Conventional rehabilitation effectively manages physical impairments in Parkinson’s disease (PD), but reduced motivation limits long-term adherence. Immersive gamification technology systems (ImGTS) offer an engaging, safe, and potentially effective approach to improve physical function. However, the scope and characteristics of current evidence remain unclear. This scoping review mapped the literature on the effects of ImGTS on physical function in people with PD. A Boolean search of six databases was conducted in March 2025, supplemented by backward snowballing, to identify all eligible English-language studies indexed up to the date of the search that involved people with PD and evaluated ImGTS for physical function outcomes. Data on study characteristics, population, intervention, comparison, outcomes, and key findings were charted using a standardized form. Screening, data charting, and methodological quality assessment were conducted independently by five reviewers, with disagreements resolved through consensus. Findings were synthesized narratively with descriptive statistics. Twenty-nine studies were included: randomized controlled trials (n = 10, 34.5
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Although its global burden is rising, PD remains underrecognized in low- and middle-income countries like the Philippines, where access to diagnosis, treatment, and support systems is limited. This research addresses the gap between clinical outcomes and the realities of patient care, thereby enabling the development of healthcare policies and the enhancement of healthcare delivery that meet the needs of both patients and caregivers. This study aims to explore the lived experiences of PD patients and their caregivers in Cebu Province, Philippines. A phenomenological qualitative design was employed. Data were gathered through structured and unstructured interviews and focus group discussions (FGDs) conducted during a Parkinson’s Awareness event in April 2025. A total of 43 patients (mean age: 66.7 years, mostly male) and 32 caregivers (mean age: 53.8 years, mostly female) participated. Caregivers included family members/relatives and paid hired caregivers who provided ongoing assistance to persons living with Parkinson’s disease. Given their differing relationships to the patient and care responsibilities, caregiver accounts were interpreted within this heterogeneous caregiving context. Thematic analysis, which was conducted manually, was guided by the constant comparative method and a standardized codebook. Five major themes emerged: (1) Acceptance and emotional adjustment to diagnosis; (2) Navigating treatment and healthcare systems; (3) Daily and emotional challenges; (4) Shifting family dynamics and caregiving roles; and (5) Limited community and institutional support. Filipino cultural values (hiya, kapwa, and pakikisama) significantly shaped caregiving responses and help-seeking behaviors. PD care in the Philippines is marked by psychological burden, caregiver strain, and systemic healthcare gaps. Culturally sensitive, multidisciplinary approaches are urgently needed, including expanded caregiver support, mental health services, and improved access to specialized care. MeSH Terms: Parkinson’s Disease, caregivers, qualitative research, Philippines, Health Services Accessibility, family, caregiver burden, cultural constructs, social support, activities of daily living, quality of life.
Diagnosis of Parkinson’s disease (PD) remains a major clinical challenge, particularly in the prodromal and early clinically evident stages, when symptoms are subtle and phenotypically overlap with other mimicking disorders. The widespread availability of smartphones equipped with inertial, acoustic, touchscreen, and geolocation sensors has enabled the emergence of smartphone-based digital biomarkers that capture continuous, real-world motor and non-motor manifestations of PD. To critically review the validation state, construct validity, clinical applications, and potential for longitudinal monitoring of smartphone-derived digital biomarkers for early PD detection and for differential diagnosis from mimicking disorders, while addressing methodological, regulatory, and implementation challenges. This manuscript reviews the current evidence on smartphone-based active and passive digital assessments for the early diagnosis and screening of PD. We examine clinical validation and implementation, as well as advances in technological processing, multimodal digital phenotyping, and machine learning models, for the early detection and screening of PD. Smartphone-derived digital markers demonstrate promising capability for detecting several symptoms and support early diagnosis of PD. A total of 30 studies showed significant correlations of such markers with established clinical scales and suggested utility in differentiating PD from other Parkinsonian syndromes and prodromal PD patients. Six major categories based on the clinical assessment were identified: 8 studies with voice-based assessment, 6 with touchscreen-based assessment, 4 with video-recording assessment, 4 with inertial measurement unit-based assessment, 7 with multimodal assessment approaches, and 1 with questionnaire-based smartphone assessment. However, substantial limitations persist, including device and protocol heterogeneity, limited external validation, small datasets, algorithmic bias, inadequate explainability, and inconsistent reporting standards. Smartphone-based digital biomarkers offer a promising approach to improving diagnostic accuracy in PD and are emerging as a frontier in precision neurology and scalable PD care. However, these findings have several limitations and should be interpreted with caution. Future research should prioritise multicentre longitudinal validation, multimodal integration, explainable AI, and real-world deployment to establish clinically actionable digital biomarkers for early PD detection and differential diagnosis.
Reduced serum uric acid (UA) has been identified as a risk factor for Parkinson’s disease (PD), prompting investigation into its relevance in atypical Parkinsonism (AP). Serum UA levels were measured in a prospective Caribbean cohort (ClinicalTrials.gov: NCT03368300, 03/08/2012) comprising patients with PD (n = 90), AP (n = 167), and healthy controls (n = 124), and associations with clinical variables were assessed. Serum UA levels were significantly lower in patients with PD and AP than in controls (p = 0.004). Across the entire cohort, patients with low UA levels had higher adjusted odds of poor neuropsychological performance, defined as Mini-Mental State Examination score < 24 (OR = 4.7), Mattis Dementia Rating Scale score < 137 (OR = 2.97), and Frontal Assessment Battery score < 13 (OR = 2.79). Survival analyses also revealed significant differences across sex-specific UA tertiles (p = 0.044). In AP, low and intermediate UA levels were associated with higher mortality (p = 0.035). Lower serum UA levels, however, were not associated with overall disease severity or functional dependence. Our findings provide further evidence supporting the relevance of UA to the pathogenesis of neurodegenerative parkinsonism. They may also offer opportunities for risk stratification and the investigation of UA-related interventions in patients with Caribbean parkinsonism.
Stressful life events are major precipitants of depressive episodes, yet their effects vary across individuals. Childhood trauma is a well-established vulnerability factor that may increase sensitivity to subsequent stress. However, the neural correlates of this interaction in major depressive disorder (MDD) remain poorly characterized. This study investigated whether childhood trauma moderates the association between recent stress exposure and brain structure and functional connectivity in MDD. Structural magnetic resonance imaging (MRI) data were obtained from 130 inpatients with MDD; resting-state functional MRI data were available for a subsample (n = 97). Whole-brain cortical thickness and surface-based functional connectivity measures, including global correlation (GCOR) and local correlation (LCOR), were examined to test interaction effects between childhood trauma and recent stress exposure. A significant interaction between childhood trauma and recent stress was observed in medial prefrontal regions, including the anterior cingulate cortex, where greater stress exposure was associated with reduced cortical thickness at higher levels of early adversity. Convergent interaction effects were also observed at the functional level, with greater recent stress associated with lower LCOR in the left superior frontal gyrus and precuneus at higher levels of childhood trauma. No interaction effects were observed for GCOR. Analyses of specific trauma dimensions indicated partially distinct effects of abuse and neglect. Childhood trauma moderated the association between recent stress exposure and structural and functional brain measures in MDD, particularly within prefrontal regulatory regions. These multimodal findings are consistent with stress sensitization models and suggest that early adversity may contribute to heterogeneity in neural correlates of stress in depression.
Behavioral disinhibition is a core feature of behavioral variant frontotemporal dementia (bvFTD) and occurs across related FTD-spectrum presentations. Serotonergic dysfunction may contribute to behavioral dysregulation; therefore, we primarily examined dorsal raphe (DR)-centered midbrain ¹²³I-FP-CIT uptake as an indirect extrastriatal signal that may partly reflect serotonin transporter-related binding. Because striatal dopaminergic circuits support reward learning, behavioral inhibition, and context-dependent behavioral updating, striatal uptake was examined exploratorily. This retrospective exploratory study included 21 patients within the FTD spectrum who underwent Neuropsychiatric Inventory (NPI) assessment, magnetic resonance imaging, and ¹²³I-FP-CIT single-photon emission computed tomography within a 3-month window. The primary outcome was the NPI disinhibition score. DR-centered midbrain and striatal specific uptake ratios (SURs) were calculated using the cerebellum as the reference region. Age- and sex-adjusted quasi-Poisson models with a log link were fitted. DR-centered midbrain SUR was not significantly associated with disinhibition in the primary model (β = −1.027, p = 0.353). In the exploratory model, higher striatal SUR was nominally associated with lower disinhibition scores (β = −0.438, p = 0.022). The negative direction of the striatal association was generally preserved across sensitivity analyses, although nominal significance was not retained in all models. DR-centered midbrain SUR was not significantly associated with behavioral disinhibition in this small FTD-spectrum cohort. Lower striatal SUR showed a directionally consistent but sensitivity-dependent nominal association with greater disinhibition. This hypothesis-generating finding may reflect broader frontostriatal disease burden, striatal neurodegeneration, parkinsonian-spectrum overlap, or partial-volume effects and does not establish a disinhibition-specific dopaminergic mechanism.
Although quetiapine is increasingly used off-label in children and adolescents with various psychiatric disorders, there is little evidence on the relationship between quetiapine dose and serum concentration, and therapeutic reference ranges (TRR) have not yet been established for this age group. The aim of this study was to evaluate whether the TRR described for adults is applicable to minors. In addition, the study aimed to investigate the relationship between the daily dose, serum concentration and clinical outcome. The clinical course of 77 patients (females = 78
Posttraumatic stress disorder (PTSD) is associated with symptoms of intrusive memories, avoidance, and hyperarousal. Accumulated evidence shows that these symptoms are related to changes in brain areas involved in memory and emotion. The purpose of this paper was to review functional brain imaging studies in PTSD. Pubmed, midline, and psych info were queried for keywords related to PTSD and brain imaging from 1990–2024. The review focused on functional brain imaging using Positron Emission Tomography (PET), single photon emission tomography (SPECT) and functional magnetic resonance imaging (fMRI) and did not include structural or spectroscopic imaging. Studies implicated a network of brain regions involved in memory and emotion including the amygdala, insula, prefrontal cortex, cingulate gyrus and hippocampus. PTSD is associated with alterations in function in brain areas mediating memory and emotion.
Tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of serotonin synthesis in the CNS, has been associated with numerous behavioural traits and psychiatric disorders. Tph2 modified mice present altered sensitivity to stress, and excessively aggressive behaviour that develops even in female animals. We have measured histochemically the activity of cytochrome c oxidase (COX) in 106 brain regions in wildtype, Tph2 heterozygous and total knockout male and female mice (n=78). In addition to direct comparisons by sex and genotype, COX activity co-variation in putative aggression networks was examined. Overall, female mice have higher COX activity than males. In regions affected by Tph2 inactivation a consistent pattern emerged, where Tph2± mice had the lowest, Tph2−/− mice had the highest COX activities, and Tph2+/+ in-between. Tph2 inactivation induced broad changes and an extensive reorganisation of neural activity as revealed by regional activity co-variation matrices of COX. These patterns of inter-regional correlations differed between sexes. Co-variation of COX activity also differed between males and females in the proposed networks for aggressiveness. In male mice, Tph2 inactivation disrupted co-variation of COX activity of the dorsal raphe and the periaqueductal grey matter with limbic regions. The septum appears as a hub of altered connectivity in females but not in males. Serotonin deficiency is associated with altered regional neural activity patterns as revealed by COX histochemistry. These alterations are profoundly different in male and female mice, and suggest that serotonin plays a partly sex-dependent role in the regulation of behaviour.
Cerebellar ataxia is characterized by incoordination and decomposition of movements, manifesting as gait instability, limb incoordination, oculomotor dysfunction, and scanning dysarthria. Ataxias may be acquired or genetic. Currently, there is a paucity of published data among Filipinos. Herein, we review the etiologies of ataxia published in the literature and discuss the current state of ataxia work-up and management in the Philippines. A literature search was conducted in March 2026 using the search terms: ataxia OR cerebellar oculomotor abnormality OR scanning speech AND ((Philippines[Affiliation]) OR Filipino OR Philippines) in PubMed, Google Scholar, and in a local research index (Health Research and Development Information Network [HeRDIN]). The search yielded 42 unique articles, most of which were case reports/case series, and a few were part of large cohorts. Acquired ataxias were limited to case reports of autoimmune, toxic, infectious, post-infectious, prion-related, and degenerative causes. Case series of genetic forms of ataxias were mostly the autosomal dominant forms (SCA2, SCA7, SCA13, and SCA27A), with some autosomal recessive forms AVED, ataxia-telangiectasia, Wilson disease, two neurodevelopmental syndromes (ZMYND11-related syndromic intellectual disability, Angelman syndrome), and one mitochondrial ataxia (MERRF). The low number of published cases was likely due to under-recognition or underreporting, given the inaccessibility of workup in most areas outside large cities, the lack of local genetic testing services for confirmatory diagnosis, limited healthcare coverage for ataxias, and a lack of movement disorder neurologists/movement disorder centers. We highlight the absence of national‑level registries and limited access to advanced diagnostics, which likely contribute to substantial underrecognition and underreporting of ataxia in the Philippines. We have also proposed an algorithm for the diagnosis and management of ataxia in low-resource settings.
Prior studies have suggested that smoking, alcohol consumption, and living situation may be associated with poststroke mortality, but evidence on how these associations vary by age, sex, and stroke type remains limited. We examined associations of alcohol consumption, smoking, and living situation with 30-day case-fatality in hospitalised patients with ischaemic stroke or intracerebral haemorrhage, stratified by age, sex, and stroke type. This nationwide cohort study included stroke patients admitted between 2015 and 2023 from the Danish Stroke Registry. Thirty-day case-fatality was analysed using Kaplan–Meier and Cox regression stratified by stroke type, age, and sex, with multiple imputation for missing data. Among 94,668 patients (median age 73 years; IQR 64–81 years; 56
Parkinson’s disease (PD) has a long prodromal phase characterised by non-motor symptoms and subtle motor dysfunction, including changes in gait. While early gait abnormalities have been described in high‑risk populations, less is known about how real‑world gait behaviour changes prior to diagnosis in the general population. To investigate whether digital gait biomarkers derived from wrist‑worn sensors are associated with future Parkinson’s disease diagnosis. The study comprised 73,413 UK Biobank participants who wore a wrist-worn device for seven days. Seventeen digital gait biomarkers were derived using the Watch Walk algorithm. Participants were followed for up to 10 years through linked electronic health records, and associations with time to PD diagnosis were assessed using Cox regression models adjusted for age and sex. Of the 73,294 participants without PD at the accelerometry assessment, 314 were diagnosed with PD during follow-up. Compared with those who did not develop PD, those who did had lower daily step counts (6370 vs. 4043–5585 steps/day), with greater differences observed closer to diagnosis, as well as slower walking speeds, altered step regularity, and reduced arm swing at baseline (all p < 0.001). Across groups stratified by time to PD onset, five gait measures (daily step count, maximum walking speed, step regularity, proportion of long walking bouts, and time spent walking with static arm positions) were consistently associated with subsequent PD diagnosis (all p < 0.001). Differences in real‑world gait behaviour were observable years before PD diagnosis in this large population cohort. These findings suggest that digital gait biomarkers may help characterise early motor changes detectable up to 6.8 years before a clinical diagnosis of PD.
Parkinson's disease multidisciplinary complex therapy (PD-MCT) has emerged as an effective, standardized inpatient treatment approach in Germany that combines individualized pharmacological optimization with intensive, coordinated non-pharmacological interventions. This multimodal regimen has consistently been associated with improvements in both motor and non-motor symptoms, as well as patient-reported outcomes. Although its clinical benefits are increasingly recognized and a first randomized controlled trial is currently underway, a comprehensive appraisal of the structural framework underpinning PD-MCT delivery remains lacking. In this expert opinion, we aim to systematically summarize the current formal structural requirements defined by the German public reimbursement system as well as guidelines by relevant professional and societal networks. We outline key elements such as indication for treatment, coding criteria, minimum therapy intensities, and interdisciplinary team composition. Furthermore, we critically examine how these regulatory and organizational specifications translate into real-world care, including potential discrepancies between formal criteria and clinical practice. We assess the utility and role of PD-MCT within existing multidisciplinary and alternative treatment approaches in Germany and international settings. Finally, we discuss future directions to refine PD-MCT from a regulatory and health policy perspective, with the goal of enhancing accessibility, at-home preservation of treatment effects, and patient-centered outcomes.
Functional motor disorders (FMD) are common and disabling conditions, but objective biomarker changes following multidisciplinary management remain limited. Our objective was to investigate changes and responsiveness of multimodal biomarkers in individuals with FMD undergoing multidisciplinary management. 34 patients with clinically definite FMD (mean age 42.76 ± 11.01 years; 85.7
The neurobiology and pathological mechanisms underlying obsessive-compulsive symptoms have been explored in the literature for more than fifty years without reaching a definitive conclusion. What is clear is that some brain areas, including the basal ganglia and connected structures, have been implicated through several different approaches, including use of animal models and examination of human subjects with different cerebral lesions and pathologies. The purpose of this narrative review is to explore how examination of disorders affecting the basal ganglia can give insights into the pathophysiology of obsessive-compulsive symptoms and obsessive-compulsive disorder. These clinical conditions include Parkinson's disease, Huntington's disease, paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), Sydenham's chorea, and Tourette's syndrome. We review neuroimaging, genetic, and clinical studies in these conditions. Overall, the literature discussed supports the idea that the reward circuitry, including the limbic and lateral orbitofrontal loops of the basal ganglia, as well as goal-directed versus habitual pathways in the dorsal striatum, are involved in obsessive-compulsive disorder and obsessive-compulsive symptoms.
To describe and compare short-term motor fluctuation-related outcomes among ambulatory Filipino patients with Parkinson’s disease receiving dopamine replacement therapy alone or with add-on safinamide or amantadine. This single-center retrospective exploratory cohort study included adult Filipino patients with idiopathic Parkinson’s disease and motor fluctuations lasting > 1.5 h, excluding morning akinesia. Eligible patients had at least three follow-up clinic visits, were receiving dopamine replacement therapy, and had a stable Levodopa-equivalent dose for at least 4 weeks before screening. Patients were grouped according to physician-directed treatment received in routine clinical practice: dopamine replacement therapy alone, dopamine replacement therapy plus amantadine, or dopamine replacement therapy plus safinamide. Outcomes assessed after 8 weeks included change in ON time, Unified Parkinson’s Disease Rating Scale parts III and IV, and modified Hoehn and Yahr stage. Thirty patients were included, with 10 patients in each treatment group. Significant baseline differences were observed in age (p = 0.01), age at Parkinson’s disease onset (p = 0.02), baseline Unified Parkinson’s Disease Rating Scale part IV score (p = 0.04), and Levodopa-equivalent dose per day (p < 0.001). In unadjusted analyses, change in ON time and Unified Parkinson’s Disease Rating Scale part IV score differed significantly across groups, while Unified Parkinson’s Disease Rating Scale part III score and modified Hoehn and Yahr stage did not. In exploratory adjusted models, the group effect for ON time change was not statistically significant after adjustment for age (p = 0.052) and Levodopa-equivalent dose per day (p = 0.093), but remained significant after separate adjustment for age at Parkinson’s disease onset (p = 0.014) and disease duration (p = 0.008). Adverse events were reported in 16 patients (53
Parkinson's disease (PD) is the fastest growing neurological disorder worldwide and is projected to affect unprecedented numbers of individuals by 2050. At the same time, PD research is undergoing a profound conceptual transformation. Advances in molecular neuropathology, genetics, biomarker science, artificial intelligence, multimodal imaging, digital medicine, and precision therapeutics are reshaping PD from a clinically defined syndrome into a biologically measurable and potentially preventable process. This Perspective is not a report of new empirical findings and should not be read as an evidence-based forecast of what will most likely occur by 2050. Rather, it deliberately formulates a normative strategic vision: clinically manifest PD should become a preventable public-health burden. In this context, "eradication" does not imply elimination of all α-synuclein pathology, genetic susceptibility, or neurodegenerative biology. It refers to the long-term objective of preventing or substantially eliminating the transition to disabling, clinically manifest PD before irreversible symptomatic neurodegeneration occurs. We outline the prerequisites for such a future, including validated biological staging, risk stratification, longitudinal biomarker trajectories, trial enrichment, preventive endpoints, regulatory qualification, scalable implementation, and equitable global access. The analogy to poliomyelitis is used as a model of strategic goal-setting and international coordination, not as a biological equivalence between an infectious disease and a heterogeneous neurodegenerative disorder. Several enabling technologies already exist in early or research form, including α-synuclein seed amplification assays, genetic and prodromal risk models, digital monitoring, multimodal imaging, and mechanism-based therapeutic development. Other components remain aspirational and will require major scientific, regulatory, ethical, and societal advances. The central purpose of this article is therefore not to predict the future from the current trajectory, but to define a desired destination around which the field can organize scientific innovation.
"What's in a name?" is more than a literary question for advanced Parkinson's disease (APD). Although APD is widely used in clinical practice, what constitutes "advanced" remains poorly defined and inconsistently applied. Existing definitions have often anchored APD to motor complications, treatment complexity, or eligibility for device-aided therapies (DATs). These approaches are useful for referral and treatment planning, but they risk mistaking a treatment phenotype for the whole disease state. They also fail to capture the broader burden of progression, including non-motor symptoms, cognitive decline, functional dependence, psychosocial consequences, caregiver burden, frailty, and biological heterogeneity. We argue that APD is best understood as a multidimensional state reflecting cumulative neurodegeneration and its lived, functional, and therapeutic consequences, rather than a single stage, motor phenotype, or treatment milestone. This narrative review reframes APD through five interconnected axes: clinical symptom burden; perceived disease impact; functional consequences and participation restriction; therapeutic complexity, refractoriness, and treatment-related complications; and markers associated with disease progression. We propose that APD is a multidimensional clinical state that emerges as PD progresses, when cumulative burden across these five domains exceeds the capacity of patients and caregivers to compensate, adapt, and maintain independence, resulting in progressive disability and reduced quality of life. This framework distinguishes DAT-eligible PD, late-stage PD, and overlapping intermediate phenotypes, while accommodating emerging markers without replacing clinical judgement. By making the name APD correspond more closely to clinical reality, this framework may support earlier recognition, appropriate referral, patient-centred therapeutic planning, and more consistent research stratification.
Non-pharmacological and non-surgical interventions are increasingly recognised as essential components of management of Parkinson’s disease (PD). However, as PD progresses to its advanced stages, limited mobility, cognitive impairment, treatment-refractory symptoms, and increasing dependence on care partners dominate. However, the evidence base for therapies in this stage becomes scarce. Most clinical practice guidelines and systematic reviews address PD as a whole, without highlighting specific recommendations tailored to advanced disease stage. This narrative review examines the current evidence for non-pharmacological and non-surgical therapies specifically in the context of advanced PD. This includes physiotherapy and exercise, freezing of gait management, dysphagia rehabilitation, nutrition and dietetics, neuropsychiatric care, autonomic dysfunction, pain management, and palliative care. We synthesised evidence from recent systematic reviews of clinical practice guidelines, scoping reviews of rehabilitation interventions in advanced PD, systematic reviews and meta-analyses of non-pharmacological treatments for specific symptom domains, the published literature on advanced PD management, and expert consensus. A recent systematic review identified 40 summary statements for non-pharmacological interventions in PD, yet these were developed without stage-specific differentiation. A scoping review of rehabilitation interventions specifically targeting advanced PD identified only 13 studies, predominantly focused on physical functioning. On the other hand, while interventions for freezing of gait, swallowing therapies, cognitive behavioural therapy for neuropsychiatric symptoms, non-invasive brain stimulation, non-pharmacological autonomic management, and multimodal exercise have demonstrated promise in PD, robust evidence for advanced PD remains largely absent. People with advanced PD represent a neglected population in non-pharmacological therapy research. There is a clear need for inclusion of people with advanced PD in guideline development and a holistic approach addressing factors such as demoralisation, caregiver strain, autonomic dysfunction, and spiritual wellbeing alongside physical rehabilitation.
