Journal Of Parkinson's Disease[JOURNAL]
Sun
200 papers
Blood and cerebrospinal fluid metallomics uncover mercury, chromium, and iron alterations in Parkinson's disease.
Dušek P, Subramanian RG, Serranová T … +3 more , Šonka K, Růžička E, Kuta J
J Parkinsons Dis · 2025 Dec · PMID 40905752 · Publisher ↗
BackgroundGiven the increasing global prevalence of Parkinson's disease (PD) and its complex etiopathogenesis, understanding the role of environmental factors is crucial. Prior investigations suggested a potential link b...
BackgroundGiven the increasing global prevalence of Parkinson's disease (PD) and its complex etiopathogenesis, understanding the role of environmental factors is crucial. Prior investigations suggested a potential link between metal exposure and PD, yet conflicting results emerged.ObjectiveTo identify differences in metal concentrations in whole blood and cerebrospinal fluid (CSF) in PD patients compared to controls.MethodsThe study involved an untreated de novo PD patient cohort from a single-center (n = 102, 38% females, mean age 59.5 (SD 12.5)) and a group of controls with comparable age and sex distribution (n = 127, 35% females, mean age 57.5 (SD 12.4)). Whole blood in all participants and CSF samples in a subgroup (n = 57/55 PD/controls) were collected and concentrations of V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Cd, Sn, Hg, and Pb, were determined through inductively coupled plasma mass spectrometry.ResultsPD patients exhibited higher concentrations of Hg in both blood and CSF (p = 0.003). Cr concentrations were lower in both blood (p = 0.004) and CSF (p < 0.001) of PD patients. Altered Fe metabolism was evident, with higher blood (p = 0.001) and lower CSF (p = 0.002) Fe concentrations. Other metal alterations in PD included higher Zn (p = 0.008) in blood and lower Co (p < 0.001), Mn (p = 0.006), V (p = 0.009), and Ni (p < 0.001) in CSF.ConclusionsThe findings highlight abnormalities in metal concentrations in biofluids associated with PD, particularly regarding Hg, Cr, and Fe which exhibited alterations in blood and CSF. These findings suggest metal dysregulation in PD, particularly Hg, Cr, and Fe, with potential implications for understanding PD pathogenesis.
Faster disease progression in Parkinson's disease with glucocerebrosidase genotype: But not apparent immediate from diagnosis.
Frequin HL, Ferwerda B, Verschuur CV … +4 more , Suwijn SR, Dijk JM, de Bie RM, LEAP Study Group
J Parkinsons Dis · 2025 Nov · PMID 40899843 · Publisher ↗
BackgroundThis study presents post-hoc analyses of the LEAP study focusing on disease progression in patients with early Parkinson's disease (PD) who either have a glucocerebrosidase gene () mutation (GBA1mut) or do not...
BackgroundThis study presents post-hoc analyses of the LEAP study focusing on disease progression in patients with early Parkinson's disease (PD) who either have a glucocerebrosidase gene () mutation (GBA1mut) or do not have a mutation (GBA1wt) over a period of up to five years.ObjectiveTo investigate the difference in disease progression between GBA1mut and GBA1wt over 80 weeks and five years.MethodsThe study analyzed the difference in disease progression between GBA1mut and GBA1wt using the UPDRS and its subscales, Levy A and B scores, and the difference in levodopa equivalent daily dose (LEDD) over 80 weeks and five years, with mixed-effects regression models.ResultsThe mutation carrier status was determined in 394 patients, with 52 being GBA1mut and 342 being GBA1wt. From baseline to 80 weeks, the change in total UPDRS score was similar for GBA1mut and GBA1wt (difference 1.7 points in favor of GBA1mut, p = 0.38). From baseline to five years, GBA1mut had 5.9 points (p = 0.04) more worsening of total UPDRS compared to GBA1wt and GBA1mut had 1.0 point (p = 0.02) more deterioration in UPDRS subscale IV, related to therapy complications, compared to GBA1wt. There were no significant between-group differences in changes in UPDRS subscales, Levy A and B scores, and LEDD.ConclusionsThese findings suggest that over the long term, PD patients with a mutation experience faster disease progression compared to those without a mutation, although this difference in progression was not apparent within the initial 80 weeks of the trial.
Pathophysiology and pharmacological management for sleep problems in Parkinson's disease.
Falup-Pecurariu C, Ungureanu L, Murasan I … +1 more , Diaconu S
J Parkinsons Dis · 2026 Jul · PMID 40891812 · Publisher ↗
Sleep problems are among the most frequently reported non-motor symptoms of Parkinson's disease (PD), with a broad range of disorders: insomnia, REM sleep behavior disorder, restless legs syndrome, excessive daytime slee...
Sleep problems are among the most frequently reported non-motor symptoms of Parkinson's disease (PD), with a broad range of disorders: insomnia, REM sleep behavior disorder, restless legs syndrome, excessive daytime sleepiness, and sleep-related breathing disorders. These disturbances evolve in complexity across PD severity stages, significantly impact the patients' quality of life and may exacerbate motor and other non-motor symptoms. Neurodegenerative processes, impaired function of neurotransmitters, medication side effects, circadian rhythm dysfunction are among the most proposed mechanisms that may explain the frequent occurrence of sleep disorders in PD. However, there are still many unanswered questions related to the pathophysiological mechanisms of sleep disorders in PD that may offer the clue to better therapeutical options. Although the prevalence of sleep disturbances is very high, the treatment options are still limited. The current review focuses on main sleep disturbances encountered in PD, pathophysiological insights, current therapeutical options and future perspectives for a better and more personalized management of these disorders in PD.
A glimpse of the end-of-life of people with Parkinson's disease and atypical parkinsonism: A descriptive analysis of electronic health records.
Lennaerts-Kats H, Elbers A, Muente C … +5 more , van Stigt R, Bloem BR, Vissers KC, Groot MM, Meinders MJ
J Parkinsons Dis · 2025 Dec · PMID 40891701 · Publisher ↗
BackgroundThe needs of people with Parkinson's disease (PD) or atypical parkinsonism (AP) change significantly in the final weeks to days of life. A better understanding of this phase can help improve care.ObjectiveTo ex...
BackgroundThe needs of people with Parkinson's disease (PD) or atypical parkinsonism (AP) change significantly in the final weeks to days of life. A better understanding of this phase can help improve care.ObjectiveTo examine healthcare use and end-of-life care in people with PD.MethodsWe conducted a retrospective study (2022-2023) in three nursing homes, four hospitals, and eleven general practices in the Netherlands. Electronic health records of deceased individuals with PD or AP were reviewed for symptoms, healthcare use, and professional involvement.ResultsWe reviewed 189 records (70.4% PD; mean age 80.2; 68.1% male). In the last two weeks of life, patients had an average of 8.4 symptoms, with a higher burden in AP. Palliative sedation was used in 60.4%, most often in nursing homes (up to 78.3%) and among AP patients. Euthanasia occurred in 11 cases (6 PD, 5 AP), mainly in nursing homes and general practices. Antibiotics and pain medications were commonly used; fluid and oxygen therapy were more frequent in hospitals. Most patients were treated by a GP and 3-4 other healthcare professionals, but only 12.7% received support from a palliative care team.ConclusionsPeople with PD and AP face a high symptom burden at the end of life, yet palliative care involvement is limited. The frequent use of palliative sedation and cases of euthanasia reflect the complexity of this care phase. Better integration of palliative expertise and research into symptom management is urgently needed.
Patients with small fiber neuropathy exhibit more pronounced non-motor symptoms in Parkinson's disease.
Xie C, Chen J, Gan R … +6 more , Gao Y, Wang L, Ma G, Zhang Y, Nie K, Wang L
J Parkinsons Dis · 2025 Dec · PMID 40891687 · Publisher ↗
BackgroundPeripheral neuropathy in Parkinson's disease (PD) may not be an isolated pathological phenomenon but may interact with other non-motor symptoms.ObjectiveTo conduct a comprehensive investigation of the non-motor...
BackgroundPeripheral neuropathy in Parkinson's disease (PD) may not be an isolated pathological phenomenon but may interact with other non-motor symptoms.ObjectiveTo conduct a comprehensive investigation of the non-motor symptoms observed in PD patients, with a comparative analysis between patients with and without peripheral neuropathy, to explore the relationships between peripheral neuropathy and non-motor symptoms.Methods100 PD patients were recruited from the Neurology Department of Guangdong Provincial People's Hospital. Extensive clinical data were collected, and assessments were performed to evaluate both motor and non-motor symptoms in patients with and without peripheral neuropathy. Spearman's rank correlation analysis was employed to evaluate the association between peripheral neuropathy and non-motor symptoms. Multiple linear regression analysis was conducted to adjust for confounding variables to clarify the impact of peripheral neuropathy on non-motor symptoms.Results57 individuals (57%) were identified as having peripheral neuropathy. Of these, 38 individuals were diagnosed with small fiber neuropathy. After adjusting for confounding variables, higher scores on the 13-item Small Fiber Neuropathy Symptom Inventory Questionnaire were significantly correlated with heightened symptoms of depression (B = 0.498, 95% CI = 0.080-0.917, p = 0.020), anxiety (B = 0.504, 95% CI = 0.099-0.908, p = 0.015), autonomic dysfunction (B = 1.118, 95% CI = 0.828-1.409, p < 0.001), and sleep disturbances (B = 0.694, 95% CI = 0.309-1.080, p = 0.001).ConclusionsPD patients with neuropathy, particularly those with small fiber neuropathy, demonstrate more pronounced non-motor symptoms. The severity of small fiber neuropathy is correlated with the extent of depression, anxiety, autonomic dysfunction, and sleep disturbances. These findings underscore the necessity for routine screening and early detection of peripheral neuropathy in PD patients.
Motor features that distinguish isolated REM sleep behavior disorder patients from healthy controls: A systematic review.
Elasfar S, Hameed H, Ehgoetz Martens K
J Parkinsons Dis · 2025 Nov · PMID 40888450 · Publisher ↗
Individuals with isolated REM sleep behavior disorder (iRBD) are at high risk of developing α-synucleinopathies, particularly Parkinson's disease (PD) and dementia with Lewy bodies (DLB). With the development of potentia...
Individuals with isolated REM sleep behavior disorder (iRBD) are at high risk of developing α-synucleinopathies, particularly Parkinson's disease (PD) and dementia with Lewy bodies (DLB). With the development of potential neuroprotective treatments for synucleinopathies, including PD, identifying clinical features that can allow for tracking subtle changes in prodromal disease and thereby monitoring risk of phenoconversion in iRBD is paramount. Subtle motor deficits have been suggested to be present in iRBD, making them potentially important clinical markers for predicting future phenoconversion. This review aims to summarize existing literature that has investigated differences in motor function between iRBD and healthy individuals, as well as progression of motor decline in iRBD. 39 eligible studies were included in this review. The results suggest that quantitative motor assessments may be more sensitive to motor impairments in this population than clinical scales. Moreover, dual-tasking tended to unmask subtle motor deficits in individuals with iRBD, particularly in gait, balance, and tapping assessments. Longitudinal studies demonstrate that motor function worsens over time in iRBD, with earliest signs of motor deficits and clear progression in tapping assessments in particular. Larger longitudinal studies that use quantitative methods of motor assessments are needed to better characterize motor progression in iRBD, and confirm the reliability of different motor markers for predicting phenoconversion of iRBD into PD and other synucleinopathies.
In situ exogenous alpha-synuclein aggregates inhibit murine ventricular voltage-gated inward sodium and outward potassium currents.
Lee B, Ahmad S, Edling CE … +4 more , Matthews HR, Huang CL, LeBeau FE, Jeevaratnam K
J Parkinsons Dis · 2025 Nov · PMID 40874712 · Publisher ↗
BackgroundAlpha-synuclein is associated with neurodegeneration in Parkinson's disease (PD). Recent studies have increasingly recognized incidences of cardiac complaints in PD patients. In particular, the occurrence of ar...
BackgroundAlpha-synuclein is associated with neurodegeneration in Parkinson's disease (PD). Recent studies have increasingly recognized incidences of cardiac complaints in PD patients. In particular, the occurrence of arrhythmias in PD patients may indicate potential electrophysiological alterations in the heart. Alpha-synuclein aggregates have been known to have disruptive effects on cell membranes. However, the effect of alpha-synuclein on the heart and sympathetic neuronal tissues remains unknown.ObjectiveThis study investigated the electrophysiological effects of alpha-synuclein aggregates in myocardium and cardiac sympathetic nervous system, potentially reflecting cardiac electrophysiological alteration in PD.MethodsWe measured the sodium and potassium currents from murine ventricular myocardium and stellate ganglia using the loose patch clamp technique. The tissues were exposed to bioactive alpha-synuclein aggregates, and currents were measured under three different conditions: baseline, alpha-synuclein treatment, and wash out.ResultsThe experiments showed that alpha-synuclein aggregates altered the maximum cardiac sodium current () (ANOVA, p < 0.008) and affected its gating properties for channel activation (ANOVA = 6.408, = 0.003) and inactivation ( = 6.32, = 0.003). The alpha-synuclein aggregates also reduced the maximum outward potassium current () during channel activation ( = 6.02, = 0.002). However, the alpha-synuclein aggregates did not affect the ionic currents in the stellate ganglia.ConclusionsOur results demonstrate that extracellular alpha-synuclein aggregates can inhibit ventricular but not stellate ganglion ionic currents, suggesting a differential sensitivity between the myocardium and the stellate ganglia, and indicating a cardiac-specific toxicity of alpha-synuclein on cardiac electrophysiology.
Peripheral inflammatory markers and clinical phenotypes reflecting the impact of diabetes on Parkinson's disease.
Kwak IH, Ma HI, Kim YJ … +4 more , Noh HM, Lee J, Yu JK, Kim YE
J Parkinsons Dis · 2025 Dec · PMID 40874566 · Publisher ↗
BackgroundType 2 diabetes mellitus (DM) can influence the phenotype and progression of Parkinson's disease (PD), as both conditions share inflammation as a common pathogenic mechanism.ObjectiveTo explore peripheral infla...
BackgroundType 2 diabetes mellitus (DM) can influence the phenotype and progression of Parkinson's disease (PD), as both conditions share inflammation as a common pathogenic mechanism.ObjectiveTo explore peripheral inflammatory indices that reflect the impact of DM on PD.MethodsWe analyzed 52 drug-naïve PD patients with DM and 182 without DM, along with age- and sex-matched healthy control (HC) with and without DM in a 1:1 ratio. Clinical features were evaluated, including the Hoehn and Yahr (H&Y) scale and the Unified Parkinson's Disease Rating Scale (UPDRS). Peripheral inflammatory markers included the count of leukocyte subpopulations, high-density lipoprotein-cholesterol (HDL-C), and markers derived from these including neutrophil-to-HDL-C ratio (NHR), monocyte-to-HDL-C ratio (MHR), and lymphocyte-to-HDL-C ratio (LHR).ResultsThere were no significant differences in age, sex, or disease duration between PD with DM and PD without DM group. The PD with DM group showed more symmetric motor features ( 0.007) compared to the PD without DM group. NHR, MHR, and LHR were elevated in the PD with DM group compared to the other groups. Notably, MHR was highest in the PD with DM group, followed by the HC with DM group and the PD without DM group, and HC without DM group (9.73 vs. 8.30 vs. 7.63 vs. 6.46, 0.001). MHR positively correlated with clinical scales, including H&Y and UPDRS, across all PD patients ( < 0.05 for all).ConclusionsOur study suggests that MHR effectively reflects the peripheral inflammatory status related to both PD and diabetes.
What medicines do people with Parkinson's disease want?
McFarthing K, Outeiro TF, Bastos MC
J Parkinsons Dis · 2026 Jul · PMID 40856637 · Publisher ↗
Parkinson's disease (PD) is a heterogeneous condition that presents variable clinical, neuropathological, and biomarker features. Disease progression can also vary significantly. It is essential to consider this heteroge...
Parkinson's disease (PD) is a heterogeneous condition that presents variable clinical, neuropathological, and biomarker features. Disease progression can also vary significantly. It is essential to consider this heterogeneity when considering the medicines that people with Parkinson's (PwP) want. Potential PD medicines may be classed as disease modifying (DMT) or symptomatic (ST). The ultimate hope of PwP is that, sooner rather than later, the core of the PD pharmacopeia will provide personalised cocktails of drugs that not only deliver motor and non-motor symptom relief, but also slow, stop and then reverse disease progression. Generally, PwP are less interested in the scientific details, they are more focused on maintaining or improving quality of life. For those people at risk of PD, diagnosis in the pre-motor stage may herald the introduction of new medicines that arrest the progress of the disease before symptoms are manifest. One way to understand the medicines that PwP want is to ask which symptoms are the most bothersome, and target them accordingly. In practice, medicines that present optimal efficacy and convenience, at an affordable price, will be more likely to be accepted. Interactions between researchers and PwP should be encouraged in order to deepen the understanding of each other's needs and motivations. Finally, it is important to remember that PwP are individuals with emotions and concerns. As such, moderation in the communication of prognosis and of the potential of new medicines is essential, so that PwP can maintain hope rather than being misled by hype.
Do we need drugs for psychiatric symptoms specifically for Parkinson's disease?
Mills KA, Pontone GM
J Parkinsons Dis · 2026 Jul · PMID 40836692 · Publisher ↗
Although the need for better medications for the treatment of psychiatric symptoms in people with Parkinson's disease (PWP) is not disputed, the approach and targets for these medications needs further attention. Psychia...
Although the need for better medications for the treatment of psychiatric symptoms in people with Parkinson's disease (PWP) is not disputed, the approach and targets for these medications needs further attention. Psychiatric symptoms occur at higher prevalence in PWP-many start in the prodromal phase of the disease-and have complex associations and interactions with the motor symptoms and their treatments, begging the question of whether they may be mechanistically connected. In this manuscript, we review the current evidence for pharmacologic treatments of psychiatric symptoms in PWP and explore the potential next steps needed to develop new medications for psychiatric symptoms in PD.
Platelet mitochondrial complex I and IV activities are not reliable stratification biomarkers in Parkinson's disease.
Kverneng SU, Mostafavi S, Mikhaleva Y … +13 more , Johanson GAS, Berven H, Lundervold K, Skeie GO, Sheard E, Søgnen M, Geijerstam SA, Vetås T, Brischigliaro M, Fernandez-Vizarra E, Torres Cleuren YN, Dölle C, Tzoulis C
J Parkinsons Dis · 2025 Nov · PMID 40808415 · Publisher ↗
BackgroundMitochondrial dysfunction, particularly complex I (CI) deficiency, is considered an integral feature of Parkinson's disease (PD). However, recent findings indicate that widespread neuronal CI deficiency in the...
BackgroundMitochondrial dysfunction, particularly complex I (CI) deficiency, is considered an integral feature of Parkinson's disease (PD). However, recent findings indicate that widespread neuronal CI deficiency in the brain is only present in a subpopulation of 20-30% of cases. This stratification may be relevant for selecting participants for clinical trials, emphasizing the need for clinically applicable biomarkers. We previously reported CI deficiency in skeletal muscle biopsies of a subpopulation of persons with PD (PwPs), suggesting potential for mitochondrial stratification using extra-neural tissues. Platelets are another tissue previously reported to exhibit mitochondrial respiratory defects in PD. However, studies have generally involved small sample sizes and reported variable results.ObjectiveTo determine whether platelets exhibit impaired mitochondrial respiratory chain complex activity in PwPs, or in a subpopulation of PwPs.MethodsUsing spectrophotometric activity assays, we assessed CI and complex IV (CIV) activities in platelet samples from 61 PwPs and 31 neurologically healthy controls from a well-characterized prospective cohort. The correlation between activities measured in platelets and skeletal muscle was also explored in 51 of the same individuals.ResultsPlatelet CI and CIV activities showed no difference between PwPs and controls at the group level, nor evidence of a subgroup with deficiency of either complex. There was no correlation between complex activities in platelet samples and skeletal muscle biopsies from the same individuals.ConclusionsBased on these results, we propose that platelet CI or CIV activities are not sensitive markers of mitochondrial dysfunction in PD.
Cortical thickness alterations in Parkinson's disease related anxiety: A cross-sectional 7 T MRI study.
van Lier M, Carey G, Viard R … +4 more , Kuijf ML, Wolters AF, Dujardin K, Leentjens AF
J Parkinsons Dis · 2025 Dec · PMID 40791173 · Publisher ↗
BackgroundAnxiety is a common non-motor symptom in Parkinson's disease (PD) and has previously been associated with changes in cortical thickness of various brain regions.ObjectiveTo identify changes in cortical thicknes...
BackgroundAnxiety is a common non-motor symptom in Parkinson's disease (PD) and has previously been associated with changes in cortical thickness of various brain regions.ObjectiveTo identify changes in cortical thickness in PD-related anxiety.Methods148 patients from an ongoing cohort study were included: 30 PD patients with anxiety, 73 PD patients without anxiety and 45 healthy controls. Anxiety was measured with the Parkinson Anxiety Scale (PAS). A 7 T structural MRI scan was performed and used to compare cortical thickness between these groups. Region of interest (ROI) as well as whole-brain analyses were performed to identify differences.ResultsROI analyses revealed a strong negative association between the cortical thickness of the left lingual gyrus and the severity of anxiety in PD patients (R = -0.71; p = 0.006). Additional significant strong negative associations with the severity of anxiety in PD patients were observed in the frontal and cingulate regions (R between -0.56 and -0.65). Whole-brain analysis revealed a significant cluster of cortical thinning in the left anterior cortex and the dorsolateral prefrontal cortex weakly associated with PAS total score across all groups (R = -0.25, p = 0.00201).ConclusionsThis study is the first to report a strong negative association between left lingual gyrus thickness and anxiety severity in PD. Additionally, anxiety in early PD is associated with cortical thinning in the fronto-cingulate region, mainly affecting left sided structures. Future studies should examine whether these cortical changes can predict the anxiety progression patterns or the treatment response in PD patients.
Body mass index, metabolically abnormal status, and incident Parkinson's disease: Data from the UK Biobank.
Yun HR, Son NH, Koh HB … +1 more , Chung SJ
J Parkinsons Dis · 2025 Nov · PMID 40791117 · Publisher ↗
BackgroundThe association between body mass index (BMI), metabolic conditions, and incident Parkinson's disease (PD) is quite complex.ObjectiveTo investigate the relationship between these variables, particularly the imp...
BackgroundThe association between body mass index (BMI), metabolic conditions, and incident Parkinson's disease (PD) is quite complex.ObjectiveTo investigate the relationship between these variables, particularly the impact of metabolically healthy overweight/obese on the risk of PD, in the general population.MethodsA total of 402,059 participants from the UK Biobank were categorized into four phenotypes according to the presence of overweight/obesity and/or metabolically abnormal status: overweight/obesity was defined as BMI ≥25 kg/m; metabolically abnormal status was defined as having one or more metabolic risk factors including elevated blood pressure, fasting glucose, or triglyceride level, or reduced high-density lipoprotein cholesterol level. Cox proportional hazard regression analyses using four different models were performed to compare the risk of developing PD among the four BMI-metabolic status phenotypes.ResultsDuring the median follow-up of 13.5 years, 2283 (0.6%) patients were newly diagnosed with PD. Cox regression models demonstrated that individuals with overweight/obesity and those with metabolic abnormalities were at a higher risk of developing PD than their counterparts. Compared with the metabolically healthy non-overweight group (reference group), the two metabolically abnormal groups (either overweight/obese or non-overweight) showed a higher incidence of PD. The metabolically healthy overweight/obese group exhibited a comparable risk of developing PD to the metabolically healthy non-overweight group.ConclusionsThis study demonstrated that metabolically abnormal conditions are more relevant to incident PD than overweight/obesity. In particular, a metabolically healthy overweight/obese status does not increase the risk of developing PD compared with a metabolically healthy non-overweight status.
A dose-finding study shows terazosin enhanced energy metabolism in neurologically healthy adults.
Schultz JL, Gander PE, Workman CD … +11 more , Boles Ponto LL, Cross S, Nance CS, Groth CL, Taylor EB, Ernst SE, Xu J, Uc EY, Magnotta VA, Welsh MJ, Narayanan NS
J Parkinsons Dis · 2025 Nov · PMID 40785306 · Publisher ↗
BackgroundParkinson's disease (PD) is a common neurodegenerative disease lacking treatments that modify progressive neuron loss. Terazosin (TZ) increases activity of the glycolytic enzyme phosphoglycerate kinase 1 and co...
BackgroundParkinson's disease (PD) is a common neurodegenerative disease lacking treatments that modify progressive neuron loss. Terazosin (TZ) increases activity of the glycolytic enzyme phosphoglycerate kinase 1 and could potentially benefit impaired brain bioenergetics in PD. Preclinical data are encouraging, but we lack human data on relationships between TZ dose and measures of TZ target engagement in women and men.ObjectiveThis study evaluated the dose-dependent effects of TZ on brain and systemic bioenergetics and safety and tolerability in neurologically healthy older adults.MethodsWe administered TZ (1, 5, and 10 mg/day) to 18 neurologically healthy 60-85-year-old people. We measured plasma and cerebrospinal fluid TZ concentrations and changes in levels of whole blood ATP, brain ATP with P magnetic resonance spectroscopy, cerebral metabolic activity with F-FDG PET imaging, and plasma metabolomics. We also assayed tolerability and safety.ResultsTZ crossed the blood-brain barrier, and 5 mg/day increased whole blood ATP and decreased brain F-FDG uptake. TZ 1 mg/day lacked significant effects, and 10 mg/day did not produce additional metabolic benefit compared to 5 mg/day. These effects were similar for both sexes. Mild dizziness occurred in 3 females and 1 male.ConclusionsThese findings in humans align with results from preclinical cell, animal, and epidemiological studies. Our data show that TZ increases markers of energy metabolism with a biphasic dose-response and suggest that 5 mg/day TZ may provide maximal benefit while minimizing adverse consequences of higher doses. These results lay groundwork for clinical trials in people with PD.
Can regulators have a role in facilitating the development of new medicines for Parkinson's disease?
Rosa MM, Balkowiec-Iskra E
J Parkinsons Dis · 2026 Jul · PMID 40770929 · Publisher ↗
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, and its prevalence has doubled in the past 25 years. New formulations of levodopa have recently been marketed that improved the ability to...
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, and its prevalence has doubled in the past 25 years. New formulations of levodopa have recently been marketed that improved the ability to treat PD, but in the European Union, no new active substance for PD has been marketed since 2015, whilst two new agents have been marketed elsewhere. In spite of being the most treatable neurodegenerative disorder, several unmet medical needs still exists in PD, and efforts both from researchers, drug developers and regulators are needed to facilitate further developments in the field. There are several reasons that may account for the lack of new treatments for PD. Regulatory agencies provide scientific advice and have developed several programs to foster drug development. This manuscript discusses the main obstacles identified in the development process, the present status of approvals in European Union and the United States, and the presently available mechanisms to optimize drug development and marketing.
DBS-STN&SNr combined stimulation versus DBS-STN monotarget stimulation for Parkinson's disease freezing: A comparative efficacy study.
Tan B, Chen T, Guo P … +7 more , Song P, Lin F, He S, Sun S, Wang X, He J, Yin X
J Parkinsons Dis · 2025 Nov · PMID 40760816 · Publisher ↗
BackgroundFreezing of gait (FOG) is a common and disabling symptom in patients with Parkinson's disease (PD), significantly impairing motor function and quality of life. While traditional deep brain stimulation (DBS) of...
BackgroundFreezing of gait (FOG) is a common and disabling symptom in patients with Parkinson's disease (PD), significantly impairing motor function and quality of life. While traditional deep brain stimulation (DBS) of the subthalamic nucleus (STN) provides some benefits, its efficacy in alleviating FOG remains limited. Combined stimulation of the STN and the substantia nigra pars reticulata (SNr) has recently emerged as a potentially superior approach.ObjectiveTo compare the efficacy of STN-only stimulation and combined STN + SNr stimulation in improving FOG symptoms and quality of life in patients with PD.MethodsThis multicenter, prospective, randomized, crossover study was conducted between May 2020 and May 2024 and enrolled patients with PD and significant FOG. All participants received bilateral DBS electrode implantation. Each subject sequentially underwent both STN-only and combined STN + SNr stimulation conditions according to a randomized crossover schedule, with each stimulation period lasting for six months. Outcome assessments, including the Freezing of Gait Questionnaire (FOG-Q) and the Parkinson's Disease Questionnaire Summary Index (PDQ-SI), were conducted at baseline, 6, 12, and 18 months. Data were analyzed using mixed-model repeated-measures analysis of variance, followed by post hoc Bonferroni-adjusted pairwise comparisons to account for the crossover design.ResultsCompared to STN-only stimulation, combined STN + SNr stimulation resulted in significantly greater improvement in FOG-Q scores and PDQ-SI scores. The benefits were observed at each assessment following the switch to combined stimulation.ConclusionsCombined STN and SNr stimulation was more effective than STN-only stimulation in alleviating FOG symptoms and improving quality of life in patients with PD. This dual-target DBS approach may represent a promising therapeutic strategy for managing refractory FOG in PD.
Shades of grey: The continuum of therapies for Parkinson's disease along the spectrum of credibility.
Alonso-Canovas A, Dekkers OM, Bloem BR
J Parkinsons Dis · 2025 Nov · PMID 40746025 · Publisher ↗
Complementary and alternative therapies (CAT) is an umbrella term applied to a diverse set of approaches, with high interest among persons with Parkinson's disease. However, scientific community regards evidence-based me...
Complementary and alternative therapies (CAT) is an umbrella term applied to a diverse set of approaches, with high interest among persons with Parkinson's disease. However, scientific community regards evidence-based medicine as the only acceptable, creating a black and white dichotomy, which is neither epistemologically correct nor workable in daily practice. CAT are heterogeneous, and the label is dynamic as new scientific insights might accrue. Medicine encompasses a wide range of interventions that can be positioned alongside a spectrum of credibility, with many shades of grey between the extremes. We define credibility along three dimensions: the underlying rationale, the scientific rigor, and patient perceptions. By no means this implies we encourage adoption of weakly grounded therapies, or favor exotic treatments over evidence-based approaches. Credibility serves as basis for a nuanced debate in clinical practice, with attention to adverse effects, interactions, and costs. The degree of credibility also informs the need for further research. This offers a practical road forward for open-minded, yet rational decisions by persons with Parkinson's disease, clinicians, funding bodies and relevant stakeholders.
Progression to Parkinson's dementia is not modulated by genetic risk variants for Alzheimer's or Parkinson's disease.
Parveen K, Ross JA, van der Wurp H … +20 more , Balzer-Geldsetzer M, Berg D, Deuschl G, Gasser T, Hilker-Roggendorf R, Kalbe E, Liepelt-Scarfone I, Mollenhauer B, Riedel O, Röske S, Schulz JB, Spottke A, Storch A, Trenkwalder C, Kassubek J, Witt K, Dodel R, Wüllner U, Ramirez A, Dalmasso MC
J Parkinsons Dis · 2025 Nov · PMID 40739885 · Publisher ↗
Parkinson's disease (PD) is marked by motor symptoms and often accompanied by mild cognitive impairment (PD-MCI), affecting up to 50% of patients and preceding PD dementia (PDD). Genetic factors may influence this progre...
Parkinson's disease (PD) is marked by motor symptoms and often accompanied by mild cognitive impairment (PD-MCI), affecting up to 50% of patients and preceding PD dementia (PDD). Genetic factors may influence this progression, yet the underlying mechanisms remain unclear. This study investigated genetic factors influencing the progression from PD-MCI to PDD using polygenic risk scores (PRS). A genome-wide association study (GWAS) was conducted using data from the LANDSCAPE study. Multivariable Cox regression, Kaplan-Meier survival analysis, and concordance statistics assessed the relationship between PRS and PDD progression. No significant association was found between PD PRS and the risk of developing PDD.
Early detection of Parkinson's disease: Machine learning-based prediction of UPDRS Part III scores in patients using smartphone assessments.
Guo WH, Yang XD, Ruan Z … +5 more , Wang X, Zhang DZ, Song SC, Chen YQ, Chan P
J Parkinsons Dis · 2025 Sep · PMID 40725991 · Publisher ↗
BackgroundDetecting motor symptoms in Parkinson's disease (PD) at home, especially in the prodromal, is crucial for disease-modifying therapies.ObjectiveTo evaluate the effectiveness of machine learning models using smar...
BackgroundDetecting motor symptoms in Parkinson's disease (PD) at home, especially in the prodromal, is crucial for disease-modifying therapies.ObjectiveTo evaluate the effectiveness of machine learning models using smartphone-based assessments in predicting motor symptoms in untreated PD.MethodsUsing a clinical trial in early patients with PD, the PDAssist smartphone application and machine learning models were investigated for eight motor tasks: resting tremor, postural tremor, finger tapping, facial expressions, rigidity, speech, walking, and pronation/supination to predict motor symptoms of PD as comparing with UPDRS Part III scores.ResultsOur prediction model demonstrated acceptable performance in detecting PD mild symptoms, with accuracy ranging from 0.87 to 0.93 for resting tremor, postural tremor, finger tapping, facial expressions and postural stability, while the rigidity model achieved 0.81 accuracy with a Kappa of 0.74, and the speech model showed 0.79 accuracy and 0.61 Kappa, emphasizing its potential for detecting subtle motor deficits and remote monitoring. External validation confirmed the model's robustness, with significantly higher predicted scores (all tasks) for PD patients (9.45 ± 3.08) compared to healthy controls (3.79 ± 1.99, t = -14.27, p < 0.001), validating its ability to differentiate between the two groups.ConclusionsSmartphone-based assessments effectively discriminate de novo PD patients from controls and monitor motor symptoms in prodromal and early PD patients. Future work will involve expanding patient cohorts and refining algorithms for better generalizability and reliability of self-collected data in home settings.
Utility of a newly created questionnaire on subtle motor symptoms in high-risk subjects with Parkinson's disease.
Tamakoshi D, Hiraga K, Fukushima T … +10 more , Uematsu T, Tsuboi T, Sato M, Hattori M, Satake Y, Hashizume A, Yamamoto M, Shimizu H, Wakai M, Katsuno M
J Parkinsons Dis · 2025 Sep · PMID 40717462 · Publisher ↗
BackgroundProdromes of Parkinson's disease (PD) include both motor and non-motor symptoms. Although questionnaires have been established for non-motor symptoms, no quantitative self-assessment tool has been developed to...
BackgroundProdromes of Parkinson's disease (PD) include both motor and non-motor symptoms. Although questionnaires have been established for non-motor symptoms, no quantitative self-assessment tool has been developed to assess subtle motor symptoms during the prodromal stage.ObjectiveTo develop a self-administered questionnaire to assess subtle motor symptoms during the prodromal stage.MethodsWe created the Screening Questionnaire for Subtle Parkinsonism (SQSP). The SQSP and questionnaires on non-motor symptoms were collected from health checkup examinees. Individuals with ≥ 2 non-motor symptoms, including autonomic dysfunction, hyposmia, and REM sleep behavior disorder, were classified as high-risk, while those without these symptoms were low-risk. We also conducted comprehensive evaluations, including neurological examinations and imaging tests, on 30 patients with PD, 71 high-risk, and 24 low-risk subjects.ResultsAmong 1183 health checkup examinees, high-risk subjects had higher SQSP scores than low-risk (9 [4-15] vs. 3 [1-6]). Patients with PD had the highest SQSP scores, followed by high-risk subjects and then low-risk. SQSP scores correlated with MDS-UPDRS II and III scores and specific binding ratios of DaT-SPECT. High-risk subjects with abnormal DaT-SPECT had higher SQSP scores than those with normal imaging (9 [7-19] vs. 5.5 [2-10]). Although 26 of the 71 high-risk and 23 of the 24 low-risk subjects scored zero on the MDS-UPDRS II, most high-risk and half low-risk subjects had SQSP scores above zero.ConclusionsThe SQSP was deemed effective for assessing subtle motor symptoms during the prodromal stage of PD and identifying prodromal PD cases within the general population.
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