA) was also measured. One-way and two-way ANOVA and Tukey’s post hoc test used for statistical analysis. Results: After 12 weeks, the body weight of obese group was higher than control (p < 0.0001) and etanercept-treated group was lower than both control and obese group (p < 0.0001). There was no significant difference between three groups in terms of TLA (F(2,30) = 2.767, p = 0.0789). In the PAT, there was no significant difference between the first day latency of animals (F(2,30) = 0.1044, p = 0.9012). Second day, obese group showed a significantly lower latency compared to control group during the retention test (p < 0.0001), which indicated impaired retention of emotional memory in this task. However, there was no difference between etanercept-treated group and control group (p > 0.05). In the MWMT, the escape latency significantly increased in acquisition sessions in all groups and the time spent in escape platforms’s quadrant in the probe trial significantly decreased in obese group compared to control group (p < 0.0001), etanercept
P.1.j. Basic and clinical neuroscience − Cognitive neuroscience treatment significantly reversed the diminished retention latency (p < 0.0001). Conclusions: The results of our study confirm that obesity causes cognitive dysfunction. Etanercept prevented the impairment of emotional and spatial memory induced by obesity, indicating that inflammation process has an important role on memory deficits in obesity. Thus, a role for inflammation in mediating memory dysfunction presents an important avenue for the development of therapies to treat memory deficits in obesity. Additionally, anti-inflammatory treatment may be a new approach to treatment of obesity. References [1] Garcia-Diaz, D.F., Campion, J., Milagro, F.I., Lomba, A., Marzo, F., Martinez, J.A., 2007. Chronic mild stress induces variations in locomotor behavior and metabolic rates in high fat fed rats. J Physiol Biochem 63(4), 337–346.
P.1.j.018 A comparative study of cognitive impairment in patients at different stages of schizophrenia
S343
those in the other groups. The study revealed no statistically significant difference in reduction of clinical symptoms or in cognitive functioning in patients taking different antipsychotic drugs. Conclusions: No significant violations of visual-spatial and visual-constructive abilities were revealed (figures correspond to “medium” or “low normal”). Saved General pattern of loss of information was similar to healthy people (no more than 30%). Regardless of disease duration reduced volume and accuracy of the stored information was reduced. Chronic patients’ perfomance is characterized by the largest decline in the accuracy of the stored information and other qualitative parameters of neuropsychological functioning. Primary patients revealed a direct correlation between the severity of cognitive impairment and positive symptoms. The nature of antipsychotic treatment did not affect cognitive dysfunction. Thus, the severity of cognitive deficits and the degree of influence of positive and negative symptoms on cognitive functions of patients at different stages of schizophrenia varies, and that can be used for optimization of pharmacotherapy and rehabilitation measures.
M. Dorofeikova1 ° , N. Petrova1 , E. Voinkova1 1 St-Petersburg State University, Medical faculty, St-Petersburg, Russia Cognitive functioning of patients with a first psychotic episode is particularly important, because their social functioning, success of rehabilitation activities and achieving compliance are largely depending on it. The aim of the study was to analyze cognitive functioning of schizophrenic patients with different duration of the disease and psychotropic treatment. Methods: Present study was conducted in 45 patients with paranoid schizophrenia: 15 patients first admitted to a psychiatric institution (24.3±5.0 years old), 15 patients who also met criteria of the first episode psychosis, but were re-hospitalized (27.3±5.5 years old), and 15 patients with a history of more than three hospitalizations (disease duration of 8.3±3.9 years, mean age 27.5±6.3 years). PANSS was used to assess the severity of psychopathological symptoms upon admission and on the formation of remission stage. Neurocognitive functioning was assessed using ReyOsterich Complex Figure (ROCF). Data were processed with Statistica for Windows 8.0, StatPlus 2009 Professional 5.8.4. Results: The initial severity of symptoms was not significantly different. At the remission stage total score in both groups of patients with a first psychotic episode was significantly lower than in the chronic patients’ group. Visuospatial abilities and constructive praxis were average for the 2nd and 3rd groups’ patients, but were on the lower limit of normal range for patients hospitalized for the first time. Short-term visuospatial memory composite score was significantly lower in patients with chronic schizophrenia. It was significantly correlated with the severity of negative symptoms (r = 0.63, p < 0.05). Also a significant correlation between constructive praxis and thought disorganization scale of PANSS was found (r = 0.55, p < 0.05). Chronic patients demonstrated a trend toward reduction of the size of the figure and confabulations. The former may be a consequence of druginduced parkinsonism. Planning score were at the average level for all groups. A significant correlation of volume of the stored information with the reduction of positive symptoms (r = 0,62, p < 0.05) and total score on the PANSS scale (r = 0,65, p < 0.05) was found in patients with first episode. In newly hospitalized patients accuracy score was significantly lower compared with
P.1.j.020 Functioning of the posterior cingulate cortex predicts development of insight into one’s illness in patients with first-episode psychosis T.T. Raij1,2 ° , T. M¨antyl¨a2,3 , J. Suvisaari3 1 Helsinki University Hospital, Department of psychiatry, Helsinki, Finland; 2 Aalto University School of Science, department of Neuroscience and Biomedical engineering and Advanced Magnetic Imaging Centre, Espoo, Finland; 3 National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland Purpose of the study: Lack of insight into one’s symptoms is integral for the definition of psychosis, and many patients remain permanently unaware of their illness and its consequences, which constitutes a major obstacle for treatment and rehabilitation. Recent neuroimaging samples in chronic patients have shown an association between poor insight and functioning of the selfreflection-related cortical midline structures (CMS), anchored in the posterior cingulate cortex [1−3]. These studies cannot tell, however, about possible causal relationship between poor insight and CMS functioning. Methods: To address relationship between CMS functioning and future change in insight, we measured metacognition- and insight-related brain activation at baseline with fMRI. We presented statements from general metacognition scales (e.g. “I know how my mind functions when I solve a problem”) and from clinical insight scales (e.g. “Some of my experiences result from psychosis”) in blocks alternated with 30-s resting periods. Participants were asked to rate these statements on a visual analog scale ranging from “I fully disagree” to “I fully agree” during scanning. Clinical insight was measured also a few days before and 2 months after scanning with Schedule for the Assessment of Insight − Expanded (SAI-E [4]). Due to planned scanner change, we analyzed separately two samples, consisting of 15 patients and 12 control subjects each. The data were preprocessed and analyzed with general linear model in SPM8. Results: In the contrast ”metacognition > rest”, patients had stronger activation (or less deactivation) than control subjects in