Abstract INTRODUCTION Clinical effects and prevalence of Lewy body (LB) pathology in patients with mild cognitive impairment (MCI) remain poorly understood. METHODS We assessed LB pathology in 339 patients with MCI from the Italian multicenter Interceptor cohort using the cerebrospinal fluid α‐synuclein seed amplification assay. Baseline assessment was followed by serial cognitive evaluations over 3 years. RESULTS LB+ participants (n = 50, 15%) were older and showed a higher frequency of parkinsonism, falls, and delirium episodes than those LB–, although these differences were not statistically significant. At follow‐up, patients with biomarker evidence of Alzheimer's disease (AD), either isolated (AD+/LB–) or with concomitant LB pathology (AD+/LB+), showed the fastest cognitive decline and progression to dementia. DISCUSSION In a multicenter MCI cohort, LB pathology was associated with older age and an increased frequency of motor/psychiatric symptoms. Larger studies are needed to clarify the independent contribution of AD and LB pathologies to the MCI phenotype and clinical progression.

Aging is a multifaceted process where physiological metrics, such as brain age and muscle age (MA), provide deeper insights than chronological age alone. These nonlinear trajectories are heavily influenced by exogenous factors like lifestyle and nutrition. In older populations, muscle age acceleration (MAA) critically impacts functional autonomy and cognitive health, necessitating research into its link with brain network organization to refine assessments and, based on these, integrated motor and cognitive rehabilitation strategies. In this study, eyes-closed resting-state electroencephalography (EEG) was recorded from 101 healthy, neurologically intact older adults. MA and MAA were quantified using a regression model incorporating the functional assessments recommended by the European Working Group on Sarcopenia in Older People (EWGSOP-2) consensus (anthropometrics, muscle strength, and motor functional tests). Participants were stratified into three groups based on their MAA: decelerated MA, normal MA, and accelerated MA. Brain connectivity was assessed through magnitude-squared coherence (MSCoh) and node strength analyses. The results demonstrated that decelerated MA subjects exhibit significantly lower MSCoh compared to the normal and accelerated groups in the Alpha 1, Alpha 2, and Beta 1 bands. Furthermore, node strength analysis revealed that the decelerated MA group possessed lower values in the right frontal area across Alpha 1, Beta 1, and Beta 2 bands. Conversely, the normal MA group exhibited lower values in the right temporal region compared to the accelerated MA group. These findings may suggest that divergent muscle aging trajectories significantly modulate brain network topography. This brain–body interconnection highlights the potential for personalized interventions designed to redirect muscle aging trajectories, ultimately enhancing global functioning and quality of life of older people.

INTRODUCTION:The aging brain's vulnerability to decline emphasizes the importance of strategies preserving cognitive function and independence. As age-related brain changes do not always match clinical symptoms, reserve, encompassing brain reserve (BR) and cognitive reserve (CR), has emerged as a key mechanism supporting resilience and mitigating cognitive decline during aging. This study adopts an exploratory approach to examine whether age- and CR-related differences are reflected in large-scale brain network organization, as assessed through electroencephalographic (EEG) connectivity metrics. METHODS:Resilience to age-related cognitive changes was investigated by relating CR, measured using the Cognitive Reserve Index (CRI), to brain network topology quantified by the Small-World (SW) index derived from resting-state EEG recordings. SW differences were first examined between age groups and then within each age group according to CRI levels, across EEG frequency bands (Delta, Theta, Alpha 1, Alpha 2, Beta 1, Beta 2, Gamma). RESULTS:The analysis of SW values showed distinct patterns between groups. Adults exhibited significant higher SW values in Delta and Theta bands, but lower values in Alpha 2 compared to Elderly. Within Elderly, higher CRI correlated with greater SW values in Delta, Beta 2, and Gamma bands, and marginally significant lower Alpha 2 values. DISCUSSION:Similar Mini-Mental State Examination (MMSE) scores across groups suggest these differences may reflect compensatory mechanisms, highlighting CR's potential role in preserving cognitive efficiency and resilience during aging. In line with the cognitive reserve framework, these findings provide supportive-though indirect-evidence that individual differences in CR are associated with distinct patterns of brain network organization during healthy aging. Overall, this study highlights the potential relevance of large-scale neural network dynamics as markers of adaptive brain functioning in later life, while underscoring the noncausal and exploratory nature of these associations.

Understanding age-related neurophysiological changes is crucial for identifying brain aging biomarkers and developing strategies against motor and cognitive decline. To explore aging-related patterns across multiple domains, this study assessed motor and cognitive performance, functional connectivity, and synaptic organization in Young (4 months), Adult (14 months), and Old (24 months) mice. Adult mice exhibited reduced locomotor activity (-50.3%) and forelimb force (-38.3%) compared to Young mice, while Old mice showed decline in spatial (-30.4%) and recognition memory (-40.3%). Golgi-Cox staining revealed region-specific changes in spine density, including an increase in motor cortex layer II/III pyramidal neurons in Old versus Adult mice and reductions in the medial prefrontal cortex and CA1 hippocampal region. Immunofluorescence analysis indicated age-related alterations in VGLUT and VGAT expression across brain regions. Local field potential recordings revealed no significant changes in functional connectivity across age groups. Integration of behavioral and electrophysiological features using machine learning for an exploratory yielded a classification accuracy of 0.798. Although this represented only a modest and non-significant improvement over behavioral features alone, the highest pairwise discrimination was observed between Adult and Old mice (AUC = 0.861). Overall, these findings provide a multilevel descriptive analysis of brain aging, highlighting distinct behavioral and structural alterations alongside preserved functional connectivity.

BACKGROUND:Mild cognitive impairment (MCI) is an intermediate stage between normal and pathological brain aging, with 30% to 50% progressing to dementia within 3 to 5 years. Early identification of individuals at high risk of progression is crucial for public health strategies. METHODS:The INTERCEPTOR project included 398 MCI individuals. Baseline assessment included harmonized procedures for sociodemographic, clinical, neuropsychological, genetic (apolipoprotein E), cerebrospinal fluid (amyloid beta tau), electroencephalogram (brain connectivity), magnetic resonance imaging (hippocampal volumetry), and fluorodeoxyglucose positron emission tomography. The baseline and follow-up were completed by 351 individuals with MCI with neuropsychological tests every 6 months for 3 years. RESULTS:Dementia developed in 104 individuals (29.6%), including 85 (22.4%) who met core clinical criteria for probable and possible Alzheimer's disease dementia. A Cox model combining clinical and sociodemographic data achieved a concordance index of 72%, which increased to 82% when neuropsychology and biomarkers were added. DISCUSSION:The INTERCEPTOR nomogram represents a tool for predicting dementia progression risk, supporting public health strategies, including screening for risk assessment and risk/benefit ratio in innovative treatments.

Background Understanding the neural organization underlying motor function is essential for explaining individual differences in motor performance and the impact of aging.Methods We examined 87 healthy older adults who underwent, in different sessions, resting state electroencephalography (EEG) recordings and Transcranial Magnetic Stimulation (TMS) applied to the hand muscles representation area in the primary motor cortex to elicit Motor Evoked Potentials (MEPs). Furthermore, Mini-Mental State Examination (MMSE) and handgrip strength evaluations were carried out on subjects. Subjects were split into two groups, Low MEP (L-MEP) and High MEP (H-MEP) groups, based on individual MEP amplitude, and age, sex, and education matched. Functional connectivity was analyzed through Magnitude-Squared Coherence (MSCoh) and Total Coherence (TotCoh) in different frequency bands and brain regions of interest.Findings The L-MEP presented decreased MSCoh in the Alpha 2 and Beta 1 bands, and decreased TotCoh in the Alpha 2 band within the Temporal region as well as in the Beta 1 band across Parietal, Occipital, and Temporal regions. No significant difference in grip strength was found while the MMSE score of L-MEP group was significantly lower compared to the H-MEP one. These findings indicate that reduced motor cortex excitability reflects decreased network integration, particularly in regions associated with cognitive and sensorimotor processing. These findings may reflect early neurophysiological vulnerability.Conclusions These results underscore the resting state EEG as a non-invasive, highly sensitive tool monitoring subtle alterations in brain functional networks that may precede clinical symptoms, offering a powerful tool for monitoring and individualized intervention.

Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice is a great challenge, especially during early disease stages with subtle or mild symptoms of cognitive decline. Moreover, robust and more accessible blood-based screening tests for early diagnosis are needed. In this study, we investigated the core AD blood biomarkers — amyloid beta 42 (Aβ42) and 40 (Aβ40) peptides, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-Tau) — and extracellular vesicle (EVs) size and concentration in individuals characterized by different stages of cognitive decline to identify biochemical markers of dementia for early diagnosis. A total of n = 800 human plasma samples were analyzed. Plasma levels of NfL, t-Tau, p-Tau181, Aβ42, Aβ40 and plasma EVs were evaluated in n = 217 elderly healthy subjects (CTRL), in individuals with subjective cognitive complaints (SCC, n = 48), pre-mild cognitive impairment (pre-MCI, n = 58) and mild cognitive impairment (MCI, n = 426), and in n = 51 probable AD dementia patients (AD-dem), using ultrasensitive Single Molecule Array technology (Simoa®) and nanoparticle tracking analysis (NTA). Logistic regression and Receiver Operating Characteristic (ROC) analyses were employed. Plasma NfL displayed increased levels in AD-dem and MCI patients, while p-Tau181, Aβ42/Aβ40 ratio, Aβ42/p-Tau181 ratio, and EVs plasma levels were altered since the early stages of the pathology: in particular, p-Tau181 levels increased as cognitive symptoms worsened, already in the SCC and pre-MCI groups compared to CTRL, while the ratio of EVs concentration and size (EVs ratio) was decreased in all groups compared to CTRL. Plasma p-Tau181 best classified AD-dem patients from CTRL with an area under the curve (AUC) equal to 0.87, while EVs ratio best differentiated SCC from CTRL (AUC = 0.78). Combining p-Tau181 and EVs ratio with Aβ42/Aβ40 ratio and NfL, respectively, significantly improved the classification of pre-MCI and MCI from CTRL (AUCcomb = 0.79 and AUCcomb = 0.85). Combining biomarkers did not improve accuracy in discriminating MCI from SCC, pre-MCI and AD-dem. p-Tau181 and EVs ratio are promising biomarkers for the identification of individuals at risk of degenerative dementia. Combining the core AD plasma biomarkers with EVs ratio can aid in diagnosing the early stages of AD dementia.

Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease-like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease-related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease-like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using the Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e. vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the second thermal stress but was impaired after the seventh thermal stress, with reduced forelimb force and increased foot faults starting from the fourth reactivation. Following the seventh reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.

Assessing quality of life (QOL) in end-of-life patients is vital for understanding the complex impacts of terminal illnesses on individual well-being. This study aims to compare two widely used QOL assessment tools: the Karnofsky Performance Status Scale (KPSS) and the Short-Form-36 (SF-36) Health Survey among patients with late-stage diseases. KPSS, a clinician-rated scale measuring functional capacity, provides an objective perspective on a patient's clinical status. Conversely, the SF-36 offers a patient-reported overview across eight dimensions, including physical and mental health. The study enrolled 68 patients with an average Karnofsky score of about 37. Results demonstrate a significant interaction between Karnofsky scores and SF-36 dimensions, indicating that patients with higher Karnofsky scores reported better physical, social, and emotional functioning. Strong positive correlations were found between high Karnofsky scores and specific SF-36 components, including Physical Functioning, Role Physical, and Social Functioning, suggesting that these aspects critically influence overall QOL. Notably, no correlation was identified between age and KPSS, highlighting that disease severity rather than age impacts QOL. Findings underscore the complementary roles of KPSS and SF-36 in assessing QOL in terminally ill patients; while some measures in SF-36 aligned closely with KPSS, others offered essential insights into patient experiences. This comprehensive approach emphasizes the need for robust QOL evaluations in palliative care, facilitating more patient-centered care aligned with individuals' values and needs.

Stroke is a leading cause of adult disability, with outcomes depending on the lesion's location and severity. While motor and language deficits are common, rare manifestations like central auditory dysfunction can be equally debilitating. This case report presents a 57-year-old woman who developed acute bilateral central deafness following a cardioembolic ischemic stroke. To investigate underlying mechanisms, advanced EEG analyses were conducted, including spectral power analysis and eLORETA-based functional connectivity, across key frequency bands. The Small World index was applied to evaluate changes in brain network organization over 6 weeks. Results revealed disrupted connectivity in bilateral auditory and associative cortices, with significant spectral power alterations. Alpha and gamma bands showed distinct recovery dynamics, while connectivity metrics indicated a shift toward global integration, possibly compensating for local disconnections. These findings demonstrate the utility of EEG biomarkers in monitoring post-stroke neural reorganization and support their potential role in guiding rehabilitation for sensory deficits.