Search Results (502)

Thermoregulatory dysfunction—temperature intolerance and/or inappropriate compensation—is an underrecognized feature of Parkinson’s disease (PD) and is linked to poor quality of life. Multiple mechanisms may underlie this dysfunction, including α-synuclein deposition in relevant structures, altered functional connectivity in thermoregulatory networks, and disrupted neurotransmitter modulation, on top of the deleterious consequences of aging. Although multiple advanced tests can confirm this dysfunction, diagnosis is largely based on a detailed history. Once this critical symptom is identified, management focuses on crisis prevention and safety, as PD-specific clinical trials are often lacking. This narrative review of the literature addresses mechanisms, clinical expression, diagnostic evaluation, and management of thermoregulatory dysfunction in PD to help guide care for this underappreciated, yet potentially debilitating, non-motor symptom of PD. Future PD-specific trials are needed to further clarify underlying mechanisms and improve treatment options. Full article

Parkinson’s Disease is a progressive neurodegenerative disorder marked by motor fluctuations in later disease stages that complicate treatment with levodopa. Traditional approaches to dosing often fail to capture the complex and dynamic nature of these fluctuations. In this study, we present the PD9™ algorithm, a novel approach to continuous motor state monitoring using data from a wrist-worn inertial measurement unit sensor. The algorithm provides minute-by-minute assessments of motor state severity on a unified scale quantifying bradykinesia, dyskinesia, and ON states. Data collected from 67 patients over 55,482 min were analyzed to assess levodopa response cycles. Across 218 identified levodopa cycles, the algorithm revealed reproducible patterns of symptom development based on the motor state at the time of levodopa administration. In particular, levodopa doses administered during non-ideal motor states (e.g., during dyskinesia) highlighted the limitations of fixed, empirically determined dosing regimens and underscore the need for individualized therapy, based on motor state. These findings demonstrate how AI-enabled continuous monitoring could help realize a more personalized treatment of Parkinson’s disease and improve patient outcomes. Full article

Background: Tremor-dominant Parkinson’s disease (TDPD) is the most common subtype of PD. Tremor is difficult to treat and less than 50% of patients respond to dopaminergic medications. Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is an incisionless noninvasive method for treating pharmacoresistant tremor in PD patients, but its effect on progression of PD is unknown. In this study, we investigate the efficacy of MRgFUS thalamotomy on progression of motor and non-motor symptoms, using a levodopa equivalent daily dose (LEDD) requirement. Methods: A total of 21 PD patients with ineffective tremor correction by medical therapy underwent MRgFUS thalamotomy. Assessments of motor and non-motor symptoms, adverse events (AE), changes in LEDD, and evolution of FUS (focused ultrasound) lesion were performed on the day before surgery, and then 2 days, as well as 3, 6, and 12 months, after the procedure. Results: On the 2nd day after FUS thalamotomy, 11 patients were tremor-free and, in 10 patients, tremor decreased by 80–90% with a concomitant reduction in hypokinesia and rigidity. By the end of the 12th month, 5 patients remained tremor-free; in 11 patients, mild/moderate tremor re-emerged; and in 5 patients, there was a relapse of severe tremor. Quality of life (QoL) and activities of daily living (ADL) improved significantly at 3 months and remained stable thereafter. Cognitive function improved in patients with baseline MoCA score < 26 points at 3 months after FUS. Anxiety progressed between baseline and end of follow-up. By the end of the follow-up period, LEDD was lowered or stable in 9 patients. Four patients had persistent mild AE. Conclusions: This open label study suggests a beneficial effect of MRgFUS in reducing tremor, hypokinesia, and rigidity and improving QoL, ADL, and cognitive function in TDPD patients in the short term, although long-term data needs to be collected in further studies. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, among which vocal impairment is one of the earliest and most prevalent. In recent years, voice analysis supported by machine learning (ML) and deep learning (DL) has emerged as a promising non-invasive method for early PD detection. We conducted a systematic review searching PubMed, Scopus, IEEE Xplore, and Web of Science databases for studies published between 2020 and September 2025. A total of 69 studies met the inclusion criteria and were analyzed in terms of dataset characteristics, speech tasks, feature extraction techniques, model architectures, validation strategies, and performance outcomes. Classical ML models such as Support Vector Machines (SVMs) and Random Forests (RFs) achieved high accuracy on small, homogeneous datasets, while DL architectures, particularly Convolutional Neural Networks (CNNs), Recurrent Neural Networks (RNNs), and Transformer-based foundation models, demonstrated greater robustness and scalability across languages and recording conditions. Despite these advances, persistent challenges such as dataset heterogeneity, class imbalance, and inconsistent validation practices continue to hinder reproducibility and clinical translation. Overall, the field is transitioning from handcrafted feature-based pipelines toward self-supervised, representation-learning frameworks that promise improved generalizability. Future progress will depend on the development of large, multilingual, and openly accessible datasets, standardized evaluation protocols, and interpretable AI frameworks to ensure clinically reliable and equitable voice-based PD diagnostics. Full article

Background/Objectives: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a safe and established therapy for management of refractory motor fluctuations and dyskinesia in Parkinson’s disease (PD). However, the relationship between stimulation site connectivity and improvement of axial gait symptoms remains poorly understood, particularly when stimulating in the GPi. This study investigated functional and structural connectivity patterns specifically associated with axial symptom outcomes following bilateral GPi-DBS, and, as a secondary exploratory analysis, examined whether Volumes of tissue activated (VTAs)-based connectivity related to overall UPDRS-III change. Methods: We retrospectively analyzed 19 PD patients who underwent bilateral GPi-DBS at the University of Florida (2002–2017). Unified Parkinson’s Disease Rating Scale (UPDRS-III) axial gait subscores were assessed at baseline and 36-month follow-up. VTAs were reconstructed using Lead-DBS and coregistered to Montreal Neurological Institute (MNI) space. Structural connectivity was evaluated with diffusion tractography, and functional connectivity was estimated using normative resting-state fMRI datasets. Correlations between VTA connectivity and clinical improvement were examined using Spearman correlation and voxelwise analyses. Results: Patients with axial improvement in motor scales demonstrated specific VTA connectivity to sensorimotor and supplementary motor networks, particularly lobule V and lobules I–IV of the cerebellum. These associations were specific to axial gait subscores. In contrast, worsening axial gait symptoms correlated with connectivity to cerebellar Crus II, cerebellum VIII, calcarine cortex, and thalamus (p < 0.05). Total UPDRS-III scores did not show a significant positive correlation with supplementary motor area or primary motor cortex connectivity; a non-significant trend was observed for VTA–M1 connectivity (R = 0.41, p = 0.078). Worsening total motor scores were associated with cerebellar Crus II and frontal–parietal networks. These findings suggest that distinct connectivity patterns underlie differential trajectories in axial and global motor outcomes following GPi-DBS. Conclusions: Distinct connectivity profiles might underlie axial gait symptom outcomes following GPi-DBS. Connectivity to motor and sensorimotor pathways supports improvement, whereas involvement of Crus II and occipital networks predicts worsening. Additional studies to confirm and expand on these findings are needed, but our results highlight the value of connectomic mapping for refining patient-specific targeting and developing future programming strategies. Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. It is characterized by the accumulation of α-synuclein, and its symptoms arise from the loss of dopaminergic neurons in the substantia nigra, contributing to the development of both motor (MS) and non-motor (NMS) symptoms. The detailed pathomechanism of the disease progression is unknown, although microglia activation and ongoing neuroinflammation are thought to play key roles. It is known that adipokines have a wide-ranging impact on various processes, including those implicated in PD. We have analyzed a series of studies regarding the significance and involvement of leptin, adiponectin, resistin, visfatin, and progranulin in neurodegeneration. Available evidence suggests that adipokines modulate PD pathology through their effects on inflammation, oxidative stress, or α-synuclein accumulation. Thus, the examined adipokines may serve as potential targets for PD treatment or as biomarkers of disease progression. Full article

Background/Objectives: Socio-cognitive disorders constitute the early-stage disabling dimension of non-motor symptoms of Parkinson’s disease (PD) and affect social functioning and interpersonal adjustment. However, current assessment tools do not adequately reveal the nature of these disorders. The Edinburgh Social Cognition Test (ESCoT) has recently been validated as a multifaceted, sensitive instrument for detecting this dysfunction in various neurological disorders. This study aimed to systematically examine socio-cognitive changes in early-stage PD using the ESCoT and their relationship with executive functions. Methods: This prospective case–control study included 27 early-stage idiopathic PD patients without cognitive impairment and 46 healthy controls. Social cognitive abilities were assessed using the ESCoT, and executive functions via the Frontal Assessment Battery (FAB). Group differences and inter-variable linear associations were evaluated using parametric inferential statistics. The independent predictive contribution of FAB to ESCoT performance was modeled through multiple linear regression. Results: Groups did not differ in age, sex, or education (p > 0.05). PD patients had significantly lower ESCoT total scores (45.67 ± 0.85 vs. 55.52 ± 0.63) and reduced performance across all subscales: Cognitive Theory of Mind (ToM), affective ToM, interpersonal, and intrapersonal norms (p < 0.001). In the PD cohort, FAB correlated strongly with ESCoT (r > 0.40, p < 0.05) and significantly predicted ESCoT total (R² = 0.247, p = 0.008), affective ToM (β = 0.221, p = 0.034), and interpersonal norms (β = 0.447, p = 0.019). Conclusions: This study demonstrates, for the first time, that ESCoT can sensitively capture multidimensional social cognitive deficits in PD, even in preserved global cognitive function. The observed link with executive dysfunction underlines the need for a more integrative approach to cognitive symptoms in PD. Full article

Background/Objectives: An individual’s quality of life is greatly impacted by the motor and non-motor symptoms of Parkinson’s disease (PD), which include anxiety and depression. Using the Hospital Anxiety and Depression Scale (HADS), this study sought to determine the prevalence of anxiety and depression in Moroccan patients with Parkinson’s disease (PD) and investigate any possible associations with clinical characteristics and pharmacological treatment. Methods: The HADS was used to assess 100 PD patients in total. Clinical and demographic information, including prescription drug use, was gathered. The relationships between HADS scores and clinical factors were evaluated using Pearson’s correlation. Results: According to the HADS assessment, 20% of respondents had no anxiety symptoms, 17% had borderline symptoms, and 63% of patients reported definite anxiety symptoms. Of those with depression, 24% showed no symptoms, 14% were borderline, and 62% were certain. The average HADS-A and HADS-D scores were 2.34 and 2.43, respectively. L-DOPA alone was used to treat half of the patients, while combinations of Trivastal, Sifrol, anticholinergics, or antidepressants were given to the other half. There were no discernible correlations between HADS scores and clinical or demographic traits. Conclusions: The HADS is a useful instrument for assessing anxiety and depression in PD patients. Regardless of the method of treatment or stage of the disease, psychiatric symptoms are prevalent. For PD patients to benefit from early interventions and achieve an improved quality of life, routine screening is crucial. Full article

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behavior disorder (iRBD), 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD, an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD. Full article

Background: This study aims to investigate the association between the presence and severity of non-motor symptoms (constipation, REM sleep behavior disorder [RBD], hyposmia, and depression) and the severity of motor impairment in Parkinson’s disease (PD). Methods: We used data from Parkinson’s Progression Markers Initiative (PPMI), comprising patients with established PD, prodromal PD, and healthy controls. Motor disability was evaluated with the MDS-UPDRS part III. Non-motor symptoms were assessed with standardized scales for constipation (MDS-UPDRS part I sub-item), depression (15-item GDS), RBD questionnaire (RBDQ), and hyposmia (UPSIT). The relationships between non-motor symptoms and motor severity were explored using linear regression models (adjusted for age/sex). Results: Constipation was significantly more prevalent in PD and prodromal PD and independently associated with greater motor severity in both groups (p < 0.001). Constipation also correlated with increased freezing and falls. Depressive symptoms were similar across groups, but in prodromal PD, higher GDS scores were associated with worse UPDRS III scores (p = 0.02), as well as higher freezing and fall scores. Hyposmia was strongly reduced in PD and prodromal PD compared with controls but was not independently associated with motor severity. Higher RBDQ scores were associated with worse motor impairment in PD, but not in prodromal PD after adjustment. Conclusions: Constipation and REM sleep behavioral disorder were independent correlates of worse motor severity in prodromal and established PD, whereas depressive symptoms predicted more severe parkinsonism only within the prodromal phase. Full article

The LRRK2+ SAA− cohort of Parkinson’s disease (PD), characterized by the absence of hallmark α-synuclein pathology, remains under-explored. This limits opportunities for early detection and targeted intervention. This study analyzes data from this under-characterized subgroup and compares it with the LRRK2+ SAA+ cohort using longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI). The PPMI dataset includes 115 LRRK2+ patients (70 SAA+, 45 SAA−) across 52 features encompassing clinical assessments, cognitive scores, DaTScan SPECT imaging, and motor severity. DaTScan binding ratios were selected as imaging-based indicators of early dopaminergic loss, while NP3TOT (MDS-UPDRS Part III total score) was used as a gold-standard clinical measure of motor symptom severity. Linear mixed-effects models were then applied to evaluate longitudinal predictors of DaTScan decline and NP3TOT progression, and statistical analyses of group comparisons revealed distinct drivers of symptoms differentiating SAA− from SAA+ patients. In SAA− patients, a decline in DaTScan was significantly associated with thermoregulatory impairment (p-value = 0.019), while NP3TOT progression was predicted by constipation (p-value = 0.030), sleep disturbances (p-value = 0.046), and longitudinal time effects (p-value = 0.043). In contrast, SAA+ patients showed significantly lower DaTScan values compared to SAA− (p-value = 0.0004) and stronger coupling with classical motor impairments, including freezing of gait (p-value = 0.016), rising from a chair (p-value = 0.007), and turning in bed (p-value = 0.016), along with cognitive decline (MoCA clock-hands test, p-value = 0.037). These findings support the hypothesis that LRRK2+ SAA− patients follow a distinct pathophysiological course, where progression is influenced more by autonomic and non-motor symptoms than by typical motor dysfunction. This study establishes a robust, multimodal modeling framework for examining heterogeneity in genetic PD and highlights the utility of combining DaTScan, NP3TOT, and symptom-specific features for early subtype differentiation. These findings have direct clinical implications, as stratifying LRRK2 carriers by SAA status may enhance patient monitoring, improve prognostic accuracy, and guide the design of targeted clinical trials for disease-modifying therapies. Full article

Background and Objectives: Apathy and sleep problems are frequently observed among non-motor symptoms (NMSs) in Parkinson’s disease (PD), but the relationship between the two has not been well investigated. This study aimed to determine the extent to which apathy and sleep disturbances are present in people with early PD and whether apathy affects sleep quality. Materials and Methods: Patients diagnosed with early PD, defined as modified Hoehn and Yahr (mHY) stages 1-3 and a disease duration of no more than 5 years, were included in the study. Demographic characteristics were collected, and motor and NMSs including apathy and sleep disturbance were investigated with relevant scales. Results: Of 302 patients with PD, apathy was found in 97 (32.1%) patients. Patients with apathetic PD had significantly less formal education, a more advanced mHY stage, and higher scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) part II, total Non-Motor Symptom Scale (NMSS), Beck Depression Inventory (BDI), Apathy Evaluation Scale (AES), and Pittsburgh Sleep Quality Index (PSQI) global scores than patients with non-apathetic PD. The PSQI global score showed significant associations with years of education, UPDRS-II, total NMSS, Mini-Mental State Examination, BDI, and AES scores. For each component of the PSQI, only sleep latency was different between patients with apathetic and non-apathetic PD. Partial correlation analyses for determining the association between apathy and sleep disturbance revealed a significant positive correlation. Conclusions: Apathy is common and associated with poor sleep quality in patients with early PD. These findings suggest that recognizing and addressing apathy may be relevant for managing sleep disturbances in this population. Full article

Background/Aims: Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the degeneration of dopaminergic neurons, leading to motor and non-motor symptoms that significantly impair quality of life (QoL). Oxidative stress (OS) and neuroinflammation play a key role in its progression. The ketogenic diet (KD) may have neuroprotective effects by reducing these factors through ketosis. The primary aim of this narrative review is to examine the impact of the ketogenic diet on the quality of life and symptomatology of patients with PD, evaluating its effects on motor and non-motor symptoms, as well as on certain metabolic parameters. Secondary aims included assessing the feasibility of and adherence to the diet, as well as its tolerability and safety. Methods: A search of PubMed, Scopus, Embase, CINAHL and Cochrane databases up to June 2025 was performed. Eligible studies included adults with PD following a KD regimen. Data were extracted regarding QoL outcomes, adverse events, and risk of bias included for synthesis. Results: A total of 152 patients were included across 6 studies. KD showed a small to moderate effect size on QoL improvements, particularly in non-motor domains such as fatigue and sleep quality. However, findings were inconsistent across studies. Risk of bias was rated moderate to high due to small sample sizes, heterogeneous methodologies, and lack of blinding. The most frequently reported adverse events were gastrointestinal disturbances (nausea, constipation), weight loss, and transient fatigue. Conclusions: Although preliminary evidence suggests a potential benefit of KD on QoL in PD patients, the small number of participants, short follow-up, and high heterogeneity significantly limit generalizability. Further large, controlled trials with rigorous methodology are warranted before relevant conclusion benefits can be drawn. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The absence of reliable fluid biomarkers continues to hinder early diagnosis and effective monitoring of disease progression. Circulating microRNAs (cmiRNAs) are potential candidates, given their stability in biofluids and their ability to mirror pathological processes. We conducted a longitudinal study in 30 early-stage levodopa-naive PD patients (22 men, 8 women). Serum samples were collected at baseline (T0) and at a follow-up time point two years later (T2). A panel of MicroRNAs (miRNAs) (miR-146a-5p, miR-34a-5p, miR-155-5p, miR-29a-3p, miR-106a-5p) were quantified by quantitative real-time PCR. Data were expressed as relative expression (2^−ΔCt), and statistical analyses included sex-stratified comparisons and paired tests for longitudinal changes. At baseline, no significant differences were found in the expression of the miRNAs between male and female PD patients. In contrast, longitudinal within-subject analysis revealed a highly significant upregulation in miR-146a-5p expression from T0 to T2 in both sexes (p < 0.0001). No other miRNAs in the panel exhibited significant changes over time. CmiR-146a-5p levels rise markedly over time in PD patients, independent of sex, suggesting that this miRNA could be a dynamic biomarker of disease progression. Full article

Background/Objective: Few treatment options improve symptoms and the quality of life of Parkinson’s disease (PD); more treatment choices are needed. This study examined the effectiveness of photobiomodulation therapy (PBMt) combined with exercise to improve PD symptoms and quality of life. Methods: Participants were randomised into Active (n = 32) or Sham (n = 31) PBMt groups. Stage 1 was an 8-week double-blind, randomised, placebo-controlled trial using either active or sham PBMt to the head, back of the neck and abdomen three times weekly at home, followed by a 4-week washout. Stage 2 was 8 weeks of active PBMt for all participants. In Stage 3, participants chose to continue active PBMt treatment (‘continuers’) or receive no PBMt treatment (‘non-continuers’) for up to 48 weeks. Participants continued vigorous exercise throughout the study. Participants were assessed on enrolment and after each stage. The primary outcome measure was timed up-and-go, with a range of secondary motor and non-motor outcomes, including UPDRS. Results: There was no significant difference between the Active and Sham Groups after Stages 1 or 2, apart from minimal increase in MoCA score/cognition (Sham Group) in Stage 1. After Stage 3, continuers showed a significant improvement in the primary outcome measure compared to non-continuers. Anxiety and the motor experiences of daily living (MDS-UPDRS Part II) were also significantly improved, while other outcomes approached significance, including MDS-UPDRS Total score (p = 0.062). Conclusions: As the largest study to date, results add increasing weight to previous clinical trials and highlight potential for at-home, scalable treatment as adjunctive therapy alongside medication and exercise. Full article