Parkinson's Disease Disorders Research Articles

Impaired Gait, Postural Instability, and Rigidity in Relation to CB1 Receptor Availability in Parkinson's Disease.

In Parkinson's disease (PD), postural instability and gait disorder (PIGD) symptoms are associated with a worse prognosis for an unknown reason. The objective was to explore the relationship between cannabinoid receptor type 1 (CB1R) availability and motor symptoms in PD with [18F]FMPEP-d2 positron emission tomography (PET). Fifteen individuals with PD underwent [18F]FMPEP-d2 PET to measure cerebral CB1R availability. The Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) was used to evaluate the motor symptoms. A negative correlation was observed between [18F]FMPEP-d2 VT and PIGD score (P = 0.002) as well as rigidity subscore (P < 0.001). Both clusters covered widespread areas of both hemispheres. In contrast, tremor or bradykinesia did not correlate to [18F]FMPEP-d2 VT. Gait, postural instability, and rigidity in PD are associated with decreased CB1R availability, unlike tremor or bradykinesia, suggesting that the endocannabinoid system has a role in the pathophysiology of different motor symptoms in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Prospective Connectomic-Based Deep Brain Stimulation Programming for Parkinson's Disease.

Efficacy of deep brain stimulation (DBS) relies on accurate lead placement as well as optimization of the stimulation parameters. Although clinical software tools are now available, programming still largely relies on a monopolar review, a tedious process for both patients and programmers. This study investigates the safety and feasibility of prospective automated connectomic DBS programming (automated connectomic programming [ACP]), focusing on the recruitment of specific white matter pathways. After DBS implantation, a detailed connectomic DBS model in patient-specific space was developed for each study participant. A driving-force model was used to quantify pathway recruitment across 2400 different DBS settings. Optimization algorithms maximized recruitment of therapeutic pathways while minimizing recruitment of side-effect pathways. Thirteen subjects were enrolled in two study phases that compared DBS settings derived from ACP to standard clinical DBS settings. Nine patients underwent reprogramming with ACP (5 globus pallidus interna [GPi], 4 subthalamic nucleus [STN]). Four patients underwent initial programming with ACP (3 GPi, 1 STN). All patients tolerated ACP without persistent side effects. In the reprogramming cohort, 3 patients preferred their ACP program, and 1 patient felt it was comparable to their clinical program. Unified Parkinson's Disease Rating Scale, Part III, scores for the initial ACP cohort (3 GPi, 1 STN) improved by an average of 43.5% (40.4-52.6 ± 5.6%). ACP appeared clinically safe and feasible. It provided reasonable motor improvement, which can be further optimized with subsequent clinical adjustment. Additional investigation is required to refine the optimization algorithm and to quantify the clinical benefit of ACP in a larger cohort. © 2024 International Parkinson and Movement Disorder Society.

Cognitive Impact of β-Amyloid Load in the Rapid Eye Movement Sleep Behavior Disorder-Lewy Body Disease Continuum.

Rapid eye movement sleep behavior disorder (RBD) is linked to the diffuse-malignant subtype and higher cognitive burden in Lewy body disease (LBD). This study explores brain β-amyloid deposition and its association with cognitive decline across the RBD-LBD continuum. Patients with isolated RBD (iRBD), Parkinson's disease with probable RBD (PDRBD), and dementia with Lewy bodies with probable RBD (DLBRBD) underwent 18F-florbetaben positron emission tomography, 3T magnetic resonance imaging scans, and comprehensive neuropsychological assessments. Subjects were categorized as cognitively normal (NC), mild cognitive impairment (MCI), or dementia. Global and regional standardized uptake value ratios (SUVR) were estimated in predefined cognitive volumes of interest (VOI) derived from voxel-wise comparison analysis among the cognitive groups, namely the prefrontal, parietal, precentral cortices, lingual gyrus, and supplementary motor area. Generalized linear models assessed the relationship between 18F-florbetaben SUVRs and neuropsychological testing, adjusting for age and sex. Subgroup analysis focused on the polysomnography-confirmed iRBD-continuum subset (n = 41) encompassing phenoconverters and nonconverters in our prospective iRBD cohort. Eighty-six subjects were classified as follows: 14 NC, 54 MCI, and 18 dementia. The proportion of positive β-amyloid scans increased with advanced cognitive stages (P = 0.038). β-Amyloid signals in cognitive VOIs were elevated in subgroups showing impairment in Trail-Making Test B (TMT-B). A linear association between TMT-B z score and global cortical β-amyloid levels was observed in the iRBD-continuum subset (P = 0.013). Cortical β-amyloid accumulates with declines in executive function within the RBD-LBD continuum. TMT-B performance may be a useful marker associating with β-amyloid load, particularly in the iRBD population. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical Utility of Neurophysiologic Classification (and Declassification) of Myoclonus.

Movement clinical neurophysiology studies can distinguish myoclonus, tremor, and other jerky movements; however, there has been limited demonstration of their real-world clinical impact. The aim was to investigate movement study utility in clarifying movement classification and guiding patient management. A retrospective study of myoclonus-related movement studies was performed. Of 262 patients referred for consideration of myoclonus, 105 (40%) had myoclonus, 156 (59%) had no myoclonus (the commonest alternative classifications were functional jerks and tremor), and 1 was uncertain. An additional 29 studies identified myoclonus without prior clinical suspicion. A total of 119 of 134 (89%) myoclonus patients had a specific neurophysiologic subtype identified, most commonly cortical (64, 54%). Diagnostic differential narrowed in 60% of patients, and a new diagnosis was made in 42 (14%) patients. Medication changes were made in 151 patients (52%), with improvement in 35 of 51 (67%) with follow-up. Movement studies effectively determined movement classification and identified unsuspected myoclonus, leading to changes in diagnosis and management. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish.

Dopaminergic (DAnergic) dysfunction and imbalanced dopamine (DA) levels are known contributors to the pathogenesis of numerous psychiatric and neurodegenerative disorders. Of the many identified risk factors for DA-associated disorders, nuclear receptor subfamily 4 group A2 (NR4A2; or nuclear receptor related-1 protein (NURR1)), a transcription factor involved in DAnergic differentiation, has been associated with Parkinson's disease and attention deficit hyperactive disorder (ADHD). In zebrafish, transient loss of nr4a2 was previously shown to decrease tyrosine hydroxylase (TH) expression and impair locomotion. To further characterize the roles of the two zebrafish nr4a2 paralogs, nr4a2a, and nr4a2b, we produced targeted loss-of-function mutants and examined DAnergic neuron regeneration, oxidative respiration, and behavioral traits. The loss of nr4a2a function more closely recapitulated Parkinsonian phenotypes and affected neurotrophic factor gene expression. Conversely, nr4a2b mutants displayed behavioral symptoms reminiscent of mice deficient in Nr4a2 with increased neurotrophic output. In contrast, nr4a2b mutants also displayed increased metabolic input from non-mitochondrial sources indicative of high cytosolic reactive oxygen species and perturbed mitochondrial function. The nr4a2a mutants also showed increased maximal respiration, which may suggest a compensatory mechanism to meet the metabolic requirements of DAnergic neuron health. Overall, the zebrafish mutants generated in this study helped uncover molecular mechanisms involved in DA-related disease pathologies, and in the regeneration of DAnergic neurons.

Heterozygous KCNJ10 Variants Affecting Kir4.1 Channel Cause Paroxysmal Kinesigenic Dyskinesia.

More than 60% of paroxysmal kinesigenic dyskinesia (PKD) cases are of uncertain variants. The aim was to elucidate novel genetic contribution to PKD. A total of 476 probands with uncertain genetic causes were enrolled for whole-exome sequencing. A method of case-control analysis was applied to identify the candidate genes. Whole-cell patch-clamp recording was applied to verify the electrophysiological impact of the identified variants. A mouse model with cerebellar heterozygous knockout of the candidate gene was developed via adeno-associated virus injection, and dystonia-like phenotype inducement and rotarod tests were performed. In vivo multiunit electrical recording was applied to investigate the change in neural excitability in knockout mice. Heterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) clustered in PKD patients were compared with those in the control groups. Fifteen variants were detected in 16 of 522 probands (frequency = 3.07%). Patients with KCNJ10 variants tended to have a milder manifestation compared to those with PRRT2 (proline-rich transmembrane protein 2) variants. KCNJ10 variants partially altered the transmembrane location of inwardly rectifying potassium channel 4.1 (Kir4.1). The Kcnj10 expression is consistent with the natural course of PKD. Variants resulted in different degrees of reduction in cell Kir4.1 currents, and mice with heterozygous conditional knockout of Kcnj10 in the cerebellum presented dystonic posture, together with poor motor coordination and motor learning ability in rotarod tests. The firing rate of deep cerebellar nuclei was significantly elevated in Kcnj10-cKO mice. We identified heterozygous variants of KCNJ10 in PKD. Impaired function of Kir4.1 might lead to abnormal neuronal excitability, which attributed to PKD. © 2024 International Parkinson and Movement Disorder Society.

Monocyte to high-density lipoprotein cholesterol ratio reflects the peripheral inflammatory state in parkinsonian disorders

BackgroundIn Parkinson’s disease (PD) and Parkinson plus syndrome (PPS), inflammation is recognized as a relevant or contributing factor in the advancement of the diseases. For this reason, numerous biomarkers signaling immune alteration in both the central and peripheral nervous systems have been evaluated in PD and PPS. Nonetheless, the comprehensive inflammatory indices derived from readily available standard blood tests in PD, PPS, and healthy controls (HC) were rarely evaluated especially in the early stage of the diseases. ObjectiveThe aim of this study is to explore the serum level of peripheral inflammatory markers among the patients and investigate whether these markers contribute to symptoms. MethodClinical data and blood test results from drug naïve, early-stage 139 PD and 87 PPS patients, along with 139 age- and sex-matched healthy controls (HC) to PD were enrolled, with exclusion criteria applied to conditions potentially affecting inflammation. The study examined the disparities in peripheral inflammation among the groups, using total and subpopulation of white blood cells (WBCs), platelet count, red cell distribution width (RDW), high-density lipoprotein cholesterol (HDL-C), and other composite values reflecting inflammation including RDW to platelet ratio (RPR), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), neutrophil to HDL-C ratio (NHR), monocyte to HDL-C ratio (MHR), lymphocyte to HDL-C ratio (LHR), platelet to HDL-C ratio (PHR), systemic inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI). ResultThe MHR values were significantly higher in both PD and PPS groups compared to HC (p < 0.001), and NHR was significantly higher in the PPS group only compared to the HC group (p < 0.001). However, no significant differences in all the inflammatory markers were observed between PPS and PD (p > 0.05). Subgroup analysis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) patients revealed significantly higher NHR and MHR levels compared to the HC group (p = 0.025, p = 0.050, respectively), with no significant difference among PSP, MSA, and PD groups. After adjustment for age, sex, and disease duration, MHR was positively associated with H&Y in the total population (β = 0.288, p < 0.001), negatively associated with MMSE in the PD group (β = −0.245, p = 0.017), and positively associated with both H&Y (β = 0.432, p < 0.001) and UPDRS part II (β = 0.295, p = 0.018) in PPS group. ConclusionNHR and MHR values are not effective as reliable diagnostic markers due to overlap among groups and their limited discriminative capacity in ROC analyses. However, MHR may potentially serve as an indicator reflecting peripheral inflammation in the early stage of PD and PPS compared to HC.

Cholinergic Basal Forebrain Integrity and Cognition in Parkinson's Disease: A Reappraisal of Magnetic Resonance Imaging Evidence.

Cognitive impairment is a well-recognized and debilitating symptom of Parkinson's disease (PD). Degradation in the cortical cholinergic system is thought to be a key contributor. Both postmortem and in vivo cholinergic positron emission tomography (PET) studies have provided valuable evidence of cholinergic system changes in PD, which are pronounced in PD dementia (PDD). A growing body of literature has employed magnetic resonance imaging (MRI), a noninvasive, more cost-effective alternative to PET, to examine cholinergic system structural changes in PD. This review provides a comprehensive discussion of the methodologies and findings of studies that have focused on the relationship between cholinergic basal forebrain (cBF) integrity, based on T1- and diffusion-weighted MRI, and cognitive function in PD. Nucleus basalis of Meynert (Ch4) volume has been consistently reduced in cognitively impaired PD samples and has shown potential utility as a prognostic indicator for future cognitive decline. However, the extent of structural changes in Ch4, especially in early stages of cognitive decline in PD, remains unclear. In addition, evidence for structural change in anterior cBF regions in PD has not been well established. This review underscores the importance of continued cross-sectional and longitudinal research to elucidate the role of cholinergic dysfunction in the cognitive manifestations of PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Beyond Vertical: Unraveling The PSP Enigma

Progressive Supranuclear Palsy (PSP) is an aberrant type of Parkinsonian disorder that cognates with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia. It is supposed to affect movement, gait, balance, speech, swallowing, vision, movements, mood, behavior and cognition. PSP increases as per age and its prevalence is 7% per 1 lakh, as reported. PSP is often misdiagnosed with Parkinson’s disease, however, PSP progresses more rapidly than Parkinson’s. people with PSP develop unique eye movement problems with looking up and down, speech and swallowing problems are much more common and severe in PSP than PD, leaning backwards and extend their neck in PSP (axial rigidity) while in PD -bending happens in forward direction than backward. Tremors are rare for PSP but very common in PD. The three most important primary motor symptoms are: tremors, bradykinesia, and rigidity (parkinsonism). Since this disease is termed as tauopathy, 4R-tau isoforms aggregate into straight filaments and appear as a major tau doublet (tau64 &amp; 69). The differential diagnosis is very difficult for PSP because many neurodegenerative disorders have similar symptoms and very less discrimination between PSP and other disorders. The main objective of our study is to create awareness about PSP and its overlapping symptoms with PD as well as other and other neuro-degenerative disorders. However, based upon detailed investigations about, tau and its isoforms, these clinical features may be distinguished. However, it would require abundant knowledge of the molecular functioning and structure of tau proteins. Keywords: tauopathy, parkinsonism, progressive axial rigidity, neuro-degenerative disorders

Bayesian estimation of trunk-leg coordination during walking using phase oscillator models

In human walking, the legs and other body parts coordinate to produce a rhythm with appropriate phase relationships. From the point of view for rehabilitating gait disorders, such as Parkinson Disorders, it is important to understand the control mechanism of the gait rhythm. A previous study showed that the antiphase relationship of the two legs during walking is not strictly controlled using the reduction of the motion of the legs during walking to coupled phase oscillators. However, the control mechanisms other than those of the legs remains unknown. In particular, the trunk moves in tandem with the legs and must play an important role in stabilizing walking because it is above the legs and accounts for more than half of the mass of the human body. This study aims to uncover the control mechanism of the leg-trunk coordination in the sagittal plane using the coupled phase oscillators model and Bayesian estimation. We demonstrate that the leg-trunk coordination is not strictly controlled, as well as the interleg coordination.

Distinct Clinical Implications of Patient- Versus Clinician-Rated Motor Symptoms in Parkinson's Disease.

Patient-rated motor symptoms (PRMS) and clinician-rated motor symptoms (CRMS) often differ in Parkinson's disease (PD). Our goal was to investigate the determinants and clinical implications of PRMS compared with CRMS in PD. This retrospective, observational cohort study analyzed the cross-sectional associations and longitudinal impacts of PRMS as assessed by the Movement Disorders Society-sponsored Unified PD Rating Scale (MDS-UPDRS) part 2, while controlling for CRMS measured by MDS-UPDRS part 3. Longitudinal analyses used Cox proportional hazards models and multiple linear mixed-effects random intercepts/slope models, adjusting for many clinical predictors. We conducted propensity score matching (PSM) to reinforce our analyses' robustness and surface-based morphometry to investigate neural correlates. We enrolled 442 patients with early-stage PD. At baseline, regardless of CRMS, PRMS were associated with the severity of postural instability and gait disturbance (PIGD). Notably, PRMS independently and more accurately predicted faster long-term deterioration in motor function than CRMS (Hoehn and Yahr 4, adjusted hazard ratio per +1 point = 1.19 [95% confidence intervals, 1.08-1.32]), particularly in PIGD (PIGD subscore, β-interaction = 0.052 [95% confidence intervals, 0.018-0.086]). PSM confirmed these findings' robustness. Surface-based morphometry suggested that enhanced sensory processing was distinctively associated with PRMS. In early-stage PD, PRMS weighed different aspects of symptoms and more effectively predicted motor deterioration compared to CRMS, with distinctive brain structural characteristics. The superior sensitivity of PRMS to subtle declines in drug-refractory symptoms like PIGD likely underlie our results, highlighting the importance of understanding the differential clinical implications of PRMS to prevent long-term motor deterioration. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia.

Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations. Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients. Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients. We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN. The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.

Frequency-Selective Suppression of Essential Tremor via Transcutaneous Spinal Cord Stimulation.

Essential tremor (ET) is a common debilitating condition, yet current treatments often fail to provide satisfactory relief. Transcutaneous spinal cord electrical stimulation (tSCS) has emerged as a potential noninvasive neuromodulation technique capable of disrupting the oscillatory activity underlying tremors. This study aimed to investigate the potential of tSCS to disrupt tremor in a frequency-dependent manner in a cohort of patients with ET. Eighteen patients with ET completed the study. The experiment consisted of 60-s postural tremor recording, during tSCS at tremor frequency, at 1 Hz, at 21 Hz, no stimulation, and trapezius stimulation. Tremor frequency and amplitude were analyzed and compared across the conditions. We found tremor amplitude reduction at tremor frequency stimulation significant only during the second half of the stimulation. The same stimulation resulted in the highest number of responders. tSCS at 1 Hz showed a trend toward decreased tremor amplitude in the latter half of stimulation. tSCS at 21 Hz did not produce any significant alterations in tremor, whereas trapezius stimulation exacerbated it. Notably, during tremor frequency stimulation, a subgroup of responders exhibited consistent synchronization between tremor phase and delivered stimulation, indicating tremor entrainment. Cervical tSCS holds promise for alleviating postural tremor in patients with ET when delivered at the subject's tremor frequency. The observed changes in tremor amplitude likely result from the modulation of spinal cord circuits by tSCS, which disrupts the oscillatory drive to muscles by affecting afferent pathways or spinal reflexes. However, the possibility of an interplay between spinal and supraspinal centers cannot be discounted. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Daily Life Experiences of People with Dementia with Lewy Bodies: A Qualitative Study

Dementia with Lewy bodies (DLB) is the second most common cause of dementia and is associated with unique difficulties due to its characteristic symptoms. This study aimed to identify daily life changes experienced by people with DLB due to characteristic symptoms other than visual hallucinations. Semi-structured interviews and content analyses were conducted on 13 people with DLB and their 17 family members. Qualitative content analysis identified three categories of difficulties experienced by people with DLB in daily life: body discomfort, obstacles in daily life, and psychological pain. Participants experienced not only physical changes due to symptoms such as cognitive fluctuations, parkinsonism, and rapid eye movement sleep behavior disorder but also psychological pain related to daily life difficulties. This suggests the need for care that appreciates the unique experiences of people with DLB and includes psychological care to develop appropriate individual coping strategies, rather than focusing solely on alleviating physical symptoms.

Role of Bβ1 overexpression in the pathogenesis of SCA12.

Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by a CAG/CTG repeat expansion at the PPP2R2B locus. We investigated how the CAG repeat expansion within the PPP2R2B 7B7D transcript influences the expression of Bβ1 and a potential protein containing a long polyserine tract. Transcript and protein expression were measured using quantitative PCR (qPCR) and Western blot, respectively, in an SK-N-MC cell model that overexpresses the full-length PPP2R2B 7B7D transcript. The apoptotic effect of a protein containing a long polyserine tract on SK-N-MC cells was evaluated using caspase 3/7 activity. The CAG repeat expansion increases the expression of the PPP2R2B 7B7D transcript, as well as Bβ1 protein, in an SK-N-MC cell model in which the full-length PPP2R2B 7B7D transcript is overexpressed. The CAG repeat expansion within the 7B7D transcript is translated into a long polyserine tract that triggers apoptosis in SK-N-MC cells. The SCA12 mutation leads to overexpression of PPP2R2B Bβ1 and to expression of a protein containing a long polyserine tract; both these effects potentially contribute to SCA12 pathogenesis. © 2024 International Parkinson and Movement Disorder Society.

Gender disparity in access to advanced therapies for patients with Parkinson's disease: a retrospective real-word study.

Gender differences in the access to advanced therapies for Parkinson's disease (PD) are poorly investigated. The objective of this study was to investigate the presence of any gender disparity in the access to advanced therapies for PD. Retrospective study. Data from patients with consistent access to the Parkinson's and Movement Disorder Center of L'Aquila over the last 10-year period were screened. Patients selected for advanced therapies were included. Out of 1,252 patients, 200 (mean age ± SD 71.02 ± 9.70; 72% males; median Hoen Yahr level: 3, minimum 1 maximum 5) were selected for advanced therapies: 133 for Magnetic Resonance guided Focused Ultrasound (MRgFUS) thalamotomy (mean age ± SD 70.0 ± 8.9; 77% males), 49 for Levodopa/Carbidopa Intestinal Gel (LCIG) infusion (mean age ± SD 74.3 ± 11.4; 59% males), 12 for Deep Brain Stimulation (DBS) (mean age ± SD 71.2 ± 6.3; 75% males), and 7 for Continuous Subcutaneous Apomorphine Infusion (CSAI) (mean age ± SD 69.7 ± 5.5; 43% males). No sex differences were found in relation to age (MRgFUS group: males vs. females 70.2 ± 8.9 vs. 70.8 ± 8.9, p-value = 0.809; LCIG group: males vs. females 73.5 ± 13.0 vs. 75.5 ± 8.5, p-value = 0.557; DBS group: males vs. females 77.2 ± 8.1 vs. 67.3 ± 8.6, p-value = 0.843; CSAI group: males vs. females 73.3 ± 4.0 vs. 67.0 ± 5.2, p-value = 0.144) and disease duration (MRgFUS group: males vs. females 8.3 ± 4.4 vs. 9.6 ± 6.7, p-value = 0.419; LCIG group: males vs. females 14.5 ± 5.81 vs. 17.3 ± 5.5; p-value = 0.205; DBS group: males vs. females 15.0 ± 9.6 vs. 15.5 ± 7.7, p-value = 0.796; CSAI group: males vs. females 11.7 ± 3.7 vs. 10.3 ± 3.7, p-value = 0.505). The predominance of males is higher than that expected based on the higher prevalence of PD in men. Women are less confident in selecting advanced therapies during the natural progression of their disease. Factors accounting for this discrepancy deserve further investigation.

ATH434, a promising iron-targeting compound for treating iron regulation disorders.

Cytotoxic accumulation of loosely bound mitochondrial Fe2+ is a hallmark of Friedreich's Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe2+ associated with FA or the neurological disorders Parkinson's disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe3+ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe2+ or exceptionally high affinities (i.e. ≤10-31) for non-pathologic Fe3+ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe2+-targeted therapeutics, we compared traditional Fe3+ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe2+ binding affinities (Kd's of 1-4 µM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe3+(0.46-9.59µM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe2+ coordination using H2O. ATH434 significantly stabilized bound Fe2+ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe2+ and Fe3+ position it to sequester excess Fe2+ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores.

Sacsin levels in PBMCs: A diagnostic assay for SACS variants in peripheral blood cells - A PROSPAX study.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a common recessive ataxia that is still underdiagnosed worldwide. An easily accessible diagnostic biomarker might help to diagnostically confirm patients presenting SACS variants of unknown significance (VUS) or atypical phenotypes. To detect sacsin in peripheral blood mononuclear cells (PBMCs) and to validate its diagnostic biomarker quality to discriminate biallelic SACS patients (including patients with VUS and/or atypical phenotypes) against healthy controls, non-ARSACS spastic ataxia patients, and heterozygous SACS carriers. Sacsin protein levels in PBMCs were assessed in patients versus controls and validated in skin-derived fibroblasts. Patients with biallelic SACS variants - including patients with VUS and/or atypical phenotypes - showed loss of sacsin in PBMCs, with discriminative performance against healthy, heterozygous, and non-ARSACS controls. This included all investigated SACS missense variants. Also, C-terminal variants escaping nonsense-mediated decay, while not differing from controls in expression level, showed lower molecular weight in this assay. Assessing sacsin levels using PBMCs offers an easy, peripherally accessible diagnostic biomarker for ARSACS, with PBMCs being much less invasive and easier to handle than fibroblasts. Additionally, this might be a potential target-engagement blood biomarker for sacsin-increasing therapies. © 2024 International Parkinson and Movement Disorder Society.

CSF α-Synuclein Seed Amplification Assay in Patients With Atypical Parkinsonian Disorders.

There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as α-synuclein (αSyn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible αSyn copathology in CBS and PSP, as detected in CSF using an αSyn SAA (αSyn-SAA). Secondary objectives were to evaluate the association of αSyn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that αSyn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and β-amyloid (Aβ) 42 levels, neurodegeneration as assessed by neurofilament light chain (NfL) levels, and symptoms associated with synucleinopathies. This cross-sectional observational study included patients clinically diagnosed with CBS and PSP who underwent a lumbar puncture between 2012 and 2021 (Toronto Western Hospital, Canada). CSF was tested for αSyn-SAA positivity, AD biomarkers, and NfL levels. Clinical data were derived from medical records. We tested the CSF of 40 patients with CBS (19 female patients, 65.9 ± 8.6 years) and 28 with PSP (13 female patients, 72.5 ± 8.7 years old), mostly White (n = 50) or Asian (n = 14). αSyn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, αSyn-SAA positivity and AD positivity were associated (odds ratio [OR] 8.8, 95% CI 1.2-82.6, p < 0.05). A multivariable linear regression analysis showed a significant interaction of αSyn-SAA status by age at onset on CSF Aβ42 levels (β = 0.3 ± 0.1, p < 0.05). Indeed, age at onset was positively related to Aβ42 levels only in αSyn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with αSyn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01). We detected a frequency of αSyn-SAA positivity in CBS and PSP in line with pathologic studies, highlighting the usefulness of SAAs for in vivo detection of otherwise undetectable neuropathologic processes. Our results also suggest that AD status (specifically low Aβ42) and older age at onset may contribute to αSyn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.

Comprehensive EEG Signal Feature Extraction for Neurological Disorder Diagnosis: Focus on Alzheimer's, Parkinson's, and Seizure Disorders

This research paper examines the use of Electroencephalogram (EEG) signal feature extraction for diagnosing neurological disorders, specifically Alzheimer's, Parkinson's, and seizure disorders. It evaluates various methods for categorizing EEG signals, including time-domain, frequency-domain, and statistical transformations emphasizing their effectiveness in distinguishing relevant brainwave patterns (beta, alpha, theta, delta) from artifacts like eye blinks and muscle movements. The study highlights the challenges in artifact removal and provides an overview of key feature extraction techniques, particularly in the time and frequency domains. The implementation section details the application of machine learning algorithms to classify mental states using statistical features from EEG signals. The research identifies specific EEG patterns associated with Alzheimer's, Parkinson's, and seizure disorders, noting alterations in alpha, theta, and delta waves. The paper underscores the critical role of EEG feature extraction in diagnosing neurological disorders and recommends incorporating additional frequency-based methods to enhance predictive accuracy in future research.