Frontiers in Aging Neuroscience

Most evidence on age-related network topology derives from resting-state paradigms, leaving unclear how aging alters brain organization during naturalistic processing and whether graph-theoretical metrics relate to emotional and cognitive functioning in ecologically valid contexts. We analyzed movie-fMRI and behavioral data from 72 younger and 68 older adults, examining global (small-worldness, clustering coefficient, characteristic path length), network (participation coefficient), and nodal (degree centrality, betweenness centrality, nodal efficiency) properties. Regression models were used to test associations between nodal measures and both the Emotional Resilience Index (ERI) and the Cognitive Function Index (CFI), while mediation analyses were conducted to test whether nodal measures mediate the relationship between age and ERI. Older adults exhibited increased characteristic path length and clustering coefficient, indicating reduced global integration and greater local segregation. Although small-world organization was preserved in two groups, there was less pronounced small-world architecture in older adults compared to younger adults, suggesting a shift toward more regularized, locally clustered networks and reduced long-range connections during dynamic stimuli. Participation coefficient values were higher in the somatomotor, frontoparietal, and default mode networks, and lower in the subcortical network, among older adults reflecting greater between-network integration in cortical networks but diminished subcortical coordination in aging. Five key nodes, two thalamic regions, hippocampus, and two insular regions, showed reduced centrality and efficiency in older adults during the negative movie, indicating weakened dominance of subcortical hubs under emotional salience condition. Right thalamic nodal properties were negatively associated with ERI and CFI and served as mediators in the relationship between age and emotional resilience. These findings suggest that reduced thalamic hub centrality may reflect adaptive recalibration of salience emotional processing, linking network reorganization to improved emotional resilience in aging. Key pointsO_LIOlder adults showed higher path length and clustering, suggesting reduced integration. C_LIO_LIReduced small-worldness reflects weaker balance of segregation and integration with age. C_LIO_LIOlder adults showed higher cortical but lower subcortical participation coefficients. C_LIO_LIKey nodes showed reduced centrality during negative stimuli, indicating weaker hubs. C_LIO_LIRight thalamus changes linked to resilience, mediating age-emotion relationships. C_LI

Healthy aging is associated with progressive structural brain decline, yet the loss of functional abilities varies across individuals, which has been linked to reserve mechanisms. Within the framework of complex systems theory, reserve is thought to manifest as resilience when the system is challenged by stressors, such as increases in task difficulty. The cerebellum has been proposed as a potential source of motor reserve, but empirical evidence linking cerebellar structure, function, and resilience remains limited. We conducted a cross-sectional study including 50 young, 80 older, and 30 older-old adults to examine resilience to increasing task demands across cerebellar-specific and general outcomes. Participants completed three motor tasks (pure elbow motion, motor timing, postural stability) and two cognitive tasks (mental rotation, spatial working memory). Structural MRI was acquired to quantify cerebellar grey matter volume within functionally defined regions. Cerebellar-specific motor measures (anticipatory muscle activation and timing variability) were preserved across age groups and remained resilient under increased task demands, including in adults over 80 years of age. In contrast, general sensorimotor performance (postural sway) declined with age and showed reduced resilience. Within the cognitive domain, both cerebellar-specific and general measures showed comparable age-related declines and reduced resilience. Resilience measures were not correlated across tasks, indicating that resilience is task- and domain-specific. Furthermore, cerebellar grey matter volume did not predict resilience in motor or cognitive outcomes. These findings support the cerebellar motor reserve hypothesis, suggesting that cerebellar-dependent motor processes remain resilient despite age-related structural decline. However, resilience appears to be function-specific rather than a generalized individual trait. Overall, the results highlight dissociations between brain structure, function, and resilience, underscoring the selective contribution of the cerebellum to motor preservation in healthy aging.

Meningeal lymphatic vessels (mLV) play essential roles in draining cerebrospinal fluid (CSF) into peripheral blood. The mLVs are hypothesized to be supportive structures to the glymphatic system, which is thought to remove metabolic byproducts from brain parenchyma and has been most directly studied in rodent models. Previous rodent studies have indicated a correlation between mLV function and cognitive performance, but this relationship in humans remains unexplored. Age-related declines in glymphatic system efficiency in humans and cognitive performance have been observed separately. This study investigates age- and sex-related differences in CSF production via choroid plexus volumes, mLV characteristics, and glymphatic system efficiency, overall elucidating the implication of cerebral lymphatic function on cognition. We recruited 26 healthy adults from Dallas-Fort Worth and acquired magnetic resonance images. mLVs along the sagittal sinus were visualized and segmented from T2-FLAIR images. The glymphatic system was evaluated by measuring diffusivity along the perivascular space. Choroid plexus volume and brain volume were estimated from T1-MPRAGE. Neuropsychological tests were conducted to assess cognitive function. Our findings indicate that glymphatic function diminishes with age, while mLV and choroid plexus volumes increase. Males displayed greater mLV volume than females, yet no sex differences were found in glymphatic function or choroid plexus volume. Notably, mLV volume increased as glymphatic function declined, independent of age. Moreover, a glymphatic-mLV latent variable significantly predicted processing speed, underscoring the influence of cerebral lymphatics on cognition. In conclusion, this study highlights a decline in glymphatic function with age, accompanied by increased mLV volumes and altered processing speed. These lymphatic system changes may underlie or contribute to the cognitive declines observed in healthy and pathological aging. Significance StatementThe glymphatic system and meningeal lymphatic vessels play crucial roles in removing brain cell waste. The relationship between these systems and their effect on human cognition, particularly processing speed, is unknown. We demonstrate that these systems change with advancing age. Variations in cerebral lymphatic function contribute to differences in processing speed independent of age, ultimately affecting higher-order cognitive function. The findings presented have implications for cognitive function in both healthy and diseased states.

Emerging preclinical and clinical evidence suggests that low frequency hemodynamic oscillations drive CSF flow, which in turn mediates glymphatic clearance. The current study investigated whether CO2-induced low frequency hemodynamic oscillations during magnetic resonance imaging would increase clearance of proteins (glial fibrillary acidic protein, neurofilament light chain, ptau217 and brain-derived tau) from brain to blood, and temporarily improve cognitive performance in individuals with chronic traumatic brain injury (TBI) and age/sex-matched healthy controls. Results indicated that cerebrovascular reactivity, normalized CSF volume, and predicted brain age significantly differed between chronic TBI and controls, while bulk CSF flow differed only at trend levels. Multiple protein concentrations were significantly increased at [~]45 minutes post-hypercapnia, decreased at [~]90 minutes, and returned to pre-hypercapnia levels by [~]150 minutes. Protein efflux was more strongly associated with total CSF volume and total white matter volume rather than cerebrovascular reactivity or bulk CSF flow. Both groups exhibited reduced cognitive interference post-hypercapnia, and hypercapnia associated symptoms quickly returned to baseline levels. In conclusion, hypercapnia temporarily increases clearance of multiple neural abundant proteins into blood, and this effect is moderated by atrophy. Current results suggest that hypercapnia may therapeutically combat pathological protein aggregation post-trauma, and prophylactically during normal aging.

Insulin-like growth factor-1 (IGF-1) plays a critical role in neuronal signaling. Disrupted insulin/IGF-1 signaling is implicated in Alzheimers disease, among other conditions, yet its specific influence on glutamate receptor-mediated calcium responses remains unclear. We examined the impacts of IGF-1 on glutamate receptor function in primary rat neurons monitored for intraneuronal calcium following stimulation with glutamate, AMPA, or NMDA/glycine. Pharmacological blockers (CNQX for AMPA receptors, APV for NMDA receptors, and nimodipine for L-type calcium channels) were applied to define receptor-specific contributions. In hippocampal neurons, IGF-1 and insulin altered responses to glutamate in different directions, with IGF-1 tending to evoke and enhanced response. In neocortical neurons, by contrast, IGF-1 consistently reduced glutamate- and AMPA-evoked calcium peaks, suggesting an inhibitory effect on AMPA receptors. To rule out effects on voltage-gated calcium channels downstream of AMPA receptors, we tested effects of IGF-1 on depolarization with potassium chloride; calcium elevation in this case was unaffected by IGF-1. Likewise, IGF-1 did not inhibit responses to NMDA/glycine; and IGF-1 did not affect glutamate responses in the presence of CNQX, a selective AMPA receptor blocker. These findings, combined with the observation that IGF-1 effects persisted in the presence of APV (an NMDA receptor antagonist), indicate that the inhibition of glutamate responses by IGF-1 is mediated by suppression of AMPA receptor activity. IGF-1 may thus contribute to normal neurophysiology, and given the role that glutamate receptors play in excitotoxicity, IGF-1 may confer neuroprotection in the neocortex. Disruption of IGF-1 signaling, as seen in states resembling insulin resistance, may therefore worsen glutamate-driven excitotoxicity and contribute to adverse outcomes.

Tauopathies, including Alzheimers disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.

Objectives. The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA). Methods. Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL [≤] 1, n = 326) and two nested case groups: (a) KL [≥] 2 (n = 197), (b) KL [≥] 3 (n = 112). Results. Compared with controls, there were 27 and 41 genes associated (FDR [≤] 0.05) with KL [≥] 2 and KL [≥] 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL [≥] 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL [≥] 2 and KL [≥] 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism. Conclusions. Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.

INTRODUCTIONHealthful dietary patterns may attenuate dementia risk by preserving cerebrovascular health. Prior work has focused on systemic arterial stiffness, but cerebrovascular measures may be more sensitive to neuroprotective effects of diet. We examined associations between Mediterranean diet adherence, prefrontal cortex (PFC) arterial elasticity, and cognition in older adults. METHODSParticipants were 198 older adults (58% female; mean age 65.6 years) from the Newcastle ACTIVate cohort. Mediterranean Diet (MedDiet) scores were derived from the Australian Eating Survey food frequency questionnaire. Pulse Relaxation Function (PReFx), an index of PFC arterial elasticity, was measured using pulse Diffuse Optical Tomography. Cognition was assessed with CANTAB and a cued task-switching paradigm. RESULTSHigher MedDiet was associated with higher PFC arterial elasticity. MedDiet was not associated with cognition, and PReFx did not mediate diet-cognition associations. DISCUSSIONGreater Mediterranean diet alignment was cross-sectionally associated with PFC arterial elasticity, suggesting a pathway through which diet may influence brain health in ageing.

Background: For early detection of Alzheimer's disease, it is essential to identify individuals showing cognitive performance consistent with the mild cognitive impairment (MCI) range during preliminary screening, ideally using methods that extend beyond conventional cognitive assessments. Non-invasive, easily accessible screening tools applicable in daily life are increasingly needed. Facial expressions, particularly during rest, may offer promising biomarkers for MCI level detection. This study aimed to identify specific facial features associated with MCI level during rest to inform development of facial expression-based screening tools. Methods: Participants were classified into an MCI level group and a healthy control (HC) group based on the Montreal Cognitive Assessment (MoCA) scores. Facial Action Units (AUs) were extracted from video recordings of resting-state facial expressions in 31 individuals with MCI level and 14 HC. Two statistical models were employed: a multilevel zero-inflated beta regression model for intensity of 17 AUs and a multilevel logistic regression model for presence or absence of 18 AUs. Results: In the zero-inflated beta regression, the AU relates to upper lip raiser showed a significant group effect (MCI level vs. HC; p <0.001), remaining significant after multiple comparison correction. The logistic regression revealed significant group differences for the AUs related to lip tightener (p <0.001) and lip suck (p <0.001), both remained significant after multiple comparison correction. Conclusions: Distinctive facial action patterns during rest were observed in individuals with MCI level. These findings highlight the potential of resting-state facial expressions as a basis for novel, unobtrusive screening tools for early MCI level detection.

Objective: Improved diet quality is increasingly important for comorbidities management and healthy aging in people with HIV (PWH). Yet, limited data exist on dietary patterns and their correlates in this population. This study aimed to (1) characterize dietary patterns among adult PWH and (2) identify demographic, clinical, and HIV related factors associated with diet quality. Methods: We conducted a cross sectional analysis of PWH enrolled in the PROSPER HIV study across four U.S. academic medical centers. Dietary intake was assessed using three 24 hour dietary recalls and scored using the Healthy Eating Index 2015 (HEI2015). Participants were categorized into tertiles based on total HEI2015 scores. Between group comparisons were performed using Kruskal Wallis and chi square tests. Factors independently associated with HEI2015 scores were identified using multivariable linear regression. Results: A total of 491 PWH were included with a median age of 54 years; 76.4% were male. Overall diet quality was low with inadequate intake of dietary protein, fiber, and micronutrients. When classified by tertiles of HEI 2015 score, higher diet quality was characterized by greater intake of fiber, protein, and key micronutrients. Older age was independently associated with higher HEI 2015 scores, while Black race was associated with lower scores. Full time employment and absence of current pain were marginally associated with better diet quality. Conclusions: Diet quality among PWH varies substantially and is influenced by age, race, and social determinants. Tailored nutritional strategies are needed to support healthy aging and reduce disparities in this population.

BackgroundBalance instability is a major contributor to disability and falls in people with Parkinsons disease (PwP) and is often insufficiently explained by motor impairment alone. Altered awareness of motor control has been suggested to contribute to sensorimotor dysfunction in PwP, but its relationship with balance performance is poorly understood. ObjectiveTo determine whether awareness of balance control, assessed using a control detection task (CDT), differs between healthy controls (HC) and PwP, and whether CDT performance is associated with balance-related measures. MethodsHealthy older adults (n=20) and PwP (n=22) performed a standing version of the CDT based on center-of-pressure (COP) control, using a force plate. CDT accuracy was used as the primary outcome measure. Static balance during quiet standing was assessed using the COP trajectory length and rectangular area. Dynamic standing balance was assessed using the Index of Postural Stability (IPS). Group differences were examined by independent-samples t-tests. Correlations between CDT accuracy and balance measures were analyzed. ResultsThe PwP group showed significantly lower CDT accuracy. Higher CDT accuracy was associated with better static balance in the HC group and the combined sample, and with higher IPS primarily in the PwP group. ConclusionsMotor awareness during postural tasks is altered in PwP and is associated with balance control. These findings suggest that balance instability in Parkinsons disease may involve altered balance-related action-outcome monitoring in addition to motor dysfunction.

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimers disease (AD). It has, however, been challenging to develop measurements of brain structure directly linked to peripheral measures of neuroinflammation. This cross-sectional study examined whether plasma levels of markers related to inflammation are associated with diffusion magnetic resonance imaging (dMRI) measures of white matter microstructure: mean diffusivity (MD) and Neurite Orientation Dispersion and Density Imaging (NODDI) free water fraction (FWF) and orientation dispersion index (ODI). Participants included 457 dementia-free individuals (mean age=63.82, SD=7.63). Blood plasma markers related to inflammation included two measures of systemic inflammation, (1) high-sensitivity C-reactive protein (CRP), and (2) a composite of pro-inflammatory cytokines (IL-1, IL-1{beta}, IL-2, IL-6, IL-8, TNF-, TNF-{beta}), as well as (3) glial fibrillary acidic protein (GFAP), a measure of astrocytic activation. Higher cytokine composite levels were associated with higher values of all three measures (FWF, ODI, MD) in cerebral white matter, and with higher ODI in the cerebellar peduncles. Higher CRP levels were associated with higher ODI in cerebral and cerebellar white matter. Associations with GFAP were not significant after adjusting for multiple comparisons. Results were consistent after accounting for plasma biomarkers of AD pathology (p-tau181/A{beta}42). Thus, higher levels of peripheral pro-inflammatory markers are associated with white matter microstructure (higher FWF, ODI, and MD), supporting the view that these dMRI-based metrics are sensitive to inflammatory processes. Additionally, the sensitivity of dMRI-based measures to inflammation may differ by inflammatory marker types.

Parkinson's Disease (PD) is a complex neurodegenerative disorder that manifests through systemic, large-scale physiological reorganizations. While research often focuses on region-specific neural changes, there is a growing need for multidomain approaches to capture the complexity of the disease and its clinical heterogeneity. This study proposes an analytical pipeline to evaluate Brain-Heart Interplay (BHI) as a novel systemic biomarker for neurodegeneration and healthy ageing. In this study we assessed BHI across three open-source datasets (EEG and ECG signals). We compared Healthy Young, Healthy Elderly, and PD patients in resting state to investigate the effects of ageing and cognitive performance. Additionally, we studied BHI trends in PD patients in the moment of freezing of gait (FOG). Methodologically, brain network organization was quantified using coherence-based EEG connectivity and graph theory, while heart activity was analyzed through Poincare plot-derived measures of cardiac autonomic activity. The coupling between these two systems was measured using the Maximal Information Coefficient to capture linear and non-linear dependencies between global cortical organization and cardiac autonomic outflow. The results demonstrate that BHI is a sensitive biomarker for detecting early multisystem dysfunction in both neurodegeneration and ageing. Furthermore, the identification of specific BHI trends during FOG onset suggests new opportunities for understanding the physiological mechanisms driving motor complications in PD. Our proposed pipeline provides a guiding tool for large-scale physiological assessment in clinical research.

Alzheimer's disease (AD) is a major cause of dementia, with polygenic risk scores (PRSs) widely used to capture cumulative genetic risk. While PRSs have been associated with cognitive decline, their relevance to clinically accessible measures in general populations is not yet fully established, particularly in non-European cohorts. In this study, we investigated the association between AD PRSs and cognitive function assessed by the Mini-Mental State Examination (MMSE) in a community-dwelling Japanese older population (N = 1,301). Three PRSs were constructed using genome-wide association study (GWAS) summary statistics derived from European and Japanese populations. Among the PRSs, the score based on Japanese GWAS showed the strongest and most consistent association with MMSE score, whereas those based on European GWAS showed weaker or no associations. Stratification analyses further demonstrated that individuals with higher PRS exhibited lower MMSE scores and a higher prevalence of cognitive impairment. Notably, these associations were attenuated after excluding participants with dementia, suggesting that PRS primarily reflects clinically relevant cognitive decline. No significant associations were observed between PRSs and hippocampal volume in our cohort. These findings highlight the importance of population-specific PRS and suggest its potential utility for stratifying cognitive impairment using simple clinical measures in community-based settings.

BackgroundAlzheimers disease (AD) can be diagnosed using cerebrospinal fluid (CSF) biomarkers reflecting amyloid and tau pathology. However, it provides no information about functional network status. We aimed to determine whether CSF biomarkers (A{beta}42, p-Tau, t-Tau, and A{beta}42/p-Tau ratio) are associated with altered stimulus differentiation in vergence and pupil responses during an oddball task, and to evaluate oculomotor metrics as predictors of CSF core AD biomarkers in patients at mild cognitive impairment (MCI) stage. MethodsThirty-eight participants with abnormal CSF core AD biomarkers at MCI stage completed a visual oddball task while oculomotor responses were recorded. Linear mixed-effects models examined condition x biomarker interactions, controlling for sex, age, and MMSE. Temporal and magnitude features were tested as predictors using linear regression. ResultsHigher p-Tau levels were negatively associated with target-distractor differentiation in cognitive vergence ({beta} = -0.035, p < 0.001) and pupil responses ({beta} = - 0.060, p < 0.001). Higher A{beta}42 and A{beta}42/p-Tau showed positive associations with vergence differentiation but opposite effects on pupil responses. Oculomotor features predicted p-Tau levels (R2 = 0.20-0.21). ConclusionOculomotor differentiation metrics capture functional signatures of tau-related network dysfunction, positioning them as accessible biomarkers complementing CSF measures for detecting network disruption at MCI stage.

Introduction: Sleep-dependent memory consolidation differs by sex and maybe disrupted by Alzheimer disease (AD) risk. Whether sex moderates associations between apolipoprotein E {varepsilon}4(APOE {varepsilon}4) status, non-rapid eye movement (NREM) sleep, and memory remains unclear. Methods: Eighty cognitively unimpaired older adults completed a word-pair memory task with encoding and immediate testing occurring prior to overnight polysomnography with high-density electroencephalography (hdEEG) and delayed recall occurring after sleep. Sleep-memory associations were examined as a function of sex and APOE {varepsilon}4 status. Results: In this sample, a sex by APOE {varepsilon}4 interaction was associated with overnight memory retention, with female carriers exhibiting less overnight forgetting than female non-carriers and male {varepsilon}4 carriers. NREM sleep differed by sex and APOE {varepsilon}4 status and was associated with memory retention in {varepsilon}4 carriers. Discussion: These findings indicate sex-specific, sleep-dependent memory mechanisms associated with genetic AD risk, highlighting sleep as a potential early target for intervention, pending replication in larger samples. This study was not a clinical trial.

Declining spatial navigation abilities are a critical hallmark of aging, where the loss of spatial abilities precedes global cognitive impairment. While navigational decline is traditionally attributed to deficits in higher-order cognitive functions, emerging cognitive-motor frameworks suggest that age-related sensorimotor alterations play a significant, yet previously overlooked, role. Here, we investigate the coupling between locomotor integrity and navigation by combining an immersive virtual-reality path-integration paradigm with systematic manipulations of landmark availability and reliability, while recording gait kinematics alongside neural dynamics using high-density mobile-EEG from 30 young and 32 older adults. We demonstrate that older adults accumulate angular homing error more rapidly than younger adults, a deficit linked to altered gait dynamics. These age-dependent differences are reflected in increased mid-frontal theta activity, highlighting a robust coupling between gait-related sensorimotor alterations and decline in navigation. Older adults also exhibited increased reliance on visual landmarks, and particularly those with degraded gait, yet this compensatory reweighting of navigational cues remained less efficient and less precise than in younger adults. These findings highlight sensorimotor gait alterations as a central determinant of age-related navigation deficits, challenging the traditional separation of motor and cognitive domains and identifying locomotor integrity as a critical target for preserving spatial navigation abilities.

Non-motor symptoms in Parkinsons disease (PD) may be influenced by the 4{beta}2* subtype of nicotinic acetylcholine receptors (nAChR) present in the hippocampus and subiculum. To continue efforts in PET diagnostics for PD, autoradiographic [18F]nifene binding to 4{beta}2* nAChR was quantitively assessed in the hippocampus-subiculum (HP-SUB) of PD (n = 27; 14 males, 13 females) and cognitively normal (CN) (n = 32; 16 males, 16 females) cases. Anti-ubiquitin for Lewy body and anti--synuclein immunostaining on adjacent slices were analyzed in QuPath and [18F]nifene binding was quantified in OptiQuant. Subiculum had greater [18F]nifene binding (51% to 85%) compared to HP in all subjects. Significantly higher [18F]nifene binding (>250%) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD=3.53 while CN=1.33, a >150% increase in PD. Binding of [18F]nifene to GM and WM individually was >250% greater in PD compared to CN. Male CN exhibited an increase while and male PD exhibited a significant decrease in [18F]nifene binding with aging, while females did not exhibit significant differences. In summary, 4{beta}2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.

PurposeThe optic nerve head (ONH) is a central feature of the retina, affected in many human ocular pathologies, yet it has remained underexplored in most mouse models of disease. We hypothesize that the analysis of the ONH can yield valuable insight into the phenotype of retinal diseases and that pathological changes can be detected using state-of-the-art optical coherence tomography (OCT). MethodsFour mouse models - the 5xFAD, PS19 and APP/PS1 models of Alzheimers disease (AD) as well as the SOD1 knockout mouse model - were imaged using a polarization-sensitive OCT system to investigate potential disease related changes of the ONH. 5xFAD and SOD1 animals were investigated longitudinally to study disease progression. Additionally, aging effects in wild type mice were studied. ResultsTwo different analysis methods for the segmentation of the ONH were implemented and evaluated. Longitudinal changes to the ONH in 5xFAD animals were observed, specifically an increase of ONH volume from 3 to 5 months of age followed by a strong decrease until 9 months of age. Significant differences between transgenic (tg) and non-transgenic (ntg) animals, as well as sex dependent distinctions were found. Also, for the APP/PS1 model disease related differences between ntg and tg APP/PS1 were significant. ConclusionsWe demonstrated a simple segmentation of the ONH structure based on OCT intensity images and show its potential as a preclinical biomarker in amyloid mouse models of AD.

BackgroundThe AT(N) biological framework classifies Alzheimers disease (AD) pathology using CSF biomarkers, with the A+T+ profile defining biological AD and the A-T+ profile representing a biologically distinct entity consistent with suspected non-Alzheimers pathophysiology, such as primary age-related tauopathy. Functional assessment capable of differentiating these profiles non-invasively remains limited. This study investigates whether cognitive vergence and pupillary temporal dynamics during a visual oddball task can distinguish A-T+ from A+T+ biological profiles in individuals with mild cognitive impairment (MCI). MethodsThirty-eight participants with MCI (12 A-T+, 26 A+T+) classified by CSF biomarkers completed a visual oddball task (80% distractors, 20% targets) under continuous eye-tracking. Linear mixed-effects models examined profile x condition interactions on full time series and six trial-level temporal features. Participant-level differentiation was assessed using binomial logistic regression, adjusting for age, sex, and MMSE. ResultsBoth profiles showed comparable overall oculomotor response magnitudes but diverged markedly in temporal organization. Significant profile x condition interactions emerged for cognitive vergence global slope, time to peak, and pupillary time to peak. Logistic regression confirmed that timing features discriminated biological profiles at the participant level, with differentiation reversing direction between distractor and target conditions. A-T+ participants also maintained superior target detection accuracy (89.3% vs. 82.4%, p = 0.001). ConclusionCognitive Vergence and pupillary temporal dynamics during an oddball task provide condition-dependent functional oculomotor signatures that systematically differentiate AT(N) biological profiles in MCI, suggesting that oculomotor assessment may offer an accessible, non-invasive complement to CSF-based profile characterization.