Frontiers in Aging Neuroscience

BackgroundThe brainstem and its different sub-systems control essential functions such as motor agility etc. that worsen with age. The purpose of this study was: 1. To assess the impact of age-related volume loss within three brainstem sub-systems on functions supported by them. 2. To use data-driven machine learning to identify different volume loss patterns or subtypes and investigate how they are associated with function. MethodsStructural MRI and behavioral data from 674 Human Connectome Project Aging (HCA) participants was used in this project. The brainstem was extracted, internal brainstem structures segmented and the segmentations warped onto a probabilistic population atlas on which the nuclei of interest had been labeled. Jacobian deformation maps were calculated, each rois mean Jacobians extracted and converted into z-scores with and without correction for age. Linear regression analyses were used to assess volume - function (cognition, motor agility, autonomic control) associations for each roi belonging to the sub-system supporting these functions. Subtype and Stage Inference (SuStaIn) was used to identify different volume loss patterns in each sub-system. ResultsAge explained larger percentage of the variation of the behavioral variables than brainstem volumes. SuStaIn identified up to 4 subtypes, one representing typical aging and the remainder atypical aging. The subtypes did not significantly differ behaviorally with the exception of grip strength and diastolic blood pressure. ConclusionAging affects brainstem systems which contributes to the worsening of these functions with increasing age. SuStaIn detected different patterns of volume loss or subtypes within each of the brainstem systems.

Sensory degradation with aging can impair balance control, partly by disrupting visual contributions to self-motion estimation. We investigated how aging affects the control of frontal plane center of mass (CoM) trajectories during walking with exposure to repeated visual perturbations. We hypothesized that aging would increase responses to visual perturbations and decrease adaptation to repeated visual perturbation exposure. We applied three visual perturbations to 14 healthy older (age: 75.0{+/-}2.4) and 16 younger adults (age: 23.4{+/-}3.9) walking on a treadmill: fixating a stationary target with the background moving to the right (MB), tracking a target moving rightward over a stationary background with head rotation (MT-HR), and tracking a moving target with eye movement only (MT-EM). Deviations of CoM position and foot placement due to the visual perturbations were assessed. Over the whole trial, the older adults exhibited larger CoM position variability in MB and MT-HR conditions. During visual perturbation epochs, both age groups deviated in the same direction except MB. In MB, the older adults deviated to an opposite direction after a few perturbation repetitions. Moreover, in MT-HR and MT-EM, the older adults deviated earlier than the younger adults and they deviated more in the MT-HR condition. This indicates that older adults exhibit reduced ability to accurately estimate self-motion through correction by other sensory modalities when exposed to visual perturbations. Over repeated perturbations, the older adults showed decreased CoM deviations in MT-EM, which suggests that they still maintain the capacity to downweight visual information after repeated exposure.

Healthy young and older adults completed two randomized sessions of split-belt treadmill walking, with and without a concurrent cognitive task. When the single-task session occurred first, both age groups showed savings in step length asymmetry during re-adaptation one week later. However, performing the dual-task session first reduced savings, and this order-effect was greater in older adults compared to young adults. These findings suggest that cognitive load during initial motor adaptation interferes with savings, but once stored, locomotor readaptation is resilient to dual-tasking.

Freezing of gait is a disabling episodic symptom of Parkinson's disease, typically emerging during complex locomotor tasks such as turning, obstacle negotiation, and gait initiation. These tasks require effective motor planning and proactive visual search of the intended walking route. Current evidence suggests that people with Parkinson's disease and freezing of gait show different patterns of visual search compared to those without freezing of gait and healthy older adults. However, existing reports are based on relatively simple tasks that lack common triggers for freezing of gait and do not adequately control for other factors likely to influence visual search, such as motor symptom severity and balance ability. This study examined visual search behaviour in 24 healthy older adults and 37 people with Parkinson's disease (21 with freezing of gait, 16 without) during a complex walking task requiring repeated turning and navigation through narrow spaces. Visual search characteristics were compared between people with Parkinson's disease and healthy controls, and relationships between visual search, freezing of gait, motor symptom severity, and balance ability were explored within the Parkinson's disease group. Compared with healthy controls, people with Parkinson's disease showed significantly fewer fixations toward areas outside the walking path, longer average fixation durations, and reduced saccade amplitudes, with no differences in proactive visual planning of the intended route. No relationship was found between visual search outcomes and freezing of gait. Reduced fixations to outside-path areas were associated with poorer functional balance independently of motor symptom severity. These findings indicate that restricted visual sampling in Parkinson's disease is primarily associated with balance impairment rather than freezing of gait or motor symptom severity.

Incomplete letter recognition tasks are frequently used to detect visual deficits arising from neurodegenerative syndromes, including Posterior Cortical Atrophy (PCA; visual-variant Alzheimers disease). A recent development of this approach is the Graded Incomplete Letters Test (GILT), which measures recognition thresholds for letters degraded by removing pixelated sections (decreasing completeness). Although GILT thresholds are strongly elevated in PCA relative to typical adults, the precise cortical visual impairments underlying these deficits are unclear, as is the potential contribution from age-related optical limitations. We compared candidate cortical factors (crowding and global integration) with optical limitations (blur and low contrast) by simulating these factors in typical adults (n=6) viewing incomplete letter stimuli. Participants identified foveally presented letters (12 alternatives), with completeness varied using QUEST. At baseline, thresholds averaged [~]5% completeness. Optical factors were simulated by separately applying blur and lowered contrast. These factors had minimal effect on thresholds, except where blur/contrast levels approached visibility limits, where thresholds rose modestly but remained far below clinical levels in PCA. Cortical factors were simulated by increasing crowding (disruptions from clutter) through peripheral presentation, with global-integration impairments simulated by varying pixel size to alter the distribution of degradation (limiting spatial integration) or degrading letters dynamically with limited-lifetime pixels (limiting temporal integration). These manipulations substantially elevated thresholds, with combined crowding and global-integration impairments increasing thresholds to levels comparable with PCA. We conclude that impaired incomplete letter recognition is driven primarily by cortical rather than optical factors, and that neurodegenerative deficits may reflect the combined impact of multiple cortical limitations.

Abstract Background: Biological systems exhibit dynamic patterns over multiple temporal scales -from minutes to months- that are poorly captured by conventional cross-sectional or low-frequency longitudinal studies. These patterns, including circadian and ultradian rhythms, may be critical determinants of health, resilience, and disease risk in aging. Existing longitudinal studies in older adults lack high-frequency, multimodal measurements that integrate molecular, physiological, and digital health data streams. Objectives: The TIME Study aims to: (i) Characterize temporal patterns in molecular, physiological, and digital health measures in healthy older adults; (ii) determine how these patterns vary across biological domains and relate to each other; and (iii) assess how physiological systems respond to defined perturbations (oral glucose tolerance and maximal exercise). Methods: TIME is a single-site, observational, longitudinal study enrolling up to 150 adults aged [≥] 55 years. Over an 11-week main phase, participants complete seven weekly low-frequency visits, two perturbation challenge visits, and two, two-day high-frequency sampling epochs. Biospecimens, clinical measures, cognitive and physical performance tests, and continuous digital health data are collected. Follow-up visits occur at 6 and 12 months. Expected Impact: By integrating multimodal, temporally resolved data, TIME will provide a foundational dataset for understanding the role of biological rhythms in aging and inform future precision health strategies.

Using data from a randomized clinical trial, we examined whether daily biofeedback training that modulates heart rate oscillations is associated with changes in microstructural brain texture in Alzheimer's disease signature cortical (ADSC) and hippocampal regions. Younger and older adults were randomly assigned to one of two daily biofeedback practices for five weeks: slow-paced breathing designed to increase heart rate oscillations (Osc+) or self-selected strategies aimed at decreasing oscillations (Osc-). Intervention effects were observed in both ADSC and hippocampus regions and were confined to a composite texture factor dominated by uniformity and entropy. Across regions, effects were expressed primarily as Time x Condition interactions, indicating differential texture trajectories between Osc+ and Osc-. In the hippocampus, this pattern was further qualified by a Time x Condition x Age Group interaction, reflecting more pronounced effects in older adults, whereas younger adults showed no reliable texture modulation. Partial least squares correlation analyses further demonstrated that training-related texture changes in the left hippocampus, right fusiform gyrus, and right entorhinal cortex covaried with concurrent changes in plasma AD-related biomarkers, with tau- and p-tau related measures contributing most strongly to the multivariate association. Together, these findings suggest that HRV biofeedback may selectively influence specific dimensions of brain microstructural texture and that such changes are meaningfully coupled with plasma AD-related biomarker profiles.

BACKGROUND: Aging and Parkinsons disease (PD) reduce gait automaticity and increase cognitive demand during walking. Although dual task (DT) paradigms investigate cognitive motor interference, evidence remains limited by heterogeneous tasks, predominant focus on prefrontal cortex (PFC) activity, and variability in functional near infrared spectroscopy (fNIRS) methods. This study investigates whether longitudinal changes in cortical activation during DT walking differ among young adults, older adults, and individuals with PD, and how these changes relate to DT costs over 5 years. METHODS: This longitudinal observational study follows STROBE and fNIRS guidelines and will be conducted in a controlled laboratory (Rede Amparo, CEPID NeuroMat, University of Sao Paulo). Participants will be evaluated annually under three randomized conditions: motor single-task walking, cognitive single task phonemic verbal fluency and DT walking with phonemic verbal fluency, each repeated 10 times. The primary outcome measure will be longitudinal changes in cortical activation during DT walking, quantified by oxygenated hemoglobin (HbO) signals measured with fNIRS in prefrontal and premotor cortical regions. The main predictors of interest will be motor and cognitive DT costs. Covariates will include age, sex, education, cognition, balance, mood, and disease severity in the PD group. Spatiotemporal gait parameters, including gait speed, step length, stride length, step time, base of support, double support, stance phase, and variability, will be recorded using the GAITRite system, and DT costs will be calculated for selected parameters. Cortical activation will be assessed using a 66 channel wearable fNIRS system with short separation channels. DISCUSSION: By combining randomized task blocks, separate motor and cognitive conditions, broader cortical coverage, and concurrent neural and gait assessment across three groups annually, this protocol is expected to provide a comprehensive characterization of cognitive motor interference during walking and its evolution, supporting interpretation of cortical and behavioral responses. The study may help distinguish age related adaptations from PD specific alterations and clarify whether increased cortical recruitment during DT gait reflects compensation, reduced neural efficiency, or ceiling effects, refining understanding of gait automaticity decline and informing rehabilitation and non invasive brain stimulation approaches.

INTRODUCTION: Neuroinflammation and immune dysregulation are increasingly recognized as early drivers of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), often emerging decades before the onset of clinical symptoms. Despite this, there remains a critical need for non-invasive biomarkers that can capture these early processes, particularly in African Americans, a population at elevated risk for AD/ADRD yet underrepresented in neuroimaging research. In this study, we investigated the relationship between systemic plasma inflammatory markers and brain microstructural integrity in cognitively unimpaired older African Americans. METHODS: Forty-one participants (mean age = 68.68 years) underwent MRI scanning and multi-plex plasma-based inflammatory marker quantification. Microstructural changes were quantified using Diffusion Weighted Imaging (DWI) metrics, including mean diffusivity (MD), radial diffusivity (RD), mean kurtosis (MK), and radial kurtosis (RK). Voxel-wise general linear models, and cluster-based models were used to examine associations between plasma-derived inflammatory markers and brain microstructure. RESULTS: Higher TARC levels were associated with widespread increases in MD and RD across both gray and white matter, implicating reduced microstructural integrity and potential myelin disruption. In contrast, kurtosis-based metrics demonstrated more spatially selective and generally weaker associations, with MK and RK showing limited decreases primarily within white matter tracts. Cluster-level analyses confirmed the robustness of diffusivity findings and highlighted consistent effect sizes across multiple regions. DISCUSSION: These findings suggest that elevated TARC is linked to early microstructural alterations detectable with diffusion MRI, with diffusivity metrics demonstrating greater sensitivity to inflammation-related changes than kurtosis measures in this cohort. This work underscores the importance of incorporating inflammatory biomarkers in neuroimaging studies of aging and highlights diffusion MRI as a promising tool for detecting early neurobiological signatures of AD/ADRD risk in African American populations. Keywords: Systemic Inflammation, TARC, Eotaxin-3, Diffusion MRI, African Americans, ADRD, Aging

Relational memory, the ability to encode and retrieve associations among multiple elements of an experience, is a core component of episodic memory that shows disproportionate age-related decline. Despite a substantial neuroimaging literature examining relational memory in aging, findings remain heterogeneous, and no quantitative synthesis has been conducted. The present study addressed this gap using Activation Likelihood Estimation (ALE) meta-analyses to characterize the neural correlates of relational memory success during encoding and retrieval in younger and older adults. Separate within-age-group, conjunction, and subtraction analyses were conducted, along with an exploratory analysis examining a general relational memory network across 70 independent studies. During encoding, younger adults showed robust convergence across medial temporal and prefrontal regions, whereas older adults showed more limited convergence. Shared convergence across age groups was observed in the left hippocampus and right inferior temporal gyrus, and direct age-group contrasts revealed greater prefrontal convergence in younger relative to older adults. During retrieval, younger adults showed convergence in posterior default mode and subcortical regions, whereas older adults showed convergence in the left angular gyrus, with no shared convergence observed across age groups. Across all studies, the hippocampus showed the most robust bilateral convergence across age groups and memory phases, underscoring its critical role in relational binding. Together, these findings provide the first quantitative characterization of the neural correlates of relational memory success in aging and highlight stable hippocampal involvement alongside age-related variability in prefrontal and posterior retrieval-related recruitment.

Anticipatory postural adjustments (APAs) scale with velocity of approaching objects, with scaling magnitude depending on whether the moving object is actively foveated and tracked, processed through fixated peripheral vision, or processed through fixated central vision. Aging preferentially degrades the magnocellular pathway underlying peripheral motion processing while sparing the extraretinal signals available during smooth pursuit. We therefore asked whether the effect of aging on velocity-dependent APA scaling differs across these three visual pathways. Eighteen young and eighteen older adults stopped a virtual object approaching at four velocities (15-33 cm/s) under three gaze conditions: active foveation via smooth pursuit, central fixation, and peripheral fixation. We measured peak anticipatory force, rate of force development, and time to contact at force onset. Despite reduced smooth pursuit gain in older adults, velocity-dependent scaling was equivalent between age groups during active foveation, and minimal in both groups during central fixation. Critically, young adults scaled force rate during peripheral fixation nearly as steeply as during active foveation, whereas older adults slope was significantly lower -- a difference not observed during the other gaze conditions. Older adults achieved comparable peak force by initiating responses earlier. These results establish that age-related decline in anticipatory motor control is pathway-specific: aging selectively impairs peripheral motion processing for APAs, while extraretinal mechanisms remain capable of sustaining velocity-dependent scaling. More broadly, peripheral motion processing emerges as a candidate physiological locus of age-related postural vulnerability, raising the question of whether magnocellular-targeted training can restore APA scaling in older adults. Key PointsO_LIYoung and older adults stopped virtual objects under three visual conditions: active foveation via smooth pursuit eye movements, and stationary gaze with the object moving through either central or peripheral vision. C_LIO_LIVelocity-dependent force rate scaling was preserved during active foveation in both age groups, minimal during fixated central vision in both age groups, and selectively impaired in older adults during fixated peripheral vision. C_LIO_LIWe found an age-induced vulnerability in peripheral visual motion processing for anticipatory posture stabilization. C_LI

Background: Despite the success of combination antiretroviral therapy (cART), vascular comorbidities, including cerebrovascular disease, are more prominent in people living with HIV (PLWH) compared to people without HIV (PWOH). However, quantitative assessments of cerebrovascular morphometry and their associations with cognitive outcomes in the context of HIV are still limited. In this study, we explore this missing link. Methods: Magnetic Resonance Angiography (MRA) data, blood markers, and neurocognitive assessments were collected from 73 PWOH subjects (male: 57, female: 16; age: 53 {+/-} 16) and 99 PLWH subjects (male: 66, female: 30, age: 53 {+/-} 11). Vessel morphometric features were quantified using intraCranial Artery Feature Extraction (iCafe) to investigate associations between vessel morphometry, markers of monocytes, endothelial cell activation, and cognitive performance. Results: HIV status predicted a lower total number of branches ({beta} = -0.224, p = 0.001, d = -0.517) and shorter total distal length ({beta} = -0.173, p = 0.021, d = -0.370) with a moderate effect size. Total branch number was found to be negatively associated with plasma levels of monocyte markers (sCD14: r = -0.167, p = 0.033; sCD163: r = -0.157, p = 0.045) and positively correlated with white matter cerebral blood flow (r = 0.550; p [≤] 0.05). HIV status was the strongest predictor of overall cognitive performance in ANCOVA model ({beta} = -0.219, p = 0.006, d = -0.453). Conclusions: Our results suggest that cognitive impairment in PLWH is associated with vessel morphology metrics. Monocyte immune activation may contribute to changes in vessel morphology.

Reading is a critical skill in modern society. Most research on reading is conducted in school age children or young adults. However, acquired brain disorders often affect reading ability, and these disorders tend to occur in older adults. It is therefore critical to examine the normative distribution of reading behavior and the brain basis of reading in older adults. Here, we provide trial-wise single word and pseudoword oral reading and lexical decision data, as well as structural, functional, and diffusion-weighted MRI data from 116 neurotypical adults aged 22 to 84 years (mean = 59). Accuracy, response times, and errors are provided for corpora that are parametrically modulated in frequency, imageability, and regularity for real words and consistency of spelling-sound mapping for pseudowords. This dataset includes both minimally processed behavior (trial-wise data) and MRI data, and participant- and item-wise summary metrics and processed MRI data. These data serve both as a normative sample for reading behavior in older adults, but also as a valuable resource for identifying novel brain-behavioral relationships.

Alzheimer's disease is a progressive neurodegenerative disorder that poses a growing global public health challenge. Early and accurate diagnosis is critical for effective treatment, clinical trial participation, and disease management. This systematic review and meta-analysis evaluates the diagnostic performance of machine learning (ML) and deep learning (DL) algorithms for detecting Alzheimer's disease (AD) and mild cognitive impairment (MCI) using neuroimaging and clinical data. Relevant studies were identified from PubMed, IEEE Xplore, and arXiv (2015 to 2025). Random-effects models were applied to estimate pooled performance metrics (AUC, sensitivity, specificity, and F1-score), and subgroup analyses compared results by model type, imaging modality, and validation strategy. Thirty studies met inclusion criteria. The pooled AUC was 0.962, indicating high overall discriminative accuracy. However, studies relying solely on internal validation or with smaller datasets often reported inflated metrics, suggesting potential overfitting and optimism bias. ML and DL methods demonstrate strong potential for early AD detection, but standardized evaluation protocols and external validation are necessary for clinical translation.

BACKGROUND: Dual task walking requires simultaneous management of cognitive and motor demands and is associated with changes in gait and cortical activation. However, the relationship between task related cortical recruitment and dual task related gait adjustments in healthy young adults remains unclear. This study aimed to investigate the effects of dual tasking on gait performance and cortical activation, and to examine the association between changes in cortical activity and dual-task costs. METHODS: This cross sectional study included 33 healthy young adults. Participants performed three conditions: single task walking, cognitive single task (verbal fluency), and dual task walking. Each condition was repeated 10 times using a repeated short block design with randomized trial presentation. Gait performance was assessed using an instrumented walkway, and cortical activation was measured using functional near infrared spectroscopy. Dual task costs were calculated for gait and cognitive outcomes. Statistical analysis included repeated measures analysis of variance (ANOVA) and Wilcoxon signed rank tests, with false discovery rate correction for multiple comparisons. Associations between changes in cortical activation and dual task costs were examined using correlation analyses. RESULTS: Dual task walking resulted in significant changes in gait, including reduced speed, step and stride length, and increased base of support, stance, and double support (all p < 0.05), while cognitive performance remained unchanged. Dual tasking was associated with increased cortical activation in left prefrontal and motor related regions. Greater increases in cortical activation were associated with lower dual task costs across most gait parameters, with significant correlations observed in the left dorsolateral prefrontal cortex (r {approx} 0.42 to 0.47 for speed and stride length; p < 0.05). Double support showed a distinct pattern, suggesting a specific temporal adjustment within the gait cycle. CONCLUSIONS: Dual task walking in young adults is associated with coordinated behavioral and cortical adaptations. Increased cortical recruitment is linked to reduced motor interference, suggesting that broader engagement of cortical networks may contribute to performance under cognitive motor load.

Background: Alzheimers disease (AD) is a multifactorial neurodegenerative disorder in which copper dyshomeostasis, mitochondrial stress, oxidative injury and immune dysregulation may contribute to pathogenesis. Cuproptosis, a copper-triggered regulated cell death pathway, has emerged as a potential mechanistic link to AD, but its therapeutic and biomarker implications remain incompletely defined. Methods: We integrated transcriptomic, machine learning, immune infiltration, QSFR, molecular docking, docking validation and ADME analyses using GEO blood- and brain-based AD cohorts. Differentially expressed genes were intersected with curated cuproptosis-related genes, followed by pathway enrichment, construction and validation of a hybrid ensemble classifier, CIBERSORT-based immune correlation analysis, QSFR-driven target prioritization, ligand docking, consensus docking validation and SwissADME profiling. Results: The transcriptomic analyses revealed reproducible AD associated signatures enriched in neurodegenerative, oxidative stress, mitochondrial and inflammatory pathways. Across multiple machine learning models, FDX1, PDHB, PDHA1, DLAT and DLD consistently emerged as the most important cuproptosis-related genes, with the hybrid ensemble achieving the best diagnostic performance. Immune profiling suggested that these genes are linked to distinct immune infiltration patterns. QSFR and docking prioritized FDX1 as a key target and Clioquinol, PBT2 and Ebselen showed the strongest and most consistent binding behavior. Docking validation confirmed reliable pose reproduction and enrichment over decoys, while ADME analysis supported Clioquinol, PBT2 and Ebselen as the most balanced candidates for further consideration. Conclusion: This integrated workflow identifies a cuproptosis-centered mitochondrial gene module as a robust AD signature and highlights Clioquinol, PBT2 and Ebselen as promising repurposing candidates. The findings provide a prioritized computational framework for future experimental validation of copper-linked therapeutic strategies in AD.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics. RESULTS: Diabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations. CONCLUSION: These findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.

CLN3 disease is an inherited neurodegenerative disease, typically with childhood onset, and characterized by vision loss, seizures, cognitive decline, and difficulties. The CLN3 Staging System (CLN3SS) characterizes disease progression. Our aim was to assess differences in cognitive test scores in relation to CLN3SS among individuals with CLN3 disease. We evaluated the relationship between cognitive test performance and the CLN3SS in individuals with genetically confirmed CLN3 disease. Participants completed tasks of verbal reasoning, vocabulary knowledge, attention, fund of information, and ability to recite the alphabet. One-way ANOVA testing assessed differences in mean cognitive test score among CLN3SS score groups, and Chi-square testing was used to compare the proportion in each CLN3SS group that could recite the alphabet. Data were evaluated from a sample of 85 individuals with a total 245 CLN3SS assessments conducted within 6 months of their cognitive testing, A significant decrease in test scores was found between CLN3SS Stages 1 (vision loss present) and 2 (vision loss and seizures present) for each of the cognitive tests. The proportion of participants able to recite the alphabet also decreased from Stage 1 to Stage 2 (X2=12.1, p<.01). Cognitive ability declines with advanced disease severity in CLN3 disease, though motor disability in Stage 3 likely contributes to difficulty participating in cognitive assessment at this later disease stage. Understanding the relationship between cognition and CLN3 disease stage may help guide decision making, i.e., determining who could or should undergo cognitive assessment for clinical care or for group stratification in disease modifying clinical trials.

Background Slow walking in older adults with mild parkinsonian signs (MPS) is a complex, multifactorial phenomenon arising from the cumulative burden of subclinical age-associated pathologies. This decline reflects age-associated neuronal loss in the dopaminergic system. A recent study suggests that levodopa treatment may enhance gait parameters. The goal of this small pilot study is to explore the effect of levodopa treatment on slow walking gait in older adults with MPS. Method This study was a randomized, placebo-controlled clinical pilot trial. Slow walking older adults without clinical evidence of PD were recruited and randomized into 2 groups (active treatment group or placebo control group). Participants in the active group were pre-treated with carbidopa for three days, followed by carbidopa-levodopa for seven days. Spatiotemporal gait parameters were evaluated at baseline and post-intervention. Results Gait factor analysis identified three main factors explaining gait characteristics at baseline, which included gait efficiency, gait rhythmicity, and gait turning.No effect of treatment was observed in the placebo group (p=0.111, p=0.616), no group difference was observed between the placebo and active group at baseline ({beta}=0.310, p=0.547), but a strong trend for a treatment-related increase was observed in the active treatment group ({beta}=0.506, p=0.076). Conclusion Our preliminary data suggest that sustained levodopa treatment (one week) in conjunction with carbidopa pre-treatment and concomitant carbidopa supplementation is feasible in slow walking older adults with MPS. Moreover, the data indicate potential efficacy, showing improvements in cadence, and step durations.

Background: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD