JOURNAL/nrgr/04.03/01300535-202512000-00025/figure1/v/2025-01-31T122243Z/r/image-tiff In clinical specialties focusing on neurological disorders, there is a need for comprehensive and integrated non-invasive, sensitive, and specific testing methods. Both Parkinson's disease and multiple system atrophy are classified as α-synucleinopathies, characterized by abnormal accumulation of α-synuclein protein, which provides a shared pathological background for their comparative study. In addition, both Parkinson's disease and multiple system atrophy involve neuronal death, a process that may release circulating cell-free DNA (cfDNA) into the bloodstream, leading to specific alterations. This premise formed the basis for investigating cell-free DNA as a potential biomarker. Cell-free DNA has garnered attention for its potential pathological significance, yet its characteristics in the context of Parkinson's disease and multiple system atrophy are not fully understood. This study investigated the total concentration, nonapoptotic level, integrity, and cell-free DNA relative telomere length of cell-free DNA in the peripheral blood of 171 participants, comprising 76 normal controls, 62 patients with Parkinson's disease, and 33 patients with multiple system atrophy. In our cohort, 75.8% of patients with Parkinson's disease (stage 1-2 of Hoehn & Yahr) and 60.6% of patients with multiple system atrophy (disease duration less than 3 years) were in the early stages. The diagnostic potential of the cell-free DNA parameters was evaluated using receiver operating characteristic (ROC) analysis, and their association with disease prevalence was examined through logistic regression models, adjusting for confounders such as age, sex, body mass index, and education level. The results showed that cell-free DNA integrity was significantly elevated in both Parkinson's disease and multiple system atrophy patients compared with normal controls ( P < 0.001 for both groups), whereas cell-free DNA relative telomere length was markedly shorter ( P = 0.003 for Parkinson's disease and P = 0.010 for multiple system atrophy). Receiver operating characteristic analysis indicated that both cell-free DNA integrity and cell-free DNA relative telomere length possessed good diagnostic accuracy for differentiating Parkinson's disease and multiple system atrophy from normal controls. Specifically, higher cell-free DNA integrity was associated with increased risk of Parkinson's disease (odds ratio [OR]: 5.72; 95% confidence interval [CI]: 1.54-24.19) and multiple system atrophy (OR: 10.10; 95% CI: 1.55-122.98). Conversely, longer cell-free DNA relative telomere length was linked to reduced risk of Parkinson's disease (OR: 0.16; 95% CI: 0.04-0.54) and multiple system atrophy (OR: 0.10; 95% CI: 0.01-0.57). These findings suggest that cell-free DNA integrity and cell-free DNA relative telomere length may serve as promising biomarkers for the early diagnosis of Parkinson's disease and multiple system atrophy, potentially reflecting specific underlying pathophysiological processes of these neurodegenerative disorders.

Accurate diagnosis of Parkinson disease (PD) remains challenging, with variability and clinical uncertainty, especially in nonspecialized settings. Despite advancements in diagnostic criteria and biological markers, misdiagnosis continues to affect patient care and research. This study aimed to assess the long-term diagnostic stability of PD and evaluate the accuracy of initial diagnoses over time in a large, consecutive cohort diagnosed by neurologists, with or without movement disorder specialization.

We conducted a retrospective longitudinal analysis of patients diagnosed with PD between 2006 and 2020. Patient records were reviewed over a median follow-up period of 10 years, with more than half of the cohort tracked from motor symptom onset to death. Diagnostic evaluations included dopamine transporter (DAT) imaging and neuropathologic examinations for a subset of patients, based on clinical indications. Two movement disorder specialists cross-validated diagnoses through retrospective chart reviews.

The cohort included 1,626 patients (mean age 69.0 years, 44.1% female). Of these, 10.6% (n = 172) had their diagnoses revised by treating neurologists, and 2.7% (n = 44) were revised based on chart reviews or neuropathologic findings. The median time to diagnosis revision was 22 months (interquartile range = 43). The most common revised diagnoses were vascular parkinsonism, progressive supranuclear palsy, and multiple system atrophy, with 4.7% (n = 77) classified as clinically undetermined parkinsonism. In a secondary analysis separating PD and dementia with Lewy bodies (DLB), the revision rate increased to 17.7%. DAT imaging had been performed on 588 patients and was more frequently used in revised cases. Postmortem neuropathologic examinations had been conducted in only 3% of deceased patients, with 64% confirming the initial PD diagnosis.

This study demonstrates significant diagnostic instability in PD, with 13.3% of diagnoses revised, primarily within 2 years. When DLB is considered separately, the revision rate increases to 17.7%. Despite frequent DAT imaging and limited postmortem examinations, clinical uncertainty persists among practicing neurologists, contrasting with lower misdiagnosis rates in specialized centers. These findings highlight the need for systematic application of diagnostic criteria, regular reevaluation of diagnoses, more frequent autopsies, and the development of accessible diagnostic biomarkers.

Beyond its hallmark motor symptoms, Parkinson's disease (PD) encompasses a range of non-motor disturbances, particularly cognitive impairment, which significantly affects patients' quality of life. Cognitive impairment is a shared manifest in both PD and Alzheimer's disease (AD), two prevalent neurodegenerative disorders. Existing literature has identified the WWOX/MAF genes as potential risk factors for AD, but their role in cognitive functions among PD remains unclear.

This study examines the influence of AD-associated risk genes, specifically WWOX/MAF, on cognitive function in PD, aiming to bridge the neuropathological gap between AD and PD.

A total of 402 participants were included in this study, comprising 150 individuals with PD and 252 healthy controls (HC).

Participants underwent comprehensive neuropsychological assessment and genotyping. A moderation regression model was employed to assess the impact of WWOX/MAF single nucleotide polymorphisms on cognitive function and the potential modulatory effect of PD.

The WWOX gene was found to influence verbal fluency performance across the entire cohort. Additionally, PD significantly moderated the effect of genetic variants on attention (p = 0.000040), non-verbal memory (p = 0.000007), and visuospatial function (p = 0.000303), suggesting a distinct impact within this group. Further analysis indicated that cognitive status moderated the effect of genetic variants on verbal memory across the entire cohort (p < 0.001). Among individuals with PD, genetic variants also influenced verbal fluency (p = 0.000113) and verbal memory (p = 0.000440 and p = 0.000032).

These findings underscore the critical role of WWOX/MAF genes in cognitive impairments associated with PD, enhancing our understanding of their connection to AD and providing deeper insights into neurodegenerative disease progression.

The loss of locus coeruleus (LC)-norepinephrine system may contribute to freezing of gait (FOG) in Parkinson's disease (PD), but free-water (FW) imaging has not been applied to investigate LC microstructural degeneration in FOG. This study was to investigate the role of the LC-norepinephrine system in FOG pathophysiology using FW imaging and resting-state functional magnetic resonance imaging.

FW metrics of LC were analyzed in 52 healthy controls, 79 PD patients without FOG (Non-FOG), and 110 PD patients with FOG (48 "Off-period" FOG and 62 "Levodopa unresponsive" FOG). Correlation between LC FW metrics and clinical scales were assessed. Functional connectivity analysis with LC as the region of interest was performed across groups during medication withdrawal. Structural and functional differences in LC between FOG subgroups and the effects of dopaminergic medication were also explored.

FOG patients had increased FW value, FW-corrected mean diffusivity, axial diffusivity, and radial diffusivity in LC, and decreased FW-corrected fractional anisotropy compared to Non-FOG patients and healthy controls. In FOG patients, FW value and FW-corrected mean axial diffusivity were positively correlated with the new FOG questionnaire scores. LC functional connectivity with occipital regions was reduced in FOG patients. No significant differences in LC microstructure or functional connectivity were observed between FOG subgroups during their "OFF" state. In contrast to "Levodopa-unresponsive" FOG patients, oral medication significantly improved LC functional connectivity with occipital regions in "Off-period" FOG patients.

LC degeneration may disrupt motor and compensatory network integration, especially in visual-motor pathways, contributing to FOG.

Epidermal growth factor (EGF) has been shown to have neuroprotective effects in Parkinson's disease (PD). However, there is a lack of research on the association between plasma EGF levels and cognitive impairments in PD patients.

The study included 135 PD patients. Plasma EGF concentrations were measured. PD patients without cognitive impairment were followed up for clinical assessment at an average of 2 ± 0.6 years.

PD patients with cognitive impairment (PD-CI) had lower baseline plasma EGF concentrations compared to PD patients without cognitive impairment. Linear regression analysis demonstrated a significant correlation between baseline plasma EGF concentrations and baseline Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST) scores in PD patients. However, no significant association was found between plasma EGF concentrations and Hopkins Verbal Learning Test-Delayed Recall (HVLT-DR), Semantic Fluency Test (SFT), Clock Drawing Test (CDT), Trail Making Test (TMT) A, or TMT B scores. Furthermore, logistic regression analysis revealed that baseline plasma EGF concentrations were associated with cognitive decline in PD patients without cognitive impairment in adjusted regression models (HR 0.977, 95% CI 0.955-0.999, p = 0.045), after adjusting for various factors. The area under the curve (AUC) for cognitive decline at follow-up time was 0.704 (95% CI 0.600-0.809), and the optimal cut-point for baseline plasma EGF concentrations was determined to be 49.56 pg/mL, with a sensitivity of 49.3% and specificity of 92.3%.

In conclusion, our study found a correlation between baseline plasma EGF concentrations and cognitive dysfunction in PD.

Anxiety disorder is one of the most common and disabling neuropsychiatric syndromes in patients with Parkinson's disease (PD), seriously affecting the quality of life and prognosis of PD patients.

The objective of this study was to analyze the risk factors for anxiety in PD patients and to evaluate the effectiveness of cognitive behavioral therapy (CBT) in treating PD with anxiety disorder (PDAD).

Baseline data were recorded for 211 PD patients and 139 PDAD patients, and multi-factorial and independent risk factors for anxiety disorder in PD patients were analyzed. ​The 139 PDAD patients were divided into clinical testing (CMO) and CBT groups. Assessments were taken at baseline and after the end of the intervention. A 5-month follow-up survey was conducted after the intervention. The mouse PD model was induced by MPTP, and the anxiety state of mice was detected by rotarod test and open-field test. The expression of BDNF/PI3K/Akt protein in serum and mouse brain was detected by western blot.

PDAD patients had significantly higher HAMA scores than PD patients. PSQI, ESS, HAMD, SCOPA-AUT, UPDRS-III and Hoehn-Yahr were independent risk factors for anxiety disorder in PD patients. After the intervention, the psychological state, cognitive function and quality of life improved in both the CMO and CBT groups, with the CBT group showing better improvement Results from follow-up showed that the number and frequency of falls was lower in the CBT group than in the CMO group, and that patients were more satisfied with the CBT intervention than the CMO group. L-dopa treatment alleviated anxiety in PD mice. L-dopa treatment increased BDNF, p-PI3K, and p-Akt protein levels. Moreover, the combination of L-dopa and CBT enhanced the boosting effect of L-dopa on these proteins.

CBT is an effective treatment for anxiety in patients with Parkinson's disease. Medications combined with CBT have been shown to be effective in improving depression, anxiety and quality of life in PDAD patients.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. The non-motor features may precede the onset of motor symptoms and occur throughout all stages of PD. The non-motor symptoms reflect multisystem involvement of the central and peripheral nervous systems, multiple neurotransmitters, and multiple pathologies. PD management necessitates a comprehensive approach to address non-motor symptoms, including pharmacologic and non-pharmacological interventions and often multiple different disciplines or specialists in the PD care team. This review article discusses symptoms and treatments for the non-motor symptoms of PD including those affecting mood, cognition, behavior, sleep, autonomic function, and sensory systems.

According to certain research, there might be a connection between Parkinson's disease and plasma lipidome. However, the causal effects between plasma lipidome and Parkinson's disease and whether immune cells act as a mediator remain unclear. According to some research, plasma lipids are an important risk factor for Parkinson's disease, however, whether there is a causative connection between the two is unclear. In this study, Mendelian randomization (MR) was utilized to investigate the causal effect of plasma lipidomics on Parkinson's disease while conducting mediation analysis to determine whether immune cells served as mediators in this association. Plasma lipidome, immune cells, and Parkinson's disease were identified from large-scale genome-wide association studies (GWAS) summary data. We explored the causal connections between the plasma lipidome, Parkinson's disease, and the immune system using Mendelian randomization (MR). Inverse variance weighting (IVW) was used as the main statistical method. Furthermore, we investigated the potential that immune cells play a mediating role in the pathway leading from the plasma lipidome to Parkinson's disease. There were two positive and four negative causal effects between genetic liability in the plasma lipidome and Parkinson's disease. In addition, there were four positive and three negative causal relationships between immune cells and Parkinson's disease. The immune cells function as a mediator. Immune cells functioned as mediating components in the pathway from plasma lipidome to Parkinson's disease, and both plasma lipidome and immune cells were causally related to Parkinson's disease. It is expected that immune cells and plasma lipid intervention can be used as a preventive and therapeutic strategy for Parkinson's disease.

Sleep disturbance (SD) is common in Parkinson's disease (PD) and adversely affect the quality of life (QOL). Although dopamine dysfunction has been implicated, the specific role of dopaminergic activity in SD among patients with PD remains unclear. Given that dopamine-related medications can affect sleep, it is essential to assess SD in drug-naïve patients. This study investigated the association between SD and uptake of striatal dopamine transporters using Dopamine Transporter Single-Photon Emission Computed Tomography with 123I-Ioflupane (DAT-SPECT).

We retrospectively analyzed 112 drug-naïve patients through the PD Sleep Scale-version-2 (PDSS-2) and DAT-SPECT. Patients were divided into SD and non-SD groups using a PDSS-2 cut-off score of 15. The Mann-Whitney U test and binomial regression were used to compare the groups.

SD was identified in 47.3 % of participants, correlating significantly with increased age, more severe motor symptoms, cognitive decline, depressive symptoms, and reduced QOL scores. Binomial regression analyses-adjusted for sex, age, motor dysfunction, cognitive function, and nocturnal autonomic cardiovascular dysfunction-showed that reduced DAT-SPECT uptake in the left anterior and posterior putamen significantly contributed to higher PDSS-2 scores.

This study demonstrated a link between SD and putamen DAT-SPECT uptake in drug-naïve patients with PD, indicating the role of dopamine in sleep regulation. These findings underscore the importance of managing SD in patients with PD to improve QOL and suggest the need for further investigation of the impact of dopaminergic dysfunction on sleep.

The most effective pharmacologic intervention used to treat motor symptoms in Parkinson's disease is levodopa, which is available in various formulations, including newer continuous subcutaneous infusions. Dopamine agonists, monoamine oxidase-B enzyme inhibitors, catechol-O-methyltransferase enzyme inhibitors, amantadine, istradefylline, and anticholinergics can be used as adjuncts to levodopa. With disease progression, pharmacologic interventions alone may not suffice to manage motor symptoms, making it necessary to consider device-aided therapies (eg, levodopa-carbidopa intestinal gel infusion, continuous subcutaneous infusions of apomorphine, levodopa, or foslevodopa) or invasive surgical techniques (eg, deep brain stimulation or MRI-guided high-frequency focused ultrasound).

ObjectiveThe study aimed to evaluate the impact of Botulinum toxin A (BoNT/A) on neuropsychiatric symptoms in Parkinson's disease (PD) patients.MethodsA total of 125 PD patients and an equal number of age- and gender-matched healthy controls were involved. Mental health status was assessed using the Cornell Medical Index (CMI) self-assessment questionnaire. Sixty-four PD patients exhibiting neuropsychiatric symptoms were selected for the controlled study and randomly grouped into treatment and control groups. The treatment group received BoNT/A injections, while the control group received a placebo. The primary outcome measures included depression scores from the CMI and the proportion of patients displaying improvement in neuropsychiatric symptoms at 8 weeks post-treatment. The secondary outcome was other CMI scores at 4, 8, and 12 weeks post-treatment.ResultsThe outcomes revealed that PD patients had significantly higher scores in various neuropsychiatric factors compared to healthy controls. At 4 weeks post-treatment, the treatment group displayed improvements in depression and tension. At 8 weeks post-treatment, they exhibited significant reductions in depression, anxiety, sensitivity, and tension compared to the control group. Moreover, a notably higher percentage of patients in the treatment group showed improvement in neuropsychiatric symptoms compared to the control group. At 12 weeks post-treatment, the treatment group exhibited significant improvements in somatization, depression, sensitivity, and tension.ConclusionPD patients commonly experience multiple neuropsychiatric symptoms, and BoNT/A has demonstrated efficacy in alleviating these symptoms. Specifically, BoNT/A was found to effectively alleviate somatization, tension, anxiety, depression, and sensitivity in PD patients.

Psychosis remains problematic in patients with Parkinson's disease and sleep disorders are frequent non-motor symptoms of PD. Few research studies have correctly assessed objective sleep architecture to determine the association between psychosis and sleep disorders. A mobile two-channel electroencephalography (EEG)/electrooculography (EOG) recording system is a self-applicable and affordable method for objectively measuring sleep at home. We studied patients with PD who were enrolled in ZEAL study of the randomized placebo-control clinical trial investigating the efficacy of zonisamide for sleep disorders to determine whether sleep disorders and psychosis are related by using the EEG/EOG recording system.

24 independent variables were evaluated and variables with a statistically significant correlation (p < 0.05) to psychosis on univariate logistic regression analyses were entered into multivariate logistic regression analysis using forced entry.

Forty-one patients with PD with no missing data, in both the potable EEG/EOG recording device and subjective clinical characteristics before the initiation of zonisamide, were analyzed. The major result was the reduced total sleep time (TST) and time spent in REM sleep, identified by univariate logistic regression analysis, in PD patients with psychosis. Multivariate logistic regression analysis identified nocturnal PD symptoms on the PDSS as a significant risk factor for psychosis (OR 1.409, 95 %CI 1.073-1.850; p = 0.014).

Our findings reveal that the nocturnal PD symptoms that affect regular home-based sleep may be associated with psychosis.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by its aggressive nature. Its main clinical features include autonomic dysfunction, Parkinson's disease, and cerebellar ataxia.

We conducted a comprehensive review of the existing literature, exploring studies and reports related to the mechanisms and treatment of multiple system atrophy related neurogenic bladder. Our aim is to provide a detailed and up-to-date overview of its underlying pathophysiology and current therapeutic strategies.

Neurogenic bladder, a common manifestation of MSA, often goes untreated or mistreated, significantly affecting patients' quality of life. Early-stage bladder dysfunction is frequent in MSA patients and correlates with disease severity. The mechanisms of MSA related neurogenic bladder are related to the autonomic nervous system, somatic nerves, frontal cortex, brainstem, and sacral medulla center. Currently, treatment for MSA related neurogenic bladder is mainly symptomatic, and specific drugs are lacking. Further in-depth research is needed to develop more effective therapeutic options that improve patients' quality of life and reduce the risk of complications.

The most characteristic motor feature of Parkinson's disease is bradykinesia. Other cardinal motor features of Parkinson's disease include tremor (particularly rest tremor), rigidity, and postural instability/gait changes. Additional motor features common to the disease include dystonia, postural abnormalities, speech and swallowing dysfunction, and levodopa-related dyskinesias. The pathophysiology of many of these motor features remains poorly understood. During the natural course of the disease, nonmotor features (discussed elsewhere) often precede the onset of motor features and meaningfully contribute to motor disability and the gradual decline in the quality of life.

Constipation is one of the most common non-motor symptoms in patients with Parkinson's disease (PD), which could manifest during the early stage of the disease. However, the etiology of constipation in PD remains largely unknown. Previous studies supported that gastrointestinal dysfunction may be associated with functional connectivity alterations in paraventricular hypothalamic nucleus (PVN). Therefore, this study aimed to investigate the potential contribution of the PVN to the pathogenesis of constipation in a cohort of early-stage patients with PD and to compare brain network organization between PD patients with and without constipation.

A total of 66 PD patients (PD with constipation and without constipation) and 30 healthy controls were prospectively enrolled. All participants acquired T1-weighted and resting-state fMRI scans. Then we employed voxel-based morphometry analysis and functional connectivity analysis.

We observed a decreased functional connectivity in the PVN-pontine tegmentum pathway in PD patients with constipation compared to the patients without constipation (p = 0.006, t = 5.37), while we did not find any changes in basal ganglia circuitry between these two groups. In addition, we found that the functional connectivity between PVN and pontine tegmentum was negatively associated with the UPDRS I, II, III and NMSS scores (p < 0.05). Meanwhile, these two types of patients also showed substantial differences in functional connections linking the inferior frontal gyrus and cerebellum with multiple brain regions. We discovered no statistical difference in gray matter volume among these two groups.

Our study provides further insights into the dysfunctional mechanisms of constipation, suggesting that abnormal PVN functional connectivity may be related to the mechanism of constipation in PD. Meanwhile, the inferior frontal gyrus and cerebellum may be involved in the occurrence of constipation in PD patients.

Isolated REM sleep behavior disorder (iRBD) is a prodromal state of α-synucleinopathies, presenting years before overt neurodegenerative disorders. Autonomic nervous system (ANS) involvement, particularly cardiovascular autonomic failure, may indicate progression. However, its role as a (multidimensional) marker for disease progression and phenoconversion remains unclear. This study aimed to investigate whether cardiovascular autonomic failure and symptoms of autonomic dysfunction serve as multidimensional markers in patients with iRBD.

We conducted a prospective cohort study of patients with iRBD (iRBDs) and controls. Participants underwent cardiovascular reflex tests (CRTs) with beat-to-beat monitoring of blood pressure (BP) and ANS symptom assessments at baseline and annually. Primary outcomes were prevalence and progression of cardiovascular autonomic failure and the risk factors of phenoconversion. Longitudinal changes were evaluated through mixed-effects regression, predictors associated with conversion with Cox regression analysis.

Sixty-four iRBDs (mean age 68.89 ± 6.75 years, 75% male) and 67 controls (66.57 ± 7.91 years, 68% male) were recruited. At baseline, iRBDs exhibited a prevalent sympathetic cardiovascular dysfunction, with more frequent neurogenic orthostatic hypotension (nOH in 9 iRBDs) and abnormal BP responses to CRTs (pathologic Valsalva maneuver [VM] overshoot in 27 iRBDs). Longitudinal data demonstrated progressive deterioration of sympathetic baroreflex function, with increased prevalence of nOH (7 iRBDs with incident nOH; yearly odds ratio [OR] = 2.44) and deterioration of parasympathetic cardiovagal function. Thirteen patients (20.3%) phenoconverted to α-synucleinopathies. Neurogenic OH (hazard ratio [HR] = 5.05), altered sympathetic baroreflex function (pathologic VM HR = 3.49), and blunted parasympathetic cardiovagal responses (pathologic deep breathing heart rate ratio HR = 3.27) were significant risk factors for phenoconversion; their early appearance 5 years from iRBD onset increased the conversion risk, up to 4-fold. Symptoms of autonomic failure were more prevalent in iRBD and deteriorated over time but failed to predict conversion.

Progressive deterioration of cardiovascular autonomic function is a feature of iRBDs and affects the risk of phenoconversion. Limitations include the relatively short follow-up period and small number of converters. This study highlights the importance of objective cardiovascular autonomic testing as a multidimensional marker for risk stratification in iRBD.

The complexity of α-synucleinopathies, namely Parkinson's disease (PD) and multiple system atrophy (MSA), calls for the adoption a multimodal approach integrating biological, morphological, and functional data. Phosphorylated α-synuclein (α-syn) detection in bodily fluids and tissues such as the skin helps provide biological characterization of the disease, but specific and accessible biomarkers are not available yet. The aim of this study was to define the role of Optical Coherence Tomography (OCT, a minimally invasive retinal imaging technique) patterns as possible biomarkers in the early stages of α-synucleinopathies, also supporting the differential diagnosis. Thirty-five (23 PD, 12 MSA), clinically, biologically and genetically characterized patients included in the PADUA-CESNE (Centro Studi per la Neurodegenerazione) cohort underwent OCT. A significant atrophy in the inferior, superior and temporal regions of the Retinal Nerve Fiber Layer (RNFL) and in the inner nuclear layer (INL) were observed in PD compared to controls, differently from MSA. Hyperreflective foci (HRF) counts were elevated across all retinal layers in all patients with PD exhibiting significantly higher numbers, suggesting microglial activation and greater retinal damage. Further research regarding OCT patterns in PD and MSA may consolidate the role of specific features, such as INL abnormalities and different HRF counts, in supporting the diagnosis and differential diagnosis in α-synucleinopathies. In light of the availability of potentially disease-modifying therapies, studies should focus on newly diagnosed patients, also undergoing thorough clinical, biological and genetic characterization.

Diffusion tensor image analysis along the perivascular space (DTI-ALPS) is a potential non-invasive marker of glymphatic function that typically relies on manual region of interest (ROI) placement. This study compared ALPS indices in treatment-naïve, de novo diagnosed patients with Parkinson's disease (PD), patients with isolated REM behavior disorder (iRBD), and healthy controls using both manual and automatic approaches to the ROI selection used in ALPS-index calculation. ALPS indices were analyzed bilaterally and correlated with clinical severity (MDS-UPDRS) and nigrostriatal denervation (DAT-SPECT). ANCOVA revealed significant inter-group differences using both manual (p = 0.018) and automatic (p = 0.002) ROI selection methods. The automatic ROI selection approach showed significantly lower ALPS indices in PD compared to controls (p = 0.001) and iRBD (p = 0.009). ALPS indices correlated with symptom severity and nigrostriatal denervation. These findings underscore the reliability of the automatic ROI placement approach for ALPS index calculation and may indicate early glymphatic alterations in Parkinson's disease.

The neurodegenerative condition known as Parkinson's disease (PD) is a long-term condition that causes both motor and non-motor symptoms. It is known that curcumin has a strong neuroprotective potential. This experimental study was designed to examine the anti-inflammatory, anti-apoptotic and neuroprotective effects of curcumin administered alone and in combination with L-DOPA in the hippocampus as well as behavioral symptoms in rotenone-induced PD model. Forty-two 4-month-old adult male Wistar rats were randomly divided into six groups as follows: Control, Curcumin, Rotenone, Rotenone plus curcumin, Rotenone plus L-DOPA and Rotenone plus curcumin plus L-DOPA. Control group received vehicles, curcumin group received curcumin (200 mg kg-1, daily for 35 days), rotenone group received rotenone (2 mg kg-1, daily for 35 days), and test groups received curcumin or L-DOPA (10 mg kg-1, daily for the last 15 days) or their combination in addition the rotenone. Pole, sucrose preference, open field, elevated plus maze, and Morris water maze tests were performed after treatment. Molecular and biochemical analyses were performed in the hippocampus tissue and serum samples. Rotenone injection caused impairments in motor activity, depressive-like behavior, and learning and memory functions. Rotenone also increased the expressions of α-synuclein, caspase 3, NF-κB, and decreased the expressions of parkin and BDNF in the hippocampus. However, especially curcumin and L-DOPA combined treatment normalized all these impaired molecular and behavioral variables. In conclusion, curcumin may exert beneficial effects in treatment strategies for PD-related hippocampal effects, especially when added to L-DOPA therapy.

Parkinson's disease (PD) is a neurodegenerative disorder with a multifactorial etiology. This study aimed to investigate the association between vitamin D receptor (VDR) gene polymorphisms (ApaI, BsmI, FokI and TaqI) and the risk of PD in a Bangladeshi population. A case-control study was conducted with 100 PD patients and 100 age- and sex-matched healthy controls. Serum vitamin D levels were measured using a chemiluminescent immunoassay, and VDR gene polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genetic models (allele, dominant, recessive and additive models) were used to assess the association between each polymorphism and PD risk. The mean age of the patients with PD was 63 years, with 65% being male, while the control group had a mean age of 54.5 years and 60% were male. In genetic models, the T allele of the ApaI gene demonstrated a significant association with PD (OR 1.92, 95% CI 1.20-3.13, p-value 0.007). This significant association persisted across both recessive and additive models (for recessive model: OR 2.17, 95% CI 1.10-4.55, p-value 0.027 and for additive model: OR 2.78, 95% CI 1.22-6.67, p-value 0.015). Similarly, the T allele of the FokI gene was found to be significantly associated with PD (OR 2.27, 95% CI 1.43-3.57, p-value 0.001). This association was also evident in both dominant and additive models (for dominant model: OR 2.56, 95% CI 1.45-4.55, p-value 0.001 and for additive model: OR 3.03, 95% CI 1.67-5.56, p-value 0.001). Conversely, no significant associations were observed for the genetic polymorphisms of the BsmI and TaqI genes across any of the genetic models examined. The findings suggest that specific VDR gene polymorphisms, particularly ApaI and FokI, are significantly associated with the risk of PD in the Bangladeshi population.

Background: This study aimed to evaluate the efficacy of a theatre-based intervention for patients with Parkinson's disease (PD). To this end, we assigned participants to two types of intervention: a) theatre-based, which included both active and passive participation activities (Teatre Lliure, Barcelona, Spain), and b) cognitive stimulation (memory and attention) at home (Barcelona, Spain).Method: Before and after the intervention, participants were assessed on cognition (memory, language, and executive functions), mood (depression and anxiety), emotional state (apathy and anhedonia), and quality of life (Parkinson's Disease Questionnaire, PDQ-39).Results: By comparing participants' performance pre- and post-intervention, it could be seen that they reported cognitive improvements on the PDQ-39. In addition, depressive symptoms and anxiety decreased significantly after the intervention in both groups. However, emotional well-being improved only in participants enrolled in the theatre-based intervention.Conclusions: In conclusion, our study findings demonstrated that theatre-based interventions have specific benefits for emotional well-being and non-specific benefits in terms of reducing depressive symptoms and anxiety, as well as self-perceived cognitive improvement.

Manual dexterity deficits impair the ability to effectively use touchscreen devices in people with Parkinson's disease (PD).

To examine the effects and feasibility of a home-based, unsupervised tablet-task training on task-specific performance in a randomized controlled trial and to determine which individuals are likely to benefit.

Thirty-four PD patients were randomized and included into an experimental training (EXP, N = 16) and passive control group (CTL, N = 18). The EXP practiced a Swipe-Slide Pattern (SSP) task on a tablet (5x/week for 2 weeks) as fast and accurately as possible in single and dual task conditions. Performance on the SSP and an untrained mobile phone task (MPT) were tested before and after two weeks of training and after four weeks follow-up. SSP-Time (primary outcome), SSP-Accuracy (% correct) and MPT-Time were recorded. Linear mixed models were used to assess training effects.

The home-based task-specific training program significantly improved the SSP-Time immediately after training (p < 0.001, d = 0.917) and at follow-up (p = 0.006, d = 0.663), and showed excellent compliance rates (average 98%). No transfer occurred to the untrained MPT. Worse baseline SSP-performance and older age were significantly associated with short- and long-term gains (p < 0.010).

Home-based, unsupervised touchscreen training is feasible and effective to improve movement time of the trained task, albeit without transfer to an untrained task. The heterogeneity and variability of the effects underscore the importance of personalizing rehabilitation programs in PD, according to baseline performance. Future studies should investigate a wider range of transfer tasks and clinical determinants that could impact the training response.

https://clinicaltrials.gov/ : NTC05696197, retrospectively registered on January 13, 2023.

The pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) and its association with neurodegenerative disorders is poorly understood.

The aim was to determine the prevalence of α-synuclein pathology in iNPH and its associations with clinical characteristics.

We used α-synuclein seed amplification assay (synSAA) to retrospectively analyze cerebrospinal fluid (CSF) from a large single-center iNPH cohort (n = 144). Clinical assessments comprised Unified Parkinson's Disease Rating Scale part III, Mini-Mental State Examination, levodopa-challenge test, and olfactory identification test. Degenerative biomarkers (total-tau, phospho-tau, β-amyloid 1-42, and β-amyloid 1-40) were measured in CSF.

A total of 30.1% of iNPH patients were synSAA+, and presented significantly more upper limb (UL) rigidity, hallucinations, and worse olfactory performance than synSAA- cases. Anosmia was higher in synSAA+ patients (64.0%) than synSAA- patients (15.3%). Clinical assessments and other biomarkers did not significantly vary with synSAA status.

Underlying α-synuclein pathology is common in iNPH and presents with UL rigidity and olfactory dysfunction, suggesting a distinct synSAA+ phenotype in iNPH. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

This systematic review and meta-analysis evaluated the diagnostic performance of skin α-synuclein (α-syn) assays, focusing on key detection techniques.

A comprehensive search of PubMed, Web of Science, Embase, and Cochrane Library was conducted on April 6, 2024. Bivariate mixed-effects models were used to calculate pooled sensitivity and specificity with 95% confidence intervals (CIs) for each group and subgroup.

In distinguishing Parkinson's disease (PD) from healthy controls (HCs) or non-neurodegenerative controls (NNCs), overall sensitivity and specificity were 0.78 (95% CI 0.75-0.80) and 0.96 (95% CI 0.94-0.97), with seed amplification assays (SAA) showing the highest sensitivity (0.89, 95% CI 0.85-0.93) compared to immunofluorescence (IF) (0.82, 95% CI 0.78-0.85) and immunohistochemistry (IHC) (0.70, 95% CI 0.66-0.74). For differentiating PD from multiple system atrophy (MSA), sensitivity remained high (0.80, 95% CI 0.76-0.83), but specificity was low (0.25, 95% CI 0.20-0.31); SAA, IF and IHC all obtained low pooled specificities (less than 0.3). Discriminating from tauopathies, the pooled sensitivity and specificity were 0.82 (95% CI 0.77-0.86) and 0.88 (95% CI 0.81-0.92), with immunological methods using phosphorylated α-synuclein (p-α-syn) outperforming those using non-phosphorylated α-synuclein (np-α-syn); SAA had a higher sensitivity than immunology techniques.

Skin α-syn assays, particularly SAA and p-α-syn immunological methods, demonstrate strong potential as diagnostic tools for PD; SAA had a higher sensitivity than immunology techniques. However, distinguishing PD from other α-synucleinopathies is still challenging and variability across methods highlight the need for standardization. Further research should focus on integrating skin α-syn detection with other biomarkers to enhance diagnostic precision.

Two distinct patterns of alpha-synuclein spread in Parkinson's disease were proposed with a body-first and a brain-first subtype. The body-first subtype originates in the periphery, while the brain-first subtype initiates in the central nervous system, notably affecting the amygdala.

This retrospective cross-sectional study compared the integrity of the substantia nigra and amygdala between body-first and brain-first Parkinson's disease subtypes.

We analyzed data from 30 Parkinson's disease patients, classified into body-first (n = 21) and brain-first (n = 9) subtypes based on REM sleep behavior disorder history. Microstructural integrity was assessed using diffusion microstructure MRI.

No significant differences were found in the substantia nigra between subtypes. However, amygdala degeneration was significantly pronounced in the "brain-first" compared to the "body-first" group reflected by increased free interstitial fluid (p = 0.02, Cohen's d = -1.22).

The degeneration of amygdala is distinctively pronounced in "brain-first" Parkinson's disease, supporting differential disease progression patterns between subtypes.

As research on microRNAs (miRNAs) advances, it is becoming increasingly clear that these small molecules play crucial roles in the central nervous system (CNS). They are involved in various essential neuronal functions, with specific miRNAs preferentially expressed in different cell types within the nervous system. Notably, certain miRNAs are found at higher levels in the brain and spinal cord compared to other tissues, suggesting they may have specialized functions in the CNS. miRNAs associated with long-term neurodegenerative changes could serve as valuable tools for early treatment decisions and disease monitoring. The significance of miRNAs such as miR-320, miR-146 and miR-29 in the early diagnosis of neurodegenerative disorders becomes evident, especially considering that many neurological and physical symptoms manifest only after substantial degeneration of specific neurons. Interestingly, serum miRNA levels such as miR-92 and miR-486 may correlate with various MRI parameters in multiple sclerosis. Targeting miRNAs using antisense strategies, such as antisense miR-146 and miR-485, may provide advantages over targeting mRNAs, as a single anti-miRNA can regulate multiple disease-related genes. In the future, anti-miRNA-based therapeutic approaches could be integrated into the clinical management of neurological diseases. Certain miRNAs, including miR-223, miR-106, miR-181, and miR-146, contribute to the pathogenesis of various neurodegenerative diseases and thus warrant greater attention. This knowledge could pave the way for the identification of new diagnostic, prognostic, and theranostic biomarkers, and potentially guiding the development of RNA-based therapeutic strategies. This review highlights recent research on the roles of miRNAs in the nervous system, particularly their protective functions in neurodegenerative disorders.

BackgroundAnxiety is poorly recognized and inadequately treated in persons with Parkinson's disease (PD).ObjectiveThe present study aimed to develop and validate a new clinical screening and research outcome measure to identify triggers and manifestations of anxiety specific to PD, the Parkinson's disease Specific Anxiety Inventory (PDSAI).MethodData from PDSAI derived from 172 people with PD across Australia and the United States was used to assess the reliability and validity of the inventory. Construct validity was assessed.ResultsFrequency analyses revealed low rates of missing data across the 40 items. The inventory demonstrated high reliability (Cronbach's a = 0.93, split-half = 0.68) and mid to high concurrent validity between the PDSAI and (i) Hamilton Anxiety Scale (r = 0.51), (ii) Liebowitz Social Anxiety Scale (r = 0.697) and Parkinson's Anxiety Scale (r = 0.747).ConclusionsThe PDSAI is a valid and reliable tool designed to capture PD specific triggers and manifestations of anxiety in people with PD.

Cerebrospinal fluid (CSF) biomarkers have been widely adopted in Alzheimer's disease (AD) diagnosis. However, no studies focused on the application of CSF biomarkers in the clinical practice of complex and atypical patients with cognitive impairment in China. This study aimed to evaluate the added value of CSF AD biomarkers in cognitively impaired patients with complex conditions in a memory clinical setting. A total of 633 participants were included from the National Center for Neurological Disorders in Shanghai, China. The CSF AD biomarkers were measured with ELISA. Cutoff values were firstly identified using Youden's index. The neurologists proposed etiology diagnosis with a percentage estimate of their confidence and prescribed medication before and after CSF disclosure. Changes in etiological diagnosis, diagnostic confidence, and management plan were compared across the groups. Of the 633 patients (mean [SD] age, 61.1 [11.3] years; 295 males [46.6%]), 372 (58.8%) were diagnosed with dementia, 103 (16.3%) with mild cognitive impairment, and 158 (24.9%) with subjective cognitive decline. Using those pre-defined cutoffs, we categorized patients into 3 groups: Alzheimer's continuum (68.1%), non-AD pathologic change (11.1%), and normal AD biomarkers (20.8%). After CSF disclosure, the proposed etiology changed in 158 (25.0%) participants and the prescribed medication changed in 200 (31.6%) patients. Mean diagnostic confidence increased from 69.5-83.0% (+13.5%; P < 0.001). In conclusion, CSF AD biomarkers significantly impacted the diagnosis, diagnostic confidence, and treatment plans for Chinese patients with complex cognitive impairment. CSF AD biomarkers are a useful tool for clinicians beyond routine clinical assessment.

Despite its potential to modulate brain and network activity, non-invasive brain stimulation is not yet clinically applied for treating Parkinson's disease. We here review recent findings that illustrate how various non-invasive stimulation techniques can modify pathological and compensatory activities. Due to unavoidable heterogeneities and low effect sizes of the reviewed studies, a deeper understanding of the mechanisms of action will be critical for refining clinical effectiveness and generating consistent results.

Identifying intrinsic pattern of Parkinson's disease (PD) helps to better understand of PD and provide insights to disease identification and treatment monitoring. Here we confirmed the PD-related covariance pattern (PDRP) by using arterial spin labelling technology (ASL-PDRP) and explore its potential for predicting motor progression and levodopa (L-DOPA) reactivity reduction.

Data from an original cohort of 179 PD and 62 normal controls (NC) and a validation cohort including 36 PD and 19 NC to construct and validate the ASL-PDRP. The correlations between the pattern and motor symptoms were analyzed cross-sectionally and longitudinally (71 PD owned longitudinal data) with hierarchical linear regression analysis. Kaplan-Meier analysis was conducted in 54 L-DOPA-managed PD patients to predict the levodopa reactivity reduction.

The first principal component was predominantly recognized as the ASL-PDRP, with its expression being higher in PD than NC in both sets (original: P = 0.017, AUC = 0.598; validation: P = 0.024, AUC = 0.661). The pattern expression was associated with UPDRS III (P = 0.006) and sub-symptoms (axial: P < 0.001; rigidity: P = 0.003; bradykinesia: P = 0.015) at baseline. The ASL-PDRP could predict the progression of UPDRS III (P = 0.021, β = 4.930). Higher expression of the pattern had slower rate of levodopa reactivity reduction in PD patients with axial symptom (P = 0.031).

The identified ASL-PDRP may have potential for characterizing PD with the ability to predict motor progression and L-DOPA reactivity reduction.

Smell loss is a frequent and early manifestation of Parkinson's disease (PD), serving as a sensitive - albeit nonspecific - clinical biomarker1. The notion that PD causes odour-selective hyposmia has been debated for three decades. Previous studies have used healthy controls as the comparator; this is problematic given the majority presumably display normal olfactory function. Using University of Pennsylvania Smell Identification Test data from the Parkinson's Progression Markers Initiative, we trained eight machine learning models to distinguish 'PD hyposmia' (n = 155) from 'non-PD hyposmia' (n = 155). The best-performing models were evaluated on an independent validation cohort. While specific responses (e.g. mistaking pizza for bubble gum) were impactful across models, at best only 63% of PD cases were correctly identified. Given we used a balanced data set, 50% accuracy would be achieved by random guessing. This suggests that PD-related hyposmia does not exhibit a unique pattern of odour selectivity distinct from general hyposmia.

Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.

Diagnosing atypical parkinsonian syndromes (APS) remains challenging due to overlapping clinical features and limited diagnostic tools. Brain-enriched microRNAs (miRNAs), which regulate neuronal development and function, are detectable in plasma and could serve as molecular biomarkers. This prospective study aimed to identify plasma brain-enriched miRNAs that can distinguish APS and elucidate affected molecular pathways. Reverse transcription-quantitative PCR (RT-qPCR) was performed on plasma samples from patients with idiopathic Parkinson's disease (iPD), multiple system atrophy (MSA), including the cerebellar subtype (MSA-C) and the parkinsonian subtype (MSA-P), progressive supranuclear palsy (PSP), and healthy controls. MiRNA expression analysis revealed distinct molecular fingerprints for each parkinsonian syndrome, with opposite trends between MSA and iPD compared to controls, suggesting distinct pathogenic mechanisms. Most dysregulated miRNAs clustered at chromosome (Chr)14q32 and shared binding sites for CREB1, CEBPB, and MAZ transcription factors. Pathway analysis revealed enrichment in prion diseases, Hippo signaling, TGF-beta signaling, and FoxO signaling pathways.

The progressive loss of dopaminergic neurons and abnormal iron deposition in the central nervous system (CNS) are key pathogenic mechanisms of Parkinson's disease (PD). This study aimed to explore the relationship between iron deposition in specific CNS regions and striatal dysfunction using 18F-AV133 PET/MR imaging.

Based on the Hoehn-Yahr stage, 24 patients with early-stage PD (EPD, stage ≤ 2.5), 17 patients with late-stage PD (LPD, stage ≥ 3), and 30 healthy controls (HCs) were recruited for scale evaluation. The specific uptake ratio (SUR) of striatal subregions was calculated using the occipital cortex as the reference region. Quantitative Susceptibility Mapping (QSM) values of major subcortical nuclei were derived through QSM imaging. Spearman correlation analysis was conducted to assess the relationships between SUR in striatal subregions, QSM values in nuclear groups, and PD clinical symptoms, as well as the correlation between SUR and QSM values.

Compared to HC, EPD and LPD patients showed significantly reduced VMAT2 distribution in the bilateral caudate nuclei and anteroposterior putamen, particularly in the contralateral posterior putamen. In PD patients, the SUR of striatal subregions and QSM values of the substantia nigra (SN), globus pallidus (GP), and external segment of the GP (GPe) were significantly correlated with disease duration, H&Y stage, UPDRS III score, and NMSS score. Moreover, SUR of striatal subregions was negatively correlated with QSM values in the SN, GP, internal segment of the GP (GPi), and GPe.

Multi-parameter analysis revealed a region-specific correlation between striatal dysfunction and iron deposition in PD, offering new avenues to elucidate the underlying mechanisms of the disease.

The value of neurofilament light chain (NfL) levels as a biomarker for the diagnosis and differential diagnosis in patients with Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) remains controversial. Furthermore, few studies have directly compared NfL levels among specific APS categories. This study aimed to compare cerebrospinal fluid (CSF) and blood NfL levels among PD, APS, other PD-related disorders, and controls, as well as rank NfL levels across these groups.

PubMed, Embase, Web of Science, and the Cochrane Library were searched from the inception up to November 1st, 2024, to identify eligible studies reporting CSF or blood NfL concentrations in PD, PD dementia (PDD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal syndrome (CBS), vascular parkinsonism (VP), essential tremor (ET), idiopathic rapid eye movement sleep behavior disorder (iRBD), and controls. The Bayesian approach was utilized to estimate the standardized mean difference (SMD) and the associated 95% credible intervals (CrIs) of NfL levels. The surface under the cumulative ranking curve (SUCRA) was employed to evaluate the ranking probabilities of NfL levels. Subgroup analysis and meta-regression were conducted to explore the sources of heterogeneity.

The present network meta-analysis (NMA) included 78 studies with 13,120 participants (4050 controls, 5021 PD, 191 PDD, 1173 MSA, 887 PSP, 1254 DLB, 319 CBS, 160 ET, 65 iRBD, and 0 VP). Of these, the NMA of CSF NfL included 34 studies with 6,013 participants, while the NMA of blood NfL included 49 studies with 7,787 participants. Both CSF and blood NfL levels were significantly elevated in patients with PD and APS compared to controls. Compared to PD patients, CSF NfL levels were significantly elevated in MSA (SMD 1.85; 95% CrI 1.55-2.15), CBS (1.42; 1.08-1.75), PSP (1.35; 1.06-1.64), and DLB 0.52; 0.20-0.85) patients. Similarly, blood NfL levels were significantly higher in patients with MSA (1.36; 1.02-1.71), PDD (1.19; 0.65-1.72), PSP (1.15; 0.77-1.54), CBS (0.92; 0.11-1.72), and DLB (0.63; 0.14-1.12) compared to PD. Among APS, CSF NfL levels in MSA patients were significantly higher than those in PSP, DLB, and CBS patients, while blood NfL levels in MSA patients were significantly higher only compared to DLB. In both CSF and blood NfL, MSA patients exhibited the highest probability of ranking first for NfL level elevations (CSF: SUCRA = 0.998; blood: SUCRA = 0.925). Age significantly influenced the SMD of the comparison between MSA and PD in CSF NfL (β = -0.15; p = 0.016).

CSF and blood NfL levels in PD and APS are higher than those in controls, and all APS categories show higher levels than PD, suggesting that NfL levels may serve as a potential biomarker for the differential diagnosis between PD and APS. However, caution is warranted when using NfL as a diagnostic biomarker for PD. Significant differences in NfL levels are also observed between certain APS categories. Patients with MSA exhibit the highest NfL levels among PD and related disorders.

List-learning tasks are important for characterizing memory in ADRD research, but the Uniform Data Set neuropsychological battery (UDS-NB) lacks a list-learning paradigm; thus, sites administer a range of tests. We developed a harmonized memory composite that incorporates UDS memory tests and multiple list-learning tasks.

Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogenous sample (n=5943) who completed the UDS-NB and one of five list-learning tasks. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, and plasma phosphorylated tau (p-tau181 and p-tau217). Test-retest reliability was assessed. Analyses were replicated in a racially/ethnically diverse cohort (n=1058).

Fit indices, loadings, distributions, and test-retest reliability were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity.

This composite enables researchers to incorporate multiple list-learning tasks with other UDS measures to create a single metric.

The diagnostic value of midbrain atrophy for distinguishing behavioral variant frontotemporal dementia (bvFTD) from progressive supranuclear palsy (PSP) is unclear.

To investigate whether measures of midbrain atrophy differentiate PSP from bvFTD.

We included four groups: healthy controls (n = 19), PSP-Richardson syndrome (n = 20), bvFTD (n = 19) and Parkinson's disease (PD; n = 12). The following quantitative and qualitative measures were calculated: Hummingbird sign rating scale [HBS-RS], global midbrain atrophy [GMA], midbrain area, midbrain/pons ratio, the Magnetic Resonance Parkinsonism Index (MRPI), the MRPI 2.0 and brainstem volume.

Compared to controls, PSP and bvFTD had lower values of midbrain area, HBS-RS and GMA, and higher MRPI and MRPI 2.0. HBS-RS, GMA, midbrain/pons ratio, midbrain area, MRPI, MRPI 2.0 and brainstem volume distinguished PSP from bvFTD with 73%, 67%, 75%, 83%, 71%, 69% and 82% accuracies, respectively.

Both quantitative and qualitative measures of midbrain atrophy provided modest accuracy in distinguishing PSP from bvFTD.

Tremor in Parkinson's disease (PD) does not always respond to dopaminergic medication, therefore new treatment strategies are needed. Preliminary evidence has suggested that manipulation of peripheral afferents may reduce tremor amplitude, but existing research is inconclusive and has not been properly controlled. Here, we explored the effects of peripheral vibrotactile stimulation (ViS) on PD tremor using a within-subjects controlled design.

Thirty PD patients with clear tremor were included. ViS (open-loop) was applied to the most affected wrist. Four stimulation conditions were compared: tremor frequency (TF), 1.5*TF, 80 Hz stimulation, and sham. We tested the effect of these stimulation conditions on tremor power (measured with accelerometry) during three contexts: rest tremor, rest tremor during cognitive load, and postural tremor. Entrainment between tremor and stimulation was tested using complex phase-locking value (PLV).

There were no significant effects on tremor power when ViS was applied. Stimulation effects did not depend on the context in which tremor occurred. PLVs showed that tremor phase was not influenced by ViS.

Open-loop ViS does not modulate PD tremor.

This study is one of the first controlled large sample studies to investigate how ViS may influence the objective measures of tremor in PD.

Evidence from a number of paradigms suggests that methamphetamine use is associated with increased risk for the development of Parkinson's disease and parkinsonism, and that it may be associated with the premature development of Parkinson's disease. Prevalence of Parkinson's disease and parkinsonism is greater in both methamphetamine users and people who previously used methamphetamine, and evidence from animal studies provides a plausible mechanism for this observation. Despite this increased risk, Parkinson's disease is rarely diagnosed in methamphetamine users. Reasons for this may include under-detection, premature mortality, and individual and substance use characteristics which moderate the risk, including higher rates of smoking. Clinicians should be vigilant to signs and symptoms of Parkinson's disease and parkinsonism in methamphetamine users.

Although α-synucleinopathy has been confirmed in the submandibular gland (SMG) tissue of Parkinson's disease (PD) patients, in-depth disease-related molecular research, such as tissue-specific transcriptional signals, has not been performed. In the present study, disease-relevant tissue-specific transcriptional signals in SMG tissue from PD patients were investigated to identify potential diagnostic, prognostic, and pathophysiologic biomarkers. Here, seven de novo drug-naïve PD patients and six age- and sex-matched individuals without neurological or psychological diseases were enrolled. Total RNA sequencing (RNA-seq) and total small RNA-seq (smRNA-seq) were performed on SMG tissue and blood samples, with 26 RNA-seq and 26 smRNA-seq samples used for the final analysis. Differentially expressed genes (DEGs) and microRNAs in SMG tissue and blood from PD patients were obtained and their functional integration and interaction network were analyzed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the DEGs interacted with cytokine-, inflammation-, and immune-related pathways. Synphilin-1 expression was significantly downregulated in SMG tissue of PD patients, and α-synuclein expression did not significantly differ between PD patients and controls in either SMG tissue or blood. Fifteen tissue-specific miRNA signals in SMG tissue were identified that showed better diagnostic ability compared with those in blood samples. The correlation between DEGs and environmental factors appeared altered in PD patients. The results indicated the DEGs and microRNA signatures identified in SMG tissue may be promising diagnostic and prognostic biomarkers. These molecular insights offer potential avenues for the development of novel therapeutic strategies targeting the underlying disease mechanisms in PD patients.