Atypical parkinsonian syndromes: a general neurologist's perspective.

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non-fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson-plus syndromes in the past, they are now classified as FTD-related disorders, reflecting that they pathologically differ from α-synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.

Differential effects of eyes open or closed in darkness on brain activation patterns in blind subjects.

In functional brain imaging, specific task conditions can be compared to a reference condition which is often eyes-open or eyes-closed in darkness without the execution of a specific task. Previous fMRI studies in sighted subjects have shown that eyes-open in darkness, without visual stimulation, increases the relative activity in cortical ocular motor and attentional areas ("exteroceptive" state; contrast OPEN>CLOSED). By contrast, eyes-closed causes a relative signal increase in sensory systems ("interoceptive" state; contrast CLOSED>OPEN). In the present study we used fMRI to determine whether these differential brain activity states can also be found in congenitally blind subjects: there were intragroup differences between the OPEN and CLOSED conditions. These differences were, however, less pronounced and occurred in other areas than in sighted controls. The contrast OPEN>CLOSED revealed a relative signal increase in the left frontal eye field, the middle occipital gyrus bilaterally and in the anterior cingulum. Relative signal increases in occipital cortex areas and the anterior cingulum were also apparent for this contrast in the intergroup comparison (congenitally totally blind subjects vs. sighted controls). They reflect the increased attentional load or arousal during the eyes-open condition and could be indicative of a functional reorganization of the occipital cortex in the blind. The contrast CLOSED>OPEN in the congenitally totally blind subjects lead to relative activations in the somatosensory cortex bilaterally, the middle temporal gyrus on the left and the frontal gyri on the right. These activations are residues of the "interoceptive" state found in sighted controls.

Differences in saccade-evoked brain activation patterns with eyes open or eyes closed in complete darkness.

In this study we attempted to differentiate distinct components of the saccade network, namely cortical ocular motor centers and parieto-occipital brain regions, by means of a "minimal design" approach. Using a blocked design fMRI paradigm we evaluated the BOLD changes in a 2 x 2 factorial design experiment which was performed in complete darkness: while looking straight ahead with eyes open (OPEN) or closed (CLOSED) as well as during the execution of self-initiated horizontal to-and-fro saccades with the eyes open (SACCopen) or closed (SACCclosed). Eye movements were monitored outside the scanner via electro-oculography and during scanning using video-oculography. Unintentional eye-drifts did not differ during OPEN and CLOSED and saccade frequencies, and amplitudes did not vary significantly between the two saccade conditions. The main findings of the functional imaging study were as follows: (1) Saccades with eyes open or closed in complete darkness lead to distinct differences in brain activation patterns. (2) A parieto-occipital brain region including the precuneus, superior parietal lobule, posterior part of the intraparietal sulcus (IPS), and cuneus was relatively deactivated during saccades performed with eyes closed but not during saccades with eyes open or when looking straight ahead. This could indicate a preparatory state for updating spatial information, which is active during saccades with eyes open even without actual visual input. The preparatory state is suppressed when the eyes are closed during the saccades. (3) Selected ocular motor areas, not including the parietal eye field (PEF), show a stronger activation during SACCclosed than during SACCopen. The increased effort involved in performing saccades with eyes closed, perhaps due to the unusualness of the task, may be the cause of this increased activation.

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.

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.

Asymmetric modulation of human visual cortex activity during 10 degrees lateral gaze (fMRI study).

We used BOLD fMRI to study the differential effects of the direction of gaze on the visual and the ocular motor systems. Fixation of a target straight ahead was compared to fixation of a target 10 degrees to the right and 10 degrees to the left from gaze straight ahead, and to eyes open in complete darkness in thirteen healthy volunteers. While retinotopic coordinates remained the same in all fixation conditions, the fixation target shifted with respect to a head-centered frame of reference. During lateral fixation, deactivations in higher-order visual areas (one ventral cluster in the lingual and fusiform gyri and one dorsal cluster in the postero-superior cuneus) and, as a trend, activations in early visual cortical areas were found predominantly in the hemisphere contralateral to the fixation target. We propose that visual processing is performed predominantly in the hemisphere contralateral to gaze direction, even during small gaze shifts into one visual hemifield. The excitability of visual neurons may be modulated depending on eye position to construct a head-centered frame of reference from a retinotopic input, thus allowing perceptual stability of space during eye movements. A further finding was that BOLD signal increases in fronto-parietal ocular motor and attentional structures were more pronounced during lateral than central fixation.

Preserved visual-vestibular interaction in patients with bilateral vestibular failure.

BACKGROUND: During caloric vestibular stimulation, subjects showed bilateral activation of the vestibular cortex in the posterior insula and retroinsular region as well as concurrent deactivation of visual cortex areas bilaterally. This finding was the basis for the concept of a reciprocal inhibitory interaction between the vestibular and the visual systems. OBJECTIVE: To analyze the modulations of this activation and deactivation pattern in patients with loss of vestibular input, that is, in patients with bilateral vestibular failure (BVF). METHODS: Modulations of regional cerebral blood flow (rCBF) in PET were measured in nine patients with BVF and compared with those in healthy volunteers using statistical group as well as single-subject analyses (Statistical Parametric Mapping 96b). RESULTS: The group analysis of the BVF patients showed only one small region of activation in the posterior insula contralateral to the stimulated ear, whereas the other areas correlating with vestibular, autonomic, and ocular motor function were not activated. Furthermore, the concurrent rCBF decreases of the primary visual cortex seen in healthy volunteers were not found in the patients. These decreases seem to be dependent on an intact vestibular input with concurrent vestibular nystagmus. CONCLUSIONS: The results are compatible with the concept of a reciprocal inhibitory sensorisensory interaction between the vestibular and visual systems that normally act together for orientation in space and perception of motion. This interaction appears to be preserved in the patients at a significantly lower level, that is, with less activation and less deactivation.

Vertical oscillopsia in bilateral superior canal dehiscence syndrome.

A patient sought treatment for vertical oscillopsia and impaired vision during locomotion, and unsteadiness of gait. Positive fistula tests and CT of the temporal bones confirmed a diagnosis of bilateral superior canal dehiscence. An impairment of the superior canal vestibulo-ocular reflex, documented by three-dimensional search coil eye movement recordings for oblique (single) and downward pitch head motion (bilateral canal testing), is proposed to induce vertical rather than torsional-vertical oscillopsia during locomotion.

Control of TCR V alpha-mediated positive repertoire selection and alloreactivity by differential J alpha usage and CDR3 alpha composition.

In rats expressing the f allele of the rat MHC (RT1f), CD8 T cells utilizing the V alpha 8.2 segment are 10-fold overselected during thymic development, resulting in V alpha 8.2 expression by 14% of mature CD8 T cells as compared to 1-2% in MHC congenic strains. In the alloreactive responses of CD8 T cells from RT1f-negative rats against RT1f, V alpha 8.2+ CD8 T cells are also preferentially expanded. Neither overselection nor alloreactivity of V alpha 8.2+ TCR require selective V beta pairing. However, RT1f alloreactive V alpha 8.2+ TCR preferentially use a related set of J alpha segments which contribute short homogeneous CDR3 alpha loops, with features suggesting peptide promiscuity, and little N additions. In contrast, only few overselected V alpha 8.2+ CD8 T cells showed an imprint of positive selection on J usage or CDR3 composition. The results demonstrate that a single V alpha segment can promote both MHC allele-specific positive selection and alloreactivity, and that the latter is more dependent on an additional contribution of CDR3 alpha, possibly by promoting reactivity with a diverse set of MHC-bound peptides or by providing additional MHC contacts.