Tremor is a common and disabling feature of Parkinson’s disease (PD) and often responds suboptimally to oral dopaminergic therapy. This post‑hoc analysis evaluated tremor outcomes associated with apomorphine sublingual film (SL‑APO) in patients with a tremor‑dominant PD phenotype, using data from a 12‑week randomised, double‑blind, placebo‑controlled trial (NCT02469090) and a 12‑month open‑label study (NCT02542696) conducted in levodopa‑responsive patients with OFF episodes. Tremor‑dominant phenotype was defined according to Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS‑UPDRS) criteria, and tremor severity was assessed using a derived tremor index. In the randomised trial, 31 of 108 patients (28.7
Autoimmune encephalitis cases continue to rise globally. Early recognition, prompt diagnosis and adequate treatment are crucial in improving patient outcomes. However, high cost and limited availability of antibody testing remain a challenge for timely definitive diagnosis. This study evaluated the diagnostic performance of the clinical criteria for pediatric anti-NMDAR (N-methyl-D–aspartate receptor) encephalitis using the Philippine Children’s Medical Center (PCMC) Algorithm. A retrospective diagnostic accuracy study was conducted among 160 patients aged 0 to < 19 years admitted at PCMC from 2011 to 2025 with a clinical suspicion of autoimmune encephalitis. Subjects underwent cerebrospinal fluid (CSF) anti-NMDAR antibody testing: 119 tested positive and 41 tested negative. Clinical data were obtained and analyzed to evaluate PCMC algorithm’s diagnostic performance using sensitivity, specificity, predictive values and likelihood ratios. Receiver operating characteristic (ROC) analysis and logistic regression were utilized to determine optimal symptom combinations. Of the 160 subjects, abnormal behavior or cognitive dysfunction was the most common symptom. Among CSF anti-NMDAR-positive cases, seizures, movement disorder, and speech dysfunction occurred more frequently than in antibody-negative cases. The number of PCMC clinical symptoms demonstrated acceptable discrimination for anti-NMDAR encephalitis, with an AUC of 0.752 (95
Autism spectrum disorder (ASD) is characterized by atypical sensory traits. The amygdala and hippocampus have been implicated in ASD, but how sensory traits relate to white matter pathways connected to these regions remains unclear. We therefore examined whether sensory traits are associated with microstructural properties of amygdala- and hippocampus-connected white matter in adults with ASD. We included 40 adults with ASD and 83 typically developing (TD) adults (all aged ≥ 18 years). Participants completed the Adolescent/Adult Sensory Profile (AASP) and underwent diffusion tensor imaging. Diffusion metrics were computed for bilateral amygdala-connected white matter (AWM) and hippocampus-connected white matter (HWM). The ASD group showed lower fractional anisotropy (FA) in both AWM and HWM than the TD group. In the ASD group, sensation-seeking scores revealed a nominal positive association with FA in the right AWM, although this association did not survive FDR correction. In the TD group, sensation-seeking scores were negatively associated with FA in the right HWM. Fisher r-to-z tests with FDR correction indicated significant group differences in the associations between sensation seeking and FA of the right AWM and right HWM. White matter microstructure in pathways connected to the amygdala and hippocampus showed group differences in FA and in how FA related to sensation seeking. These findings suggest that atypical sensory traits in ASD may be linked to microstructural differences in amygdala- and hippocampus-connected pathways.
Adolescent depression shows marked heterogeneity in symptom severity, yet mechanisms linking early-life adversity to severe depressive presentations remain unclear. Childhood maltreatment may induce persistent alterations in immune and stress-regulatory systems, increasing vulnerability to severe depression. This study examined whether childhood adversity, circulating biomarkers, and recent stress contribute to differences between severe and non-severe adolescent depression. Seventy adolescents with depressive disorder were classified into severe (SD, n = 40, HAMD-17 ≥ 24) and non-severe (NSD, n = 30, HAMD-17 < 24) groups, along with 39 healthy controls (HC). Childhood maltreatment was assessed using the Maltreatment and Abuse Chronology of Exposure (MACE), and recent stress using the Adolescent Life Events Scale. Serum levels of Pentraxin-3 (PTX3), S100B, matrix metalloproteinases (MMP-8, MMP-9), FKBP5, oxytocin, epidermal growth factor, and APCDD1 were measured by enzyme-linked immunosorbent assays. Adolescents with SD reported significantly higher childhood maltreatment than those with NSD. PTX3 and FKBP5 levels were significantly elevated in the severe group compared with both non-severe patients and HC and were positively associated with symptom severity. Receiver operating characteristic analyses showed that childhood maltreatment had good discriminative ability for depressive severity, whereas PTX3 and FKBP5 showed moderate discriminative performance. Multivariable logistic regression identified childhood maltreatment and PTX3 as independent predictors of SD. Hierarchical regression showed that recent life stress explained additional variance in self-reported symptom severity and partly attenuated the associations of early adversity and inflammatory markers. These findings suggest that severe adolescent depression represents a clinically defined severity stratum associated with neuroimmune alterations in the context of childhood adversity and recent life stress, rather than a discrete biological subtype.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95
Dystonia is conventionally attributed to dysfunction in central motor circuits, yet several clinical features, including sensory tricks, task specificity, and abnormalities in somatosensory processing, indicate an influence of sensory input. Whether peripheral sensory afferents are passive conduits to central circuits or contribute to dystonia pathophysiology remains unresolved. To examine whether peripheral sensory afferents participate in dystonia networks beyond their role as upstream inputs. Evidence was synthesized across five domains: phenomenology, electrophysiology, neuroimaging, genetics, and treatment. Priority was given to studies that manipulated or quantified peripheral afferent input and assessed effects on motor output or network physiology. Sensory tricks produce rapid improvement across dystonia phenotypes, indicating that afferent input can influence motor output. Electrophysiological studies demonstrate impaired afferent modulation of intracortical inhibition, abnormal integration of converging sensory inputs, and reduced reflex suppression at spinal and brainstem levels. Neuroimaging studies show somatosensory representations and changes in network activity. Genetic and animal studies implicate dystonia-associated pathways in the regulation of proprioceptive afferent signaling, and sensory-neuron-specific manipulations can induce or reduce abnormal movements. Therapeutic interventions, including peripheral stimulation, botulinum toxin, and sensory blockade, have been associated with reductions in dystonic symptoms through mechanisms that alter afferent input. Findings from phenomenological, electrophysiological, neuroimaging, genetic, and therapeutic studies indicate that peripheral sensory afferents contribute to dystonia networks. These observations are consistent with a model in which abnormalities of afferent gating, sensory integration, and somatosensory representation contribute to dystonic expression across multiple levels of the neuraxis, with potential implications for therapeutic targeting.
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.
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.
