Prediction of the disease course in Friedreich ataxia

We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA

Cerebellar Structure Segmentation and Shape Analysis with Application to Cerebellar Ataxia

The cerebellum plays an important role in motor control and cognitive functions. Cerebellar dysfunction can lead to a wide range of movement disorders. Despite the significant impact on the lives of patients, the current standard of diagnosis, prognosis, and treatment for cerebellar disease is limited. Magnetic resonance (MR) imaging based morphometric analysis of the cerebellum, which studies the brain structural pattern associated with disease and functional decline, is of great interest and importance. It sets the stage for developing disease-modifying therapies, monitoring individual patient progress, and designing efficient therapeutic trials. Compared to the cerebrum, morphometric analysis in the cerebellum has been limited. Automated and accurate volumetric analysis techniques are lacking. Methods using MR based morphometric biomarkers to predict disease type and functional decline have been lacking or inconclusive. The work presented in this thesis is motivated by the need for better cerebellar structure segmentation and effective structure-function correlation and prediction methods in cerebellar disease. The thesis makes four major contributions. First, we proposed an automated method for segmenting cerebellar lobules from MR images. The proposed method achieved better performance than two state-of-the-art segmentation methods when validated on a cohort of 15 subjects including both healthy controls and patients with various degrees of cerebellar atrophy. Second, we presented two highly-informative shape representations to characterize cerebellar structures: a landmark shape representation of the collection of cerebellar lobules and a level set based whole cerebellar shape representation. Third, we developed an analysis pipeline to classify healthy controls and different ataxia types and to visualize disease specific cerebellar atrophy patterns based on the proposed shape representations and high-dimensional pattern classification methods. The classification performance is evaluated on a cohort consisting of healthy controls and different cerebellar ataxia types. The visualized cerebellar atrophy patterns are consistent with the regional volume decreases observed in previous studies in cerebellar ataxia. Compared to existing analysis methods, the proposed method provides intuitive and detailed visualization of the differences of overall size and shape of the cerebellum, as well as that of individual lobules. Fourth and the last, we developed and tested a similar analysis pipeline for functional score prediction and function specific cerebellar atrophy pattern visualization

Advanced MRI techniques in the study of cerebellar cortex

The cerebellum (from the Latin "little brain") is the dorsal portion of the metencephalon and is located in the posterior cranial fossa. Although representing only 10% of the total brain volume, it contains more than 50% of the total number of neurons of the central nervous system (CNS). Its organization resembles the one found in the telencephalon, with the presence of a superficial mantle of gray matter (GM) known as the cerebellar cortex, covering the cerebellar white matter (WM) in which three pairs of deep cerebellar GM nuclei are embedded. The number of studies dedicated to the study of the cerebellum and its function has significantly increased during the last years. Nevertheless, although many theories on the cerebellar function have been proposed, to date we still are not able to answer the question about the exact function of this structure. Indeed, the classical theories focused on the role of the cerebellum in fine-tuning for muscle control has been widely reconsidered during the last years, with new hypotheses that have been advanced. These include its role as sensory acquisition device, extending beyond a pure role in motor control and learning, as well as a pivotal role in cognition, with a recognized cerebellar participation in a variety of cognitive functions, ranging from mood control to language, memory, attention and spatial data management. A huge contribution to our understanding of how the cerebellum participates in all these different aspects of motor and non-motor behavior comes from the application of advanced imaging techniques. In particular, Magnetic Resonance Imaging (MRI) can provide a non-invasive evaluation of anatomical integrity, as well as information about functional connections with other brain regions. This thesis is organized as follows: - In Chapter 1 is presented a general introduction to the cerebellar anatomy and functions, with particular reference to the anatomical organization of cerebellar cortex and its connections with the telencephalon - Chapter 2 will contain a general overview about some of the major advanced MRI methods that can be applied to investigate the anatomical integrity and functional status of the cerebellar cortex - In Chapter 3 will be presented a new method to evaluate the anatomy and integrity of cerebellar cortex using ultra-high field MRI scanners - Chapters 4, 5 and 6 will contain data obtained from the application of some of the previously described advanced imaging techniques to the study of cerebellar cortex in neurodegenerative and neuroinflammatory disorders affecting the CNS

Italian version of the Cerebellar Cognitive Affective Syndrome Scale: Preliminary data collection and analysis.

openThe Cerebellar Cognitive Affective Syndrome (CCAS) is caused by various types of cerebellare disease and injury and consists in deficit in the domains of executive functions, visuospatial and linguistic abilities and affects regulation. To detect the presence of this syndrome, Hoche et al. (2018) have developed the CCAS scale, that is now widely validated. The goal of the present project is to describe the preliminary collection of the CCAS scale italian population normative data and to conduct an initial analysis of the obtained results.The Cerebellar Cognitive Affective Syndrome (CCAS) is caused by various types of cerebellare disease and injury and consists in deficit in the domains of executive functions, visuospatial and linguistic abilities and affects regulation. To detect the presence of this syndrome, Hoche et al. (2018) have developed the CCAS scale, that is now widely validated. The goal of the present project is to describe the preliminary collection of the CCAS scale italian population normative data and to conduct an initial analysis of the obtained results

NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms.

Mitochondrial complex I (CI) deficiency is the most common oxidative phosphorylation disorder described. It shows a wide range of phenotypes with poor correlation within genotypes. Herein we expand the clinics and genetics of CI deficiency in the brazilian population by reporting three patients with pathogenic (c.640G>A, c.1268C>T, c.1207dupG) and likely pathogenic (c.766C>T) variants in the NDUFV1 gene. We show the mutation c.766C>T associated with a childhood onset phenotype of hypotonia, muscle weakness, psychomotor regression, lethargy, dysphagia, and strabismus. Additionally, this mutation was found to be associated with headaches and exercise intolerance in adulthood. We also review reported pathogenic variants in NDUFV1 highlighting the wide phenotypic heterogeneity in CI deficiency

Spinocerebellar Ataxia Type 2

1. Introduction: The autosomal dominant cerebellar ataxias (ADCA) are a clinically, pathologically and genetically heterogeneous group of neurodegenerative disorders caused by degeneration of cerebellum and its afferent and efferent connections. The degenerative process may additionally involves the ponto- medullar systems, pyramidal tracts, basal ganglia, cerebral cortex, peripheral nerves (ADCA I) and the retina (ADCA II), or can be limited to the cerebellum (ADCA III) (Harding et al., 1993). The most common of these dominantly inherited autosomal ataxias, ADCA I, includes many Spinocerebellar Ataxias (SCA) subtypes, some of which are caused by pathological CAG trinucleotide repeat expansion in the coding region on the mutated gene. Such is the case for SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA17 and Dentatorubral-pallidoluysian atrophy (DRPLA) (Matilla et al., 2006). Among the almost 30 SCAs, the variant SCA2 is the second most prevalent subtype worldwide, only surpassed by SCA3 (Schöls et al., 2004; Matilla et al., 2006; Auburger, 2011)..

Long term sequelae of multisystem Langerhans' cell histiocytosis

Langerhans' cell histiocytosis (LCH), a chronic granulomatous disorder, can involve one or more organs/tissues including bone, skin, lungs, liver, spleen, bone marrow, pituitary gland and brain. Long term sequelae involving these organs have been reported, but their true prevalence is unknown. In order to assess long term outcome in survivors of multisystem LCH, we performed a cross-sectional study of 40 patients, all of whom were more than 5 years from treatment. Most of the patients had had involvement of bone and/or skin, with other organs being affected less often. They had received a wide range of treatments, including surgery, steroids, radiotherapy and chemotherapy. The study involved clinical examination, MRI scan of brain, endocrine function tests, neuropsychometry, respiratory function tests and audiometry. Most patients had one or more long term sequelae. Half of the patients had endocrine abnormalities, ranging from isolated diabetes insipidus to panhypopituitarism. Brain involvement, including cerebellar involvement, was the most worrying problem, occurring in 10 patients, with severe abnormalities in seven. New findings include the presence of significant learning deficit in 20% of patients, psychological and behavioural abnormalities in 11 patients (27.5%), and an acquired abnormality of the skull base, basilar invagination, in 8 patients (20%). A specific morbidity score was devised and provided an objective measure of outcome. Using this scale only 10 patients (25%) had no sequelae. Eleven (27.5%) had mild impairment which required no specific treatment, 9 (22.5%) had moderate disability, including diabetes insipidus, growth hormone insufficiency and moderate hearing loss, while 10 (25%) had severe disabilities such as panhypopituitarism, learning difficulty, motor deficit and psychological abnormalities resulting in significant handicap and inability to lead an independent adult life. We assessed the Health-Related Quality of Life and found that this correlated with the Morbidity score. Both these measures can easily be applied to any patient with LCH and can be incorporated into long term follow up studies. In conclusion, long term sequelae are more common in survivors of multisystem LCH than previously recognised and cause significant long term morbidity. An important implication of the work presented in this thesis is that carefully planned regular long-term follow up is essential for all patients 'cured' of LCH to ensure that sequelae are recognised early and the appropriate interventions made to improve the patients' "quality of life"

Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.Peer reviewe

Spatio-Temporal and Multisensory Integration: the relationship between sleep and the cerebellum

Does the cerebellum sleep? If so, does sleep contribute to cerebellar cognition? In this thesis, the sleep contribution to the consolidation process of spatial-temporal and multisensory integration was investigated in relation to the human cerebellum. Multiple experimental approaches were used to answer research questions addressed in the various chapters. Summarizing the evidence of the electrophysiology and neuroimaging studies, in Chapter1 we present intriguing evidence that the cerebellum is involved in sleep physiology, and that cerebellar-dependent memory formation can be consolidated during sleep. In Chapter 2, using functional neuroimaging in healthy participants during various forms of the Serial interception sequential learning (SISL) task, i.e., predictive timing, motor coordination, and motor imagination, we assessed the cerebellar involvement in spatio-temporal predictive timing; and possible cerebellar interactions with other regions, most notably the hippocampus. In Chapter 3, we add to the findings of Chapter 2 that indicate the cerebellum and hippocampus are involved in the task, by showing that more than simply activated, the cerebellum is a necessary and responsible region for the establishment of the spatio-temporal prediction. This follows from the deficits in behavioral properties of the predictive and reactive timing in the cerebellar ataxia type 6 patients, using the modified version of the SISL task. In Chapter 4, we assessed the subsequent post-interval behavioral performances on the learning of the fixed and random timing sequences in the SISL task, comparing a sleep group and wake group in healthy participants. Our findings show that sleep consolidates the process of cerebellar-dependent spatio-temporal integration. In Chapter 5, we investigated the establishment of visual-tactile integration during sleep through the examination of tactile motion stimulation during sleep and showed that, subsequent to sleep, directional visual motion discrimination i

Cerebellar Motor Learning Deficits: Structural mapping, neuromodulation and training-related interventions

Movement allows us to interact with our direct environment, manipulate objects and communicate with each other. Moreover, we can adjust our movements to fit a remarkable range of situations and circumstances. The ability to adjust movements in response to changes in the environment and task demands is referred to as motor learning. The cerebellum is a key neural structure for motor learning. As such, disease of the cerebellum, in addition to the clinical symptom of ataxia, results in various motor learning deficits. There is a consensus that supportive therapy (e.g. physiotherapy, occupational therapy or speech therapy) can reduce ataxia symptoms of cerebellar patients, but little is known about the mechanisms underlying the improvements, and how patients can benefit most. Additionally, motor learning deficits are associated with reduced efficacy of supportive therapy. With the work described in this thesis, we sought to unravel the structural components of cerebellar disease and the relationship between cerebellar integrity and motor learning. Furthermore, we investigated whether motor learning deficits in cerebellar patients could be ameliorated with neuromodulation or training-related interventions, under experimental conditions, hoping to support the development of interventions relevant for application in a clinical setting