Katharina Hüfner

The Polarization Defect of Wiskott-Aldrich Syndrome Macrophages Is Linked to Dislocalization of the Arp2/3 Complex

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally characterized by the clinical triad eczema, thrombocytopenia, and severe immunodeficieny, with recurrent bacterial and viral infections, indicating a profound immune cell defect. Such altered immune cells include monocytes, macrophages, and dendritic cells, which were reported to display disturbed cell polarization or chemotaxis. WAS is caused by mutations in the WAS protein (WASp), which is thought to organize the actin cytoskeleton through the Arp2/3 complex. Here we show that the Arp2/3 complex is an integral part of podosomes, actin-rich adhesion structures of macrophages, and that WAS macrophages fail to organize the Arp2/3 complex into podosomes. We also demonstrate that microinjection of a C-terminal acidic stretch of WASp into normal macrophages displaces Arp2/3 from podosomes and, in combination with chemoattractant stimulation of cells, induces a phenotype resembling the polarization-defective phenotype of stimulated WAS macrophages. These findings point to an important role of the Arp2/3 complex in polarization and migration of immune cells.

Supraspinal locomotor control in quadrupeds and humans

Locomotion in humans and other vertebrates is based on spinal pattern generators, which are regulated by supraspinal control. Most of our knowledge about the hierarchical network of supraspinal locomotion centres derives from animal experiments, mainly in the cat. Here we summarize evidence that the supraspinal network of quadrupeds is conserved in humans despite their transition to bipedalism. By use of mental imagery of locomotion in fMRI we found (1), locomotion modulates sensory systems and is itself modulated by sensory signals. During automated locomotion in healthy subjects cortical sensory inhibition occurs in vestibular and somatosensory areas; this inhibition is cancelled in the congenitally blind; (2), we delineated separate and distinct areas in the brainstem and cerebellum which are remarkably similar to the feline locomotor network. The activations found here include homologues to the pacemakers for gait initiation and speed regulation in the interfastigial cerebellum and bilateral midbrain tegmentum (cerebellar and mesencephalic locomotor regions), their descending target regions in the pontine reticular formation, and the rhythm generators in the cerebellar vermis and paravermal cerebellar cortex. This conservation of the basic organization of supraspinal locomotor control during vertebrate phylogeny opens new perspectives for both, the diagnosis and treatment of common gait disorders. It is conceivable that electrical stimulation of locomotor brain stem centres may initiate and improve gait in selected patients suffering from Parkinsons disease or progressive supranuclear palsy.

Detection of floccular hypometabolism in downbeat nystagmus by fMRI

The authors evaluated floccular activity with fMRI during the performance of vertical smooth pursuit eye movements in four patients with downbeat nystagmus (DBN) due to cerebellar degeneration and in 16 healthy controls. Region of interest analysis revealed a significantly diminished activation of both floccular lobes during downward but not upward pursuit in DBN. These imaging data support the view that a functional deficiency of the flocculi in downward pursuit causes DBN.

Structural and functional plasticity of the hippocampal formation in professional dancers and slackliners

The acquisition of special skills can induce plastic changes in the human hippocampus, a finding demonstrated in expert navigators (Maguire et al. ( 2000 ) Proc Natl Acad Sci USA 97:4,398–403). Conversely, patients with acquired chronic bilateral vestibular loss develop atrophy of the hippocampus, which is associated with impaired spatial memory (Brandt et al. ( 2005 ) Brain 128:2,732–741). This suggests that spatial memory relies on vestibular input. In this study 21 professional dancers and slackliners were examined to assess whether balance training with extensive vestibulo‐visual stimulation is associated with altered hippocampal formation volumes or spatial memory. Gray matter voxel‐based morphometry showed smaller volumes in the anterior hippocampal formation and in parts of the parieto‐insular vestibular cortex of the trained subjects but larger volumes in the posterior hippocampal formation and the lingual and fusiform gyri bilaterally. The local volumes in the right anterior hippocampal formation correlated negatively and those in the right posterior hippocampal formation positively with the amount of time spent training ballet/ice dancing or slacklining at the time of the study. There were no differences in general memory or in spatial memory as assessed by the virtual Morris water task. Trained subjects performed significantly better on a hippocampal formation‐dependent task of nonspatial memory (transverse patterning). The smaller anterior hippocampal formation volumes of the trained subjects may be the result of a long‐term suppression of destabilizing vestibular input. This is supported by the associated volume loss in the parieto‐insular vestibular cortex. The larger volumes in the posterior hippocampal formation of the trained subjects might result from their increased utilization of visual cues for balance. This is supported by the concomitant larger volumes in visual areas like the lingual and fusiform gyri. Our findings indicate that there is a spatial separation of vestibular and visual processes in the human hippocampus.

Structural and functional MRIs disclose cerebellar pathologies in idiopathic downbeat nystagmus.

Background: Neurologic disorders in which the etiology and pathogenesis are not yet understood are termed idiopathic. Downbeat nystagmus (DBN) is a frequent eye movement disorder that clinically manifests with oscillopsia and postural instability. Forty percent of patients with DBN are classified as having idiopathic DBN, because no underlying pathology can be demonstrated by conventional MRI or laboratory tests. Methods: We evaluated gray matter brain volumes of 11 patients with idiopathic DBN and compared them to those of healthy controls using voxel-based morphometry. In a second, functional MRI experiment, patients and controls performed downward smooth pursuit eye movements (DOWN), which were then compared with straight-ahead fixation of a stationary target (MID). Results: Small areas of localized gray matter atrophy were detected in the lateral cerebellar hemispheres (lobule VI) and ocular motor vermis of patients with idiopathic DBN, but not in the flocculus and paraflocculus. The functional imaging data, however, revealed reduced activation in the parafloccular lobule and in the ponto-medullary brainstem of the patients when they performed smooth pursuit eye movements downwards. Conclusions: The applied specialized imaging and data analysis techniques disclosed pathologies in an idiopathic eye movement disorder. The focal atrophy found in the vermal and lateral cerebellar regions in downbeat nystagmus (DBN) may lead to deficits in smooth pursuit eye movement initiation, which in turn causes hypofunction of the parafloccular lobe, associated with DBN. Our data are in line with experiments in primates showing that ablation of the floccular and parafloccular lobes disrupts smooth pursuit and causes DBN.

Long-term course and relapses of vestibular and balance disorders

The long-term course and the frequency of relapses for various peripheral vestibular disorders and somatoform phobic postural vertigo are discussed with respect to the clinically most important questions for thus afflicted patients. This review is mainly based on our own long-term follow-up studies and takes into consideration the most relevant literature. The following syndromes are discussed in detail. Vestibular neuritis: the recovery rate of peripheral vestibular function lies between 40-63% depending on early-onset treatment with corticosteroids; the recurrence rate within 10 years is 2%. Menières disease} loss of auditory and vestibular function occurs mainly in the first 5 to 10 years; frequency of vertigo attacks may decline after 5 to 10 years; bilateral involvement increases with increasing duration of the condition in up to 30-50%; vestibular drop attacks may occur early or late within the course, mostly with spontaneous remission; high-dose and long-term treatment with betahistine significantly reduces attack frequency in Menières disease, Benign paroxysmal positioning vertigo: the recurrence rate is 50% within 10 years (in females 58%, in males 39%), most recurrences (80%) being observed within the first year after initial relief; recurrence rate in the seventh decade is half of that in the sixth decade. Vestibular paroxysmia: medical treatment with carbamazepine or oxcarbazepine leads to a continuous significant reduction in attack frequency, intensity, and duration of 10-15% of baseline. Bilateral vestibulopathy: recovery of vestibular function is limited to single cases depending on their etiology. Phobic postural vertigo: within 5 to 16 years 27% of the patients are symptom-free, 48% improve, 22% remain unchanged, and 3% worsen; a detailed explanation of the mechanisms that cause and the factors that provoke attacks is imperative, as well as instructions for self-controlled desensitization within the context of behavioral therapy.

Latency of alpha-herpes viruses is accompanied by a chronic inflammation in human trigeminal ganglia but not in dorsal root ganglia

The immune response to latent herpesvirus infections was compared in human trigeminal ganglia (TG) and dorsal root ganglia (DRG) of 15 dead individuals. On the basis of our previous findings, we hypothesized that T-cells would be attracted to sensory neurons latently infected with herpes simplex virus type 1 (HSV-1), but not to those harboring latent varicella zoster virus (VZV). We showed that the TG contain a positive hybridization signal for HSV-1 latency-associated transcript (LAT), whereas the DRG from the same individuals lack detectable LAT. In contrast, immunohistochemistry revealed that latent VZV protein 62 stained positive in the vast majority of all tested TG and DRG. T-cell infiltrates prominently surrounded individual neurons in the TG but not in the DRG. TaqMan polymerase chain reaction also showed higher expression of CD8 and RANTES transcripts in the TG versus DRG. Only the infiltrates in the TG, but not in the DRG, produced RANTES at the protein level. Because it has been shown that RANTES protein is produced only after T-cell receptor stimulation, we assume that T-cell infiltration is associated with antigen recognition in the TG but not in the DRG.

Central oculomotor disturbances and nystagmus: a window into the brainstem and cerebellum.

BACKGROUND Oculomotor disturbances and nystagmus are seen in many diseases of the nervous system, the vestibular apparatus, and the eyes, as well as in toxic and metabolic disorders. They often indicate a specific underlying cause. The key to diagnosis is systematic clinical examination of the patients eye movements. This review deals mainly with central oculomotor disturbances, i.e., those involving smooth pursuit, saccades, gaze-holding, and central types of nystagmus. METHODS We searched the current literature for relevant publications on the diagnosis and treatment of oculomotor disturbances and nystagmus, and discuss them selectively in this review along with the German Neurological Societys guidelines on the topic. RESULTS A detailed knowledge of the anatomy and physiology of eye movements usually enables the physician to localize the disturbance to a specific area in the brainstem or cerebellum. The examination of eye movements is an even more sensitive method than magnetic resonance imaging for the diagnosis of acute vestibular syndromes and for the differentiation of peripheral from central lesions. For example, isolated dysfunction of horizontal saccades is due to a pontine lesion, while isolated dysfunction of vertical saccades is due to a midbrain lesion. Generalized gaze-evoked nystagmus (GEN) has multiple causes; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. Internuclear ophthalmoplegia involves a constellation of findings, the most prominent of which is impaired adduction to the side of the causative lesion in the ipsilateral medial longitudinal fasciculus. The most common pathological types of central nystagmus are downbeat and upbeat nystagmus (DBN, UBN). DBN is generally due to cerebellar dysfunction, e.g., because of a neurodegenerative disease. CONCLUSION This short review focuses on the clinical characteristics, pathophysiology and current treatment of oculomotor disorders and nystagmus.

Clinical, electrophysiological, and MRI findings in patients with cerebellar ataxia and a bilaterally pathological head-impulse test

A significant number of patients with bilateral vestibulopathy suffer from cerebellar ataxia and central vestibular symptoms and vice versa. We examined 31 patients presenting with the combination of gait and stance ataxia, cerebellar ocular motor signs, and a bilaterally pathological head‐impulse test (HIT). Tests included neuro‐orthoptical examination, electromyography and neurography, caloric irrigation, pure‐tone audiogram, vestibular‐evoked myogenic potentials, and volumetric magnetic resonance imaging (MRI). Only 17 of 31 patients had a pathological caloric irrigation. Twenty‐three patients had evidence of polyneuropathy (predominantly mixed sensorimotor involving axonal loss and demyelination) and twenty of hypoacusis (1 unilateral and 19 bilateral). Voxel‐based morphometry comparing local gray matter brain volume between patients and controls revealed cerebellar atrophy involving both the vermis and the hemispheres. We conclude that there is a clinically relevant combination of cerebellar ataxia with cerebellar atrophy, bilaterally pathological HIT, polyneuropathy, and hypoacusis. This multisensory syndrome is most likely caused by a neurodegenerative disorder affecting different systems, leading to severe impairment of affected patients.

Aminopyridines for the treatment of cerebellar and ocular motor disorders.

Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus. It is hypothesized to occur when physiological inhibitory cerebellar input, namely of the flocculus, to the vestibular nuclei is inhibited. The second most frequent form of acquired nystagmus is upbeat nystagmus (UBN). UBN is probably caused by an imbalance of vertical vestibulo-ocular reflex tone. GABA-ergic substances like baclofen have been used to treat DBN and UBN, but they have had only moderate success. Animal experiments have shown that aminopyridines [3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP)], nonselective blockers of the Kv family of voltage-gated potassium channels, increase Purkinje-cell (PC) excitability. It was assumed that such enhancement of PC activity could restore to normal levels the inhibitory influence of the cerebellar cortex on vertical eye movements. On the basis of these assumptions, we evaluated the efficacy and underlying mechanisms of aminopyridines in DBN and UBN as well as in another cerebellar disorder with an impaired PC function: episodic ataxia type 2 (EA2), which is caused by mutations of the PQ-calcium channel. In a placebo-controlled trial on 17 patients we demonstrated that 3,4-DAP significantly reduces the intensity of DBN. This was confirmed in a recent study with 4-AP, which also showed that 4-AP restores gaze-holding ability independently of fixation in DBN. The efficacy of 4-AP in UBN was demonstrated in single patients. Finally, in an open trial on three patients with EA2 we showed that 4-AP prevents attacks of ataxia. This was also found in an animal model (the tottering mouse) of EA2. The clinical efficacy of 4-AP in EA2 is being further evaluated in an ongoing randomized controlled crossover trial. In conclusion, the use of aminopyridines in DBN, UBN, and EA2 is a new treatment principle for vestibular, cerebellar, and ocular motor disorders.