BACKGROUND:Physical Training (PT), defined a planned, structured, and long-term exercise intervention, is recognized as an important non-pharmacological therapy in Parkinson's disease (PD). Beyond its symptomatic benefits, experimental evidence suggests that PT may also modulate pathological mechanisms involved in dopaminergic neurodegeneration. This systematic review summarizes the neurobiological and neurophysiological adaptations induced by PT in animal models of PD and in patients with PD, and proposes mechanistically driven recommendations for personalized exercise prescription. SUMMARY:MEDLINE and Web of Science were searched from January 1, 1974, to April 3, 2026. The PRISMA 2020 guidelines were followed, and two reviewers independently screened titles and abstracts to identify studies that reporting neurobiological or neurophysiological effects of PT performed for at least 4 weeks, in both animal models of PD or in patients with PD. Risk of bias were assessed using validated tools for animal studies (SYRCLE), and for randomized (RoB 2) or non-randomized controlled trials (ROBINS-I) in humans. A total of 78 studies were included, comprising 55 animal studies and 23 studies in patients with PD. In parkinsonian animals, PT consisted mainly of forced treadmill training, performed 20-60 min/day, 5 days/week, typically for 4 weeks. PT reduced oxidative stress and mitochondrial dysfunction, enhanced antioxidant defences, and regulated mitochondrial dynamics. Exercise also decreased α-synuclein accumulation, attenuated neuroinflammation, and increased neurotrophic factor expression. These adaptations promoted synaptic plasticity, neurogenesis, and preservation of nigrostriatal dopaminergic neurons. In patients with PD, aerobic training (AT), resistance training (RT) and balance training (BT) have been tested, and multimodal interventions have been investigated, most commonly involving 120-150 min/week for 6-12 weeks, sometimes combined with virtual reality or exergaming. PT induced structural and functional adaptations across the brain-muscle axis, including modulation of dopaminergic signalling, reorganization of cortico-striatal and cerebellar connectivity, improved cortical inhibitory control, enhanced corticospinal drive, and neuromuscular remodelling. AT mainly improved fatigability and cardiorespiratory fitness, whereas RT and BT appear to preferentially enhance muscle strength, rate of force development, gait automaticity, and balance control. KEY MESSAGES:Current evidence indicates that PT acts as a multimodal intervention capable of inducing adaptations ranging from molecular pathways to large-scale motor networks in PD. These findings support the implementation of personalized multimodal programmes combining AT, RT and BT, with progressive intensity and long-term adherence. Future studies should better define dose-response relationships, identify biomarkers of responsiveness, and determine whether exercise may exert disease-modifying effects on PD.
BACKGROUND:Lewy body dementia (LBD) is characterized by pervasive cognitive, motor, and neuropsychiatric symptoms. Although cognitive decline has traditionally shaped staging and prognosis, accumulating evidence indicates that gait and postural disturbances follow partially independent trajectories and may remain preserved even as cognition deteriorates. These observations challenge conventional assumptions about late-stage decline and suggest that locomotor function may complement cognitive measures when assessing late-stage transition in LBD. SUMMARY:This review synthesizes current evidence on gait disturbances across the LBD spectrum and their neural substrates, in comparison with Alzheimer's disease (AD) and Parkinson's disease (PD). Gait impairment in LBD arises from distributed network dysfunction involving dopaminergic and cholinergic pathways, fronto-striatal, parietal, and cerebellar contributions, resulting in greater gait variability, reduced automaticity, and heightened dual-task costs relative to AD and PD. Despite this vulnerability, preserved procedural memory, brainstem locomotor circuits, and cerebellar-cortical compensation may allow walking to persist longer than cognition in some individuals. In advanced disease, rapid gait deterioration has been described near the end of life, suggesting that gait trajectories may capture aspects of late-stage decline that cognitive measures, affected by fluctuations and attentional instability, may not reliably reflect. KEY MESSAGES:-Gait and cognition do not decline in parallel in LBD; in some individuals, walking may outlast cognitive abilities.-Gait disturbances reflect distributed network dysfunction rather than isolated motor system degeneration.-In late stages, gait performance may offer a clinically useful indicator of disease transition when cognitive testing becomes less reliable. -Integrating gait assessment into clinical evaluation may enhance prognostication and support palliative care planning in LBD.
INTRODUCTION:The current diagnosis of Alzheimer's disease (AD) is shaped by the Alzheimer's Association (AA) and the International Working Group (IWG) criteria. While both frameworks lead to similar physician-patient conversations when disclosing biomarker results to patients with cognitive impairment, they diverge significantly for cognitively unimpaired individuals. The aim of this paper is to explore these differences and their associated epistemological and ethical implications, through simulated, case-based physician-patient conversations. METHODS:The conversations were developed on the basis of clinical experience, exchanges with patients and carers, insights from a targeted narrative literature review and were subsequently refined with large language model assistance. RESULTS:Our analysis highlights that the AA framework reinforces a deterministic narrative by equating amyloid biomarker positivity with disease and raising a misunderstanding of illness. In contrast, the IWG framework is consistent with the incomplete penetrance of AD pathology and frames biomarker positivity in cognitively unimpaired individuals as a risk condition. We acknowledge that the IWG framework enables more complex but also more realistic physician-patient conversations. CONCLUSION:Physician-patient conversations employing a carefully selected lexicon, reflecting patient-centred outcomes, may promote patient engagement, compliance with medical recommendations, and, ultimately, societal trust in medicine and physicians.
BACKGROUND:Hearing impairment has emerged as a consistently associated and potentially modifiable risk factor for cognitive decline and dementia, including Alzheimer's disease (AD). Epidemiological studies demonstrate an increased dementia risk among individuals with hearing loss, with evidence of dose-response relationships across levels of auditory decline. Despite the robustness of this association, the mechanisms linking auditory dysfunction to cognitive deterioration remain multifactorial and incompletely understood. SUMMARY:By integrating biological, cognitive, and psychosocial perspectives while explicitly addressing persistent uncertainties, this critical narrative review provides a balanced framework for interpreting the relationship between hearing impairment and AD. Current evidence points to several interacting pathways, including sensory deprivation, cortical reorganization, increased cognitive load, and psychosocial consequences like social isolation. Furthermore, emerging research suggests that central auditory processing deficits may represent early functional markers of cortical vulnerability associated with neurodegeneration. Clinically, these insights emphasize the importance of routine hearing assessment in older adults, while observational evidence indicates that hearing rehabilitation, particularly hearing aid use, may be associated with more favorable cognitive outcomes. KEY MESSAGES:Association vs. causation: hearing loss should be regarded as a robustly associated and potentially modifiable marker of dementia risk rather than a confirmed causal determinant. Neurological implication: from a neurological standpoint, central auditory dysfunction may reflect underlying brain vulnerability in aging rather than acting as a direct causal driver of AD. Clinical outlook: while causal effects of hearing rehabilitation have yet to be firmly established, prioritizing hearing health offers a promising and practical avenue for dementia prevention and clinical practice.
INTRODUCTION:Elders with essential tremor (ET) are at a heightened risk for incident dementia. Although the consequences of this diagnosis are formidable, we know little about what factors elevate the risk of ET-dementia. We analyzed data from a large, prospective, longitudinal study of cognitive status in an ET cohort to examine whether a range of demographic, lifestyle, and clinical variables contribute to dementia risk. METHODS:The cognitive status (normal cognition [NC], mild cognitive impairment [MCI], or dementia) of a baseline sample of 350 ET cases (M age = 79.5 years) was tracked for up to 7.5 years (M follow-up = 4.7 years). Cox proportional hazards regressions identified baseline characteristics that predicted the development of dementia. RESULTS:Older age and greater cognitive impairment at baseline (MCI versus NC) each predicted incident dementia, HR > 1.10, p < 0.0001. Diminished functional abilities (HR = 0.39), greater gait impairment (HR = 1.30), lower confidence in one's balance skills (HR = 0.98), and more depressive symptoms at baseline (HR = 1.08) further predicted conversion to dementia, all p < 0.006. Neither continuous nor categorical measures of ET onset age predicted incident ET-dementia. CONCLUSIONS:These data represent the most comprehensive assessment to date of risk factors for ET-dementia in terms of number of factors studied and cohort size. At least one of these risk factors - depression - is modifiable and may offer intervention points to reduce risk of dementia. Older age of ET onset, previously viewed as a risk factor, did not predict incident ET-dementia.
Introduction: Neurocognitive disorders (NCD) are frequently accompanied by motor impairments that may precede overt cognitive decline. However, most motor markers remain coarse and do not disentangle global motor deterioration from disruptions of specific motor control processes. Motor planning, a process relying on both motor and cognitive resources, may be particularly vulnerable to cognitive impairment yet has rarely been investigated using process-specific motor control frameworks. Methods: We assessed motor planning abilities in 57 older adults, including cognitively impaired (CI; n = 27) and healthy adult (HA; n = 30) participants. Using a gravity-related motor planning paradigm, participants performed vertical arm movements requiring different interactions with gravitational torque. Directional asymmetries in movement kinematics were used as a process-specific proxy of motor planning. Movement smoothness was quantified using jerk-based measures as a complementary index of global motor execution. Movement duration was carefully controlled across groups and directions, and age effects were accounted for in the analyses. Results: Movement duration did not differ between groups. Compared with HA participants, the CI group exhibited reduced directional asymmetries, indicating altered motor planning. Within the CI group, the magnitude of directional asymmetries was positively correlated with cognitive status, as assessed by the Mini-Mental State Examination. In contrast, although movement smoothness was globally reduced in CI participants, jerk-based measures were not associated with cognitive status after controlling for age and movement duration. Conclusion: These findings suggest that cognitive impairment in older adults is specifically associated with a disruption of motor planning processes rather than a uniform degradation of motor execution. By dissociating global motor deterioration from planning-related decompensation, this study highlights the value of process-specific motor control measures for understanding sensorimotor alterations in NCD and their potential relevance for early detection.
Background: The blood-brain barrier (BBB) is a specialized multicellular interface that maintains the central nervous system’s tightly regulated microenvironment. BBB disruption is increasingly recognized as a key feature of neurodegeneration, documented across disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), and cerebral small vessel disease (cSVD). While the extent to which BBB breakdown is a cause or consequence of neuronal pathology remains unclear, its pronounced presence in disease states suggests a significant contributory role in progression. Summary: This review provides a neuroradiological overview of advanced MRI approaches for assessing BBB integrity in neurodegenerative diseases. The primary quantitative biomarkers discussed are the volume transfer constant (Ktrans) derived from dynamic contrast-enhanced MRI (DCE), reflecting paracellular gadolinium leakage, and the water exchange rate (kw) from arterial spin labeling (ASL), capturing trans-endothelial water permeability. Disease-specific BBB signatures across AD, PD, and cSVD are systematically described, alongside complementary indirect markers including diffusion MRI, dynamic susceptibility contrast, and vessel architecture imaging. Current technological advances, including ultra-high-field MRI and AI-assisted post-processing, are discussed in relation to their potential to enhance detection sensitivity. With continued technical refinement and standardization, MRI-based BBB metrics are transitioning from research tools into candidate neurovascular biomarkers with growing potential for early diagnosis, treatment monitoring, and longitudinal follow-up. Key Messages: MRI-based BBB imaging represents an emerging neurovascular biomarker under active investigation for future diagnostic and therapeutic applications. DCE and ASL provide complementary BBB metrics (Ktrans, kw), illuminating distinct and complementary facets of barrier dysfunction. BBB disruption is a key and early feature across AD, PD, and cSVD, with disease-specific regional patterns that may guide patient stratification and therapeutic monitoring. Ultra-high-field MRI and AI-assisted post-processing are advancing BBB imaging sensitivity; however, multicenter standardization and normative validation remain critical prerequisites for clinical translation.
Background: Effective screening and cohort enrichment remain major challenges in clinical trials for Alzheimer’s disease (AD), where traditional diagnostic pathways rely on costly, invasive, and time-consuming procedures. Speech and language analysis has emerged as a scalable, low-burden approach for detecting subtle cognitive-linguistic and motor-speech changes that may appear early in the disease course. Summary: This review synthesizes current evidence on acoustic, prosodic, lexical, semantic, and syntactic speech features associated with AD and mild cognitive impairment (MCI) and evaluates their reported utility across a range of elicitation tasks including picture description, verbal fluency, narrative recall, spontaneous speech, and reading. Across studies, machine-learning models trained on speech and language features have reported consistent performance, although results vary substantially depending on task design, feature sets, and cohort characteristics. Task-dependent variability is evident, with picture description and verbal fluency tasks capturing lexical-semantic and timing markers, while narrative and spontaneous speech tasks capture impairments in coherence, information content, and prosody. Hybrid approaches integrating hand-crafted and machine-extracted features have also been explored to improve interpretability and model performance. Speech and language analytics may support digital prescreening, cohort enrichment, and quality-assurance monitoring within clinical trials; however, their application depends on methodological considerations and validation across diverse settings. Key Messages: Despite encouraging findings, several methodological challenges persist, including interindividual variability, limited dataset sizes, differences in recording conditions, and limitations in automatic speech recognition performance in cognitively impaired populations. Continued development of standardized protocols, disorder-adapted speech models, and multimodal analytic pipelines is needed to support clinical translation. Collectively, current evidence suggests that speech and language features represent candidate digital markers that may improve screening efficiency and support clinical trial enrichment in AD, although further validation is required to establish their reliability and generalizability.
Introduction: Mild behavioral impairment (MBI) is a late-life neurobehavioral syndrome associated with increased risk of incident cognitive decline and dementia. Facial emotion recognition (FER), a core component of social cognition, is impaired across neurodegenerative disorders, yet its association with MBI remains underexplored. We examined cognitive/socio-emotional profiles and resting-state electroencephalogram (EEG) in individuals with MBI. Methods: A total of 120 older adults with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) were classified into MBI (n = 57) and non-MBI (n = 63) using the MBI Checklist. Participants underwent comprehensive clinical and neuropsychological evaluation and neuropsychological assessments including Mini-Mental State Examination (MMSE) and the Korean Facial Affect Battery (K-FAB subtests 1-5). Resting-state EEG was analyzed using an automated platform to derive sensor-level spectral power and source-level connectivity measures. Group comparisons used appropriate tests; K-FAB analyses were adjusted for age, education, MMSE, and Geriatric Depression Scale (GDS). Results: The MBI group showed greater functional impairment (higher CDR-SOB, p = 0.019) and higher depressive symptom severity (GDS, p = 0.004), with a trend toward fewer years of education (p = 0.090). Neuropsychological domain scores were broadly comparable, although the MBI group showed a trend toward lower frontal executive composite performance after covariate adjustment (p = 0.076). On K-FAB, the MBI group demonstrated significantly poorer affect selection performance (FAB4; adjusted p = 0.031), with additional trend-level differences in affect naming (FAB3; adjusted p = 0.084) and in negative emotion recognition (fear and sadness). Resting-state EEG findings indicated elevated Beta1-3 and gamma absolute power in the MBI group across multiple scalp regions (p < 0.05), as well as frequency-specific source connectivity differences, including widespread delta band hyperconnectivity, relatively stronger Alpha1 connectivity in the non-MBI group, and increased Beta1 connectivity within fronto-parietal and fronto-temporal circuits in the MBI group. Conclusion: In this clinic-based SCD/MCI cohort, MBI was associated with greater functional impairment and depressive symptom burden, selective FER deficits - particularly in affect selection - and distinct resting-state EEG spectral and connectivity patterns. These findings suggest that socio-emotional measures and EEG markers may provide complementary information for characterizing neurobehavioral alterations associated with MBI, although interpretations should remain cautious given the cross-sectional design and methodological constraints of automated EEG analyses.
