Twelve Years of Drug Prioritization to Help Accelerate Disease Modification Trials in Parkinson's Disease: The International Linked Clinical Trials initiative.

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

The impact of subthalamic deep-brain stimulation in restoring motor symmetry in Parkinson's disease patients: a prospective study.

BACKGROUND AND OBJECTIVES: The impact of subthalamic deep-brain stimulation (STN-DBS) on motor asymmetry and its influence on both motor and non-motor outcomes remain unclear. The present study aims at assessing the role of STN-DBS on motor asymmetry and how its modulation translates into benefits in motor function, activities of daily living (ADLs) and quality of life (QoL). METHODS: Postoperative motor asymmetry has been assessed on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. Asymmetry was evaluated at both baseline (pre-DBS) and 1 year after STN-DBS. A patient was considered asymmetric when the right-to-left MDS-UPDRS part III difference was ≥ 5. In parallel, analyses have been carried out using the absolute right-to-left difference. The proportion of asymmetric patients at baseline was compared to that in the post-surgery evaluation across different medication/stimulation conditions. RESULTS: 537 PD patients have been included. The proportion of asymmetric patients was significantly reduced after both STN-DBS and medication administration (asymmetric patients: 50% in pre-DBS MedOFF, 35% in MedOFF/StimON, 26% in MedON/StimOFF, and 12% in MedON/StimON state). Older patients at surgery and with higher baseline UPDRS II scores were significantly less likely to benefit from STN-DBS at the level of motor asymmetry. No significant correlation between motor asymmetry and ADLs (UPDRS II) or overall QoL (PDQ-39) score was observed. Asymmetric patients had significantly higher mobility, communication, and daily living PDQ-39 sub-scores. CONCLUSIONS: Both STN-DBS and levodopa lead to a reduction in motor asymmetry. Motor symmetry is associated with improvements in certain QoL sub-scores.

The Use of Image Guided Programming to Improve Deep Brain Stimulation Workflows with Directional Leads in Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a preferred treatment for parkinsonian patients with severe motor fluctuations. Proper targeting of the STN sensorimotor segment appears to be a crucial factor for success of the procedure. The recent introduction of directional leads theoretically increases stimulation specificity in this challenging area but also requires more precise stimulation parameters. OBJECTIVE: We investigated whether commercially available software for image guided programming (IGP) could maximize the benefits of DBS by informing the clinical standard care (CSC) and improving programming workflows. METHODS: We prospectively analyzed 32 consecutive parkinsonian patients implanted with bilateral directional leads in the STN. Double blind stimulation parameters determined by CSC and IGP were assessed and compared at three months post-surgery. IGP was used to adjust stimulation parameters if further clinical refinement was required. Overall clinical efficacy was evaluated one-year post-surgery. RESULTS: We observed 78% concordance between the two electrode levels selected by the blinded IGP prediction and CSC assessments. In 64% of cases requiring refinement, IGP improved clinical efficacy or reduced mild side effects, predominantly by facilitating the use of directional stimulation (93% of refinements). CONCLUSIONS: The use of image guided programming saves time and assists clinical refinement, which may be beneficial to the clinical standard care for STN-DBS and further improve the outcomes of DBS for PD patients.

ON/OFF non-motor evaluation: a new way to evaluate non-motor fluctuations in Parkinson's disease.

BACKGROUND: NMF are currently poorly evaluated in therapeutic decisions. A quantification of their severity would facilitate their integration. The objective of this study was to validate an autoquestionnaire evaluating the severity of non-motor fluctuations (NMF) in Parkinson's disease (PD). METHODS: Patients with PD were included in presurgical situation for deep brain stimulation of subthalamic nuclei. They participated in the PREDISTIM cohort (a study evaluating the predictive factors for therapeutic response of subthalamic stimulation in PD) in 17 centres in France. Our questionnaire, resulting from previous phases of development, included 11 non-motor symptoms (NMS). Their severity ranged from 0 to 10 and was assessed in OFF and then ON-Dopa to study their fluctuations. RESULTS: 310 patients were included, of whom 98.8% had NMS and 98.0% had NMF. Each NMS was significantly improved by L-Dopa (decrease in severity score ranging from 43.1% to 69.9%). Fatigue was the most frequent and most severe NMS. NMS were considered more bothersome than motor symptoms by 37.5% of patients in OFF-Dopa and 34.9% in ON-Dopa. CONCLUSIONS: This is the first questionnaire allowing a real-time quantification of the severity of NMS and their fluctuation with levodopa. It was able to confirm and measure the effect of L-dopa and show differences according to the patients and the NMS. It differs from other questionnaires by its measurement at a precise moment of the severity of the NMS, allowing its use during pretherapeutic assessments.Our questionnaire has been validated to measure the severity of NMF. It will be able to quantify the non-motor effect of anti-parkinsonian treatments and could facilitate the integration of NMF in therapeutic decisions.

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

Overview on wearable sensors for the management of Parkinson's disease.

Parkinson's disease (PD) is affecting about 1.2 million patients in Europe with a prevalence that is expected to have an exponential increment, in the next decades. This epidemiological evolution will be challenged by the low number of neurologists able to deliver expert care for PD. As PD is better recognized, there is an increasing demand from patients for rigorous control of their symptoms and for therapeutic education. In addition, the highly variable nature of symtoms between patients and the fluctuations within the same patient requires innovative tools to help doctors and patients monitor the disease in their usual living environment and adapt treatment in a more relevant way. Nowadays, there are various body-worn sensors (BWS) proposed to monitor parkinsonian clinical features, such as motor fluctuations, dyskinesia, tremor, bradykinesia, freezing of gait (FoG) or gait disturbances. BWS have been used as add-on tool for patients' management or research purpose. Here, we propose a practical anthology, summarizing the characteristics of the most used BWS for PD patients in Europe, focusing on their role as tools to improve treatment management. Consideration regarding the use of technology to monitor non-motor features is also included. BWS obviously offer new opportunities for improving management strategy in PD but their precise scope of use in daily routine care should be clarified.

Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Enhancing paracellular and transcellular permeability using nanotechnological approaches for the treatment of brain and retinal diseases.

Paracellular permeability across epithelial and endothelial cells is, in large part, regulated by apical intercellular junctions also referred to as tight junctions (TJs). These junctions contribute to the spatial definition of different tissue compartments within organisms, separating them from the outside world as well as from inner compartments, with their primary physiological role of maintaining tissue homeostasis. TJs restrict the free, passive diffusion of ions and hydrophilic small molecules through paracellular clefts and are important for appropriate cell polarization and transporter protein localisation, supporting the controlled transcellular diffusion of smaller and larger hydrophilic as well as hydrophobic substances. This traditional diffusion barrier concept of TJs has been challenged lately, owing to a better understanding of the components that are associated with TJs. It is now well-established that mutations in TJ proteins are associated with a range of human diseases and that a change in the membrane fluidity of neighbouring cells can open possibilities for therapeutics to cross intercellular junctions. Nanotechnological approaches, exploiting ultrasound or hyperosmotic agents and permeation enhancers, are the paradigm for achieving enhanced paracellular diffusion. The other widely used transport route of drugs is via transcellular transport, allowing the passage of a variety of pro-drugs and nanoparticle-encapsulated drugs via different mechanisms based on receptors and others. For a long time, there was an expectation that lipidic nanocarriers and polymeric nanostructures could revolutionize the field for the delivery of RNA and protein-based therapeutics across different biological barriers equipped with TJs (e.g., blood-brain barrier (BBB), retina-blood barrier (RBB), corneal TJs, etc.). However, only a limited increase in therapeutic efficiency has been reported for most systems until now. The purpose of this review is to explore the reasons behind the current failures and to examine the emergence of synthetic and cell-derived nanomaterials and nanotechnological approaches as potential game-changers in enhancing drug delivery to target locations both at and across TJs using innovative concepts. Specifically, we will focus on recent advancements in various nanotechnological strategies enabling the bypassing or temporally opening of TJs to the brain and to the retina, and discuss their advantages and limitations.

Therapeutic inhibition of ferroptosis in neurodegenerative disease.

Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification of clinically relevant biomarkers, and which patients might benefit most. Clinical trials of iron- and ferroptosis-targeted therapies are beginning to provide some answers, but there is growing interest in developing new ferroptosis inhibitors. We describe newly identified ferroptosis targets, opportunities, and challenges in NDD, as well as key considerations for progressing new therapeutics to the clinic.

Heimdall, an alternative protein issued from a ncRNA related to kappa light chain variable region of immunoglobulins from astrocytes: a new player in neural proteome.

The dogma "One gene, one protein" is clearly obsolete since cells use alternative splicing and generate multiple transcripts which are translated into protein isoforms, but also use alternative translation initiation sites (TISs) and termination sites on a given transcript. Alternative open reading frames for individual transcripts give proteins originate from the 5'- and 3'-UTR mRNA regions, frameshifts of mRNA ORFs or from non-coding RNAs. Longtime considered as non-coding, recent in-silico translation prediction methods enriched the protein databases allowing the identification of new target structures that have not been identified previously. To gain insight into the role of these newly identified alternative proteins in the regulation of cellular functions, it is crucial to assess their dynamic modulation within a framework of altered physiological modifications such as experimental spinal cord injury (SCI). Here, we carried out a longitudinal proteomic study on rat SCI from 12 h to 10 days. Based on the alternative protein predictions, it was possible to identify a plethora of newly predicted protein hits. Among these proteins, some presented a special interest due to high homology with variable chain regions of immunoglobulins. We focus our interest on the one related to Kappa variable light chains which is similarly highly produced by B cells in the Bence jones disease, but here expressed in astrocytes. This protein, name Heimdall is an Intrinsically disordered protein which is secreted under inflammatory conditions. Immunoprecipitation experiments showed that the Heimdall interactome contained proteins related to astrocyte fate keepers such as "NOTCH1, EPHA3, IPO13" as well as membrane receptor protein including "CHRNA9; TGFBR, EPHB6, and TRAM". However, when Heimdall protein was neutralized utilizing a specific antibody or its gene knocked out by CRISPR-Cas9, sprouting elongations were observed in the corresponding astrocytes. Interestingly, depolarization assays and intracellular calcium measurements in Heimdall KO, established a depolarization effect on astrocyte membranes KO cells were more likely that the one found in neuroprogenitors. Proteomic analyses performed under injury conditions or under lipopolysaccharides (LPS) stimulation, revealed the expression of neuronal factors, stem cell proteins, proliferation, and neurogenesis of astrocyte convertor factors such as EPHA4, NOTCH2, SLIT3, SEMA3F, suggesting a role of Heimdall could regulate astrocytic fate. Taken together, Heimdall could be a novel member of the gatekeeping astrocyte-to-neuroprogenitor conversion factors.

Astrocytes express aberrant immunoglobulins as putative gatekeeper of astrocytes to neuronal progenitor conversion.

Using multi-omics analyses including RNAseq, RT-PCR, RACE-PCR, and shotgun proteomic with enrichment strategies, we demonstrated that newborn rat astrocytes produce neural immunoglobulin constant and variable heavy chains as well as light chains. However, their edification is different from the ones found in B cells and they resemble aberrant immunoglobulins observed in several cancers. Moreover, the complete enzymatic V(D)J recombination complex has also been identified in astrocytes. In addition, the constant heavy chain is also present in adult rat astrocytes, whereas in primary astrocytes from human fetus we identified constant and variable kappa chains as well as the substitution lambda chains known to be involved in pre-B cells. To gather insights into the function of these neural IgGs, CRISPR-Cas9 of IgG2B constant heavy chain encoding gene (Igh6), IgG2B overexpression, proximal labeling of rat astrocytes IgG2B and targets identification through 2D gels were performed. In Igh6 KO astrocytes, overrepresentation of factors involved in hematopoietic cells, neural stem cells, and the regulation of neuritogenesis have been identified. Moreover, overexpression of IgG2B in astrocytes induces the CRTC1-CREB-BDNF signaling pathway known to be involved in gliogenesis, whereas Igh6 KO triggers the BMP/YAP1/TEAD3 pathway activated in astrocytes dedifferentiation into neural progenitors. Proximal labeling experiments revealed that IgG2B is N-glycosylated by the OST complex, addressed to vesicle membranes containing the ATPase complex, and behaves partially like CD98hc through its association with LAT1. These experiments also suggest that proximal IgG2B-LAT1 interaction occurs concomitantly with MACO-1 and C2CD2L, at the heart of a potentially novel cell signaling platform. Finally, we demonstrated that these chains are synthesized individually and associated to recognize specific targets. Indeed, intermediate filaments Eif4a2 and Pdia6 involved in astrocyte fate constitute targets for these neural IgGs. Taken together, we hypothese that neural aberrant IgG chains may act as gatekeepers of astrocytes' fate.

Symptoms assessment and decision to treat patients with advanced Parkinson's disease based on wearables data.

Body-worn sensors (BWS) could provide valuable information in the management of Parkinson's disease and support therapeutic decisions based on objective monitoring. To study this pivotal step and better understand how relevant information is extracted from BWS results and translated into treatment adaptation, eight neurologists examined eight virtual cases composed of basic patient profiles and their BWS monitoring results. Sixty-four interpretations of monitoring results and the subsequent therapeutic decisions were collected. Relationship between interrater agreements in the BWS reading and the severity of symptoms were analyzed via correlation studies. Logistic regression was used to identify associations between the BWS parameters and suggested treatment modifications. Interrater agreements were high and significantly associated with the BWS scores. Summarized BWS scores reflecting bradykinesia, dyskinesia, and tremor predicted the direction of treatment modifications. Our results suggest that monitoring information is robustly linked to treatment adaptation and pave the way to loop systems able to automatically propose treatment modifications from BWS recordings information.

Novel variant c.92T > G (p.Val31Gly) in the PFN1 gene (ALS18) responsible for a specific phenotype in a large Bulgarian amyotrophic lateral sclerosis pedigree.

Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of motor function, disability, and death. Variants in the PFN1 gene, encoding the Profilin-1 protein, are related to ALS18. Methods: We present a pedigree consisting of 3 generations and 4 affected individuals, 3 of which carry a novel heterozygous variant: c.92T > G (p.Val31Gly) in the PFN1 gene. This variant was discovered through means of whole exome sequencing (WES) and targeted analysis of ALS-related genes. Results: The mean age of onset in our pedigree was 59.75 (±10.11 SD) years with a significant difference between the first two generations (females) and the third (male) of 22.33 (±3.4 SD) years. For this ALS form, we observed a longer disease progression of 4 (±1.87 SD) years (three of four affected are still alive). Clinical manifestations displayed predominant impairment of the lower motor neuron (LMN) in one limb, with gradual involvement of other limbs. A novel heterozygous missense variant c.92T > G, p. Val31Gly (NM_005022.4) in exon 1 in the PFN1 gene was discovered through means of whole exome sequencing (WES). Segregation analysis in the family showed that the detected variant was inherited from the affected mother, and the affected aunt also turned out to be a variant carrier. Conclusions: ALS18 is a very rare form of the disease. We report here a relatively large pedigree with a novel variant, leading to late onset (after 50 years), initial involvement of the lower limbs and relatively slow progression.

Neuroprotective activity of a virus-safe nanofiltered human platelet lysate depleted of extracellular vesicles in Parkinson's disease and traumatic brain injury models.

Brain administration of human platelet lysates (HPL) is a potential emerging biotherapy of neurodegenerative and traumatic diseases of the central nervous system. HPLs being prepared from pooled platelet concentrates, thereby increasing viral risks, manufacturing processes should incorporate robust virus-reduction treatments. We evaluated a 19 ± 2-nm virus removal nanofiltration process using hydrophilic regenerated cellulose hollow fibers on the properties of a neuroprotective heat-treated HPL (HPPL). Spiking experiments demonstrated >5.30 log removal of 20-22-nm non-enveloped minute virus of mice-mock particles using an immuno-quantitative polymerase chain reaction assay. The nanofiltered HPPL (NHPPL) contained a range of neurotrophic factors like HPPL. There was >2 log removal of extracellular vesicles (EVs), associated with decreased expression of pro-thrombogenic phosphatidylserine and procoagulant activity. LC-MS/MS proteomics showed that ca. 80% of HPPL proteins, including neurotrophins, cytokines, and antioxidants, were still found in NHPPL, whereas proteins associated with some infections and cancer-associated pathways, pro-coagulation and EVs, were removed. NHPPL maintained intact neuroprotective activity in Lund human mesencephalic dopaminergic neuron model of Parkinson's disease (PD), stimulated the differentiation of SH-SY5Y neuronal cells and showed preserved anti-inflammatory function upon intranasal administration in a mouse model of traumatic brain injury (TBI). Therefore, nanofiltration of HPL is feasible, lowers the viral, prothrombotic and procoagulant risks, and preserves the neuroprotective and anti-inflammatory properties in neuronal pre-clinical models of PD and TBI.

Quantitative susceptibility mapping demonstrates different patterns of iron overload in subtypes of early-onset Alzheimer's disease.

OBJECTIVES: We aimed to define brain iron distribution patterns in subtypes of early-onset Alzheimer's disease (EOAD) by the use of quantitative susceptibility mapping (QSM). METHODS: EOAD patients prospectively underwent MRI on a 3-T scanner and concomitant clinical and neuropsychological evaluation, between 2016 and 2019. An age-matched control group was constituted of cognitively healthy participants at risk of developing AD. Volumetry of the hippocampus and cerebral cortex was performed on 3DT1 images. EOAD subtypes were defined according to the hippocampal to cortical volume ratio (HV:CTV). Limbic-predominant atrophy (LPMRI) is referred to HV:CTV ratios below the 25th percentile, hippocampal-sparing (HpSpMRI) above the 75th percentile, and typical-AD between the 25th and 75th percentile. Brain iron was estimated using QSM. QSM analyses were made voxel-wise and in 7 regions of interest within deep gray nuclei and limbic structures. Iron distribution in EOAD subtypes and controls was compared using an ANOVA. RESULTS: Sixty-eight EOAD patients and 43 controls were evaluated. QSM values were significantly higher in deep gray nuclei (p < 0.001) and limbic structures (p = 0.04) of EOAD patients compared to controls. Among EOAD subtypes, HpSpMRI had the highest QSM values in deep gray nuclei (p < 0.001) whereas the highest QSM values in limbic structures were observed in LPMRI (p = 0.005). QSM in deep gray nuclei had an AUC = 0.92 in discriminating HpSpMRI and controls. CONCLUSIONS: In early-onset Alzheimer's disease patients, we observed significant variations of iron distribution reflecting the pattern of brain atrophy. Iron overload in deep gray nuclei could help to identify patients with atypical presentation of Alzheimer's disease. KEY POINTS: • In early-onset AD patients, QSM indicated a significant brain iron overload in comparison with age-matched controls. • Iron load in limbic structures was higher in participants with limbic-predominant subtype. • Iron load in deep nuclei was more important in participants with hippocampal-sparing subtype.

ACSL4 and the lipoxygenases 15/15B are pivotal for ferroptosis induced by iron and PUFA dyshomeostasis in dopaminergic neurons.

Ferroptosis, an iron-dependent regulated cell death triggered by high lipid peroxide levels, has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD). Brain regions such as the striatum are highly rich in both peroxidation susceptible PUFAs and iron, which accumulate at a greater rate than age in PD. The exact molecular pathways and patho-physiological conditions promoting cell death in the dopaminergic neurons that are particularly susceptible in PD remain elusive. In the current work, we show that modifying the PUFA composition in membranes of dopaminergic neurons using arachidonic acid (AA) can determine ferroptosis susceptibility. Furthermore, cotreatment with iron (Fe), increases AA-containing phospholipid association and synergistically promotes high lipid peroxidation to facilitate ferroptosis. Ex vivo analysis with organotypic brain slices, confirm that AA + Fe induces cell death in the nigrostriatal pathway and can be rescued by the anti-ferroptotic drug Ferrostatin-1. Prevention of ferroptotic AA + Fe induced cell death through inhibition of ACSL4, ALOX15 or ALOX15B provides mechanistic support of this lipid peroxidation pathway being involved in dopaminergic neuronal death and novel potential pharmacological targets for neuroprotective strategies in PD.

Functional changes in prefrontal cortex following frequency-specific training.

Numerous studies indicate a significant role of pre-frontal circuits (PFC) connectivity involving attentional and reward neural networks within attention deficit hyperactivity disorder (ADHD) pathophysiology. To date, the neural mechanisms underlying the utility of non-invasive frequency-specific training systems in ADHD remediation remain underexplored. To address this issue, we created a portable electroencephalography (EEG)-based wireless system consisting of a novel headset, electrodes, and neuro program, named frequency specific cognitive training (FSCT). In a double-blind, randomized, controlled study we investigated the training effects in N = 46 school-age children ages 6-18 years with ADHD. 23 children in experimental group who underwent FCST training showed an increase in scholastic performance and meliorated their performance on neuropsychological tests associated with executive functions and memory. Their results were compared to 23 age-matched participants who underwent training with placebo (pFSCT). Electroencephalogram (EEG) data collected from participants trained with FSCT showed a significant increase in 14-18 Hz EEG frequencies in PFC brain regions, activities that indicated brain activation in frontal brain regions, the caudate nucleus, and putamen. These results demonstrate that FSCT targets specific prefrontal and striatal areas in children with ADHD, suggesting a beneficial modality for non-invasive modulation of brain areas implicated in attention and executive functions.