Irene Pulido-Valdeolivas

Abnormal motor phenotype at adult stages in mice lacking type 2 deiodinase.

Background Thyroid hormones have a key role in both the developing and adult central nervous system and skeletal muscle. The thyroid gland produces mainly thyroxine (T4) but the intracellular concentrations of 3,5,3′-triiodothyronine (T3; the transcriptionally active hormone) in the central nervous system and skeletal muscle are modulated by the activity of type 2 deiodinase (D2). To date no neurological syndrome has been associated with mutations in the DIO2 gene and previous studies in young and juvenile D2-knockout mice (D2KO) did not find gross neurological alterations, possibly due to compensatory mechanisms. Aim This study aims to analyze the motor phenotype of 3-and-6-month-old D2KO mice to evaluate the role of D2 on the motor system at adult stages in which compensatory mechanisms could have failed. Results Motor abilities were explored by validated tests. In the footprint test, D2KO showed an altered global gait pattern (mice walked slower, with shorter strides and with a hindlimb wider base of support than wild-type mice). No differences were detected in the balance beam test. However, a reduced latency to fall was found in the rotarod, coat-hanger and four limb hanging wire tests indicating impairment on coordination and prehensile reflex and a reduction of muscle strength. In histological analyses of cerebellum and skeletal muscle, D2KO mice did not present gross structural abnormalities. Thyroid hormones levels and deiodinases activities were also determined. In D2KO mice, despite euthyroid T3 and high T4 plasma levels, T3 levels were significantly reduced in cerebral cortex (48% reduction) and skeletal muscle (33% reduction), but not in the cerebellum where other deiodinase (type 1) is expressed. Conclusions The motor alterations observed in D2KO mice indicate an important role for D2 in T3 availability to maintain motor function and muscle strength. Our results suggest a possible implication of D2 in motor disorders.

Putamina involvement in Wernicke encephalopathy induced by Janus Kinase 2 inhibitor.

ObjectiveThe aim of the study was to report a case of Wernicke encephalopathy (WE) due to fedratinib (Janus Kinase 2 inhibitor) treatment with atypical neuroimaging findings. MethodsWe present a detailed report of the case and literature review. ResultsA 68-year-old woman under treatment with fedratinib (investigational JAK2 inhibitor) developed memory impairment, diplopia, and ataxia compatible with WE. Brain magnetic resonance imaging showed extensive lesions involving medial thalami, periaqueductal gray, caudate nuclei, and putamina. Thiamine supplementation provided clinical recovery and radiological improvement of the lesions described. Basal ganglia lesions have been previously described in children with this disease, but this is rarely found in adults. Clinical trials including fedratinib have been recently discontinued, and its involvement in pathogenesis of WE may be related to thiamine-transporter inhibition. ConclusionsOur case represents an example of drug-related WE, with a rare radiological pattern. Precocious diagnosis and treatment are essential to prevent irreversible brain injury.

Predictors of vision impairment in Multiple Sclerosis

Visual impairment significantly alters the quality of life of people with Multiple Sclerosis (MS). The objective of this study was to identify predictors (independent variables) of visual outcomes, and to define their relationship with neurological disability and retinal atrophy when assessed by optical coherence tomography (OCT). We performed a cross-sectional analysis of 119 consecutive patients with MS, assessing vision using high contrast visual acuity (LogMar), 2.5% and 1.25% low contrast visual acuity (Sloan charts), and color vision (Hardy-Rand-Rittler plates). Quality of vision is a patient reported outcome based on an individuals unique perception of his or her vision and was assessed with the Visual Functioning Questionnaire-25 (VFQ-25) with the 10 neuro-ophthalmologic items. MS disability was assessed using the expanded disability status scale (EDSS), the MS functional composite (MSFC) and the brief repetitive battery-neuropsychology (BRB-N). Retinal atrophy was assessed using spectral domain OCT, measuring the thickness of the peripapillar retinal nerve fiber layer (pRNFL) and the volume of the ganglion cell plus inner plexiform layer (GCIPL). The vision of patients with MS was impaired, particularly in eyes with prior optic neuritis. Retinal atrophy (pRNFL and GCIPL) was closely associated with impaired low contrast vision and color vision, whereas the volume of the GCIPL showed a trend (p = 0.092) to be associated with quality of vision. Multiple regression analysis revealed that EDSS was an explanatory variable for high contrast vision after stepwise analysis, GCIPL volume for low contrast vision, and GCIPL volume and EDSS for color vision. The explanatory variables for quality of vision were high contrast vision and color vision. In summary, quality of vision in MS depends on the impairment of high contrast visual acuity and color vision due to the disease.

Characterizing Normal and Pathological Gait through Permutation Entropy

Cerebral palsy is a physical impairment stemming from a brain lesion at perinatal time, most of the time resulting in gait abnormalities: the first cause of severe disability in childhood. Gait study, and instrumental gait analysis in particular, has been receiving increasing attention in the last few years, for being the complex result of the interactions between different brain motor areas and thus a proxy in the understanding of the underlying neural dynamics. Yet, and in spite of its importance, little is still known about how the brain adapts to cerebral palsy and to its impaired gait and, consequently, about the best strategies for mitigating the disability. In this contribution, we present the hitherto first analysis of joint kinematics data using permutation entropy, comparing cerebral palsy children with a set of matched control subjects. We find a significant increase in the permutation entropy for the former group, thus indicating a more complex and erratic neural control of joints and a non-trivial relationship between the permutation entropy and the gait speed. We further show how this information theory measure can be used to train a data mining model able to forecast the child’s condition. We finally discuss the relevance of these results in clinical applications and specifically in the design of personalized medicine interventions.

Gait phenotypes in paediatric hereditary spastic paraplegia revealed by dynamic time warping analysis and random forests

The Hereditary Spastic Paraplegias (HSP) are a group of heterogeneous disorders with a wide spectrum of underlying neural pathology, and hence HSP patients express a variety of gait abnormalities. Classification of these phenotypes may help in monitoring disease progression and personalizing therapies. This is currently managed by measuring values of some kinematic and spatio-temporal parameters at certain moments during the gait cycle, either in the doctor´s surgery room or after very precise measurements produced by instrumental gait analysis (IGA). These methods, however, do not provide information about the whole structure of the gait cycle. Classification of the similarities among time series of IGA measured values of sagittal joint positions throughout the whole gait cycle can be achieved by hierarchical clustering analysis based on multivariate dynamic time warping (DTW). Random forests can estimate which are the most important isolated parameters to predict the classification revealed by DTW, since clinicians need to refer to them in their daily practice. We acquired time series of pelvic, hip, knee, ankle and forefoot sagittal angular positions from 26 HSP and 33 healthy children with an optokinetic IGA system. DTW revealed six gait patterns with different degrees of impairment of walking speed, cadence and gait cycle distribution and related with patient’s age, sex, GMFCS stage, concurrence of polyneuropathy and abnormal visual evoked potentials or corpus callosum. The most important parameters to differentiate patterns were mean pelvic tilt and hip flexion at initial contact. Longer time of support, decreased values of hip extension and increased knee flexion at initial contact can differentiate the mildest, near to normal HSP gait phenotype and the normal healthy one. Increased values of knee flexion at initial contact and delayed peak of knee flexion are important factors to distinguish GMFCS stages I from II-III and concurrence of polyneuropathy.

Muscle imaging in laminopathies: synthesis study identifies meaningful muscles for follow-up: Muscle MRI progression in LMNA

Introduction: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA‐related muscular dystrophies (LMNA‐RD). Methods: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA‐RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. Results: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. Discussion: In LMNA‐RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA‐RD. Muscle Nerve 58:812–817, 2018

Precision medicine for multiple sclerosis: an update of the available biomarkers and their use in therapeutic decision making

ABSTRACT Introduction: Precision medicine is an approach to disease prevention and treatment that takes into account individual variability in terms of genetics, environment and lifestyle. This approach depends on clinical, imaging and biological markers to define the optimal therapeutic approach for a given patient. Areas covered: Although many biomarkers have been proposed for MS, at present only oligoclonal bands (OCBs), magnetic resonance imaging, optical coherent tomography measurements and the JCv antibody index have been implemented in clinical practice. Expert commentary: Validation of biomarkers in multicentric prospective studies is necessary to improve the application of precision medicine for MS patients. New tools will open new avenues to improve our ability to provide personalized therapy to individuals with MS, including those aimed at the extraction of medical information from electronic health records, or those involving the application of machine learning tools to combine different types of information and biomarkers.

Patterns of motor signs in spinocerebellar ataxia type 3 at the start of follow-up in a reference unit

BackgroundSpinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder that affects the cerebellar system and other subcortical regions of the brain. As for other cerebellar diseases, the severity of this type of ataxia can be assessed with the Scale for Assessment and Rating of Ataxia (SARA) which gives a total score that reflects functional impairment out of 8 cerebellar function tests. SCA3 patients score profile is heterogeneous on at the start of follow up. This study investigates possible patterns in those profiles and analyses the impact of other usually concurrent signs of impairment of extracerebellar motor systems in that profile variability by means of multivariate statistical approaches.MethodsSeventeen patients with SCA3 underwent systematic anamnesis, neurological and SARA assessment, visual evaluation of 123I-Ioflupane (DaTSCAN) single-photon emission computed tomography (SPECT) imaging and electrophysiological studies (nerve conduction and electromyography). Patterns in the profiles of SARA item scores were investigated by hierarchical clustering after multivariate correspondence analysis. A network analysis was used to represent relationships between SARA item scores, clinical, genetic and neurological examination parameters as well as abnormalities of DaTSCAN SPECT imaging and electrophysiological studies.ResultsThe most frequently altered SARA items in all patients are gait and stance, and three profiles of SCA3 patients can be distinguished depending mainly on their degree of impairment in those two items. Other SARA items like the score on heel-shin slide contribute less to the classification. Network analysis shows that SARA item scores configure a single domain that is independent of the size of the mutated expanded allele and age of onset, which are, in turn closely and inversely correlated. The severity of cerebellar dysfunction is correlated with longer disease duration, altered visual evaluation of DaTSCAN SPECT imaging and decreased patellar reflexes. Neither the presence of pyramidal or extrapyramidal signs nor the intensity of polyneuropathy is correlated with the SARA items scores.ConclusionsPattern recognition approaches are useful tools to describe clinical phenotypes of ataxias and to identify particular configurations of cerebellar signs.

Substantia Nigra Echogenicity in Hereditary Ataxias With and Without Nigrostriatal Pathology: a Pilot Study

Our objective was to determine whether substantia nigra (SN) hyperechogenicity is greater in spinocerebellar ataxias (SCA) with nigrostriatal affectation than in ataxias without it. A cross-sectional case-control study analyzing four groups of patients was conducted: 1) nigrostriatal ataxias (SCA3 and SCA6), 2) nigrostriatal healthy controls matched by age and sex, 3) non-nigrostriatal ataxias (FRDA and SCA7), and 4) non-nigrostriatal healthy controls matched by age and sex. All the patients underwent a transcranial ultrasound performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The SN area was measured and compared in the four groups. The SN area was also correlated with clinical features and genetic data in the two ataxia groups. We examined 12 patients with nigrostriatal ataxia (11 SCA3 and 1 SCA6), 12 nigrostriatal healthy control patients, 7 patients with non-nigrostriatal ataxia (5 FRDA and 2 SCA7), and 7 non-nigrostriatal healthy control patients. The median (IQR) SN area (cm2) was greater in the nigrostriatal ataxias compared with the controls (right SN, 0.43 [0.44] vs. 0.11 [0.25]; P = 0.001; left SN, 0.32 [0.25] vs. 0.11 [0.16]; P = 0.001), but was similar among the non-nigrostriatal ataxias and controls. There were no statistically significant differences in the SN area between the nigrostriatal and non-nigrostriatal ataxias, although there was a tendency for a greater left SN area in the nigrostriatal compared with the non-nigrostriatal ataxias (0.32 [0.25] vs. 0.16 [0.24], P = 0.083). SN echogenicity is markedly greater in ataxias with nigrostriatal pathology than in controls. The role of SN hyperechogenicity in differentiating ataxias with and without nigrostriatal pathology should be elucidated in future studies.