Parkinson's Disease Disorders Research Articles

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.

Evaluation of Cerebrospinal Fluid α-Synuclein Seed Amplification Assay in Progressive Supranuclear Palsy and Corticobasal Syndrome.

Seed amplification assay (SAA) testing has been developed as a biomarker for the diagnosis of α-synuclein-related neurodegenerative disorders. The objective of this study was to assess the rate of α-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) and to analyze clinical and pathological features of SAA-positive and -negative cases. A total of 96 cerebrospinal fluid samples from clinically diagnosed PSP (n = 59) and CBS (n = 37) cases were analyzed using α-synuclein SAA. Six of 59 (10.2%) PSP cases were α-synuclein SAA positive, including one case who was MSA-type positive. An exploratory analysis showed that PSP cases who were Parkinson's disease-type positive were older and had a shorter disease duration compared with SAA-negative cases. In contrast, 11 of 37 (29.7%) CBS cases were α-synuclein SAA positive, including two cases who were MSA-type positive. Our results suggest that α-synuclein seeds can be detected in PSP and CBS using a cerebrospinal fluid α-synuclein SAA, and in PSP this may impact on clinical course. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

New Insights into Freezing of Gait in Parkinson's Disease from Spectral Dynamic Causal Modeling.

Freezing of gait is one of the most disturbing motor symptoms of Parkinson's disease (PD). However, the effective connectivity between key brain hubs that are associated with the pathophysiological mechanism of freezing of gait remains elusive. The aim of this study was to identify effective connectivity underlying freezing of gait. This study applied spectral dynamic causal modeling (DCM) of resting-state functional magnetic resonance imaging in dedicated regions of interest determined using a data-driven approach. Abnormally increased functional connectivity between the bilateral dorsolateral prefrontal cortex (DLPFC) and the bilateral mesencephalic locomotor region (MLR) was identified in freezers compared with nonfreezers. Subsequently, spectral DCM analysis revealed that increased top-down excitatory effective connectivity from the left DLPFC to bilateral MLR and an independent self-inhibitory connectivity within the left DLPFC in freezers versus nonfreezers (>99% posterior probability) were inversely associated with the severity of freezing of gait. The lateralization of these effective connectivity patterns was not attributable to the initial dopaminergic deficit nor to structural changes in these regions. We have identified novel effective connectivity and an independent self-inhibitory connectivity underlying freezing of gait. Our findings imply that modulating the effective connectivity between the left DLPFC and MLR through neurostimulation or other interventions could be a target for reducing freezing of gait in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Unilateral Magnetic Resonance-Guided Focused Ultrasound Lesion of the Subthalamic Nucleus in Parkinson's Disease: A Prospective Study.

Unilateral subthalamic nucleus (STN) ablation using magnetic resonance-guided focused ultrasound (MRgFUS) is being explored as a new treatment for asymmetric Parkinson's disease (PD). The aims were to study the efficacy and safety of this treatment in asymmetric PD patients and to characterize the lesions. This prospective, single-center, open-label study evaluated asymmetric PD patients at 6 (n = 20) and 12 months (n = 12) after MRgFUS lesion of the STN. The primary outcome was the change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III), score in off medication on the treated side and the adverse events (AEs) at 6-month follow-up. We also evaluated cognitive-neuropsychological changes, self-assessment of clinical improvement, and the correlation of the lesion volume with the motor outcomes. On the treated side, the MDS-UPDRS III score (mean difference = 13.8) and the scores in rigidity, bradykinesia, and tremor improved (P < 0.001) throughout the follow-up compared to baseline (at 6 months: rigidity mean difference = 2.8, improvement: 83.5%; bradykinesia mean difference = 6.0, improvement: 69.4%; tremor mean difference = 4.7, improvement: 91.5%). One patient had severe weakness in the treated hemibody, 1 had moderate dyskinesia, and 1 was in moderate confusional state that became mild (weakness) or completely resolved (dyskinesia and confusional state) at 6 months. The rest of the AEs were mild. We observed no clinically relevant changes in cognitive-neuropsychological tests. The percentage of ablation of the STN correlated with the improvement in the total MDS-UPDRS III and contralateral tremor scores (P < 0.05). Unilateral MRgFUS lesion of the STN resulted in a significant motor improvement. We observed no persistent severe AEs, although mild, mostly transient AEs were frequent. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Immediate Effect of Continuous Positive Airway Pressure Therapy on Sleep and Respiration in Patients with Multiple System Atrophy and Sleep-Disordered Breathing.

Sleep-disordered breathing (SDB; including stridor and sleep apnea syndromes) is frequent in multiple system atrophy (MSA), but the immediate effect of continuous positive airway pressure (CPAP) therapy is incompletely determined. We sought to evaluate the acute effect and safety of CPAP therapy on SDB and sleep architecture, as well as the clinical characteristics of nonresponders to CPAP therapy. The measures of 63 consecutive patients with MSA who underwent a video-polysomnography during two consecutive nights (a first night in ambient air, a second night with or without CPAP, depending on the presence of SDB and availability of CPAP) in routine care were retrospectively collected. Linear mixed models assessed the two-night change in sleep and respiratory measures, comparing those with and without the CPAP therapy on the second night. SDB was frequent and mainly associated with the cerebellar phenotype. The introduction of CPAP had immediate benefits, including the normalization of the apnea-hypopnea index and a resolution of stridor in more than two-thirds of the cases, decreased arousal index, and increased rapid eye movement sleep. CPAP therapy was well tolerated, and only two patients had emergent central apneas. Nonresponse to CPAP was generally associated with more severe motor disease. CPAP seems a well-tolerated and effective therapy in patients with MSA and SDB in the short term. This treatment shows remarkable immediate benefits by objectively improving both respiratory disturbances and sleep architecture. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations.

Commercial genome-wide genotyping arrays have historically neglected coverage of genetic variation across populations. We aimed to create a multi-ancestry genome-wide array that would include a wide range of neuro-specific genetic content to facilitate genetic research in neurological disorders across multiple ancestral groups, fostering diversity and inclusivity in research studies. We developed the Illumina NeuroBooster Array (NBA), a custom high-throughput and cost-effective platform on a backbone of 1,914,934 variants from the Infinium Global Diversity Array and added custom content comprising 95,273 variants associated with more than 70 neurological conditions or traits, and we further tested its performance on more than 2000 patient samples. This novel platform includes approximately 10,000 tagging variants to facilitate imputation and analyses of neurodegenerative disease-related genome-wide association study loci across diverse populations. In this article, we describe NBA's potential as an efficient means for researchers to assess known and novel disease genetic associations in a multi-ancestry framework. The NBA can identify rare genetic variants and accurately impute more than 15 million common variants across populations. Apart from enabling sample prioritization for further whole-genome sequencing studies, we envisage that NBA will play a pivotal role in recruitment for interventional studies in the precision medicine space. From a broader perspective, the NBA serves as a promising means to foster collaborative research endeavors in the field of neurological disorders worldwide. Ultimately, this carefully designed tool is poised to make a substantial contribution to uncovering the genetic etiology underlying these debilitating conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Immunometabolic Signature and Tauopathy Markers in Blood Cells of Progressive Supranuclear Palsy.

Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed. PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p-tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society.

Medical Foods for the management of Chronic Illness and their Regulations in India, US and European Union

As many chronic illnesses are incurable and require repeated treatments, this problem contributes to long-term drug use. But when it comes to managing and treating chronic illnesses, medical foods can provide an alternative to natural medications. Medical foods are foods that have been particularly prepared to meet the unique dietary needs of people with specific illnesses. When it comes to therapeutic applications such as deglutition, dyspepsia, or eating disorders, they are crucial in providing patients with nutritional support. In addition, they significantly improve patients' quality of life by lowering drug use, averting problems that could result from an excessive reliance on pharmaceuticals, and saving treatment costs. Depending on the illness, medical foods' nutritional content can be adjusted and customized. They are exempt from laws pertaining to drugs since they are not drugs. Every medical food is created especially for the chronic condition in question. As a result, the purpose of this review is to clarify the use of medical foods for conditions such as Parkinson's, Alzheimer's, anxiety and sleep disorders, pain syndrome, cancer, congenital metabolic disorders, and diabetes mellitus, and to suggest their use as a dietary supplement for these long-term illnesses.

Consensus Guidance for Genetic Counseling in GBA1 Variants: A Focus on Parkinson's Disease.

Glucocerebrosidase (GBA1) variants constitute numerically the most common known genetic risk factor for Parkinson's disease (PD) and are distributed worldwide. Access to GBA1 genotyping varies across the world and even regionally within countries. Guidelines for GBA1 variant counseling are evolving. We review the current knowledge of the link between GBA1 and PD, and discuss the practicalities of GBA1 testing. Lastly, we provide a consensus for an approach to counseling people with GBA1 variants, notably the communication of PD risk. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amelioration of Focal Hand Dystonia via Low-Frequency Repetitive Somatosensory Stimulation.

Dystonia presents a growing concern based on evolving prevalence insights. Previous research found that, in cervical dystonia, high-frequency repetitive somatosensory stimulation (RSS; HF-RSS) applied on digital nerves paradoxically diminishes sensorimotor inhibitory mechanisms, whereas low-frequency RSS (LF-RSS) increases them. However, direct testing on affected body parts was not conducted. This study aims to investigate whether RSS applied directly to forearm muscles involved in focal hand dystonia can modulate cortical inhibitory mechanisms and clinical symptoms. We applied HF-RSS and LF-RSS, the latter either synchronously or asynchronously, on forearm muscles involved in dystonia. Outcome measures included paired-pulse somatosensory evoked potentials, spatial lateral inhibition measured by double-pulse somatosensory evoked potentials, short intracortical inhibition tested with transcranial magnetic stimulation, electromyographic activity from dystonic muscles, and behavioral measures of hand function. Both synchronous and asynchronous low-frequency somatosensory stimulation improved cortical inhibitory interactions, indicated by increased short intracortical inhibition and lateral spatial inhibition, as well as decreased amplitude of paired-pulse somatosensory evoked potentials. Opposite effects were observed with high-frequency stimulation. Changes in electrophysiological markers were paralleled by behavioral outcomes: although low-frequency stimulations improved hand function tests and reduced activation of dystonic muscles, high-frequency stimulation operated in an opposite direction. Our findings confirm the presence of abnormal homeostatic plasticity in response to RSS in the sensorimotor system of patients with dystonia, specifically in inhibitory circuits. Importantly, this aberrant response can be harnessed for therapeutic purposes through the application of low-frequency electrical stimulation directly over dystonic muscles. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions.

International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions.

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10−8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson’s disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.

Precision Imaging in Neurodegeneration: The Superiority of Diffusion Tensor Imaging Over Conventional MRI in Differentiating Parkinson's Disease From Atypical Parkinsonian Syndromes.

Background Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor and non-motor symptoms. Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP) and essential tremor (ET), present with overlapping clinical features, making differential diagnosis challenging. Conventional MRI has limitations in distinguishing PD from APS, necessitating advanced imaging techniques like diffusion tensor imaging (DTI) for more accurate diagnosis. Objectives This retrospective study aimed to evaluate the diagnostic accuracy of DTIin diagnosing PDand APS, particularly assessing its ability to differentiate these conditions from each other compared to conventional MRI. Additionally, the study sought to determine if DTI could diagnose PD in cases where conventional MRI results were normal, thereby highlighting the potential role of DTI in enhancing diagnostic precision in neurodegenerative disorders. Methodology The study included 30 patients with clinically diagnosed PD or APS who underwent both conventional MRI and DTI. Data were collected retrospectively. Imaging was performed using a Philips Multiva 1.5-Tesla MRI scanner (Philips, Amsterdam, Netherlands). DTI sequences were analyzed for fractional anisotropy (FA)values in the substantia nigra, superior cerebellar peduncle, middle cerebellar peduncle, transverse pontine fibers, and dentate nucleus. The FA values were compared with established normal values, and the findings from DTI were correlated with clinical diagnoses and conventional MRI results. Results Among the 30 patients, 53.3% were clinically diagnosed with PDand 46.7% with APS, including PSP and ET. Conventional MRI findings were normal in 46.7% of cases, indicating its limitations in detecting early or subtle changes in neurodegenerative disorders. In contrast, DTI identified abnormalities in 83.3% of cases, demonstrating its superior diagnostic sensitivity. DTI detected significant FA value reductions in the substantia nigra in PD patients (mean FA: 0.440), which is consistent with the degeneration of dopaminergic neurons characteristic of PD. In PSP patients, the superior cerebellar peduncle showed marked FA reductions (mean FA: 0.523), correlating with the clinical features of PSP, such as bradykinesia and postural instability. ET was identified by reduced FA values in the superior cerebellar peduncle and dentate nucleus, distinguishing it from other forms of parkinsonism. DTI was particularly effective in cases where conventional MRI results were inconclusive or normal, identifying early-stage PD and differentiating it from APS with greater accuracy. The study demonstrated a sensitivity of 95.8% and specificity of 93.8% for DTI in differentiating PD from APS compared to conventional MRI. Conclusion This study highlights DTI as a superior imaging modality for the early diagnosis and differentiation of parkinsonian disorders, particularly when conventional MRI results are inconclusive. DTI's ability to detect significant microstructural changes in specific brain regions, evidenced by FA value reductions, enhances diagnostic accuracy. Incorporating DTI into routine clinical practice is essential for accurate differentiation between PD and APS, facilitating better patient management.

The Neurostimulationist will see you now: prescribing direct electrical stimulation therapies for the human brain in epilepsy and beyond.

As the pace of research in implantable neurotechnology increases, it is important to take a step back and see if the promise lives up to our intentions. While direct electrical stimulation applied intracranially has been used for the treatment of various neurological disorders, such as Parkinson's, epilepsy, clinical depression, and Obsessive-compulsive disorder, the effectiveness can be highly variable. One perspective is that the inability to consistently treat these neurological disorders in a standardized way is due to multiple, interlaced factors, including stimulation parameters, location, and differences in underlying network connectivity, leading to a trial-and-error stimulation approach in the clinic. An alternate view, based on a growing knowledge from neural data, is that variability in this input (stimulation) and output (brain response) relationship may be more predictable and amenable to standardization, personalization, and, ultimately, therapeutic implementation. In this review, we assert that the future of human brain neurostimulation, via direct electrical stimulation, rests on deploying standardized, constrained models for easier clinical implementation and informed by intracranial data sets, such that diverse, individualized therapeutic parameters can efficiently produce similar, robust, positive outcomes for many patients closer to a prescriptive model. We address the pathway needed to arrive at this future by addressing three questions, namely: (1) why aren't we already at this prescriptive future?; (2) how do we get there?; (3) how far are we from this Neurostimulationist prescriptive future? We first posit that there are limited and predictable ways, constrained by underlying networks, for direct electrical stimulation to induce changes in the brain based on past literature. We then address how identifying underlying individual structural and functional brain connectivity which shape these standard responses enable targeted and personalized neuromodulation, bolstered through large-scale efforts, including machine learning techniques, to map and reverse engineer these input-output relationships to produce a good outcome and better identify underlying mechanisms. This understanding will not only be a major advance in enabling intelligent and informed design of neuromodulatory therapeutic tools for a wide variety of neurological diseases, but a shift in how we can predictably, and therapeutically, prescribe stimulation treatments the human brain.

A Homozygous Variant in NAA60 Is Associated with Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a monogenic disorder characterized by bilateral calcifications in the brain. The genetic basis remains unknown in over half of the PFBC patients, indicating the existence of additional novel causative genes. NAA60 was a recently reported novel causative gene for PFBC. The aim was to identify the probable novel causative gene in an autosomal recessive inherited PFBC family. We performed a comprehensive genetic study on a consanguineous Chinese family with 3 siblings diagnosed with PFBC. We evaluated the effect of the variant in a probable novel causative gene on the protein level using Western blot, immunofluorescence, and coimmunoprecipitation. Possible downstream pathogenic mechanisms were further explored in gene knockout (KO) cell lines and animal models. We identified a PFBC co-segregated homozygous variant of c.460_461del (p.D154Lfs*113) in NAA60. Functional assays showed that this variant disrupts NAA60 protein localization to Golgi and accelerated protein degradation. The mutant NAA60 protein alters its interaction with the PFBC-related proteins PiT2 and XPR1, affecting intracellular phosphate homeostasis. Further mass spectrometry analysis in NAA60 KO cell lines revealed decreased expression of multiple brain calcification-associated proteins, including reduced folate carrier (RFC), a folate metabolism-related protein. Our study replicated the identification of NAA60 as a novel causative gene for autosomal recessive PFBC, demonstrating our causative variant leads to NAA60 loss of function. The NAA60 loss of function disrupts not only PFBC-related proteins (eg, PiT2 and XPR1) but also a wide range of other brain calcification-associated membrane protein substrates (eg, RFC), and provided a novel probable pathogenic mechanism for PFBC. © 2024 International Parkinson and Movement Disorder Society.

The AAV-α-Synuclein Model of Parkinson's Disease: An Update.

Targeted delivery of α-synuclein using AAV vectors has over the two decades since its introduction developed into a versatile tool for modeling different aspects of synucleinopathy, mimicking those seen in Parkinson's disease and related Lewy body disorders. The viral vector approach to disease modeling is attractive in that the expression of α-synuclein, wild-type or mutated, can be confined to defined anatomical structures and targeted to selected cell populations using either cell-type specific promoter constructs or different natural or engineered AAV serotypes. AAV-α-synuclein was initially used to model progressive α-synuclein pathology in nigral dopamine neurons, and, like the standard 6-OHDA model, it has most commonly been applied unilaterally, using the non-injected side as a reference and control. In recent years, however, the AAV-α-synuclein model has become more widely used to induce Parkinson-like synuclein pathology in other relevant neuronal systems, such as the brainstem noradrenergic and serotonergic neurons, the vagal motor neurons, as well as in oligodendrocytes, the prime target relevant to the pathology seen in multiple system atrophy. The purpose of this review is to give an overview of the progress made in the use of the AAV-α-synuclein model over the last two decades and summarize the state-of-the art in the use of the AAV-α-synuclein model for disease modeling in rats and mice.

IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA.

Childhood neurodegenerative diseases often pose a challenge to clinicians to diagnose because of the degree of genetic heterogeneity and variable presentations. Here, we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia in which postmortem pathological analysis led to the diagnosis of interferon regulatory factor 2 binding protein like (IRF2BPL)-related disorder. Detailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral-pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions. Follow up testing for the CAG repeat expansion at ATN1 was non-diagnostic. Subsequent exome sequencing reanalysis of the research exome identified a pathogenic de novo IRF2BPL variant. The IRF2BPL c.562C>T, p.(Arg188Ter) variant, distal to the polyQ repeat tract, results in variable mRNA levels depending on the cell type examined with decreased mRNA in the brain, as well as destabilization of the protein product and corresponding downstream molecular abnormalities in patient derived cells. We provide the first detailed pathological description for IRF2BPL-related disorder, termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures; Mendelian Inheritance in Man, 618088) and evidence for the inclusion of this condition in the differential diagnosis of spastic-ataxic neurodegenerative conditions, reminiscent of DRPLA. Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats. © 2024 International Parkinson and Movement Disorder Society.