Changes In Memory Performance Research Articles

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories.

Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

Stably and reliably targeting parietal-hippocampal function connectivity for personalized transcranial magnetic stimulation: A pilot study

ObjectiveTo assess the variability and repeatability of transcranial magnetic stimulation (TMS) target identified by functional connectivity (FC) between the hippocampus and parietal lobes after repeated (multi-run) or a single (one-run) resting-state functional magnetic resonance imaging (fMRI), and to introduce a stable and reliable FC-based target positioning method. MethodsTen runs resting-state fMRI scans were conducted. The FC between the hippocampus and the parietal lobes using each run and the mean FC using multi-run was calculated, respectively. With that, the coordinate of the parietal region with the strongest FC in the aforementioned results was separately set as one- and multi-run targets. The variability and repeatability of the one- and multi-run targets were compared. Finally, five days of rTMS over one- and multi-run targets were performed. Memory tests and Electroencephalography (EEG) was used to assess the effects of rTMS. ResultsThe variability of one- and multi-run targets was 12.96 ± 1.19 mm and 5.33 ± 4.39 mm, respectively. The repeatability of multi-run targets was increased by 22.5 times compared to one-run targets. Compared with one-run targets, rTMS over multi-targets showed more significant results in memory performance, which reduced the event-related potential (ERP) amplitude of the parietal region during memory recollection and improved the FC between the parietal and frontal cortices. We noted significant correlations between changes in memory performance and changes in EEG features. ConclusionStimulation target identified by multiple runs of resting-state fMRI is more stable and reliable than one identified by one run of resting-state fMRI for personalized rTMS.

The Effect of Spermidine Supplementation on Cognitive Function in Adults: A Mini-Review

Introduction: Spermidine, a naturally occurring polyamine found in various foods, has been linked to enhanced autophagy and has shown potential cognitive benefits in previous human studies. This mini-review aimed to evaluate the evidence on spermidine’s effect on the adult population’s cognitive functions. Methods: Randomized clinical trials, controlled cohort/cross-sectional, and controlled before-after studies assessing spermidine consumption/supplementation compared to placebo, non-placebo comparators, or regular diet evaluating cognitive function in adults were included. A comprehensive search in MEDLINE, EMBASE, and CENTRAL yielded 1726 records. After duplicate title/abstract and full-text screening, 17 studies were assessed for eligibility, and three were included in the review. Results: All studies were randomized controlled trials in adults aged 60-96. Doses of spermidine supplementation ranged from 0.9mg to 3.3mg. Wirth 2018 (30 participants) and Pekar 2021 (85 participants) showed an improvement in cognitive performance after three months of spermidine supplementation measured with the Mnemonic Similarity Task (MST) and the CERAD-Plus test, respectively. Schwarz 2022 (100 participants) did not find a significant change in memory performance after 12 months of spermidine supplementation compared to placebo measured with MST. Two studies were at high risk of bias, while one study was judged to have a low risk of bias using the Cochrane risk of-bias tool for randomized trials 2 (RoB 2). Conclusion: Current evidence of the effect of spermidine on cognitive function shows inconsistent results based on a few studies with low spermidine doses and a small number of participants. Further evidence is needed to assess its actual effect.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.

Electromagnetic Fields: Insight into Sources, and Their Effects on Vital Organs and the Risk of Cancer

Background: Electromagnetic radiation has become an extensive new pollution source in modern civilization. Therefore, the biological effects of electromagnetic radiation have attracted considerable attention worldwide. Objectives: The current review was aimed to highlight on sources of electromagnetic fields and their effects on vital organs and the risk of cancer. Electromagnetic sources can be classified into natural electromagnetic sources (sun, some distant stars, atmospheric discharges like thunder, or human body) and unnatural or human made sources (printers, vacuum cleaners, cellular phones, hair dryers, refrigerators, washing machines, kettles microwaves, cables that carry electrical currents, television and computers, electrical home gadgets, radio and television base stations, mobile phone base stations and phone equipment), home wiring airport, and transformers. Electromagnetic fields (EMFs) are electromagnetic waves less than 300 GHz, that are divided into extremely low frequencies (ELFs; 3–3,000 Hz), involving high-voltage transmission lines and in-house wiring; and radiofrequencies (RFs; 30 kHz to 300 GHz), involving mobile phones, smart devices, base stations, WiFi, and 5G technologies. Cell phone technology is an integral part of everyday life and its use is not only restricted to voice conversations but also conveying news, high-resolution pictures, and the internet. Exposure to electromagnetic fields might produce oxidative stress, sperm damage, DNA damage, changes in the chromatin conformation, formation of micronucleus in different cell types, gene expression, enzyme activity, and changes in the structure and function of cell membrane, stimulated an increase in apoptosis and biosynthesis of plasma metallothionein and corticosterone. It causes headaches, chronic fatigue, heart problems, stress, nausea, chest pain, gastrointestinal issues, pain in the muscles and joints, sweating, neurocognitive disturbances, eye burning, nose, ear, and throat issues, bad effects on reproductive, central nervous, endocrine, cardiovascular, and immune systems. Also, it increases anxiety-related behavior; spatial memory, and learning deficits in male mice offspring, decreased thermal pain perception, induced a sleep disturbance, latency, and day dysfunction especially in females, a change in memory performance, damage to the lens epithelial cells of rabbits after 8 hours of exposure to microwave radiation, produced lens opacity in rats, which is linked to the production of cataracts, and derangement of chicken embryo retinal differentiation. There are a relationship between exposure to electromagnetic fields and the increased incidence of the occurrence of some tumors types, particularly brain cancer and leukemia. EMFs induce damage of tissues by increasing free radicals and changing the antioxidant defense systems of tissues, eventually leading to oxidative stress which leads to behavioral, histopathological and biochemical alterations. Exposure to radar, which uses RF fields above 6 GHz similar to 5 G causes effects on production of cancer at different sites, and other diseases. The possible mechanism proposed of how EMFs lead to cancer is the impact of EMFs on free radical combination rates in certain enzymes, such as coenzyme B12-dependent ethanolamine ammonia lyase. The enzyme reaction rate may be amplified by a factor of up to 100. A case-control studies found an increased risk of gliomas, acoustic neuromas, and temporal lobe tumours in users with highest self-reported cell phone use. Exposure of experimental animals to microwave radiation caused a decrease in learning and memory ability, abnormal hippocampal morphology and abnormal Electroencephalogram. Also, it could lead to a decrease in norepinephrine and epinephrine contents in the brain, leading to neurotransmitter production disorders. Conclusion: It can be concluded that electromagnetic sources classified into natural electromagnetic and human made sources. EMFs) are electromagnetic waves less than 300 GHz are divided into extremely low frequencies and radiofrequencies. Exposure to electromagnetic fields might produce oxidative stress, which leads to histopathological and biochemical alterations in different body organs and increased risk of gliomas, acoustic neuromas, and temporal lobe tumours in users with highest self-reported cell phone use. Further studies are needed to confirm these effects in human and experimental animals.

Encoding of everyday objects in older adults: Episodic memory assessment in virtual reality.

Age-related decline in episodic memory performance in otherwise healthy older adults is indisputably evident. Yet, it has been shown that under certain conditions episodic memory performance in healthy older adults' barely deviates from those seen in young adults. Here we report on the quality of object encoding in an ecologically valid, virtual-reality based memory assessment in a sample of healthy older and younger adults with comparable memory performance. We analyzed encoding by establishing both a serial and semantic clustering index and an object memory association network. As expected, semantic clustering was superior in older adults without need for additional allocation of executive resources whereas young adults tended more to rely on serial strategies. The association networks suggested a plethora of obvious but also less obvious memory organization principles, some of which indicated converging approaches between the groups as suggested by a subgraph analysis and some of which indicated diverging approaches as suggested by the respective network interconnectivity. A higher interconnectivity was observed in the older adults' association networks. We interpreted this as a consequence of superior semantic memory organization (extent to which effective semantic strategies diverged within the group). In conclusion, these results might indicate a diminished need for compensatory cognitive effort in healthy older adults when encoding and recalling everyday objects under ecologically valid conditions. Due to an enhanced and multimodal encoding model, superior crystallized abilities might be sufficient to counteract an age-related decline in various other and specific cognitive domains. This approach might potentially elucidate age-related changes in memory performance in both healthy and pathological aging.

Longitudinal association between changes in resting-state network connectivity and cognition trajectories: The moderation role of a healthy diet.

Healthy diet has been shown to alter brain structure and function and improve cognitive performance, and prior work from our group showed that Mediterranean diet (MeDi) moderates the effect of between-network resting-state functional connectivity (rsFC) on cognitive function in a cross-sectional sample of healthy adults. The current study aimed to expand on this previous work by testing whether MeDi moderates the effects of changes in between- and within-network rsFC on changes in cognitive performance over an average of 5 years. At baseline and 5-year follow up, 124 adults aged 20-80 years underwent resting state fMRI to measure connectivity within and between 10 pre-defined networks, and completed six cognitive tasks to measure each of four cognitive reference abilities (RAs): fluid reasoning (FLUID), episodic memory, processing speed and attention, and vocabulary. Participants were categorized into low, moderate, and high MeDi groups based on food frequency questionnaires (FFQs). Multivariable linear regressions were used to test relationships between MeDi, change in within- and between-network rsFC, and change in cognitive function. Results showed that MeDi group significantly moderated the effects of change in overall between-network and within-network rsFC on change in memory performance. Exploratory analyses on individual networks revealed that interactions between MeDi and between-network rsFC were significant for nearly all individual networks, whereas the moderating effect of MeDi on the relationship between within-network rsFC change and memory change was limited to a subset of specific functional networks. These findings suggest healthy diet may protect cognitive function by attenuating the negative effects of changes in connectivity over time. Further research is warranted to understand the mechanisms by which MeDi exerts its neuroprotective effects over the lifespan.

Longitudinal tau accumulation interacts with cortical thinning to predict steeper memory decline in cognitively normal older adults

AbstractBackgroundCross‐sectional measures of tau pathology, a hallmark of Alzheimer’s disease (AD), have been associated with brain structure and memory performance in cognitively normal older adults (OA). Fewer studies have explored the downstream effects of longitudinal tau accumulation in OA. Here, we investigated relationships between tau accumulation, atrophy, and memory performance change over time.MethodSeventy cognitively normal OA (age = 77 ± 5 years; Table1) underwent longitudinal flortaucipir (FTP) PET, structural MRI scanning, and neuropsychological assessment. Annual change slopes for entorhinal cortex (EC) and a temporal meta‐ROI partial‐volume corrected FTP, cortical thickness, and an episodic memory (EM) composite were estimated using linear mixed effects models. Linear methods (Pearson correlation, multiple regression, mixed effects models) were used to relate regional tau slopes to atrophy and EM change. We used elastic net regression to select the best predictors of EM slope, including all FTP and structural ROIs, age, education, beta‐amyloid burden, and sex. Voxel‐wise FTP slope images were also generated to explore associations with atrophy and EM slope across the cortex.ResultHigher FTP slope in EC and meta‐ROI significantly predicted EM decline (β= ‐.26 p=.03 & β= ‐.38 p=.001, respectively; Fig.1). FTP slope did not significantly predict longitudinal atrophy in EC or meta‐ROI (ps>.10). A multiple regression with predictors selected via an elastic net model (Table2) showed a significant interaction between meta‐ROI FTP slope and EC cortical thickness slope such that tau accumulation and EM decline were more strongly related in OA with a higher rate of entorhinal cortical thinning (β=.23 p=.02; Fig.2). Voxel‐wise models with tau slope and memory showed interesting findings in the temporal lobe but clusters did not reach statistical significance. A one‐sample t‐test showed significant tau accumulation in frontal, parietal, and temporal lobe regions (Fig.3).ConclusionEC and meta‐ROI tau accumulation predicts memory decline in cognitively normal OA. EC atrophy moderated the effect of meta‐ROI tau accumulation on memory decline, suggesting a synergic effect of tau pathology and structural atrophy on memory decline in early AD. These novel findings provide insights into mechanisms of memory decline in typical aging and early AD.

Independent Component and Graph Theory Analyses Reveal Normalized Brain Networks on Resting-State Functional MRI After Working Memory Training in People With HIV.

Cognitive training may partially reverse cognitive deficits in people with HIV (PWH). Previous functional MRI (fMRI) studies demonstrate that working memory training (WMT) alters brain activity during working memory tasks, but its effects on resting brain network organization remain unknown. To test whether WMT affects PWH brain functional connectivity in resting-state fMRI (rsfMRI). Prospective. A total of 53 PWH (ages 50.7 ± 1.5 years, two women) and 53 HIV-seronegative controls (SN, ages 49.5 ± 1.6 years, six women). Axial single-shot gradient-echo echo-planar imaging at 3.0 T was performed at baseline (TL1), at 1-month (TL2), and at 6-months (TL3), after WMT. All participants had rsfMRI and clinical assessments (including neuropsychological tests) at TL1 before randomization to Cogmed WMT (adaptive training, n=58: 28 PWH, 30 SN; nonadaptive training, n=48: 25 PWH, 23 SN), 25 sessions over 5-8 weeks. All assessments were repeated at TL2 and at TL3. The functional connectivity estimated by independent component analysis (ICA) or graph theory (GT) metrics (eigenvector centrality, etc.) for different link densities (LDs) were compared between PWH and SN groups at TL1 and TL2. Two-way analyses of variance (ANOVA) on GT metrics and two-sample t-tests on FC or GT metrics were performed. Cognitive (eg memory) measures were correlated with eigenvector centrality (eCent) using Pearson's correlations. The significance level was set at P < 0.05 after false discovery rate correction. The ventral default mode network (vDMN) eCent differed between PWH and SN groups at TL1 but not at TL2 (P=0.28). In PWH, vDMN eCent changes significantly correlated with changes in the memory ability in PWH (r=-0.62 at LD=50%) and vDMN eCent before training significantly correlated with memory performance changes (r=0.53 at LD=50%). ICA and GT analyses showed that adaptive WMT normalized graph properties of the vDMN in PWH. 1 TECHNICAL EFFICACY: 1.

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline

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. To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. 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. 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. 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. 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. 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. ClinicalTrials.gov Identifier: NCT03094546.

Development of Visual Memory Capacity Following Early-Onset and Extended Blindness

It is unknown whether visual memory capacity can develop if onset of pattern vision is delayed for several years following birth. We had an opportunity to address this question through our work with an unusual population of 12 congenitally blind individuals ranging in age from 8 to 22 years. After providing them with sight surgery, we longitudinally evaluated their visual memory capacity using an image-memorization task. Our findings revealed poor visual memory capacity soon after surgery but significant improvement in subsequent months. Although there may be limits to this improvement, performance 1 year after surgery was found to be comparable with that of control participants with matched visual acuity. These findings provide evidence for plasticity of visual memory mechanisms into late childhood but do not rule out vulnerability to early deprivation. Our computational simulations suggest that a potential mechanism to account for changes in memory performance may be progressive representational elaboration in image encoding.

Effect of Early Surgical Intervention for Brain Tumors Associated with Epilepsy on the Improvement in Memory Performance.

We evaluated the effect of early surgical intervention on the change in memory performance of patients with low-grade brain tumors associated with epilepsy. Twenty-three adult patients with low-grade brain tumors and epilepsy who underwent surgery at our institution between 2010 and 2019 were included. The Wechsler Memory Scale-Revised (WMS-R) was used to assess cognitive memory performance. Memory performance before and after surgery was retrospectively evaluated. In addition, the relationships among preoperative memory function, postoperative seizure outcome, preoperative seizure control, temporal lobe lesion, and change in memory function were examined. There were statistically significant improvements from median preoperative to postoperative WMS-R subscale scores for verbal memory, general memory, and delayed recall (p<0.001, p<0.001, and p=0.0055, respectively) regardless of preoperative sores and tumor location. Good postsurgical seizure control was associated with significant improvements in postoperative WMS-R performance. Our results indicated that early surgical intervention might improve postoperative memory function in patients with low-grade brain tumors and epilepsy.

A3 adenosine receptor agonist IB-MECA reverses chronic cerebral ischemia-induced inhibitory avoidance memory deficit

BackgroundChronic cerebral ischemia (CCI) is a major cause of subcortical ischemic vascular dementia. Here, we examined the neuroprotective action of the A3 adenosine receptor agonist N6-(3-iodobenzyl)-adenosine-5′-N-methylcarboxamide (IB-MECA) on white matter lesions following CCI. MethodsA CCI mouse model was established using unilateral common carotid artery occlusion. IB-MECA and 3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate (MRS1523), an antagonist of the A3 adenosine receptor, were administered by intraperitoneal injection. The inhibitory avoidance test was used to examine changes in memory performance. Microtubule-associated protein 2 (MAP-2) and neurofilament were assessed by immunohistochemistry, while expressions of phosphorylated extracellular signal-regulated kinase (ERK), ERK, interferon-beta (IFN-β), and glial fibrillary acidic protein (GFAP) were assessed by western blot assay. ResultsThe memory retention score was reduced in vehicle-treated mice compared with IB-MECA-treated (p < 0.05) mice. Compared to sham-operated mice, p-ERK, GFAP and IFN-β were increased, while MAP-2 and neurofilament were reduced in vehicle-treated mice (p < 0.01 for each). IB-MECA reduced ERK phosphorylation (p < 0.01) and GFAP expression (p < 0.05), but upregulated MAP-2 and IFN-β (p < 0.01 for both), compared with vehicle. MRS1523 suppressed the effects of IB-MECA on the memory deficit, ERK phosphorylation, and on MAP-2, neurofilament, GFAP and IFN-β levels. ConclusionOur results suggest that A3 adenosine receptor stimulation ameliorates CCI-induced memory deficits, modulates the ERK signaling pathway, preserves MAP-2 and neurofilament expression, regulates GFAP expression, and upregulates the anti-inflammatory cytokine IFN-β. Thus, the A3 adenosine receptor may be a therapeutic target for treatment of cognitive disorders and cerebral inflammatory diseases.

Effects of N-acetylcystein on changes in parvalbumin-positive interneurons in the hippocampus after carbon monoxide poisoning

Purpose: The purpose of this study was to investigate effect of N-acetylcysteine (NAC) on the injury of putative parvalbumin positive interneurons defined by molecular marker and hippocampal long-term potentiation (LTP), a marker of neural plasticity following acute carbon monoxide (CO) poisoning. Methods: Adult Sprague-Dawley rats were exposed to 1100 ppm CO for 40 minutes followed by 3000 ppm CO for 20 minutes. Animals received daily intraperitoneal injection of NAC (150 mg/kg) for 5 days after CO exposure. Changes in learning and spatial memory were evaluated by Y-maze test 5 days after the poisoning. In vivo LTP in hippocampal CA1 area was evaluated by using extracellular electrophysiological technique. Immunohistochemical staining were adopted to observe expressional damages of parvalbumin (PV) immunoreactive interneurons in the hippocampus following the poisoning. Results: Acute CO intoxication resulted in no changes in memory performance at Y-maze test but a significant reduction of LTP in the in hippocampal CA1 area. There was also a significant reduction of PV (+) interneurons in the hippocampal CA1 area 5 days after CO poisoning. Daily treatment of NAC significantly improved hippocampal LTP impairment and reduced immunoreactivity for PV in the hippocampus following the acute CO poisoning. Conclusion: The results of this study suggest that reduction of hippocampal LTP and PV (+) interneurons in the hippocampus is sensitive indicator for brain injury and daily NAC injections can be the alternative therapeutics for the injury induced by acute CO poisoning.

Sex-specific genetic predictors of memory performance.

There are notable sex differences in the clinical manifestation of Alzheimer's disease (AD), including differences in baseline and longitudinal changes in memory performance. However, sex-stratified models have not been routinely incorporated into genetic studies of cognitive performance or decline. We sought to identify sex-specific genetic predictors of memory performance in aging adults. We obtained harmonized memory scores from 11,601 females and 8,885 males from 7 cohorts of cognitive aging. We calculated scores using latent variable modeling techniques anchored on overlapping neuropsychological test items across datasets to perform both sex-stratified and sex-interaction genome-wide association studies in each cohort using mixed-effects regression models to assess genetic associations with baseline memory score and rate of memory decline. Covariates included age at baseline and population principal components. We then combined results in a fixed-effect meta-analysis. As expected, we observed robust associations at the APOE locus in males and females in both baseline and longitudinal models. Additionally, we identified a sex-specific locus for longitudinal memory performance (interaction-p=2.54e-6) on chromosome 7 within LINC-PINT that was genome-wide significant in males (index SNP= rs66754621; p=1.62e-8; MAF=0.20), but not females (p=0.65). This variant is in an enhancer region within several brain regions, as well as within a promoter-anchored chromatin interaction loop and a methylation eQTL in the prefrontal cortex. No female-specific loci were identified. Interestingly, we did observe nominal associations in baseline memory at some known AD loci, including male-specific effects at MS4A6A, FERMT2, and KAT8 (interaction ps=0.0026, 0.027, and 0.0058, respectively) and opposing effects between males and females at INPP5D (interaction p=0.0021). These results highlight a novel male-specific locus of memory performance on chromosome 7 near the LINC-PINT gene. LINC-PINT is upregulated in the substantia nigra in Parkinson's disease and is downregulated in multiple brain regions over the course of normal aging, making it a fascinating male-specific candidate gene. Replicate and functional analyses of the region are ongoing to verify our finding and elucidate the biological mechanism. Our results add to the growing body of literature suggesting that there are sex-specific genetic contributors to cognitive decline.

Slow waves contribute to memory consolidation only in older adults without sleep‐disordered breathing

AbstractBackgroundSleep‐dependent memory consolidation, which is thought to rely on the dialogue between the hippocampus and the medial prefrontal cortex (mPFC) during NREM sleep, is mediated by slow waves (SW) and sleep spindles. Some studies indicate that this process is impaired in ageing but also in sleep‐disordered breathing (SDB), a very common sleep disorder in ageing. In this study, we investigated sleep‐dependent memory consolidation in older adults with or without SDB and explored the underlying mechanisms.MethodBaseline data of 57 cognitively unimpaired older adults (mean age ± SD: 68.6 ± 3.3 years) from the Age‐Well cohort were analysed. Participants underwent a structural MRI scan to obtain mPFC and hippocampal grey matter volumes, and performed a visuospatial memory task until reaching a learning criterion of 66.6% of correct answers. Post‐learning sleep was monitored using polysomnography, and delayed recall was probed the next morning. An overnight change in memory performance (OCMP) was computed as follows: (recall performance – learning performance) / learning performance. SW, slow and fast spindles during N2 and N3 sleep were automatically detected using the SleepTrip toolbox. Based on the standard apnea‐hypopnea index (AHI) cutoff of 15 events/h, participants were classified as having SDB (SDB+, n=47) or not (SDB‐, n=10).ResultThere was no between‐group difference in OCMP, as well as in amplitude, duration and frequency of SW, slow and fast spindles (p&gt;0.05). However, we found a significant group by SW density interaction after controlling for age, sex, education, total sleep time and trait‐anxiety (p=0.03). Thus, a positive association was only found between SW density and OCMP in the SDB‐ group (p=0.02; Fig 1). No correlation was found between slow or fast spindle density and OCMP in either group. Finally, mPFC and hippocampal volumes did not differ between SDB+ and SDB‐ participants (p&gt;0.05), but SW density positively correlated with the volume of the mPFC (p=0.01; Fig 2).ConclusionOur findings suggest that the contribution of SW to sleep‐dependent memory consolidation is impaired in participants with SDB and incriminate the mPFC. We plan to conduct connectivity and SW‐spindle coupling analyses to unravel the functional substrates of this deficit.

Area‐level deprivation is associated with rate of memory decline in late life within a community‐based cohort

AbstractBackgroundResiding in a disadvantaged neighborhood is associated with adverse health outcomes, as well as increased risk for dementia. However, it remains unclear whether area‐level deprivation impacts the rate of age‐related memory decline, especially in community‐based populations.MethodWe quantified late life neighborhood level disadvantage using the 2013 Area Deprivation Index (ADI) for 2,554 participants with complete data of interest within the Wisconsin Longitudinal Study – a same‐aged, community‐based cohort of randomly selected 1957 Wisconsin high school graduates. Delayed recall for a 10‐item word list was assessed at two timepoints in mid to late life (Time 1 (∼2004): age 64.39 + 0.74 years; and Time 2 (∼2011): age 71.28 + 0.97 years). We used multivariate linear regression models to evaluate whether ADI was associated with memory performance at each time point, and with the annualized rate of change in memory performance over time.ResultIncreasing ADI was significantly correlated with lower adolescent IQ, less educational attainment, lower net worth, higher vascular risk scores, elevated depression metrics, and increasing age (all p&lt;0.001). Mean ADI did not differ by sex, but was significantly higher in ApoE‐4 positive carriers (t(2552) =2.257, p=0.024). Results of multivariate regression indicated that greater area‐level deprivation (higher ADI) was not associated with delayed recall performance at Time 1 (b = 0.001; 95% CI: ‐0.003 to 0.005, P=0.790), but was associated with poorer delayed recall performance at Time 2 (B = ‐0.004; 95% CI: ‐0.007 to ‐0.001, P=0.019). Higher ADI also predicted greater annualized rate of decline in delayed recall between timepoints (B = ‐0.001; 95% CI: ‐0.001 to ‐9.9^10‐5, P=0.025). These findings held after controlling for individual‐level demographic and socioeconomic variables (age, sex, adolescent IQ, years of education, net worth), genetic risk (ApoE‐4 carrier status), depression, hearing loss, and a modified CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) risk score calculated at Time 1.ConclusionEven after accounting for established individual‐level demographic, socioeconomic, health, and genetic risk factors for cognitive decline, greater neighborhood disadvantage is associated with an accelerated rate of annualized decline in delayed recall performance across mid to late life in a community sample.

Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design.

Default mode network (DMN) dysfunction is well established in Alzheimer's disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE) ɛ4 allele. We will recruit 64 older participants without cognitive deficits, 32 APOE ɛ4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ɛ4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD.

Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer\u2019s dementia

BackgroundLeukotriene receptor antagonists (LTRAs) alleviate Alzheimer’s disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time.MethodsThis longitudinal observational study used data from the National Alzheimer’s Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models.ResultsIn AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = −0.200 [−0.380, −0.019] points/year, n = 800) and AD dementia (B = −0.321 [−0.597, −0.046] points/year, n = 604) as measured by CDR Sum of Boxes.ConclusionsThe use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.

Sense of Purpose Promotes Resilience to Cognitive Deficits Attributable to Depressive Symptoms.

ObjectiveIndividuals higher in depressive symptoms commonly present with neuropsychological deficits including poorer memory performance. Sense of purpose in life has been shown to promote resilience to cognitive impairment in older adulthood, but it is unclear whether it may also protect against cognitive deficits associated with higher depressive symptoms.MethodCognitive functioning among 4599 older American adults (Mage = 74.33 years, range = 65–104 years, 56.84% female) was examined across a 12-year follow-up period. Depressive symptomatology was assessed at each wave using the 8-item Center for Epidemiologic Studies Depression Scale. Multilevel models assessed the influence of depressive symptoms and the interaction with sense of purpose in life on changes in memory performance and mental status.ResultsHigher depressive symptoms were associated with poorer memory performance at baseline, but did not predict rate of change over time. A negative interaction was observed between sense of purpose in life and depressive symptoms such that individuals higher in purpose experienced a less negative association between depressive symptoms and baseline memory performance. No significant interaction of sense of purpose and depressive symptoms was observed on mental status.ConclusionHaving a sense of purpose in life may help protect older adults from memory deficits associated with higher depressive symptoms. The present findings underscore the potential for sense of purpose to promote cognitive reserve in older adulthood, allowing individuals to maintain cognitive performance in the face of accruing neurological insults.