ArcheD, a residual neural network for prediction of cerebrospinal fluid amyloid-beta from amyloid PET images.

Detection and measurement of amyloid-beta (Aß) in the brain is a key factor for early identification and diagnosis of Alzheimer's disease (AD). We aimed to develop a deep learning model to predict Aß cerebrospinal fluid (CSF) concentration directly from amyloid PET images, independent of tracers, brain reference regions or preselected regions of interest. We used 1870 Aß PET images and CSF measurements to train and validate a convolutional neural network ("ArcheD"). We evaluated the ArcheD performance in relation to episodic memory and the standardized uptake value ratio (SUVR) of cortical Aß. We also compared the brain region's relevance for the model's CSF prediction within clinical-based and biological-based classifications. ArcheD-predicted Aß CSF values correlated with measured Aß CSF values (r = 0.92; q < 0.01), SUVR (rAV45 = -0.64, rFBB = -0.69; q < 0.01) and episodic memory measures (0.33 < r < 0.44; q < 0.01). For both classifications, cerebral white matter significantly contributed to CSF prediction (q < 0.01), specifically in non-symptomatic and early stages of AD. However, in late-stage disease, the brain stem, subcortical areas, cortical lobes, limbic lobe and basal forebrain made more significant contributions (q < 0.01). Considering cortical grey matter separately, the parietal lobe was the strongest predictor of CSF amyloid levels in those with prodromal or early AD, while the temporal lobe played a more crucial role for those with AD. In summary, ArcheD reliably predicted Aß CSF concentration from Aß PET scans, offering potential clinical utility for Aß level determination.

Co-twin design in brain imaging-review on biomarkers of Alzheimer's disease.

Twin samples allow to conduct a quasi-experimental co-twin case-control approach that can control for genetic and environmental confounding in brain-cognition associations, being more informative on causality compared with studies in unrelated individuals. We conducted a review of studies that have utilized discordant co-twin design to investigate the associations of brain imaging markers of Alzheimer's disease and cognition. Inclusion criteria encompassed twin pairs discordant for cognition or Alzheimer's disease imaging markers and reporting of within-twin pair comparison on the association between cognition and brain measures. Our PubMed search (2022 April 23, updated 2023 March 9) resulted in 18 studies matching these criteria. Alzheimer's disease imaging markers have been addressed only by few studies, most with small sample size. Structural magnetic resonance imaging studies have indicated greater hippocampal volume and thicker cortex in co-twins with better cognitive performance compared with their co-twins with poorer cognitive performance. No studies have looked at cortical surface area. Positron emission tomography imaging studies have suggested that lower cortical glucose metabolism rate and higher cortical neuroinflammation, amyloid, and tau accumulations are related to poorer episodic memory in within-twin pair comparisons. Thus far, only cross-sectional within-twin pair associations of cortical amyloid and hippocampal volume with cognition have been replicated.

Association of spermidine plasma levels with brain aging in a population-based study.

INTRODUCTION: Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD). METHODS: Data from 659 participants (age range: 21-81 years) of the population-based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]). RESULTS: Higher spermidine levels were significantly associated with lower hippocampal volume (ß = -0.076; 95% confidence interval [CI]: -0.13 to -0.02; q = 0.026), higher AD score (ß = 0.118; 95% CI: 0.05 to 0.19; q = 0.006), lower global CT (ß = -0.104; 95% CI: -0.17 to -0.04; q = 0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis. DISCUSSION: Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.

Spermidine intake is associated with cortical thickness and hippocampal volume in older adults.

BACKGROUND: The natural polyamine spermidine, known to be important for cellular function, decreases during aging. Previous research has demonstrated beneficial impact of spermidine intake on memory functions in both animal models and humans, suggesting that spermidine may be a preventive approach to delay age-related cognitive decline and possibly even Alzheimer's disease (AD). However, the association of spermidine intake with brain health in humans is still unknown. In this study, we aimed to determine the association between dietary spermidine intake and structural brain measures in older individuals with subjective cognitive decline (SCD) and healthy controls (HC). METHODS: Dietary spermidine intake and adherence to Mediterranean Diet (MeDi) were assessed by a self-reported food frequency questionnaire in 90 older adults with SCD and 47 HC. Processing of structural MRI data yielded global brain volumes, hippocampal volume, mean and regional cortical thickness, and cortical thickness in a template encompassing AD-vulnerable regions. In exploratory analyses, the association between spermidine intake and structural brain measures was assessed using adjusted and unadjusted linear regression models. Additionally, we tested for differential associations as a function of group. Mediation analyses were performed to examine whether dietary spermidine intake mediates the associations between adherence to MeDi and structural brain measures. RESULTS: Higher spermidine intake was associated with larger hippocampal volume (standardized ߠ​= â€‹0.262, p â€‹= â€‹0.002), greater mean cortical thickness (standardized ߠ​= â€‹0.187, p â€‹= â€‹0.031), and greater cortical thickness in AD-vulnerable brain regions (standardized ߠ​= â€‹0.176, p â€‹= â€‹0.042), the parietal (standardized ߠ​= â€‹0.202, p â€‹= â€‹0.020), and temporal lobes (standardized ߠ​= â€‹0.217, p â€‹= â€‹0.012). No significant differential effect emerged between older adults with SCD and HC. Moreover, a substantial mediating effect of dietary spermidine intake on the associations between adherence to MeDi and structural brain measures was observed. CONCLUSION: Higher dietary spermidine intake was positively associated with several structural brain measures, irrespective of the presence of SCD, and substantially mediated the relationship of adherence to MeDi and structural brain measures. Our data suggest that higher spermidine intake might be a promising dietary approach to preserve brain health in older adults, a hypothesis currently tested in an interventional trial.

Highly Porous Platinum Electrodes for Dry Ear-EEG Measurements.

The interest in dry electroencephalography (EEG) electrodes has increased in recent years, especially as everyday suitability earplugs for measuring drowsiness or focus of auditory attention. However, the challenge is still the need for a good electrode material, which is reliable and can be easily processed for highly personalized applications. Laser processing, as used here, is a fast and very precise method to produce personalized electrode configurations that meet the high requirements of in-ear EEG electrodes. The arrangement of the electrodes on the flexible and compressible mats allows an exact alignment to the ear mold and contributes to high wearing comfort, as no edges or metal protrusions are present. For better transmission properties, an adapted coating process for surface enlargement of platinum electrodes is used, which can be controlled precisely. The resulting porous platinum-copper alloy is chemically very stable, shows no exposed copper residues, and enlarges the effective surface area by 40. In a proof-of-principle experiment, these porous platinum electrodes could be used to measure the Berger effect in a dry state using just one ear of a test person. Their signal-to-noise ratio and the frequency transfer function is comparable to gel-based silver/silver chloride electrodes.

Reserve, resilience and maintenance of episodic memory and other cognitive functions in aging.

We tested if cognitive and brain reserve and maintenance explain individual differences in episodic memory and other cognitive domains from late middle to early older adulthood. We used The Vietnam Era Twin Study of Aging data (n=1604 men) with episodic memory measured at mean ages of 56, 62 and 68 years, and magnetic resonance imaging data for a subsample of participants (n=321). Cognitive reserve -young adult general cognitive ability at a mean age of 20 years and, to a lesser degree, educational attainment- was positively related to episodic memory performance at each assessment, but not to memory change. We found no evidence for the associations of brain reserve or brain maintenance on memory change. Results were highly similar when looking at processing speed, executive function and verbal fluency. In conclusion, higher young adult cognitive reserve was related to better episodic memory in midlife and older adulthood, but it did not confer better cognitive maintenance with respect to memory. This supports the importance of early cognitive development in dementia prevention.

Association of spermidine blood levels with microstructure of sleep-implications from a population-based study.

Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer's disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50-81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.

Intravenous Injection of PEI-Decorated Iron Oxide Nanoparticles Impacts NF-kappaB Protein Expression in Immunologically Stressed Mice.

Nanoparticle-based formulations are considered valuable tools for diagnostic and treatment purposes. The surface decoration of nanoparticles with polyethyleneimine (PEI) is often used to enhance their targeting and functional properties. Here, we aimed at addressing the long-term fate in vivo and the potential "off-target" effects of PEI decorated iron oxide nanoparticles (PEI-MNPs) in individuals with low-grade and persistent systemic inflammation. For this purpose, we synthesized PEI-MNPs (core-shell method, PEI coating under high pressure homogenization). Further on, we induced a low-grade and persistent inflammation in mice through regular subcutaneous injection of pathogen-associated molecular patterns (PAMPs, from zymosan). PEI-MNPs were injected intravenously. Up to 7 weeks thereafter, the blood parameters were determined via automated fluorescence flow cytometry, animals were euthanized, and the organs analyzed for iron contents (atomic absorption spectrometry) and for expression of NF-κB associated proteins (p65, IκBα, p105/50, p100/52, COX-2, Bcl-2, SDS-PAGE and Western blotting). We observed that the PEI-MNPs had a diameter of 136 nm and a zeta-potential 56.9 mV. After injection in mice, the blood parameters were modified and the iron levels were increased in different organs. Moreover, the liver of animals showed an increased protein expression of canonical NF-κB signaling pathway members early after PEI-MNP application, whereas at the later post-observation time, members of the non-canonical signaling pathway were prominent. We conclude that the synergistic effect between PEI-MNPs and the low-grade and persistent inflammatory state is mainly due to the hepatocytes sensing infection (PAMPs), to immune responses resulting from the intracellular metabolism of the uptaken PEI-MNPs, or to hepatocyte and immune cell communications. Therefore, we suggest a careful assessment of the safety and toxicity of PEI-MNP-based carriers for gene therapy, chemotherapy, and other medical applications not only in healthy individuals but also in those suffering from chronic inflammation.

ArcheD, a residual neural network for prediction of cerebrospinal fluid amyloid-beta from amyloid PET images.

Detection and measurement of amyloid-beta (Aß) aggregation in the brain is a key factor for early identification and diagnosis of Alzheimer's disease (AD). We aimed to develop a deep learning model to predict Aß cerebrospinal fluid (CSF) concentration directly from amyloid PET images, independent of tracers, brain reference regions or preselected regions of interest. We used 1870 Aß PET images and CSF measurements to train and validate a convolutional neural network ("ArcheD"). We evaluated the ArcheD performance in relation to episodic memory and the standardized uptake value ratio (SUVR) of cortical Aß. We also compared the brain region's relevance for the model's CSF prediction within clinical-based and biological-based classifications. ArcheD-predicted Aß CSF values correlated strongly with measured Aß CSF values ( r =0.81; p <0.001) and showed correlations with SUVR and episodic memory measures in all participants except in those with AD. For both clinical and biological classifications, cerebral white matter significantly contributed to CSF prediction ( q <0.01), specifically in non-symptomatic and early stages of AD. However, in late-stage disease, brain stem, subcortical areas, cortical lobes, limbic lobe, and basal forebrain made more significant contributions (q<0.01). Considering cortical gray matter separately, the parietal lobe was the strongest predictor of CSF amyloid levels in those with prodromal or early AD, while the temporal lobe played a more crucial role for those with AD. In summary, ArcheD reliably predicted Aß CSF concentration from Aß PET scans, offering potential clinical utility for Aß level determination and early AD detection.

Streptococcus pneumoniae re-emerges as a cause of community-acquired pneumonia, including frequent co-infection with SARS-CoV-2, in Germany, 2021.

In Germany, the proportion of community-acquired pneumonia due to Streptococcus pneumoniae rebounded to a near-pandemic level in the second half of 2021. Vaccination uptake against respiratory pathogens, including S. pneumoniae, should be strengthened. https://bit.ly/3JMlwFt.

A FinnGen pilot clinical recall study for Alzheimer's disease.

Successful development of novel therapies requires that clinical trials are conducted in patient cohorts with the highest benefit-to-risk ratio. Population-based biobanks with comprehensive health and genetic data from large numbers of individuals hold promise to facilitate identification of trial participants, particularly when interventions need to start while symptoms are still mild, such as for Alzheimer's disease (AD). This study describes a process for clinical recall studies from FinnGen. We demonstrate the feasibility to systematically ascertain customized clinical data from FinnGen participants with ICD10 diagnosis of AD or mild cognitive disorder (MCD) in a single-center cross-sectional study testing blood-based biomarkers and cognitive functioning in-person, computer-based and remote. As a result, 19% (27/140) of a pre-specified FinnGen subcohort were successfully recalled and completed the study. Hospital records largely validated registry entries. For 8/12 MCD patients, other reasons than AD were identified as underlying diagnosis. Cognitive measures correlated across platforms, with highest consistencies for dementia screening (r = 0.818) and semantic fluency (r = 0.764), respectively, for in-person versus telephone-administered tests. Glial fibrillary acidic protein (GFAP) (p < 0.002) and phosphorylated-tau 181 (pTau-181) (p < 0.020) most reliably differentiated AD from MCD participants. We conclude that informative, customized clinical recall studies from FinnGen are feasible.

Negative affective burden is associated with higher resting-state functional connectivity in subjective cognitive decline.

Subjective cognitive decline (SCD), as expressed by older adults, is associated with negative affect, which, in turn, is a likely risk factor for Alzheimer's Disease (AD). This study assessed the associations between negative affective burden, cognitive functioning, and functional connectivity in networks vulnerable to AD in the context of SCD. Older participants (60-90 years) with SCD (n = 51) and healthy controls (n = 50) were investigated in a cross-sectional study. Subclinical negative affective burden, quantified through a composite of self-reported negative affective factors, was related to cognitive functioning (self-perceived and objective) and functional connectivity. Seed-to-voxel analyses were carried out in default mode network (DMN) and salience network (SAL) nodes using resting-state functional magnetic resonance imaging. Greater negative affective burden was associated with lower self-perceived cognitive functioning and lower between-network functional connectivity of DMN and SAL nodes in the total sample. In addition, there was a significant moderation of SCD status. Greater negative affective burden related to higher functional connectivity within DMN (posterior cingulate-to-precuneus) and within SAL (anterior cingulate-to-insula) nodes in the SCD group, whereas in controls the inverse association was found. We show that negative affective burden is associated with functional brain alterations in older adults, regardless of SCD status. Specifically in the SCD phenotype, greater negative affective burden relates to higher functional connectivity within brain networks vulnerable to AD. Our findings imply that negative affective burden should be considered a potentially modifiable target for early intervention.

Injection Molding of Magnesium Aluminate Spinel Nanocomposites for High-Throughput Manufacturing of Transparent Ceramics.

Transparent ceramics like magnesium aluminate spinel (MAS) are considered the next step in material evolution showing unmatched mechanical, chemical and physical resistance combined with high optical transparency. Unfortunately, transparent ceramics are notoriously difficult to shape, especially on the microscale. Therefore, a thermoplastic MAS nanocomposite is developed that can be shaped by polymer injection molding at high speed and precision. The nanocomposite is converted to dense MAS by debinding, pre-sintering, and hot isostatic pressing yielding transparent ceramics with high optical transmission up to 84 % and high mechanical strength. A transparent macroscopic MAS components with wall thicknesses up to 4 mm as well as microstructured components with single micrometer resolution are shown. This work makes transparent MAS ceramics accessible to modern high-throughput polymer processing techniques for fast and cost-efficient manufacturing of macroscopic and microstructured components enabling a plethora of potential applications from optics and photonics, medicine to scratch and break-resistant transparent windows for consumer electronics.

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial.

Importance: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. Objective: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. Design, Setting, and Participants: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. Interventions: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. Main Outcomes and Measures: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. Results: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. Conclusions and Relevance: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage. Trial Registration: ClinicalTrials.gov Identifier: NCT03094546.

Severity of Subjective Cognitive Complaints and Worries in Older Adults Are Associated With Cerebral Amyloid-ß Load.

Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-ß) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-ß load measured by positron emission tomography (PET) with 18F-florbetaben in 40 cognitively normal older individuals. Global amyloid-ß, as well as regional amyloid-ß load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-ß load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-ß load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-ß load in the parietal cortex. Higher levels of worry were associated with higher amyloid-ß load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-ß burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline.

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial.

BACKGROUND: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer's disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. METHODS: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18 months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. DISCUSSION: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094546 . Registered 29 March 2017-retrospectively registered. PROTOCOL VERSION: Based on EA1/250/16 version 1.5.

Functional connectivity in cognitive control networks mitigates the impact of white matter lesions in the elderly.

BACKGROUND: Cerebrovascular pathology, quantified by white matter lesions (WML), is known to affect cognition in aging, and is associated with an increased risk of dementia. The present study aimed to investigate whether higher functional connectivity in cognitive control networks mitigates the detrimental effect of WML on cognition. METHODS: Nondemented older participants (≥ 50 years; n = 230) underwent cognitive evaluation, fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and resting state functional magnetic resonance imaging (fMRI). Total WML volumes were quantified algorithmically. Functional connectivity was assessed in preselected higher-order resting state networks, namely the fronto-parietal, the salience, and the default mode network, using global and local measures. Latent moderated structural equations modeling examined direct and interactive relationships between WML volumes, functional connectivity, and cognition. RESULTS: Larger WML volumes were associated with worse cognition, having a greater impact on executive functions (ß = -0.37, p < 0.01) than on memory (ß = -0.22, p < 0.01). Higher global functional connectivity in the fronto-parietal network and higher local connectivity between the salience network and medial frontal cortex significantly mitigated the impact of WML on executive functions, (unstandardized coefficients: b = 2.39, p = 0.01; b = 3.92, p = 0.01) but not on memory (b = -5.01, p = 0.51, b = 2.01, p = 0.07, respectively). No such effects were detected for the default mode network. CONCLUSION: Higher functional connectivity in fronto-parietal and salience networks may protect against detrimental effects of WML on executive functions, the cognitive domain that was predominantly affected by cerebrovascular pathology. These results highlight the crucial role of cognitive control networks as a neural substrate of cognitive reserve in older individuals.

The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial.

INTRODUCTION: Nutritional intervention with the natural polyamine spermidine, an autophagy-enhancing agent, can prevent memory loss in aging model organisms. This is the first human study to evaluate the impact of spermidine supplementation on memory performance in older adults at risk for the development of Alzheimer's disease. METHODS: Cognitively intact participants with subjective cognitive decline (n = 30, 60-80 years of age) were included in this three-months, randomized, placebo-controlled, double-blind Phase IIa pilot trial with a spermidine-rich plant extract supplement. Effects of intervention were assessed using the behavioral mnemonic similarity task, measured at baseline and post-intervention visits. Data analysis was focused on reporting and interpreting effectiveness based on effect sizes. RESULTS: Memory performance was moderately enhanced in the spermidine group compared with placebo at the end of intervention [contrast mean = .17, 95% confidence interval (CI): -.01, .35, Cohen's d = .77, 95% CI: 0, 1.53]. Mnemonic discrimination ability improved in the spermidine-treated group with a medium effect size (mean difference = -.11, 95% CI: -.19, -.03, Cohen's d = .79, 95% CI: .01, 1.55). A similar effect was not found in the placebo-treated group (mean difference = .07, 95% CI: -.13, .27, Cohen's d = -.20, 95% CI: -.94, .54). DISCUSSION: In this pilot trial, nutritional spermidine was associated with a positive impact on memory performance in older adults with subject cognitive decline. The beneficial effect might be mediated by stimulation of neuromodulatory actions in the memory system. A follow-up Phase IIb randomized controlled trial will help validate the therapeutic potential of spermidine supplementation and delineate possible neurophysiological mechanisms of action. TRIAL REGISTRATION: Registered in ClinicalTrials.gov with the Identifier NCT02755246.

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract 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 increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). 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 above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.