Region-specific impairment of the cervical spinal cord (SC) in amyotrophic lateral sclerosis: A preliminary study using SC templates and quantitative MRI (diffusion tensor imaging/inhomogeneous magnetization transfer)

International audienceIn this preliminary study, our objective was to investigate the potential of high-resolution anatomical imaging, diffusion tensor imaging (DTI) and conventional/inhomogeneous magnetization transfer imaging [magnetization transfer (MT)/inhomogeneous magnetization transfer (ihMT)] at 3 T, analyzed with template-extracted regions of interest, to measure the atrophy and structural changes of white (WM) and gray (GM) matter spinal cord (SC) occurring in patients with amyotrophic lateral sclerosis (ALS). Ten patients with ALS and 20 age-matched healthy controls were recruited. SC GM and WM areas were automatically segmented using dedicated templates. Atrophy indices were evaluated from T2 *-weighted images at each vertebral level from cervical C1 to C6. DTI and ihMT metrics were quantified within the corticospinal tract (CST), posterior sensory tract (PST) and anterior GM (aGM) horns at the C2 and C5 levels. Clinical disabilities of patients with ALS were evaluated using the Revised ALS Functional Rating Scale, upper motor neuron (UMN) and Medical Research Council scorings, and correlated with MR metrics. Compared with healthy controls, GM and WM atrophy was observed in patients with ALS, especially at lower cervical levels, where a strong correlation was also observed between GM atrophy and the UMN score (R = -0.75, p = 0.05 at C6). Interestingly, a significant decrease in ihMT ratio was found in all regions of interest (p \textless 0.0008), fractional anisotropy (FA) and MT ratios decreased significantly in CST, especially at C5 (p \textless 0.005), and λ// (axial diffusivity) decreased significantly in CST (p = 0.0004) and PST (p = 0.003) at C2. Strong correlations between MRI metrics and clinical scores were also found (0.47 \textless \textbarR\textbar \textless 0.87, p \textless 0.05). Altogether, these preliminary results suggest that high-resolution anatomical imaging and ihMT imaging, in addition to DTI, are valuable for the characterization of SC tissue impairment in ALS. In this study, in addition to an important SC WM demyelination, we also observed, for the first time in ALS, impairments of cervical aGM

Could conservative iron chelation lead to neuroprotection in amyotrophic lateral sclerosis?

Iron accumulation has been observed in mouse models and both sporadic and familial forms of Amyotrophic lateral sclerosis. Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e. chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span as compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index (BMI) were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata and motor cortex (according to MRI), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS

Biomarkers in motor neuron disease: A state of the art review

Motor neuron disease can be viewed as an umbrella term describing a heterogeneous group of conditions, all of which are relentlessly progressive and ultimately fatal. The average life expectancy is 2 years, but with a broad range of months to decades. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. It also allows differentiation of the disease population into sub-groups, which serves two general purposes: (a) provides clinicians with information to better guide their patients in terms of disease progression, and (b) guides clinical trial design so that an intervention may be shown to be effective if population variation is controlled for. Biomarkers also have the potential to provide monitoring during clinical trials to ensure target engagement. This review highlights biomarkers that have emerged from the fields of systemic measurements including biochemistry (blood, cerebrospinal fluid, and urine analysis); imaging and electrophysiology, and gives examples of how a combinatorial approach may yield the best results. We emphasize the importance of systematic sample collection and analysis, and the need to correlate biomarker findings with detailed phenotype and genotype data

Prognosis factors of handicap in neurodegenerative disorders : example of the amyotrophic lateral sclerosis and the Parkinson’s disease

Les maladies neurodégénératives nécessitent une meilleure connaissance du pronostic fonctionnel afin de pouvoir évaluer les réponses éventuelles aux thérapeutiques et de connaître le risque individuel de complications. A travers l’exemple de la sclérose latérale amyotrophique (SLA) et de la maladie de Parkinson (MP), notre objectif est de définir des marqueurs prospectifs de handicap et d’insuffisance respiratoire dans la SLA, de troubles de la marche, de dysarthrie et de déclin cognitif dans la MP.Nous avons inclus 41 patients atteints de SLA, 26 patients atteints de MP, 21 témoins pour la SLA et 11 pour la MP. Les patients atteints de SLA ont bénéficié d’une IRM cérébrale et médullaire cervicale à l’inclusion et à 3 mois et d’évaluations cliniques du handicap et de la fonction respiratoire itératives jusqu’au décès ou à la perte de vue. Les patients atteints de MP ont bénéficié d’évaluations cliniques motrices, cognitives et de la dysarthrie sur une période de 6 ans. Ils ont bénéficié d’une analyse du mouvement et d’une IRM fonctionnelle durant laquelle ils réalisaient le Symbol Digit Modalities Test (SDMT).Dans la SLA l’atteinte du faisceau pyramidal est liée au handicap global, la progression de l’atrophie médullaire cervicale est liée au pronostic respiratoire. Dans la MP la sévérité initiale des échelles comportementales, du handicap global et de l’analyse du mouvement aux membres supérieurs à 4 Hz sont corrélées à la sévérité du freezing de la marche 6 ans plus tard. En IRM fonctionnelle les performances au SDMT sont corrélées au degré d’activation cérébrale.Nous montrons que l’étude de marqueurs simples, cliniques ou non invasifs est reliée au pronostic fonctionnel dans la SLA et la MP.There is a need for a better assessment of functional prognosis in neurodegenerative disorders to define the response to experimental treatment or for the individual prognosis. Here we used the example of the amyotrophic lateral sclerosis (ALS) and the Parkinson’s disease (PD). Our aim is to assess prospective biomarkers of handicap and respiratory involvement in ALS and biomarkers of gait disorders, dysarthria and cognitive impairment in PD.We included 41 patients with ALS, 26 with PD, 21 controls for ALS and 11 for PD. ALS had an MRI examination at baseline and 3 months later, they had clinical and respiratory assessment until death or loss of view. PD patients had motor, cognitive and voice clinical assessment along a 6 years period.In ALS the decline of brain motor pathway is related to the global handicap, the atrophy progression in cervical spinal cord is related to respiratory insufficiency. In PD initial severity of behavioural scales, global handicap scale and movement analysis at 4 Hz are correlated to the freezing of gait severity at 6 years. Functional MRI performance are correlated to the brain activation during the SDMT.Here we show that simple clinical and non-invasive markers are closely related to the functional prognosis in ALS and PD

Role and regulation of the trpm8 channel in progression and metastatic dissemination of prostate cancer

Plusieurs études ces dernières décennies suggèrent l’importance des canaux TRPs dont TRPM8 dans le développement et la dissémination du cancer de la prostate. Néanmoins, les différentes études menées sur ce canal sont contradictoires. L’objectif de ma thèse a été d’étudier le rôle précis de TRPM8 dans le cancer prostatique par des études in vivo afin d’évaluer l’impact de TRPM8 sur la croissance tumorale, la dissémination de ces cellules et la formation de métastases. De plus, nous avons approfondi les mécanismes moléculaires sous-jacents régulant l’effet anti-migratoire de TRPM8.Grâce à l’utilisation de nanocapsules lipidiques contenant un agoniste du canal TRPM8, nous avons confirmé par des études in vitro et in vivo un rôle inhibiteur de TRPM8 sur les capacités de migration et d’invasion des cellules cancéreuses prostatiques. De plus, nous avons également déterminer un rôle de TRPM8 sur la croissance tumorale grâce à l’utilisation de greffes orthotopiques dans des prostates murines. Nous avons également déterminé les mécanismes de régulation de la migration cellulaire par le canal TRPM8 et des protéines partenaires à ce canal. Dans ce cadre, nous avons défini et déterminé une régulation du canal TRPM8 par les androgènes modulant la migration cellulaire mais également les mécanismes sous-jacents de l’inhibition de la migration cellulaire induite par TRPM8 et impliquant la petite GTPase Rap1.L’ensemble de nos résultats démontrent un rôle antiprolifératif et anti-migratoire du canal TRPM8 sur les cellule cancéreuses prostatiques, suggérant ainsi une action protectrice de ce canal dans la dissémination des métastases prostatiques.Several studies in recent decades suggest the importance of TRP channel including TRPM8 in the development and metastatic dissemination of prostate cancer. Nevertheless, the different studies conducted on this channel are contradictory. The aim of my thesis was to study the precise role of TRPM8 in prostate cancer by in vivo studies to study the impact of TRPM8 on tumor growth and metastatic dissemination. In addition, we determined the underlying molecular mechanisms regulating the anti-migratory effect of TRPM8.Due to the use of lipid nanocapsules containing a TRPM8 channel agonist, we have confirmed by in vitro and in vivo studies an inhibitory role of TRPM8 on the migration and invasion capacities of prostatic cancer cells. In addition, we also determined an inhibitory role of TRPM8 on tumor growth through the use of orthotopic grafts in murine prostates. We also determined the regulatory mechanisms of cell migration by TRPM8 channel and its partner proteins. In this context, we defined and determined a regulation of the TRPM8 channel by androgens modulating cell migration. Moreover, we determined also the mechanisms underlying the inhibition of TRPM8-induced cell migration involving the small Rap1 GTPase.All of my results demonstrate an anti-proliferative and anti-migratory role of the TRPM8 channel on prostatic cancer cells, suggesting a protective action of this channel in the dissemination of prostatic metastases

TRPM8 Puts the Chill on Prostate Cancer

Prostate cancer (PCa) is one of the most frequently diagnosed cancers in developed countries. Several studies suggest that variations in calcium homeostasis are involved in carcinogenesis. Interestingly, (Transient Receptor Potential Melastatin member 8) TRPM8 calcium permeable channel expression is differentially regulated during prostate carcinogenesis, thereby suggesting a potential functional role for this channel in those cell processes, which are important for PCa evolution. Indeed, several studies have shown that TRPM8 plays a key role in processes such as the proliferation, viability and cell migration of PCa cells. Where cell migration is concerned, TRPM8 seems to have a protective anti-invasive effect and could be a particularly promising therapeutic target. The goal of this review is to inventory advances in understanding of the role of TRPM8 in the installation and progression of PCa