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P58. Sleep in humans stabilizes hippocampal pattern separation performance
Abstracts / Clinical Neurophysiology 129 (2018) e48–e116
P57. Safety and tolerability of spermidine supplementation: A translational study in mice and older adults with subjective cognitive decline—C. Schwarz 1,*, M. Wirth 1, G. Benson 1, T. Köbe 1, S. Stekovic 2, F. Madeo 2, A. Flöel 3 (1 Charité – Universitätsmedizin Berlin, NeuroCure Clinical Research Center NCRC, Berlin, Germany , 2 Universität Graz, Graz, Austria, 3 Universitätsmedizin Greifswald, Greifswald, Germany) ⇑
Presenting author.
Background: Supplementation of spermidine, an autophagyinducing agent, has been shown to protect against neurodegeneration and memory impairment in aged animal models. We report a translational study aiming to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations in murine model and a human cohort of older adults with subjective cognitive decline (SCD), a risk factor of dementia. Methods: In murine model, safety of various dosing strategies was assessed using a sub-chronic, oral administration scenario. Post mortem examination of mice included macroscopic inspection of organs, organ weighing and neoplastic examination after 28 days of spermidine supplementation at various concentrations. In addition, animal behavior and animal bodyweight were controlled during the treatment to detect any negative effects. In the human cohort, a randomized, placebo-controlled, double-blind Phase II study was carried out over 3 months to assess safety and tolerability of spermidine supplementation. Safety assessments included vital signs, weight, clinical chemistry and hematological parameters of safety, as well as self-reported health status at the end of intervention. Frequency, duration and severity of adverse event was monitored throughout the trial. Results: In the preclinical toxicity study, spermidine supplementation did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no significant increase in tumorigenic and fibrotic events. In the human cohort, no differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates were above 85% and indicated excellent tolerability. Conclusion: Findings of this translational study demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings call for longer-term intervention studies in humans to investigate the impact of spermidine treatment on memory function and brain integrity. doi:10.1016/j.clinph.2018.04.694
P58. Sleep in humans stabilizes hippocampal pattern separation performance—A. Hanert 1,*, F.D. Weber 2, A. Pedersen 3, J. Born 2, T. Bartsch 1 (1 University Hospital Schleswig-Holstein, University of Kiel, Department of Neurology, Kiel, Germany , 2 University of Tübingen, Institute for Medical Psychology and Behavioral Neurobiology, Tübingen, Germany, 3 University of Kiel, Department of Psychology, Kiel, Germany) ⇑
Presenting author.
Sleep supports the formation of long-term memories in an active system consolidation process. Episodic memories encoded during wakefulness are temporarily stored in the hippocampus before they are transferred to the neocortex for the long term storage. During NonREM sleep, especially slow wave sleep, a reactivation of
e91
hippocampal neural representations is thought to promote this transfer, via synchronization of distinct oscillatory activity in hippocampus and neocortex. However, how this reprocessing of memory during sleep affects the memory representation in the hippocampus itself, is unclear. For this purpose, we tested hippocampal stimulus processing, i.e., pattern separation, before and after periods of sleep and wakefulness in humans. Pattern separation refers to the capability of the hippocampus to form non-overlapping orthogonal neural representations from similar episodic stimulus inputs. We found that pattern separation performance deteriorated across the wake period but remained stable across sleep (p = 0.013). Stimuli with highest similarity showed a reversed pattern with reduced pattern separation after sleep (p < 0.01). Thus, sleep compared to wakefulness shaped the neural representation towards a reduced stimulus overlap only for dissimilar stimuli. In addition, polysomnography demonstrated that pattern separation performance was positively correlated with sleep spindle density, slow oscillation density, and theta power phase-locked to slow oscillations. With those features of NonREM sleep, serving as markers of sleep-dependent memory consolidation and hippocampal reactivation, our findings provide first-time evidence in humans supporting the notion that reactivation-based consolidation processes during sleep affect the hippocampal representation itself.
doi:10.1016/j.clinph.2018.04.695
P60. Direct and long term influence of cardiovascular training on cognition in subacute stroke patients—T. Rackoll 1,*, A. Nave 2, U. Grittner 2, H. Mousa 2, K. Villringer 2, M. Ebinger 2, A. Flöel 2 (1 Charité – Universitätsmedizin Berlin, Center for Stroke Research Berlin, Berlin, Germany, 2 Charité – Universitätsmedizin Berlin, Berlin, Germany) ⇑
Presenting author.
Introduction: Rehabilitation of cognitive deficits has been voted ‘#1 research priority’ for patients suffering from stroke (Saunders et al., 2014). Aerobic fitness training may modulate cognitive performance either by enhancing neuroplasticity or by increasing brain oxygenation. The majority of studies in this area have focused on motor function; its effect on cognitive performance is not well understood yet. The current study therefore aims to evaluate the influence of aerobic fitness intervention on cognitive functions in subacute stroke patients, and tries to elucidate the mechanisms underlying this effect. Methods: The endpoint-blinded multicenter trial Physical Activity in Subacute Stroke (Flöel et al., 2014) (NCT01953549) randomized 194 patients (5–45 days post stroke, Barthel-Index 6 65) to receive either a 4 week aerobic fitness intervention (PHYS) or a relaxation program (RELAX) of equal length. 100 patients additionally received an MRI pre and post intervention (Biomarkers and Perfusion – TrainingInduced changes after Stroke (BAPTISe), NCT01954797). Image acquisition included T1 MPRAGE (1 mm isovoxel), Resting State fMRI (3 3v4 mm 150 scans, TR = 2.3 s) and DTI (64 directions plus 9 B0, 2.3 mm isovoxel). Cognition was assessed via neuropsychological tests (MoCA, Trail Making Test Part A & B (TMT)) in all patients pre and post intervention and 6 months poststroke. Statistical modeling accounted for age, functional ambulation and center effects. Results: In 70/190 BAPTISe patients (60 PHYS, 49 RELAX, median 70 yrs, median NIHSS 9), T1-weighted images were available for Baseline and post intervention. Mean (standard deviation) Hippocampus
P57. Safety and tolerability of spermidine supplementation: A translational study in mice and older adults with subjective cognitive decline—C. Schwarz 1,*, M. Wirth 1, G. Benson 1, T. Köbe 1, S. Stekovic 2, F. Madeo 2, A. Flöel 3 (1 Charité – Universitätsmedizin Berlin, NeuroCure Clinical Research Center NCRC, Berlin, Germany , 2 Universität Graz, Graz, Austria, 3 Universitätsmedizin Greifswald, Greifswald, Germany) ⇑
Presenting author.
Background: Supplementation of spermidine, an autophagyinducing agent, has been shown to protect against neurodegeneration and memory impairment in aged animal models. We report a translational study aiming to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations in murine model and a human cohort of older adults with subjective cognitive decline (SCD), a risk factor of dementia. Methods: In murine model, safety of various dosing strategies was assessed using a sub-chronic, oral administration scenario. Post mortem examination of mice included macroscopic inspection of organs, organ weighing and neoplastic examination after 28 days of spermidine supplementation at various concentrations. In addition, animal behavior and animal bodyweight were controlled during the treatment to detect any negative effects. In the human cohort, a randomized, placebo-controlled, double-blind Phase II study was carried out over 3 months to assess safety and tolerability of spermidine supplementation. Safety assessments included vital signs, weight, clinical chemistry and hematological parameters of safety, as well as self-reported health status at the end of intervention. Frequency, duration and severity of adverse event was monitored throughout the trial. Results: In the preclinical toxicity study, spermidine supplementation did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no significant increase in tumorigenic and fibrotic events. In the human cohort, no differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates were above 85% and indicated excellent tolerability. Conclusion: Findings of this translational study demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings call for longer-term intervention studies in humans to investigate the impact of spermidine treatment on memory function and brain integrity. doi:10.1016/j.clinph.2018.04.694
P58. Sleep in humans stabilizes hippocampal pattern separation performance—A. Hanert 1,*, F.D. Weber 2, A. Pedersen 3, J. Born 2, T. Bartsch 1 (1 University Hospital Schleswig-Holstein, University of Kiel, Department of Neurology, Kiel, Germany , 2 University of Tübingen, Institute for Medical Psychology and Behavioral Neurobiology, Tübingen, Germany, 3 University of Kiel, Department of Psychology, Kiel, Germany) ⇑
Presenting author.
Sleep supports the formation of long-term memories in an active system consolidation process. Episodic memories encoded during wakefulness are temporarily stored in the hippocampus before they are transferred to the neocortex for the long term storage. During NonREM sleep, especially slow wave sleep, a reactivation of
e91
hippocampal neural representations is thought to promote this transfer, via synchronization of distinct oscillatory activity in hippocampus and neocortex. However, how this reprocessing of memory during sleep affects the memory representation in the hippocampus itself, is unclear. For this purpose, we tested hippocampal stimulus processing, i.e., pattern separation, before and after periods of sleep and wakefulness in humans. Pattern separation refers to the capability of the hippocampus to form non-overlapping orthogonal neural representations from similar episodic stimulus inputs. We found that pattern separation performance deteriorated across the wake period but remained stable across sleep (p = 0.013). Stimuli with highest similarity showed a reversed pattern with reduced pattern separation after sleep (p < 0.01). Thus, sleep compared to wakefulness shaped the neural representation towards a reduced stimulus overlap only for dissimilar stimuli. In addition, polysomnography demonstrated that pattern separation performance was positively correlated with sleep spindle density, slow oscillation density, and theta power phase-locked to slow oscillations. With those features of NonREM sleep, serving as markers of sleep-dependent memory consolidation and hippocampal reactivation, our findings provide first-time evidence in humans supporting the notion that reactivation-based consolidation processes during sleep affect the hippocampal representation itself.
doi:10.1016/j.clinph.2018.04.695
P60. Direct and long term influence of cardiovascular training on cognition in subacute stroke patients—T. Rackoll 1,*, A. Nave 2, U. Grittner 2, H. Mousa 2, K. Villringer 2, M. Ebinger 2, A. Flöel 2 (1 Charité – Universitätsmedizin Berlin, Center for Stroke Research Berlin, Berlin, Germany, 2 Charité – Universitätsmedizin Berlin, Berlin, Germany) ⇑
Presenting author.
Introduction: Rehabilitation of cognitive deficits has been voted ‘#1 research priority’ for patients suffering from stroke (Saunders et al., 2014). Aerobic fitness training may modulate cognitive performance either by enhancing neuroplasticity or by increasing brain oxygenation. The majority of studies in this area have focused on motor function; its effect on cognitive performance is not well understood yet. The current study therefore aims to evaluate the influence of aerobic fitness intervention on cognitive functions in subacute stroke patients, and tries to elucidate the mechanisms underlying this effect. Methods: The endpoint-blinded multicenter trial Physical Activity in Subacute Stroke (Flöel et al., 2014) (NCT01953549) randomized 194 patients (5–45 days post stroke, Barthel-Index 6 65) to receive either a 4 week aerobic fitness intervention (PHYS) or a relaxation program (RELAX) of equal length. 100 patients additionally received an MRI pre and post intervention (Biomarkers and Perfusion – TrainingInduced changes after Stroke (BAPTISe), NCT01954797). Image acquisition included T1 MPRAGE (1 mm isovoxel), Resting State fMRI (3 3v4 mm 150 scans, TR = 2.3 s) and DTI (64 directions plus 9 B0, 2.3 mm isovoxel). Cognition was assessed via neuropsychological tests (MoCA, Trail Making Test Part A & B (TMT)) in all patients pre and post intervention and 6 months poststroke. Statistical modeling accounted for age, functional ambulation and center effects. Results: In 70/190 BAPTISe patients (60 PHYS, 49 RELAX, median 70 yrs, median NIHSS 9), T1-weighted images were available for Baseline and post intervention. Mean (standard deviation) Hippocampus