Parkinson's Disease Subjects Research Articles

Cerebrospinal fluid alpha-synuclein, amyloid beta, total tau, and phosphorylated tau in tremor-dominant Parkinson's disease.

Protein misfolding within specific brain regions is a common characteristic of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease (PD). Therefore, a common term often used for these disorders is "proteinopathy". Currently, there has been increasing attention toward the overlap of pathogenesis between proteinopathies. We aimed to explore the cross-sectional and longitudinal level of the CSF α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in PD subjects with tremor dominant (TD) and a non-tremor dominant (nonTD) subtype from the Parkinson Progression Markers Initiative (PPMI). We enrolled 411 early-stage PD patients and 187 healthy controls (HCs) from the PPMI. We compared the level of CSF biomarkers at four time points including baseline, 6months, 1year, and 2years. To investigate longitudinal changes in CSF proteins within each group, we used linear mixed models. The level of CSF biomarkers was significantly lower in PD patients compared to HCs at any visit. Moreover, there was no statistically significant difference in the level of CSF α-syn, Aβ1-42, t-tau, and p-tau between PD-TD and PD-nonTD. Longitudinal analysis showed significant CSF α-syn reduction after one year from baseline in PD-TD patients (P = 0.047). Also, there was a significant reduction in the level of CSF Aβ1-42 after two years in PD-nonTD patients but not HCs and PD-TD (P = 0.033). Our results indicate that different patterns in longitudinal changes of CSF biomarkers could be due to different pathophysiological mechanisms involved in each PD motor subtype.

Postsurgical morbidity and mortality favorably informs deep brain stimulation for new indications including schizophrenia and schizoaffective disorder.

Deep brain stimulation (DBS) shows promise for new indications like treatment-refractory schizophrenia in early clinical trials. In the first DBS clinical trial for treatment refractory schizophrenia, despite promising results in treating psychosis, one of the eight subjects experienced both a symptomatic hemorrhage and an infection requiring device removal. Now, ethical concerns about higher surgical risk in schizophrenia/schizoaffective disorder (SZ/SAD) are impacting clinical trial progress. However, insufficient cases preclude conclusions regarding DBS risk in SZ/SAD. Therefore, we directly compare adverse surgical outcomes for all surgical procedures between SZ/SAD and Parkinson's disease (PD) cases to infer relative surgical risk relevant to gauging DBS risks in subjects with SZ/SAD. In the primary analysis, we used browser-based statistical analysis software, TriNetX Live (trinetx.com TriNetX LLC, Cambridge, MA), for Measures of Association using the Z-test. Postsurgical morbidity and mortality after matching for ethnicity, over 39 risk factors, and 19 CPT 1003143 coded surgical procedures from over 35,000 electronic medical records, over 19 years, from 48 United States health care organizations (HCOs) through the TriNetX Research Network™. TriNetXis a global, federated, web-based health research network providing access and statistical analysis of aggregate counts of deidentified EMR data. Diagnoses were based on ICD-10 codes. In the final analysis, logistic regression was used to determine relative frequencies of outcomes among 21 diagnostic groups/cohorts being treated with or considered for DBS and 3 control cohorts. Postsurgical mortality was 1.01-4.11% lower in SZ/SAD compared to the matched PD cohort at 1 month and 1 year after any surgery, while morbidity was 1.91-2.73% higher and associated with postsurgical noncompliance with medical treatment. Hemorrhages and infections were not increased. Across the 21 cohorts compared, PD and SZ/SAD were among eight cohorts with fewer surgeries, nine cohorts with higher postsurgical morbidity, and fifteen cohorts within the control-group range for 1-month postsurgical mortality. Given that the subjects with SZ or SAD, along with most other diagnostic groups examined, had lower postsurgical mortality than PD subjects, it is reasonable to apply existing ethical and clinical guidelines to identify appropriate surgical candidates for inclusion of these patient populations in DBS clinical trials.

A descriptive study on symptoms of Parkinson’s disease in an Indian cohort from Karnataka

Introduction and Aim: Parkinson’s Disease (PD) is a multifactorial neurodegenerative disorder with ever-changing motor and nonmotor symptoms. Disease treatment is modified accordingly with the progression of the disease. The present study was carried out to understand the symptoms reported by PD subjects in different phases of the disease.
 
 Materials and Methods: Demographic and clinical details were obtained using questionnaires to evaluate the frequency and severity of various motor and nonmotor symptoms experienced by the PD subjects.
 
 Results: Ageing was strongly associated with the onset of disease, whereas the BMI category adversely correlated with other motor symptoms (OMS), nonmotor symptoms (NMS), and specifically gastrointestinal symptoms. Tremors were the most troublesome cardinal motor symptoms, followed by stiffness and bradykinesia. The most common NMS were fatigue/tiredness, anxiety/depression, insomnia, constipation, and cognitive impairment. Anxiety and depression were positively associated with other NMS symptoms such as insomnia, fatigue and exhaustion, apathy, and gastrointestinal problems. More than half of our patients reported gastrointestinal discomfort, early satiety, appetite decrease, and bloating. In our present investigation, the most common gastrointestinal symptoms linked with constipation were straining evacuation, lumpy hard stool, and incomplete evacuation.
 
 Conclusion: We have analysed the frequency and trend of various symptoms associated with PD in an Indian population from Karnataka. A significant correlation exists between motor and nonmotor symptoms, which impacts the quality of life in PD during the course of the disease.

Central and peripheral α-synuclein in Parkinson disease detected by seed amplification assay.

Detection of α-synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α-synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α-synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α-synuclein measures, and investigate within-subject relationships. The Systemic Synuclein Sampling Study aimed to characterize α-synuclein in multiple tissues and biofluids within Parkinson disease subjects (n=59) and compared to healthy controls (n=21). Motor and non-motor measures and dopamine transporter scans were obtained. Four measures of α-synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin-fixed paraffin-embedded submandibular gland, total α-synuclein quantified in biofluids using enzyme-linked immunoassay, and aggregated α-synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within-subject α-synuclein measures were compared. Sensitivity and specificity of α-synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different α-synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index=83.1%). 98.3% of all Parkinson disease cases had ≥1 measure of α-synuclein positive. α-synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total α-synuclein measures, and within-subject relationships of central and peripheral α-synuclein measures emerged.

Meta-analysis of the relations between gut microbiota and pathogens and Parkinson's disease.

The motor symptoms in patients with Parkinson's disease (PD) are commonly preceded by gastrointestinal (GI) symptoms. The enteric nervous system (ENS) has also been reported to exhibit neuropathological characteristics of PD. To evaluate the relationship between the incidence of parkinsonism and alteration in gut microbiota and pathogens. Studies in different languages that evaluate the relationship between gut microorganisms and PD were included into this meta-analysis. The outcomes of these studies were analyzed using a random effects model; it was also used to calculate the mean difference (MD) with 95% confidence interval (95% CI) in order to quantify the impact of different rehabilitation techniques on clinical parameters. Dichotomous and continuous models were used for the analysis of extracted data. A total of 28 studies were included in our analysis. The analysis of small intestinal bacterial overgrowth showed a significant correlation with Parkinson's subjects compared with controls (p < 0.001). In addition, the presence of Helicobacter pylori (HP) infection was significantly related to the Parkinson's group (p < 0.001). On the other hand, there was a significantly higher abundance level of Bifidobacteriaceae (p = 0.008), Verrucomicrobiaceae (p < 0.001) and Christensenellaceae (p = 0.003) in Parkinson's subjects. In contrast, a significantly lower abundance levels in Parkinson's subjects were found in Faecalibacterium (p = 0.03), Lachnospiraceae (p = 0.005) and Prevotellaceae (p = 0.005). No significant difference was related to Ruminococcaceae. Parkinson's subjects showed a higher degree of alteration of gut microbiota and pathogens compared with normal human subjects. Future multicenter randomized trials are needed.

NF-κB/c-Rel DNA-binding is reduced in substantia nigra and peripheral blood mononuclear cells of Parkinson's disease patients

Although Parkinson's disease (PD) key neuropathological hallmarks are well known, the underlying pathogenic mechanisms of the disease still need to be elucidated to identify innovative disease-modifying drugs and specific biomarkers. NF-κB transcription factors are involved in regulating several processes associated with neurodegeneration, such as neuroinflammation and cell death, that could be related to PD pathology. NF-κB/c-Rel deficient (c-rel−/−) mice develop a progressive PD-like phenotype. The c-rel−/− mice present both prodromal and motor symptoms as well as key neuropathological features, including nigrostriatal dopaminergic neurons degeneration, accumulation of pro-apoptotic NF-κB/RelA acetylated at the lysine 310 residue (Ac-RelA(lys310)) and progressive caudo-rostral brain deposition of alpha-synuclein. c-Rel inhibition can exacerbate MPTP-induced neurotoxicity in mice. These findings support the claim that misregulation of c-Rel protein may be implicated in PD pathophysiology. In this study, we aimed at evaluating c-Rel levels and DNA-binding activity in human brains and peripheral blood mononuclear cells (PBMCs) of sporadic PD patients. We analyzed c-Rel protein content and activity in frozen substantia nigra (SN) samples from post-mortem brains of 10 PD patients and 9 age-matched controls as well as in PBMCs from 72 PD patients and 40 age-matched controls. c-Rel DNA-binding was significantly lower and inversely correlated with Ac-RelA(lys310) content in post-mortem SN of sporadic PD cases, when compared to healthy controls. c-Rel DNA-binding activity was also reduced in PBMCs of followed-up PD subjects. The decrease of c-Rel activity in PBMCs from PD patients appeared to be independent from dopaminergic medication or disease progression, as it was evident even in early stage, drug-naïve patients. Remarkably, the levels of c-Rel protein were comparable in PD and control subjects, pointing out a putative role for post-translational modifications of the protein in c-Rel dysfunctions.These findings support that PD is characterized by the loss of NF-κB/c-Rel activity that potentially has a role in PD pathophysiology. Future studies will be aimed at addressing whether the reduction of c-Rel DNA-binding could constitute a novel biomarker for PD.

Brain and Systemic Inflammation in De Novo Parkinson's Disease.

To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson's disease (PD). Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression. We enrolled subjects with de novo PD (n = 58) and age-matched controls (n = 62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson's Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18 F-DPA-714, a translocator protein 18kd ligand, and lumbar puncture if eligible and consented. Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. Positron emission tomography imaging showed increased 18 F-DPA-714 signal in PD subjects. 18 F-DPA-714 signal correlated with several cognitive measures and some chemokines. 18 F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Exaggerated pressor response to static squats in Parkinson's disease (PD) and healthy subjects is likely an individual trait, not influenced by whole body vibration (WBV).

Reduced muscle strength is one symptom of Parkinson's disease (PD). Strength can be increased by strength training, which may cause exaggerated blood pressure (BP) rise. It is believed that exercises performed on vibrating platform can strengthen leg muscles without excessive BP increase. To measure the pressor response to static exercises performed during whole body vibration in PD patients. Twenty-four aged PD patients and twelve healthy young volunteers participated in the study. PD subjects performed six repetitions of deep-, semi-squat, and calves at vibration frequency of 30 Hz. Each 30 s exercise was followed by 30 s rest. The young volunteers performed two sessions of above-mentioned exercises with and without vibration. BP was measured continuously. In PD patients, the highest BP values were observed during deep squat; systolic blood pressure rose 10 mmHg in 'weak responders', and 50 mmHg in 'strong responders'. This difference correlated with the rise in pulse pressure suggesting indirectly the role of stoke volume in individual response. In healthy subjects pressor response was also individually differentiated and not influenced by vibration. Deep and semi squat can evoke a strong cardiovascular response in some PD and healthy subjects. Low-magnitude vibrations likely did not affect pressor response.

ATP and NAD+ Deficiency in Parkinson’s Disease

The goal of this study is to identify a signature of bioenergetic and functional markers in the muscles of individuals with Parkinson's disease (PD). Quantitative physiological properties of in vivo hand muscle (FDI, first dorsal interosseus) and leg muscle (TA, Tibialis Anterior) of older individuals with PD were compared to historical age/gender-matched controls (N = 30). Magnetic resonance spectroscopy and imaging (MRS) were used to assess in vivo mitochondrial and cell energetic dysfunction, including maximum mitochondrial ATP production (ATPmax), NAD concentrations linked to energy/stress pathways, and muscle size. Muscle function was measured via a single muscle fatigue test. TA ATPmax and NAD levels were significantly lower in the PD cohort compared to controls (ATPmax: 0.66 mM/s ± 0.03 vs. 0.76 ± 0.02; NAD: 0.75 mM ± 0.05 vs. 0.91 ± 0.04). Muscle endurance and specific force were also lower in both hand and leg muscles in the PD subjects. Exploratory analyses of mitochondrial markers and individual symptoms suggested that higher ATPmax was associated with a greater sense of motivation and engagement and less REM sleep behavior disorder (RBD). ATPmax was not associated with clinical severity or individual symptom(s), years since diagnosis, or quality of life. Results from this pilot study contribute to a growing body of evidence that PD is not a brain disease, but a systemic metabolic syndrome with disrupted cellular energetics and function in peripheral tissues. The significant impairment of both mitochondrial ATP production and resting metabolite levels in the TA muscles of the PD patients suggests that skeletal muscle mitochondrial function may be an important tool for mechanistic understanding and clinical application in PD patients. This study looked at individuals with mid-stage PD; future research should evaluate whether the observed metabolic perturbations in muscle dysfunction occur in the early stages of the disease and whether they have value as theragnostic biomarkers.

An Individualized Multi-Modal Approach for Detection of Medication "Off" Episodes in Parkinson's Disease via Wearable Sensors.

The primary treatment for Parkinson's disease (PD) is supplementation of levodopa (L-dopa). With disease progression, people may experience motor and non-motor fluctuations, whereby the PD symptoms return before the next dose of medication. Paradoxically, in order to prevent wearing-off, one must take the next dose while still feeling well, as the upcoming off episodes can be unpredictable. Waiting until feeling wearing-off and then taking the next dose of medication is a sub-optimal strategy, as the medication can take up to an hour to be absorbed. Ultimately, early detection of wearing-off before people are consciously aware would be ideal. Towards this goal, we examined whether or not a wearable sensor recording autonomic nervous system (ANS) activity could be used to predict wearing-off in people on L-dopa. We had PD subjects on L-dopa record a diary of their on/off status over 24 hours while wearing a wearable sensor (E4 wristband®) that recorded ANS dynamics, including electrodermal activity (EDA), heart rate (HR), blood volume pulse (BVP), and skin temperature (TEMP). A joint empirical mode decomposition (EMD) / regression analysis was used to predict wearing-off (WO) time. When we used individually specific models assessed with cross-validation, we obtained > 90% correlation between the original OFF state logged by the patients and the reconstructed signal. However, a pooled model using the same combination of ASR measures across subjects was not statistically significant. This proof-of-principle study suggests that ANS dynamics can be used to assess the on/off phenomenon in people with PD taking L-dopa, but must be individually calibrated. More work is required to determine if individual wearing-off detection can take place before people become consciously aware of it.

Plasma and cerebrospinal fluid pharmacokinetics of vodobatinib, a neuroprotective c-Abl tyrosine kinase inhibitor for the treatment of Parkinson's disease

BackgroundPreclinical evidence suggests that c-Abl is critical in the pathogenesis of Parkinson's Disease (PD). Vodobatinib (K0706) is a potent, specific Abl kinase inhibitor currently being developed for the treatment of PD. In previously reported studies, nilotinib, a multikinase c-Abl inhibitor, did not show clinical activity as evidenced by no improvement of symptoms or the rate of decline after one to six months of treatment at the maximum permissible dose, presumably because of insufficient CNS penetration. Here we report clinical PK and safety data for vodobatinib. ObjectivesTo determine safety, plasma PK, and CSF penetration of vodobatinib in healthy volunteers and PD subjects following oral administration, and compare CSF levels to in vitro concentrations required for c-Abl inhibition relative to data reported for nilotinib. MethodsInhibition of c-Abl kinase activity and c-Abl binding affinity were first assessed in vitro. Healthy human volunteers and PD patients received various oral doses of vodobatinib once-daily for seven and fourteen days respectively, to assess safety, and plasma and CSF PK. ResultsIn in vitro assays, vodobatinib was more potent (kinase IC50 = 0.9 nM) than nilotinib (kinase IC50 = 15–45 nM). Administration of vodobatinib 48, 192 and 384 mg to healthy subjects for 7 days yielded mean Cmax, CSF values of 1.8, 11.6, and 12.2 nM respectively, with the two highest doses exceeding the IC50 over the entire dosing interval. Cavg, CSF values were 6–8 times greater than the IC50. Comparable CSF levels were observed in PD patients. All doses were well tolerated in both cohorts. ConclusionBased on achieved CSF concentrations, the potential for c-Abl inhibition in the brain is substantially higher with vodobatinib than with nilotinib. The CSF PK profile of vodobatinib is suitable for determining if c-Abl inhibition will be neuroprotective in PD patients.

Humanin gene expression in subjects with Parkinson's disease.

Bradykinesia, tremor, rigidity and postural instability are the hallmark of Parkinson's disease (PD). Non-motor symptoms including cognitive, behavioral, and neuropsychiatric changes, sensory and sleep disturbances that may precede the motor symptoms by years. The peculiar pathological features of PD are decreased dopaminergic neurons and dopamine levels in the substantia nigra pars compacta and pontine locus coeruleus. Humanin is produced by a small gene peptide, which is located in the mitochondria genome. Inflammation, oxidative stress, mitochondrial dysfunction and altered transcription have been recognized as causative factors of PD. This evidence has prompted many researchers to focus on studying the functions of DNA and mitochondria. The purpose of the present study was to evaluate Humanin mRNA levels in peripheral blood mononuclear cells (PBMCs) of PD subjects, compared with those in PBMCs of normal control (NC) subjects. A total of 220 participants, including 154 PD patients (57 females and 97 males; mean age 71.54 years, SD 7.8) and 66 CN (28 females and 38 males; mean age 70.54 years, SD 9.45) were enrolled for the qRT-PCR analysis. Increased Humanin mRNA levels were found in PD samples, compared to controls. In conclusion, the present data confirm the tendency of mitochondria to overexpress mRNA in PD, which could be a cellular attempt to reduce apoptotic damage in PD subjects. Humanin might be useful as a marker for a better diagnosis of PD, and we cannot exclude that in the future it might also play a role on prognosis and in the possible therapies for PD.

Motor and non-motor features in Parkinson's Disease patients carrying GBA gene mutations.

Mutations of the Glucocerebrosidase (GBA) gene are the most common genetic risk factor yet discovered for Parkinson's Disease (PD), being found in about 5-14% of Caucasian patients. We aimed to assess motor and non-motor symptoms (NMS) in patients with GBA-related PD (GBA-PD) in comparison with idiopathic PD (iPD) subjects using standardized and validated scales. Eleven (4M, 7 F) patients with GBA-PD and 22 iPD patients, selected from the same cohort and matched for gender, age, and disease duration, were enrolled. The disease severity was assessed by Unified Parkinson's Disease Rating Scale-section III, gait disorder and falls by Freezing of Gait Questionnaire, and motor fluctuations by Wearing off questionnaire. NMS were evaluated using the following scales: Mini-Mental State Examination and extended neuropsychological battery, if required, Non-Motor Symptoms Scale, SCOPA-AUT Questionnaire, Apathy Evaluation Scale, Beck Depression Inventory, Epworth Sleepiness Scale, Restless Legs Syndrome Rating Scale, REM Sleep Behavior Disorder Screening Questionnaire, and Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease. GBA-PD patients showed a more severe and rapidly progressive disease, and more frequent positive family history for PD, akinetic-rigid phenotype, postural instability, dementia, and psychosis in comparison to iPD. Two of three subjects carrying L444P mutation presented with early dementia. We also found a higher occurrence of fatigue, diurnal sleepiness, and intolerance to heat/cold in the carriers group. Our results confirm that NMS and a more severe and faster disease course more frequently occur among GBA-PD patients in comparison to iPD.

Subjective Assessments of Voice in Parkinson's Disease Subjects with and without STN-DBS Therapy.

The causal relation between STN-DBS and speech problems and the associated clinical features are in the incipient stages of being investigated. All the Parkinson's disease (PD) subjects with and without STN-DBS who applied to our movement disorders outpatient clinics between January 2022 and June 2022 and agreed to participate in the study were enrolled. The demographic data and clinical features were noted. Besides, the MDS-UPDRS was administered during the medication off-state in all subjects. All the participants completed the voice handicap index (VHI). Besides, the Freezing of Gait Questionnaire (FOGQ) and the quality of life (QoL) scales including the Parkinson's Disease Questionnaire (PDQ-39) and the Schwab and England Activities of Daily Living (ADL) scale were also administered to all the individuals. We have included 66 patients with PD (F/M = 23/43). Thirty-five patients were those with DBS therapy whereas 31 patients were without. The results of the comparative analyses between the patients with and without DBS therapy revealed that the DBS group had a higher disease duration (P = 0.006) and FOGQ scores (P = 0.008). The VHI scores did not differ between groups (P = 0.577), and the correlation analyses did not reveal an association between the VHI scores and the duration of DBS therapy. However, the VHI scores correlated with the disease duration as well as the FOG scores. We did not find convincing evidence supporting the increased risk of speech disturbance with STN-DBS therapy. We suggest that the frequent existence of speech disturbance in this patient subgroup with STN-DBS is associated with the classical nature of PD.

Geometria orofaríngea e parâmetros acústicos vocais de indivíduos hígidos e com doença de Parkinson

ABSTRACT Purpose to verify whether there are differences in acoustic measures and oropharyngeal geometry between healthy individuals and people with Parkinson's disease, according to age and sex, and to investigate whether there are correlations between oropharyngeal geometry measures in this population. Methods 40 individuals participated, 20 with a diagnosis of Parkinson's disease and 20 healthy individuals, matched by age, sex, and body mass index. Acoustic variables included fundamental frequency, jitter, shimmer, glottal-to-noise excitation ratio, noise, and mean intensity. Oropharyngeal geometry variables were measured with acoustic pharyngometry. Results geometry variables were smaller in the group with Parkinson's disease, and older adults with Parkinson's disease had a smaller oropharyngeal junction area than healthy older adults. Regarding acoustic parameters of voice, fundamental frequency values were lower in males with Parkinson's disease, and jitter values were higher in the non-elderly subjects with Parkinson's disease. There was a moderate positive correlation between oral cavity length and volume, pharyngeal cavity length and vocal tract length, and pharyngeal cavity volume and vocal tract volume. Conclusion individuals with Parkinson's disease had smaller glottal areas and oropharyngeal junction areas than healthy individuals. When distributed into sex and age groups, the fundamental frequency was lower in males with Parkinson's disease. There was a moderate positive correlation between oropharyngeal length and volume measures in the study sample.

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials.

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

Electroencephalogram-Driven Machine-Learning Scenario for Assessing Impulse Control Disorder Comorbidity in Parkinson's Disease Using a Low-Cost, Custom LEGO-Like Headset.

Patients with Parkinson's disease (PD) may develop cognitive symptoms of impulse control disorders (ICDs) when chronically treated with dopamine agonist (DA) therapy for motor deficits. Motor and cognitive comorbidities critically increase the disability and mortality of the affected patients. This study proposes an electroencephalogram (EEG)-driven machine-learning scenario to automatically assess ICD comorbidity in PD. We employed a classic Go/NoGo task to appraise the capacity of cognitive and motoric inhibition with a low-cost, custom LEGO-like headset to record task-relevant EEG activity. Further, we optimized a support vector machine (SVM) and support vector regression (SVR) pipeline to learn discriminative EEG spectral signatures for the detection of ICD comorbidity and the estimation of ICD severity, respectively. With a dataset of 21 subjects with typical PD, 9 subjects with PD and ICD comorbidity (ICD), and 25 healthy controls (HC), the study results showed that the SVM pipeline differentiated subjects with ICD from subjects with PD with an accuracy of 66.3% and returned an around-chance accuracy of 53.3% for the classification of PD versus HC subjects without the comorbidity concern. Furthermore, the SVR pipeline yielded significantly higher severity scores for the ICD group than for the PD group and resembled the ICD vs. PD distinction according to the clinical questionnaire scores, which was barely replicated by random guessing. Without a commercial, high-precision EEG product, our demonstration may facilitate deploying a wearable computer-aided diagnosis system to assess the risk of DA-triggered cognitive comorbidity in patients with PD in their daily environment.

Kinect-based objective evaluation of bradykinesia in patients with Parkinson's disease.

To quantify bradykinesia in Parkinson's disease (PD) with a Kinect depth camera-based motion analysis system and to compare PD and healthy control (HC) subjects. Fifty PD patients and twenty-five HCs were recruited. The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was used to evaluate the motor symptoms of PD. Kinematic features of five bradykinesia-related motor tasks were collected using Kinect depth camera. Then, kinematic features were correlated with the clinical scales and compared between groups. Significant correlations were found between kinematic features and clinical scales (P < 0.05). Compared with HCs, PD patients exhibited a significant decrease in the frequency of finger tapping (P < 0.001), hand movement (P < 0.001), hand pronation-supination movements (P = 0.005), and leg agility (P = 0.003). Meanwhile, PD patients had a significant decrease in the speed of hand movements (P = 0.003) and toe tapping (P < 0.001) compared with HCs. Several kinematic features exhibited potential diagnostic value in distinguishing PD from HCs with area under the curve (AUC) ranging from 0.684-0.894 (P < 0.05). Furthermore, the combination of motor tasks exhibited the best diagnostic value with the highest AUC of 0.955 (95% CI = 0.913-0.997, P < 0.001). The Kinect-based motion analysis system can be applied to evaluate bradykinesia in PD. Kinematic features can be used to differentiate PD patients from HCs and combining kinematic features from different motor tasks can significantly improve the diagnostic value.

Oligomers and Neurodegeneration: New Evidence.

In the last few months new results in Alzheimer's (AD) and Parkinson's disease (PD) have converged, attracting attention to oligomer species of misfolded proteins, β-amyloid (Aβ and α-synuclein (α-Syn), in the pathogenesis. The high affinity for Aβ protofibrils and oligomers of lecanemab, an antibody recently approved as a disease-modifying drug in AD, and the identification of Aβ-oligomers in blood samples as early biomarkers in subjects with cognitive decline, indicate the oligomers as a therapeutic target and diagnostic tool in AD. α-Syn oligomers were identified by new histopathological techniques in the hippocampus and visual cortex of PD subjects with a distribution distinct from the Lewy body pathologies but associated with cognitive impairment; these species purified from PD brain were highly neurotoxic. In a PD experimental model, we confirmed the presence of α-Syn oligomers associated with cognitive decline and sensitive to drug treatment.

Understanding the role of "sunshine vitamin D" in Parkinson's disease: A review.

Next to Alzheimer's disease, Parkinson's disease constitutes the second most widespread neurological disorder, primarily affecting the older population. Its symptoms are noticeable with advancing age including tremors, postural imbalance, and slow movements, and over time, these symptoms get aggravated, progressing to osteoporosis, osteopenia, and risk of fractures. These symptoms correlate to low bone density and hence weakened bones; thus, vitamin D proves to be an intricate component of the pathogenesis of the disease. Moreover, lower serum concentrations of vitamin D have been found in diseased subjects. Supplementation with vitamin D can retard the aggravation of non-motor as well as motor symptoms of Parkinson's disease that include cognitive improvement along with the decline in risk of fractures. Also, vitamin D is extremely crucial for brain functioning, targeting dopaminergic neurons, and almost the entire functioning of the brain is affected. However, further exploration is required to determine the toxic dose of vitamin D in Parkinson's subjects. This "sunshine vitamin" surely can be a ray of sunshine for neurologically diseased subjects.