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Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD): A collaborative platform for behavioral analysis across the lifespan.

Understanding cognitive aging requires approaches that capture individual variability while enabling integration across studies. In rodent models, behavioral data are central to this effort, yet cross-laboratory differences in experimental design limit comparability and constrain secondary analysis. To address this gap, we developed the Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD), a first-of-its-kind collaborative repository aggregating trial-level Morris water maze data from multiple laboratories. ID-CARD is designed to support large-scale, integrative analyses and to facilitate secondary use of existing behavioral data in alignment with emerging data-sharing and transparency initiatives. Rather than imposing retrospective harmonization of experimental protocols, we implemented a normalization and modeling framework that enables comparison of learning trajectories while preserving meaningful variation across studies. Behavioral data from > 5000 rats spanning common strains, both sexes, and multiple ages were normalized in training and performance domains and fit with a logarithmic function to derive an error accumulation rate coefficient (EARC) as a measure of spatial learning. Age was strongly associated with increased EARC, indicating attenuated learning, even after adjusting for non-spatial cue performance. Analyses of goodness of fit revealed systematic structure in learning dynamics, where age was associated with reduced learning-curve conformity after accounting for overall performance. Inter-individual variability in spatial learning also increased with age, with strain-specific interactions. These findings demonstrate that integrated analysis of heterogeneous behavioral datasets can yield robust, individual-level insights into cognitive aging. ID-CARD provides a scalable resource and analytic framework to advance discovery in behavioral neuroscience by enabling reuse, integration, and comparative analysis of existing data.

Cognitive aging

Free-water: A promising structural biomarker for cognitive decline in aging and mild cognitive impairment.

Diffusion MRI derived free-water (FW) metrics show promise in predicting cognitive impairment and decline in aging and Alzheimer's disease (AD). FW is sensitive to subtle changes in brain microstructure, so it is possible these measures may be more sensitive than traditional structural neuroimaging biomarkers. In this study, we examined the associations among FW metrics (measured in the hippocampus and two AD signature meta-ROIs) with cognitive performance, and compared FW findings to those from more traditional neuroimaging biomarkers of AD. We leveraged data from a longitudinal cohort (nparticipants = 296, nobservations = 870, age at baseline: 73 ± 7 years, 40% mild cognitive impairment [MCI]) of older adults who underwent serial neuropsychological assessment (episodic memory, information processing speed, executive function, language, and visuospatial skills) and brain MRI over a maximum of four time points, including baseline (n = 284), 18-month (n = 246), 3-year (n = 215), and 5-year (n = 125) visits. The mean follow-up period was 2.8 ± 1.3 years. Structural MRI was used to quantify hippocampal volume, in addition to Schwarz and McEvoy AD Signatures. FW and FW-corrected fractional anisotropy (FAFWcorr) were quantified in the hippocampus (hippocampal FW) and the AD signature areas (SchwarzFW, McEvoyFW) from diffusion-weighted (dMRI) images using bi-tensor modeling (FW elimination and mapping method). Linear regression assessed the association of each biomarker with baseline cognitive performance. Additionally, linear mixed-effects regression assessed the association between baseline biomarker values and longitudinal cognitive performance. A subsequent competitive model analysis was conducted on both baseline and longitudinal data to determine how much additional variance in cognitive performance was explained by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein-ε4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. All analyses were corrected for multiple comparisons using an FDR procedure. Cross-sectional results indicate that hippocampal volume, hippocampal FW, Schwarz and McEvoy AD Signatures, and the SchwarzFW and McEvoyFW metrics are all significantly associated with memory performance. Baseline competitive model analyses showed that the McEvoy AD Signature and SchwarzFW explain the most unique variance beyond covariates for memory (ΔRadj 2 = 3.47 ± 1.65%) and executive function (ΔRadj 2 = 2.43 ± 1.63%), respectively. Longitudinal models revealed that hippocampal FW explained substantial unique variance for memory performance (ΔRadj 2 = 8.13 ± 1.25%), and outperformed all other biomarkers examined in predicting memory decline (pFDR = 1.95 x 10-11). This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.

Alzheimer’s disease (AD)

Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.

Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL/6J mice. Volume electron microscopy of the mPFC revealed age-related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria-targeted antioxidant MitoQ improved attentional set-shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.

Animals

GHSR suppression in neurons protects against aging-associated metabolic and cognitive impairments.

Aging is accompanied by progressive declines in metabolic and cognitive functions. Growth hormone secretagogue receptor (GHSR), a receptor for the gut hormone ghrelin, is highly expressed in neurons and plays a crucial role in metabolic regulation. We previously reported that aged global GHSR-ablated mice are lean and insulin-sensitive, and that neuronal GHSR-deleted mice (Syn1-cre;Ghsrf/f) completely prevent diet-induced obesity. However, the role of neuronal GHSR in metabolic and cognitive aging has not been elucidated. The current study aims to determine the roles of neuronal GHSR in aging metabolism and cognitive dysfunction. Syn1-cre;Ghsrf/f mice were subjected to cold stress, glucose- and insulin-tolerance tests, behavioral tests, and tissue analysis. Aging is accompanied by glycemic dysregulation and insulin resistance; old Syn1-cre;Ghsrf/f mice showed improved glucose tolerance and insulin sensitivity. Aging is associated with thermogenic impairment and cognitive decline; old Syn1-cre;Ghsrf/f mice showed better cold resistance and retained better recognition memory. Noticeably, there were increased expression of thermogenic makers (PGC1α and UCP1) and elevated sympathetic innervation markers (tyrosine hydroxylase and synaptophysin) in brown adipose tissue of old Syn1-cre;Ghsrf/f mice. Lastly, old Syn1-cre;Ghsrf/f mice exhibited decreased pro-inflammatory cytokines and increased neural plasticity-related markers (brain-derived neurotrophic factor, synaptophysin, and tyrosine hydroxylase) in metabolic and cognitive-relevant brain regions such as hypothalamus, cortex, and hippocampus. In conclusion, neuronal inhibition of GHSR promotes a healthy aging phenotype showing improved energy metabolism and cognitive function, which is likely contributed to the improved thermogenesis and insulin sensitivity, reduced inflammation, and restored neuronal plasticity.

Animals

Epigenetic Clocks of Biological Aging and Cognitively Healthy Longevity: The Women's Health Initiative Memory Study.

BACKGROUND: Little is known about whether epigenetic age acceleration (EAA) clocks are capable of predicting exceptional longevity with or without preserved cognitive function. METHODS: We examined 5844 women from the Women's Health Initiative Memory Study. Fifteen epigenetic clocks were measured at baseline (1996-1999). Longevity outcomes were defined as: 1) survival to age 90 with preserved cognition (n = 1726, 29.5%); or 2) survival to age 90 with cognitive impairment (n = 956, 16.4%); vs. 3) death before age 90 (n = 2611, 44.7%). Logistic regression models examined associations between the 15 clocks and survival to age 90 (vs. death before age 90), adjusting for covariates. Multinomial logistic regression models examined associations with survival to age 90 without cognitive impairment and survival to age 90 with cognitive impairment (each vs. death before age 90), also adjusting for covariates. RESULTS: Each standard deviation increase in EAA for the first-generation clocks was associated with 7%-18% reduced odds of survival to age 90 vs. earlier death. Stronger associations were observed for second- and third-generation clocks, including AgeAccelGrim2 (OR = 0.66; 95% CI 0.61-0.71), PCGrimAge (OR = 0.64; 95% CI 0.59-0.69), PCPhenoAge (OR = 0.73; 95% CI 0.68-0.78) and DunedinPACE (OR = 0.77; 95% CI 0.72-0.82). None of the clocks was more strongly associated with survival to age 90 with preserved cognition than with survival to age 90 with cognitive impairment, relative to death before age 90. CONCLUSION: All epigenetic clocks were associated with exceptional longevity, but none were associated with cognitive healthspan. Developing clocks that can differentiate long survival with and without preserved cognitive function is critical.

Healthspan

Differential methylation clock ages across buffy coat (BC), peripheral blood mononuclear cells (PBMC), and saliva in individuals approaching midlife.

Understanding epigenetic aging prior to midlife is gaining interest as a potentially intervenable period to address factors that influence health and cognitive aging. Epigenetic changes associated with aging may point to differential biological aging rates; however, methylation profiles may not be substitutable across tissues. We compared DNA methylation in three tissues collected in 91 siblings and twins from the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1): saliva, buffy coat (BC), and peripheral blood mononuclear cells (PBMC). Overall, across five methylation clocks and two blood-derived and one saliva-derived tissues, moderate to strong associations between chronological age and methylation ages were observed. Moreover, PBMC methylation age values correlate more strongly with BC values (Spearman r = 0.66 - 0.87), whereas saliva showed weaker correlations with either form of blood-derived measures (Spearman r = 0.25 - 0.69) although still moderate to strong magnitudes. Saliva demonstrated significantly older methylation ages across four of five clocks, whereas PBMC and BC did not differ. Twins were more strongly correlated for BC and PBMC derived clocks with weaker and inconsistent patterns among Saliva clocks. DunedinPACE age acceleration showed no significant tissue differences and on average demonstrated the largest divergence of similarity between monozygotic (MZ) versus dizygotic (DZ) twins (rMZ= .56, rDZ= .21). In summary, saliva-derived methylation is not a direct substitute for blood-derived methylation whereas blood-derived methylation values were comparable across buffy coat and peripheral blood mononuclear cell tissues.

age acceleration

DNA methylation age deviation and cognitive status among older adults in the US, NHANES 1999-2002.

Biological aging, measured using DNA methylation, is a potential biomarker for cognitive health outcomes. We evaluated associations between DNA methylation measures of aging and cognition in a nationally representative sample of adults aged 60+ in the National Health and Nutrition Examination Survey (NHANES), 1999-2002. Genome-wide DNA methylation data were used to create 13 measures of biological aging trained on different aging phenotypes. Cognition was assessed with the Digit Symbol Substitution Test (DSST). To evaluate associations between each DNA methylation measure and DSST score, survey-weighted linear regression models adjusted for age, sex, race/ethnicity, education, smoking, serum cotinine, and BMI were run. We assessed effect modification by sex, education, and race and ethnicity. Included participants (N=1,463) were an average of 70.5 years old and 82.7% non-Hispanic White. The average DSST score was 46.9 (SD 17.6). Ten of 13 DNA methylation measures were associated with DSST (adjusted p<0.05). One year of GrimAge2 accelerated aging was associated with -0.41 points lower DSST score (95% CI: -0.61, -0.21; adjusted p=5&#xd7;10-4). In stratified analyses, higher magnitudes of association were observed among male and non-Hispanic White participants across multiple aging measures. DNA methylation may be a useful biomarker of cognitive status among older adults.

DNA methylation

Genetic modifiers of APOE-&#x3b5;4-associated cognitive decline.

The APOE-&#x3b5;4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-&#x3b5;4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-&#x3b5;4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-&#x3b5;4-associated cognitive decline. We conduct cross-ancestry APOE-&#x3b5;4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-&#x3b5;4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-&#x3b5;4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-&#x3b5;4 carriers.

Humans

Age at menopause and subjective cognitive symptoms predict digital cognitive outcomes at the gynecological Well-Woman visit.

INTRODUCTION: Women are at increased risk for Alzheimer's Disease (AD). Growing evidence suggests that the menopausal transition may represent a vulnerable window for development of AD-related pathology. Yet, women are diagnosed with AD later than men. Conducting routine cognitive screenings and integrating information about both cognitive symptoms and age at menopause may help address sex-based disparities in detection and prevention. This study investigated whether subjective cognitive symptoms, in combination with age at menopause, were associated with performance on a digital cognitive task in postmenopausal women. METHODS: 183 postmenopausal women (mean age&#x2009;=&#x2009;63.8, range&#x2009;=&#x2009;45-85) were recruited after their Well-Woman visit. Participants completed the Screener for Cognitive Problems in Everyday Life (SCoPE) to assess subjective cognitive symptoms, followed by a sensitive measure of objective cognition: the Linus Health Digital Clock and Recall (DCR&#x2122;). Information was also collected on age at menopause. We examined associations of subjective cognitive symptoms and age at menopause with digital cognitive performance, adjusting for age, education and depression. Model fit was evaluated using adjusted R2, AIC, and BIC. RESULTS: 48.1% of women reported one or more cognitive symptoms on the SCoPE. On objective testing, 73.2% scored in the normal range, 20.8% in the borderline range, and 6.0% in the impaired range. SCoPE total score was negatively associated with objective cognitive performance in adjusted models (B&#x2009;=&#x2009;-.12, p&#x2009;=&#x2009;.03). Age at menopause showed a significant quadratic association with cognitive performance (B&#x2009;=&#x2009;-0.006, p<.001). SCoPE total was not associated with DCR subtests, while age at menopause predicted both Delayed Recall and Clock Drawing. CONCLUSION: Subjective cognitive symptoms and age at menopause were associated with lower performance on a sensitive, objective cognitive test. Findings support routine cognitive screening and suggest that subjective cognitive symptoms as well as age at menopause are associated with cognitive function.

Humans

[Aging in cities and in the country (author's transl)].

A growing concern with ecological issues has led gerontologist to analyze the life-situation of aged people in cities and in the country more precisely. While it is generally assumed that aging in the country has advantages to aging in the city, statistical figures (e.g. income, living conditions, health status, educational opportunities, institutions for the aged) show that country dweller's "cumulative disadvantages" have to be taken into consideration, disadvantages caused by interacting societal and individual factors in rural life. Psychological investigations--as e.g. the Bonn Longitudinal Study of Aging (BLSA)--show positive correlations between a central location of the home and increased general activity, broader scope of interests, more frequent use of communication media (newspapers, newscasts), better mood, greater readiness for involvement. While city-dwellers are more frequently engaged in social contacts outside of the family, country dwellers are more involved in interactions with the immediate family. The following practical considerations for the improvement of the situation of the aged in the country are presented: beginning in childhood and youth, conditions should be granted which allow the individual to live in ways which prevent too early aging; this ought to be supplemented by providing activating and stimulating environments for aging people and help for the aged, be it in special institutions or through activities in their familiar environment. It is shown that a differential ecogerontology is required, since (1) a simple distinction between city and country is by far too global, (2) similar ecological conditions are known to have different effects, depending on inter-individual differences, and (3) intraindividual patterns, and (4) it becomes evident that objective ecological conditions do not as clearly determine behavior in age as do cognitive representations of these ecological variables. This last statement is in accordance with the cognitive theory of aging. There can be no doubt that ecological variables influence the process of aging, but there is nothing like the aging in the country.

Adaptation, Psychological

Effects of Exergame Balance Training with Variable Cognitive Motor Challenges on Serum BDNF, p-tau181, and Cognitive Functions in Adults with Mild Cognitive Impairment: A Randomized Trial.

INTRODUCTION: Cognitive-motor exergame balance training may increase attentional demands and neuronal processing, potentially affecting serum levels of brain-derived neurotrophic factor (BDNF), A&#x3b2;1-42, and p-tau181, as well as train cognitive abilities in adults with mild cognitive impairment (MCI). This study aimed to compare the effects of exergame balance training of mild, moderate, high-difficulty, and Wii Fit&#x2122; groups on blood serum levels of BDNF, A&#x3b2;1-42, p-tau181, and cognition function in adults with MCI. METHODS: In this four-arm, parallel group randomized clinical trial, 97 adults with MCI were randomly assigned to exergame balance training groups of mild, moderate, high-difficulty, and Wii Fit exergame as a control group. All participants received 40 min/session, 3 times/week for 8 weeks. Assessment of serum levels of p-tau181, A&#x3b2;1-42, BDNF, and cognitive functions was conducted at baseline, after weeks 4 and 8. A mixed-model analysis of covariance was used, with post-baseline measurements (weeks 4 and 8) specified as the within-subject factor and the corresponding baseline value entered as a covariate to adjust for initial between-group variability. RESULTS: A significant group &#xd7; time interaction was found for BDNF, F(3,92) = 6.413, P = 0.017, &#x3b7;p2 = 0.181; p-tau181, F(3,92) = 4.640, P = 0.040, &#x3b7;p2 = 0.138; attention, F(3,92) = 4.171, P = 0.045, &#x3b7;p2 = 0.057; abstraction, F(3,92) = 4.263, P = 0.043, &#x3b7;p2 = 0.058; and visuospatial skills, F(3,92) = 6.931, P < 0.001, &#x3b7;p2 = 0.234. CONCLUSION: Cognitive-motor challenge-based exergame balance training was associated with an increase in serum BDNF, a reduction in p-tau181. In contrast, the A&#x3b2;1-42 levels remained stable. These changes were accompanied by improvement in selective cognitive functions (attention, abstraction, and visuospatial skills) in individuals with MCI. Greater effects were observed in moderate and high-difficulty groups, suggesting the importance of intervention intensity in promoting cognitive and neurobiological outcomes in MCI.

Humans

Life-course stress exposure and cognitive decline in middle-aged and older Chinese adults: The role of sex differences and educational protection.

BACKGROUND: Stressful life events (SLEs) across the life course have been associated with cognitive decline, but evidence on their cumulative impact and potential modifiers remains limited. We aimed to examine the associations between SLE exposure in childhood, adulthood, or both life stages and cognitive trajectories, and to investigate whether these associations vary by sex and education. METHODS: We used data from the China Health and Retirement Longitudinal Study, a nationally representative cohort of adults aged &#x2265;45 years. Participants with complete data on SLEs, cognition, and covariates were included (n&#x202f;=&#x202f;5922). SLEs were retrospectively assessed for childhood and adulthood. Cognitive function was measured using a composite score (range 0-21) across three waves (2011-2015). Linear mixed-effects models examined longitudinal associations, adjusting for sociodemographic factors, health behaviors, and chronic conditions, with interaction analyses for sex and education. RESULTS: Compared with participants reporting no SLEs, cumulative exposure showed the strongest association with cognitive decline (&#x3b2;&#x202f;=&#x202f;-0.52, 95% CI -0.69 to -0.35), followed by childhood-only (&#x3b2;&#x202f;=&#x202f;-0.34, -0.48 to -0.20) and adulthood-only exposure (&#x3b2;&#x202f;=&#x202f;-0.22, -0.37 to -0.07). Sex significantly moderated the associations for childhood and cumulative exposure, with women exhibiting greater cognitive vulnerability. Higher educational attainment attenuated the associations between single-period stress and cognitive decline, with only partial protection observed against cumulative adversity. CONCLUSION: Cumulative life-course stress is associated with accelerated cognitive decline in Chinese middle-aged and older adults. Women appear more vulnerable to stress-related cognitive effects, whereas higher education confers partial resilience, highlighting the need for sex-sensitive and education-informed prevention strategies.

Humans

Heterogeneity Analysis of Associations Involving the Large-Scale Online MindCrowd Survey Memory Test.

INTRODUCTION: Alzheimer's disease and related disorders (ADRDs), as well as general age-related cognitive decline, are known to be multifactorial with heterogeneous etiologies. Identifying and accommodating heterogeneity in any one ADRD-related data set can be pursued using different analytical techniques, each with different assumptions or purposes. For example, whereas a great deal of research has explored clustering individuals or variables that exhibit greater similarity in some way, little research has explored evidence for heterogeneity in the relationships between relevant outcomes, such as performance on a memory test, and risk factors such as environmental exposures, behaviors, or genetic factors among individuals. METHODS: We explored evidence of heterogeneity in the relationships between ability on a memory test, specifically the paired associate learning (PAL) test, and multiple social and demographic risk factors using the large MindCrowd study database (n > 90,000 individuals). We focused on mixtures of regression models but compared models assuming many interaction effects among independent variables as well as random effects. RESULTS: We ultimately find substantial evidence for heterogeneity and offer an intuitive explanation for it involving individual motivation for participating in the MindCrowd study. Basically, we argue that our mixture of regression model analysis results suggest that a smaller group of individuals (&#x223c;16%) likely participated in the MindCrowd study out of a concern for their cognitive abilities as they exhibit stronger and statistically significant negative associations between age, number of medications they are on, some ancestries, and the number correct on the PAL test. They also exhibit stronger positive associations between education and PAL test results in a dose-dependent manner suggesting that a "cognitive reserve" associated with greater education could benefit them. Analysis models assuming interaction terms and random effects suggested that other forms of heterogeneity in the relationships between variables exist in the data set, but their results do not carry with them the same intuitive explanation that the results of the mixture model analyses do. CONCLUSION: We find evidence for heterogeneity in the relationships between social and demographic variables and PAL test results in the large MindCrowd study database. This heterogeneity is likely due to individuals with and without concerns for their cognitive abilities participating in the study. We also find other types of evidence in the data set. Our results should motivate caution in the use of large epidemiological study or survey-oriented data sets to build predictive models of clinical or subclinical pathologies without exploring or accommodating heterogeneity. Our results also suggest that one should include questions about motivation to participate in large epidemiological studies since different motivations may impact important relationships between independent and dependent variables.

Humans

Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.

Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.

Amyotrophic Lateral Sclerosis

Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.

Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been investigated. We hypothesise that peripheral metabolic or protein features are associated with hippocampal vulnerability in middle age. Therefore, young adult and middle-aged rats were assessed for behavioural, proteomic, metabolic, and gut microbiota differences. Proteomic profiling of the hippocampus revealed differential expression of proteins indicative of altered synaptic signalling. Concurrently, adult hippocampal neurogenesis was decreased in middle age. Hippocampal microglia exhibited a lipid rich, inflammatory phenotype in middle age which correlated with poorer memory performance. CSF and serum proteomic and metabolomic analyses identified dysregulated lipid-related pathways potentially contributing to hippocampal vulnerability in middle age. Furthermore, 16S rRNA sequencing revealed reduced abundance of bacteria involved in lipid metabolism regulation. However, faecal microbiota transfer from young to middle aged rats was not sufficient to robustly improve hippocampus-dependent spatial memory. Together, these findings highlight dysfunctional lipid metabolism as a key feature of middle age that may contribute to decline in hippocampal function. Given that the scope for intervention is limited during older age, targeting biomarkers involved in metabolic and lipid homeostasis may be pivotal for the development of pharmacological or lifestyle-based interventions during middle age which could ultimately delay future cognitive ageing.

Animals

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

BACKGROUND: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these clinical groups. CONCLUSIONS: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Humans

Pretest activity and intellectual performance in middle-aged and older persons.

The present study investigated the effects of three conditions of pretest activity on the intellectual performance of 90 middle aged (50-61) and elderly (62-72) individuals. The Primary Mental Abilities Test was presented under three pretest conditions: physical, mental and physical, and no activity. Multi- and univariate analyses revealed significant age (or cohort) and sex differences in intellectual performance, but no significant pretest treatment effects. These results, when combined with similar recent findings of other investigators, indicate that pretest activity effects are less powerful than some widely cited previous research has suggested.

Aged

Pharmacological and non-pharmacological modulation of striatal dopamine release: a meta-analysis of [11C]raclopride PET studies.

The dopaminergic system has long been a central focus of functional neuroimaging. Positron emission tomography (PET) with the D2/D3 receptor radioligand [11C]raclopride remains the most widely used method for indirectly quantifying striatal dopamine release in vivo. However, no previous meta-analysis has studied the relative magnitude and regional distribution of dopamine release across different interventions or cognitive interventions overall. To address this gap, in this meta-analysis of 92 [11C]raclopride PET studies (n&#x2009;=&#x2009;1640), we compared the magnitude and regional distribution of dopamine release induced by amphetamine, methylphenidate, ketamine, alcohol, and cognitive challenges with and without reward. Amphetamine induced approximately four-fold greater dopamine release than cognitive challenges (10.9 vs. 2.7%, p&#x2009;<&#x2009;0.001), and approximately twice that of alcohol (4.8%, p&#x2009;<&#x2009;0.001), with effects comparable to methylphenidate (11.5%) and slightly greater than ketamine (9.8%). Psychostimulant-induced increase in synaptic dopamine was greater in putamen and ventral striatum than in caudate, whereas alcohol preferentially engaged ventral striatum. Dopamine release did not differ between rewarded and non-rewarded cognitive tasks in the ventral striatum (p&#x2009;>&#x2009;0.14) or overall striatum (p&#x2009;>&#x2009;0.10). Methylphenidate-induced increases in synaptic dopamine appeared to attenuate with advancing age, whereas cognitive challenges were associated with greater dopamine release in older individuals. These findings demonstrate that individual pharmacological and cognitive interventions differ markedly in both magnitude and regional pattern of dopamine release. They also suggest that [&#xb9;&#xb9;C]raclopride PET may have limited sensitivity for distinguishing reward-related from non-reward-related dopamine release. These findings have implications for the design and interpretation of future neuroimaging studies of dopaminergic function in health and disease.

Journal Article