Notch1 is required for neuronal and glial differentiation in the cerebellum.

The mechanisms that guide progenitor cell fate and differentiation in the vertebrate central nervous system (CNS) are poorly understood. Gain-of-function experiments suggest that Notch signaling is involved in the early stages of mammalian neurogenesis. On the basis of the expression of Notch1 by putative progenitor cells of the vertebrate CNS, we have addressed directly the role of Notch1 in the development of the mammalian brain. Using conditional gene ablation, we show that loss of Notch1 results in premature onset of neurogenesis by neuroepithelial cells of the midbrain-hindbrain region of the neural tube. Notch1-deficient cells do not complete differentiation but are eliminated by apoptosis, resulting in a reduced number of neurons in the adult cerebellum. We have also analyzed the effects of Notch1 ablation on gliogenesis in vivo. Our results show that Notch1 is required for both neuron and glia formation and modulates the onset of neurogenesis within the cerebellar neuroepithelium.

Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

Sudden unexpected death in an infant with L-2-hydroxyglutaric aciduria.

Inherited metabolic disorders are the cause of a small but significant number of sudden unexpected deaths in infancy. We report a girl who suddenly died at 11 months of age, during an intercurrent illness. Autopsy showed spongiform lesions in the subcortical white matter, in the basal ganglia, and in the dentate nuclei. Investigations in an older sister with developmental delay, ataxia, and tremor revealed L-2-hydroxyglutaric aciduria and subcortical white matter changes with hyperintensity of the basal ganglia and dentate nuclei at brain magnetic resonance imaging. Both children were homozygous for a splice site mutation in the L2HGDH gene. Sudden death has not been reported in association with L-2-hydroxyglutaric aciduria so far, but since this inborn error of metabolism is potentially treatable, early diagnosis may be important.

Ophthalmic features of PLA2G6-related paediatric neurodegeneration with brain iron accumulation.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) refers to genetically heterogenous paediatric neurodegenerative disorders characterised by basal ganglia iron deposition. One major cause is recessive mutations in the PLA2G6 gene. While strabismus and optic nerve pallor have been reported for PLA2G6-related disease, the ophthalmic phenotype is not carefully defined. In this study we characterise the ophthalmic phenotype of PLA2G6-related NBIA. METHODS: Prospective cohort study. RESULTS: The eight patients were 4-26 years old when examined. All had progressive cognitive and motor regression first noted between 9 months and 6 years of age that typically first manifested as difficulty walking (ataxia). Ophthalmic examination was sometimes limited by cognitive ability. Four of eight had exotropia, 7/7 bilateral supraduction defect, 5/7 poor convergence, 6/8 saccadic pursuit, 4/8 saccadic intrusions that resembled square-wave jerks, and 8/8 bilateral optic nerve head pallor. All patients lacked Bell phenomenon. CONCLUSIONS: Upgaze palsy, although not a previously reported finding, was confirmed in all patients (except in one for whom assessment could not be performed) and thus can be considered part of the phenotype in children and young adults. Other frequent findings not previously highlighted were abnormal convergence, saccadic pursuit, and saccadic intrusions. Optic nerve head pallor and strabismus, previously reported findings in the disease, were found in 100% and 50% of our cohort, respectively, and the strabismus in our series was always exotropia. Taken together, these clinical findings may be helpful in distinguishing PLA2G6-related neurodegeneration from the other major cause of NBIA, recessive PANK2 mutations.

In vivo Structural Imaging of the Cerebellum, the Contribution of Ultra-High Fields.

This review covers some of the contributions to date from cerebellar imaging studies performed at ultra-high magnetic fields. A short overview of the general advantages and drawbacks of the use of such high field systems for imaging is given. One of the biggest advantages of imaging at high magnetic fields is the improved spatial resolution, achievable thanks to the increased available signal-to-noise ratio. This high spatial resolution better matches the dimensions of the cerebellar substructures, allowing a better definition of such structures in the images. The implications of the use of high field systems is discussed for several imaging sequences and image contrast mechanisms. This review covers studies which were performed in vivo in both rodents and humans, with a special focus on studies that were directed towards the observation of the different cerebellar layers.

Visual vertigo: an observational case series of eleven patients.

BACKGROUND: Dizziness is a common symptom which is frequently due to either peripheral or central vestibular dysfunction. However, some patients may lack typical signs suggesting a vestibular or cerebellar lesion and they mostly complain of vertigo or posture imbalance induced by visual stimulation. The symptoms immediately improve either on cessation of the visual input or upon closure of the eyes. Such a presentation is typical of visual vertigo. PATIENTS AND METHODS: From 1993 to 2003, 242 patients were examined for either "vertigo" or "dizziness". The diagnosis of visual vertigo was based on both history and clinical examination and was present in 11 patients. RESULTS: Visual vertigo was diagnosed in 11/242 patients (4.5 %). Age range was 31 - 77 years (mean 47 years) with a sex ratio of 8 females for 3 males. Neuro-ophthalmological examination was normal in all cases. CONCLUSIONS: Visual vertigo is not a rare condition but the disease is underdiagnosed. The symptoms result from a mismatch between vestibular, proprioceptive and visual inputs. Neuro-ophthalmological, neurological and neuro-otological examination are often normal or not relevant and the diagnosis is largely based on history. It is important to recognize this entity because the symptoms might improve if the patients are treated with psycho-motor rehabilitation.

Patterns of neurovascular compression in patients with classic trigeminal neuralgia: A high-resolution MRI-based study.

PURPOSE: To describe the anatomical characteristics and patterns of neurovascular compression in patients suffering classic trigeminal neuralgia (CTN), using high-resolution magnetic resonance imaging (MRI). MATERIALS AND METHODS: The analysis of the anatomy of the trigeminal nerve, brain stem and the vascular structures related to this nerve was made in 100 consecutive patients treated with a Gamma Knife radiosurgery for CTN between December 1999 and September 2004. MRI studies (T1, T1 enhanced and T2-SPIR) with axial, coronal and sagital simultaneous visualization were dynamically assessed using the software GammaPlan?. Three-dimensional reconstructions were also developed in some representative cases. RESULTS: In 93 patients (93%), there were one or several vascular structures in contact, either, with the trigeminal nerve, or close to its origin in the pons. The superior cerebellar artery was involved in 71 cases (76%). Other vessels identified were the antero-inferior cerebellar artery, the basilar artery, the vertebral artery, and some venous structures. Vascular compression was found anywhere along the trigeminal nerve. The mean distance between the nerve compression and the origin of the nerve in the brainstem was 3.76±2.9mm (range 0-9.8mm). In 39 patients (42%), the vascular compression was located proximally and in 42 (45%) the compression was located distally. Nerve dislocation or distortion by the vessel was observed in 30 cases (32%). CONCLUSIONS: The findings of this study are similar to those reported in surgical and autopsy series. This non-invasive MRI-based approach could be useful for diagnostic and therapeutic decisions in CTN, and it could help to understand its pathogenesis.

Acute stroke chameleons in a university hospital : Risk factors, circumstances, and outcomes.

OBJECTIVE: To identify risk factors, circumstances, and outcomes for individuals with acute ischemic stroke (AIS) chameleons (AIS-C) arriving in the emergency department of a university hospital. METHODS: We retrospectively reviewed all patients with AIS from the prospectively constructed Acute Stroke Registry and Analysis of Lausanne during 8.25 years. AIS-C were defined as a failure to suspect stroke or as incorrect exclusion of stroke diagnosis. They were compared with patients diagnosed correctly at the time of admission. RESULTS: Forty-seven of 2,200 AIS were missed (2.1%). These AIS-C were either very mild or very severe strokes. Multivariate analysis showed a younger age in patients with AIS-C (odds ratio [OR] per year 0.98, p < 0.01), less prestroke statin treatment (OR 0.29, p = 0.04), and lower diastolic admission blood pressure (OR 0.98 p = 0.04). They showed less eye deviation (OR 0.21, p = 0.04) and more cerebellar strokes (OR 3.78, p < 0.01). AIS-C were misdiagnosed as other neurologic (42.6% of cases) or nonneurologic (17.0%) disease, as unexplained decreased level of consciousness (21.3%), and as concomitantly present disease (19.1%). At 12 months, patients with AIS-C had less favorable outcomes (adjusted OR 0.21, p < 0.01) and higher mortality (adjusted OR 4.37, p < 0.01). CONCLUSIONS: AIS are missed in patients with younger age with a lower cerebrovascular risk profile and may be masked by other acute conditions. Patients with chameleons present more often with milder strokes or coma, fewer focal signs and cerebellar strokes, and have higher disability and mortality rates at 12 months. These findings may be used to raise awareness in emergency departments to recognize and treat such patients appropriately.

Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. METHODS: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. RESULTS: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. CONCLUSION: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage. Hum Brain Mapp 36:1609-1619, 2015. © 2014 Wiley Periodicals, Inc.

The Vitamin A Derivative All-Trans Retinoic Acid Repairs Amyloid-β-Induced Double-Strand Breaks in Neural Cells and in the Murine Neocortex.

The amyloid-β peptide or Aβ is the key player in the amyloid-cascade hypothesis of Alzheimer's disease. Aβ appears to trigger cell death but also production of double-strand breaks (DSBs) in aging and Alzheimer's disease. All-trans retinoic acid (RA), a derivative of vitamin A, was already known for its neuroprotective effects against the amyloid cascade. It diminishes, for instance, the production of Aβ peptides and their oligomerisation. In the present work we investigated the possible implication of RA receptor (RAR) in repair of Aβ-induced DSBs. We demonstrated that RA, as well as RAR agonist Am80, but not AGN 193109 antagonist, repair Aβ-induced DSBs in SH-SY5Y cells and an astrocytic cell line as well as in the murine cortical tissue of young and aged mice. The nonhomologous end joining pathway and the Ataxia Telangiectasia Mutated kinase were shown to be involved in RA-mediated DSBs repair in the SH-SY5Y cells. Our data suggest that RA, besides increasing cell viability in the cortex of young and even of aged mice, might also result in targeted DNA repair of genes important for cell or synaptic maintenance. This phenomenon would remain functional up to a point when Aβ increase and RA decrease probably lead to a pathological state.

An unusual cause of high anion gap metabolic acidosis: pyroglutamic acidemia. A case report.

Pyroglutamic acidemia is an uncommon metabolic disorder, which is usually diagnosed at early ages. The mechanism of action is thought to be glutathione depletion, and its clinical manifestations consist of hemolytic anemia, mental retardation, ataxia, and chronic metabolic acidosis. However, an acquired form has been described in adult patients, who usually present with confusion, respiratory distress, and high anion gap metabolic acidosis (HAGMA). It is also associated with many conditions, including chronic acetaminophen consumption. A 68-year-old white male, with chronic acetaminophen use presented to our service on multiple occasions with severe HAGMA. The patient was admitted to the intensive care unit and required mechanical ventilation and aggressive supportive measures. After ruling out the most frequent etiologies for his acid-base disorder and considering the long history of Tylenol ingestion, his 5-oxiproline (pyroglutamic acid) levels were sent to diagnose pyroglutamic acidemia. Clinicians need to be aware of this cause for metabolic acidosis since it might be a more common metabolic disturbance in compromised patients than would be expected. Subjects with HAGMA that cannot be explained by common causes should be tested for the presence of 5-oxoproline. Discontinuation of the offending drug is therapeutic.

Characterisation of anatomical properties of the human basal ganglia using magnetic resonance imaging

The detailed in-vivo characterization of subcortical brain structures is essential not only to understand the basic organizational principles of the healthy brain but also for the study of the involvement of the basal ganglia in brain disorders. The particular tissue properties of basal ganglia - most importantly their high iron content, strongly affect the contrast of magnetic resonance imaging (MRI) images, hampering the accurate automated assessment of these regions. This technical challenge explains the substantial controversy in the literature about the magnitude, directionality and neurobiological interpretation of basal ganglia structural changes estimated from MRI and computational anatomy techniques. My scientific project addresses the pertinent need for accurate automated delineation of basal ganglia using two complementary strategies: ? Empirical testing of the utility of novel imaging protocols to provide superior contrast in the basal ganglia and to quantify brain tissue properties; ? Improvement of the algorithms for the reliable automated detection of basal ganglia and thalamus Previous research demonstrated that MRI protocols based on magnetization transfer (MT) saturation maps provide optimal grey-white matter contrast in subcortical structures compared with the widely used Tl-weighted (Tlw) images (Helms et al., 2009). Under the assumption of a direct impact of brain tissue properties on MR contrast my first study addressed the question of the mechanisms underlying the regional specificities effect of the basal ganglia. I used established whole-brain voxel-based methods to test for grey matter volume differences between MT and Tlw imaging protocols with an emphasis on subcortical structures. I applied a regression model to explain the observed grey matter differences from the regionally specific impact of brain tissue properties on the MR contrast. The results of my first project prompted further methodological developments to create adequate priors for the basal ganglia and thalamus allowing optimal automated delineation of these structures in a probabilistic tissue classification framework. I established a standardized workflow for manual labelling of the basal ganglia, thalamus and cerebellar dentate to create new tissue probability maps from quantitative MR maps featuring optimal grey-white matter contrast in subcortical areas. The validation step of the new tissue priors included a comparison of the classification performance with the existing probability maps. In my third project I continued investigating the factors impacting automated brain tissue classification that result in interpretational shortcomings when using Tlw MRI data in the framework of computational anatomy. While the intensity in Tlw images is predominantly