Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience.

Over the past few decades, several radiotracers have been developed for neuroimaging applications, especially in PET. Because of their low steric hindrance, PET radionuclides can be used to label molecules that are small enough to cross the blood brain barrier, without modifying their biological properties. As the use of 11C is limited by its short physical half-life (20 min), there has been an increasing focus on developing tracers labeled with 18F for clinical use. The first such tracers allowed cerebral blood flow and glucose metabolism to be measured, and the development of molecular imaging has since enabled to focus more closely on specific targets such as receptors, neurotransmitter transporters, and other proteins. Hence, PET and SPECT biomarkers have become indispensable for innovative clinical research. Currently, the treatment options for a number of pathologies, notably neurodegenerative diseases, remain only supportive and symptomatic. Treatments that slow down or reverse disease progression are therefore the subject of numerous studies, in which molecular imaging is proving to be a powerful tool. PET and SPECT biomarkers already make it possible to diagnose several neurological diseases in vivo and at preclinical stages, yielding topographic, and quantitative data about the target. As a result, they can be used for assessing patients' eligibility for new treatments, or for treatment follow-up. The aim of the present review was to map major innovative radiotracers used in neuroscience, and explain their contribution to clinical research. We categorized them according to their target: dopaminergic, cholinergic or serotoninergic systems, β-amyloid plaques, tau protein, neuroinflammation, glutamate or GABA receptors, or α-synuclein. Most neurological disorders, and indeed mental disorders, involve the dysfunction of one or more of these targets. Combinations of molecular imaging biomarkers can afford us a better understanding of the mechanisms underlying disease development over time, and contribute to early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up in both research and clinical settings

Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting.

BACKGROUND: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders. METHODS: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later. RESULTS: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year. CONCLUSIONS: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients

Effectiveness of anti-psychotics and related drugs in the Huntington French-speaking group cohort.

PURPOSE: Huntington's disease is a rare condition. Patients are commonly treated with antipsychotics and tetrabenazine. The evidence of their effect on disease progression is limited and no comparative study between these drugs has been conducted. We therefore compared the effectiveness of antipsychotics on disease progression. METHODS: 956 patients from the Huntington French Speaking Group were followed for up to 8 years between 2002 and 2010. The effectiveness of treatments was assessed using Unified Huntington's Disease Rating Scale (UHDRS) scores and then compared using a mixed model adjusted on a multiple propensity score. RESULTS: 63% of patients were treated with antipsychotics during the survey period. The most commonly prescribed medications were dibenzodiazepines (38%), risperidone (13%), tetrabenazine (12%) and benzamides (12%). There was no difference between treatments on the motor and behavioural declines observed, after taking the patient profiles at the start of the drug prescription into account. In contrast, the functional decline was lower in the dibenzodiazepine group than the other antipsychotic groups (Total Functional Capacity: 0.41 ± 0.17 units per year vs. risperidone and 0.54 ± 0.19 vs. tetrabenazine, both p<0.05). Benzamides were less effective than other antipsychotics on cognitive evolution (Stroop interference, Stroop color and Literal fluency: p<0.05). CONCLUSIONS: Antipsychotics are widely used to treat patients with Huntington's disease. Although differences in motor or behavioural profiles between patients according to the antipsychotics used were small, there were differences in drug effectiveness on the evolution of functional and cognitive scores

Interferon β-1a in relapsing multiple sclerosis: four-year extension of the European IFNβ-1a Dose-C omparison Study

Background: Multiple sclerosis (MS) is a chronic disease requiring long-term monitoring of treatment. Objective: To assess the four-year clinical efficacy of intramuscular (IM) IFNb-1a in patients with relapsing MS from the European IFNb-1a Dose-C omparison Study. Methods: Patients who completed 36 months of treatment (Part 1) of the European IFNb-1a Dose-C omparison Study were given the option to continue double-blind treatment with IFNb-1a 30 mcg or 60 mcg IM once weekly (Part 2). Analyses of 48-month data were performed on sustained disability progression, relapses, and neutralizing antibody (NA b) formation. Results: O f 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. IFNb-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months. There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48 and 43, respectively), and annual relapse rates; relapses tended to decrease over 48 months. The incidence of patients who were positive for NAbs at any time during the study was low in both treatment groups. Conclusion: C ompared with 60-mcg IM IFNb-1a once weekly, a dose of 30 mcg IM IFNb-1a once weekly maintains the same clinical efficacy over four years

Coenzyme Q10 and the exclusive club of diseases that show a limited response to treatment

Introduction: Coenzyme Q10 (CoQ10) is a ubiquitous organic molecule with a significant role in the mitochondrial electron transport chain (ETC). As a result of its role in such an important biological process, CoQ10 deficiency has been implicated in the pathogenesis of numerous diseases such as Parkinson’s disease (PD) and multiple sclerosis (MS). This has led to multiple attempts to use CoQ10 supplementation as a treatment or pre-treatment with varying degrees of success. Areas covered: The present review will identify evidence of mitochondrial dysfunction in MS, PD and mitochondrial ETC disorders. In addition, the inability of Co10 supplementation to elicit significant clinical outcome in these disorders and possible flaws in these studies will be discussed. The databases utilized for this review were the Web of science and PubMed, with inclusive dates (1957–2021). Expert opinion: A lack of improved neurological outcome in these disorders post treatment with CoQ10 may be attributable to the limited ability of CoQ10 to cross the blood–brain barrier. Thus, CoQ10 alternatives should also be considered. Other factors including time of disease diagnosis, dosage, administration, and duration of CoQ10 therapy may have a significant influence on the efficacy of this treatment

Colloids as Mobile Substrates for the Implantation and Integration of Differentiated Neurons into the Mammalian Brain

Neuronal degeneration and the deterioration of neuronal communication lie at the origin of many neuronal disorders, and there have been major efforts to develop cell replacement therapies for treating such diseases. One challenge, however, is that differentiated cells are challenging to transplant due to their sensitivity both to being uprooted from their cell culture growth support and to shear forces inherent in the implantation process. Here, we describe an approach to address these problems. We demonstrate that rat hippocampal neurons can be grown on colloidal particles or beads, matured and even transfected in vitro, and subsequently transplanted while adhered to the beads into the young adult rat hippocampus. The transplanted cells have a 76% cell survival rate one week post-surgery. At this time, most transplanted neurons have left their beads and elaborated long processes, similar to the host neurons. Additionally, the transplanted cells distribute uniformly across the host hippocampus. Expression of a fluorescent protein and the light-gated glutamate receptor in the transplanted neurons enabled them to be driven to fire by remote optical control. At 1-2 weeks after transplantation, calcium imaging of host brain slice shows that optical excitation of the transplanted neurons elicits activity in nearby host neurons, indicating the formation of functional transplant-host synaptic connections. After 6 months, the transplanted cell survival and overall cell distribution remained unchanged, suggesting that cells are functionally integrated. This approach, which could be extended to other cell classes such as neural stem cells and other regions of the brain, offers promising prospects for neuronal circuit repair via transplantation of in vitro differentiated, genetically engineered neurons

Survivin Mutant Protects Differentiated Dopaminergic SK-N-SH Cells Against Oxidative Stress

Oxidative stress is due to an imbalance of antioxidant/pro-oxidant homeostasis and is associated with the progression of several neurological diseases, including Parkinson's and Alzheimer's disease and amyotrophic lateral sclerosis. Furthermore, oxidative stress is responsible for the neuronal loss and dysfunction associated with disease pathogenesis. Survivin is a member of the inhibitors of the apoptosis (IAP) family of proteins, but its neuroprotective effects have not been studied. Here, we demonstrate that SurR9-C84A, a survivin mutant, has neuroprotective effects against H2O2-induced neurotoxicity. Our results show that H2O2 toxicity is associated with an increase in cell death, mitochondrial membrane depolarisation, and the expression of cyclin D1 and caspases 9 and 3. In addition, pre-treatment with SurR9-C84A reduces cell death by decreasing both the level of mitochondrial depolarisation and the expression of cyclin D1 and caspases 9 and 3. We further show that SurR9-C84A increases the antioxidant activity of GSH-peroxidase and catalase, and effectively counteracts oxidant activity following exposure to H2O2. These results suggest for the first time that SurR9-C84A is a promising treatment to protect neuronal cells against H2O2-induced neurotoxicity

The Neuromelanin-related T2* Contrast in Postmortem Human Substantia Nigra with 7T MRI

High field magnetic resonance imaging (MRI)-based delineation of the substantia nigra (SN) and visualization of its inner cellular organization are promising methods for the evaluation of morphological changes associated with neurodegenerative diseases; however, corresponding MR contrasts must be matched and validated with quantitative histological information. Slices from two postmortem SN samples were imaged with a 7 Tesla (7T) MRI with T1 and T2* imaging protocols and then stained with Perl???s Prussian blue, Kluver-Barrera, tyrosine hydroxylase, and calbindin immunohistochemistry in a serial manner. The association between T2* values and quantitative histology was investigated with a co-registration method that accounts for histology slice preparation. The ventral T2* hypointense layers between the SNr and the crus cerebri extended anteriorly to the posterior part of the crus cerebri, which demonstrates the difficulty with an MRI-based delineation of the SN. We found that the paramagnetic hypointense areas within the dorsolateral SN corresponded to clusters of neuromelanin (NM). These NM-rich zones were distinct from the hypointense ventromedial regions with high iron pigments. Nigral T2* imaging at 7T can reflect the density of NM-containing neurons as the metal-bound NM macromolecules may decrease T2* values and cause hypointense signalling in T2* imaging at 7T.ope

IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism

Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine

The development of molecular probes that allow in vivo imaging of neural signaling processes with high temporal and spatial resolution remains challenging. Here we applied directed evolution techniques to create magnetic resonance imaging (MRI) contrast agents sensitive to the neurotransmitter dopamine. The sensors were derived from the heme domain of the bacterial cytochrome P450-BM3 (BM3h). Ligand binding to a site near BM3h's paramagnetic heme iron led to a drop in MRI signal enhancement and a shift in optical absorbance. Using an absorbance-based screen, we evolved the specificity of BM3h away from its natural ligand and toward dopamine, producing sensors with dissociation constants for dopamine of 3.3–8.9 μM. These molecules were used to image depolarization-triggered neurotransmitter release from PC12 cells and in the brains of live animals. Our results demonstrate the feasibility of molecular-level functional MRI using neural activity–dependent sensors, and our protein engineering approach can be generalized to create probes for other targets.Charles A. Dana Foundation. Brain and Immuno-ImagingRaymond and Beverley Sackler FoundationNational Institutes of Health (U.S.) (grant R01-DA28299)National Institutes of Health (U.S.) (grant DP2-OD2441)National Institutes of Health (U.S.) (grant R01-GM068664)Jacobs Institute for Molecular Engineering for Medicine. Jacobs Institute for Molecular Engineering for MedicineNational Institutes of Health (U.S.) (grant R01-DE013023