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| ID | Type | Description | Link |
|---|---|---|---|
| 508402643 | Other Grant/Funding Number | Deutsche Forschungsgemeinschaft (DFG) |
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| Name | Class |
|---|---|
| Department of Experimental Neuroimmunology, University Medicine | UNKNOWN |
| Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald | UNKNOWN |
| Institute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin |
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This clinical trial investigates the effects of spermidine supplementation on sleep quality and sleep-dependent memory consolidation in older adults with Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI), two populations at increased risk of future cognitive decline and dementia. Impaired sleep has been identified as a modifiable factor contributing to cognitive decline, and interventions targeting sleep architecture could offer therapeutic potential to prevent or slow down this decline.
Spermidine is a naturally occurring polyamine found in foods such as wheat germ and soybeans. It induces autophagy, a cellular degradation and recycling process essential for neuronal maintenance and function. In animal studies, spermidine has been shown to improve memory performance, reduce neuroinflammation, and support mitochondrial health. Preliminary findings from human trials in individuals with SCD or MCI suggest potential cognitive benefits of spermidine, but results are not unequivocal, and the impact on sleep has not been systematically evaluated.
In this randomized, double-blind, placebo-controlled trial, 76 participants aged 55 to 70 years with SCD or MCI will receive either spermidine (6 mg/day) or a placebo for 12 weeks. Sleep will be evaluated using overnight EEG in a controlled laboratory setting, focusing on measures such as slow-wave sleep and sleep spindle activity. Memory performance will be assessed before and after the intervention using standardized neuropsychological testing. Numerical skills will be tested at baseline only to compare SCD and MCI participants with healthy controls.
Blood samples will be collected to quantify metabolic indicators, neurodegeneration-related biomarkers, and autophagy-associated proteins. A control group of 38 cognitively healthy individuals will undergo comparable sleep and cognitive assessments without receiving any supplementation.
The primary objective of the study is to characterize the impact of spermidine on sleep-dependent memory consolidation and to identify associated biological changes relevant to aging and neurodegeneration. The results may inform the development of non-pharmacological strategies aimed at preserving cognitive function in individuals at risk for dementia.
Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) represent early stages along the continuum of cognitive decline preceding dementia. Individuals with SCD report persistent cognitive complaints despite normal performance on standardized cognitive testing, whereas MCI is characterized by objective cognitive impairment that does not yet interfere substantially with activities of daily living. Both conditions are associated with an elevated risk of progression to Alzheimer's disease and other dementias. Disruption of sleep architecture is increasingly implicated in the pathophysiology of neurodegenerative disorders, and early interventions targeting sleep-related mechanisms could help delay further cognitive decline. This clinical trial evaluates the effects of spermidine supplementation on sleep quality and sleep-dependent memory consolidation in older adults with SCD or MCI.
Following an adaptation night and an initial baseline sleep assessment with overnight electroencephalography (EEG), participants will be randomly assigned to either the spermidine or placebo group. The intervention consists of a daily oral dose of 6 mg spermidine (administered as three 2 mg sachets), continued over a 12-week period. The trial employs a randomized, double-blind, placebo-controlled design. Placebo sachets, identical in appearance and taste, contain only microcrystalline cellulose. After the 12-week supplementation period, participants will return for a second overnight EEG assessment.
A healthy control group (n=38), matched for age and sex, will undergo comparable baseline assessments but will not receive any intervention. These data will provide normative reference values for sleep and cognitive parameters.
The primary objective of the study is to assess the impact of spermidine on sleep architecture, measured via overnight polysomnography, with a specific focus on slow-wave sleep and sleep spindle activity, EEG markers associated with sleep-dependent memory consolidation and known to decline with age and neurodegeneration. Secondary outcomes include changes in memory consolidation (assessed using a battery of cognitive tasks that target declarative, procedural, and visuospatial memory domains), as well as numerical skills (tested via e.g., digit-letter-decision task, Berlin Numeracy Test). Testing occurs before and after each EEG night to evaluate overnight consolidation effects. All participants will wear actigraphs prior to both EEG nights to monitor sleep-wake cycles and physical activity.
Additional biological endpoints will examine changes in circulating neuropeptides, insulin-glucose homeostasis, and autophagy-related biomarkers. Blood samples are collected at each EEG session and two weeks after the start of supplementation. Physiological assessments include measurements of inflammatory markers (e.g., interleukin (IL)-6, tumor necrosis factor (TNF-α), neuroprotective factors (e.g., Neuropeptide Y, eukaryotic translation initiation factor 5A (eIF5A) hypusination), and metabolic indicators (e.g., fasting insulin, glucose, and lipid profiles).
Participants will undergo structural brain imaging using a 3-Tesla MRI scanner to exclude individuals with comorbid neurological conditions (e.g., prior stroke, other neurodegenerative diseases) and to assess brain morphology. Eligibility is determined through standardized pre-screening procedures, including clinical interviews and neuropsychological assessments.
The study includes 76 participants with SCD or MCI, aged 55-70 years, randomly allocated to either the spermidine or placebo group (n=38 per group). The sample size provides adequate statistical power to detect medium-to-large effect sizes, based on previous pilot findings and anticipated attrition rates.
This study aims to investigate the effects of spermidine supplementation on neurophysiological and cognitive outcomes in individuals with early-stage cognitive decline. The results are expected to contribute to the growing body of evidence evaluating spermidine as a safe, nutrition-based strategy for maintaining brain health and cognitive function in the context of aging.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy elderly controls | No Intervention | baseline comparison, healthy controls are not part of the intervention | |
| Dietary Placebo | Placebo Comparator |
| |
| Dietary Supplement | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Spermidine Supplementation | Dietary Supplement | supplementation of 6 mg Spermidine per day across 3 doses |
|
| Measure | Description | Time Frame |
|---|---|---|
| Effects of spermidine supplementation on sleep quality as measured by electroencephalography (EEG) mean power spectra | Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow oscillations (0.5-1 Hz), low delta (1-1.5 Hz), delta (1-4 Hz), theta (4-8 Hz), and beta (15-25 Hz). For the spermidine effect, baseline and follow-up EEG data are compared with each other. | baseline, 12-week follow-up |
| Effects of spermidine supplementation on sleep quality as measured by sleep spindle count assessed from EEG | Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz), and the number of slow frontal and fast parietal discrete spindles are counted. Spindle detection is performed based on an algorithm adopted from previous studies. For the spermidine effect, baseline and follow-up EEG data are compared with each other. | baseline, 12-week follow-up |
| Effects of spermidine supplementation on sleep quality as measured by sleep spindle power assessed from EEG | Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz). Spindle power is analyzed as a further measure of spindle activity. Spindle detection is performed based on an algorithm adopted from previous studies. For the spermidine effect, baseline and follow-up EEG data are compared with each other. | baseline, 12-week follow-up |
| Effects of spermidine supplementation on sleep-related alertness as measured by computer-based task | The alertness task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. It comprises two runs without and two runs with a prior warning tone. For the spermidine effect, baseline and follow-up task performances of SCD and MCI participants are compared with each other. Task performance is measured by speed (in ms) and hit/false or miss. |
| Measure | Description | Time Frame |
|---|---|---|
| Differences in autophagy-related blood markers pre and post spermidine intervention in SCD and MCI as measured by polyamine concentration | concentration in nmol / mg Protein assessed via Peripheral Blood Mononuclear Cells (PBMCs) | baseline, 2 weeks after baseline, 12-week follow-up |
| Differences in sleep quality between SCD or MCI and healthy controls (HC) as measured by electroencephalography (EEG) mean power spectra |
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Inclusion Criteria (SCD participants):
Men and women
Written consent to participate in the study
German at native speaker level
Age between 55 and 70 years
Subjective Cognitive Decline operationalized as:
Inclusion Criteria (MCI patients):
Men and women
Written consent to participate in the study
German at native speaker level
Age between 55 and 70 years
Mild cognitive impairment (MCI) operationalized as:
Exclusion Criteria (SCD and MCI participants):
Inclusion criteria (healthy controls):
Exclusion criteria (healthy controls):
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Agnes Flöel, Prof. Dr. | Contact | +49 (0)3834 86-6815 | agnes.floeel@med.uni-greifswald.de | |
| Silke M Wortha, Dr. | Contact | +49 3834 86 - 6704 | SilkeMaria.Wortha@med.uni-greifswald.de |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Neurology, University Medicine Greifswald | Recruiting | Greifswald | Mecklenburg-Vorpommern | 17475 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17086200 | Background | Marshall L, Helgadottir H, Molle M, Born J. Boosting slow oscillations during sleep potentiates memory. Nature. 2006 Nov 30;444(7119):610-3. doi: 10.1038/nature05278. Epub 2006 Nov 5. | |
| 27684064 | Background | Gupta VK, Pech U, Bhukel A, Fulterer A, Ender A, Mauermann SF, Andlauer TF, Antwi-Adjei E, Beuschel C, Thriene K, Maglione M, Quentin C, Bushow R, Schwarzel M, Mielke T, Madeo F, Dengjel J, Fiala A, Sigrist SJ. Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release. PLoS Biol. 2016 Sep 29;14(9):e1002563. doi: 10.1371/journal.pbio.1002563. eCollection 2016 Sep. |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| UNKNOWN |
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| Dietary Placebo | Dietary Supplement | supplementation of 6 mg Placebo per day across 3 doses (placebo consists of maltodextrin, rice extract microcrystalline cellulose mixture, citric acid (anhydrous), silicon oxide (precipitated, E551)) |
|
| baseline, 12-week follow-up |
| Effects of spermidine supplementation on sleep-related visual-spatial memory as measured by computer-based task | The visual-spatial memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 60 objects (e.g., photo of a band-aid) placed in front of a background (e.g., photo of a treatment room in a doctor's office), a retrieval phase follows directly after encoding in the evening before bedtime, in which 30 randomly selected images from the total of 60 are tested. Participants should memorize the position of the object placed in front of the background and select the correct position by pressing a button. In the next morning, the remaining 30 images are tested in a recall phase. Task performance is measured by speed (in ms) and hit/false or miss. For the spermidine effect, baseline and follow-up task performances of SCD and MCI participants are compared with each other. | baseline, 12-week follow-up |
| Effects of spermidine supplementation on sleep-related verbal memory as measured by computer-based task | The verbal memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 44 word pairs, a retrieval phase follows directly after encoding in the evening before bedtime, in which all word pairs are tested in randomized order. The next morning, all word pairs are tested in a recall phase. Task performance is measured by hit/false or miss. For the spermidine effect, baseline and follow-up task performances of SCD and MCI participants are compared with each other. | baseline, 12-week follow-up |
Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow oscillations (0.5-1 Hz), low delta (1-1.5 Hz), delta (1-4 Hz), theta (4-8 Hz), and beta (15-25 Hz). The differences between SCD / MCI and healthy controls are assessed from baseline EEG data. |
| baseline data |
| Differences in sleep quality between SCD or MCI and healthy controls (HC) as measured by sleep spindle count assessed from EEG | Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz), and the number of slow frontal and fast parietal discrete spindles are counted. Spindle detection is performed based on an algorithm adopted from previous studies. The differences between SCD / MCI and healthy controls are assessed from baseline EEG data. | baseline data |
| Differences in sleep quality between SCD or MCI and healthy controls (HC) as measured by sleep spindle power assessed from EEG | Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz). Spindle power is analyzed as a further measure of spindle activity. Spindle detection is performed based on an algorithm adopted from previous studies. The differences between SCD / MCI and healthy controls are assessed from baseline EEG data. | baseline data |
| Differences in autophagy-related blood markers pre and post spermidine intervention in SCD or MCI as measured by eIF5A hypusination | assessed via Hypusinated eIF5A levels (Western Blot) from Peripheral Blood Mononuclear Cells (PBMCs) | baseline, 2 weeks after baseline, 12-week follow-up |
| Differences in neuropeptide Y blood levels pre and post spermidine intervention in SCD or MCI | Neuropeptide Y blood levels in pg/ml analyzed from serum blood sample | baseline, 12-week follow-up |
| Differences in sleep-related alertness between SCD or MCI participants and healthy controls as measured by computer-based task | The alertness task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. It comprises two runs without and two runs with a prior warning tone. The differences between SCD / MCI and healthy controls are assessed from baseline task data. Task performance is measured by speed (in ms) and hit/false or miss. | baseline |
| Differences in sleep-related visual-spatial memory between SCD or MCI participants and healthy controls as measured by computer-based task | The visual-spatial memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 60 objects (e.g., photo of a band-aid) placed in front of a background (e.g., photo of a treatment room in a doctor's office), a retrieval phase follows directly after encoding in the evening before bedtime, in which 30 randomly selected images from the total of 60 are tested. Participants should memorize the position of the object placed in front of the background and select the correct position by pressing a button. In the next morning, the remaining 30 images are tested in a recall phase. Task performance is measured by speed (in ms) and hit/false or miss. The differences between SCD / MCI and healthy controls are assessed from baseline task data. | baseline |
| Differences in sleep-related verbal memory between SCD or MCI participants and healthy controls as measured by computer-based task | The verbal memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 44 word pairs, a retrieval phase follows directly after encoding in the evening before bedtime, in which all word pairs are tested in randomized order. The next morning, all word pairs are tested in a recall phase. Task performance is measured by hit/false or miss. The differences between SCD / MCI and healthy controls are assessed from baseline task data. | baseline |
| Differences in neuropeptide Y blood levels between SCD or MCI and healthy controls | blood levels in pg/ml analyzed from serum blood sample | baseline data |
| Differences in autophagy-related blood markers between SCD or MCI and healthy controls as measured by polyamine concentration | concentration in nmol / mg Protein assessed via Peripheral Blood Mononuclear Cells (PBMCs) | baseline data |
| Differences in autophagy-related blood markers between SCD or MCI and healthy controls as measured by eIF5A hypusination | assessed via Hypusinated eIF5A levels (Western Blot) from Peripheral Blood Mononuclear Cells (PBMCs) | baseline data |
| Differences in numerical skills between SCD or MCI patients and healthy controls as measured by lexical decision task | Participants complete a computer-based lexical decision task, in which a row of six symbols is presented after a fixation cross. Depending on the condition, the test subjects must decide by pressing a key on the keyboard whether the row presented contains a letter (e.g., condition 1) or a digit (e.g., condition 2). Each condition consists of two blocks. After the first block, there is a short pause before the second block starts. The condition (digit or letter) with which the trial starts is randomized for each test subject. | assessed at baseline only |
| Differences in numerical skills between SCD or MCI participants and healthy controls as measured by Berlin Numeracy Test | The Berlin Numeracy Test contains 4 short, text-based questions testing statistical numeracy and risk literacy, requiring Bayesian inference for problems like understanding probabilities in health concerns (e.g., poisonous mushrooms) or lotteries, often presenting data in relative/absolute numbers and asking for probability estimates. Correct answers scored for a total of 0-4 points. | assessed at baseline only |
| 21869457 | Background | Minois N, Carmona-Gutierrez D, Madeo F. Polyamines in aging and disease. Aging (Albany NY). 2011 Aug;3(8):716-32. doi: 10.18632/aging.100361. |
| 29371440 | Background | Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374):eaan2788. doi: 10.1126/science.aan2788. |