Anatomical categorization of isolated non-focal dystonia: novel and existing patterns using a data-driven approach.

According to expert consensus, dystonia can be classified as focal, segmental, multifocal, and generalized, based on the affected body distribution. To provide an empirical and data-driven approach to categorizing these distributions, we used a data-driven clustering approach to compare frequency and co-occurrence rates of non-focal dystonia in pre-defined body regions using the Dystonia Coalition (DC) dataset. We analyzed 1,618 participants with isolated non-focal dystonia from the DC database. The analytic approach included construction of frequency tables, variable-wise analysis using hierarchical clustering and independent component analysis (ICA), and case-wise consensus hierarchical clustering to describe associations and clusters for dystonia affecting any combination of eighteen pre-defined body regions. Variable-wise hierarchical clustering demonstrated closest relationships between bilateral upper legs (distance = 0.40), upper and lower face (distance = 0.45), bilateral hands (distance = 0.53), and bilateral feet (distance = 0.53). ICA demonstrated clear grouping for the a) bilateral hands, b) neck, and c) upper and lower face. Case-wise consensus hierarchical clustering at k = 9 identified 3 major clusters. Major clusters consisted primarily of a) cervical dystonia with nearby regions, b) bilateral hand dystonia, and c) cranial dystonia. Our data-driven approach in a large dataset of isolated non-focal dystonia reinforces common segmental patterns in cranial and cervical regions. We observed unexpectedly strong associations between bilateral upper or lower limbs, which suggests that symmetric multifocal patterns may represent a previously underrecognized dystonia subtype.

Connectomic Basis for Tremor Control in Stereotactic Radiosurgical Thalamotomy.

BACKGROUND AND PURPOSE: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy. MATERIALS AND METHODS: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps. RESULTS: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (r = 0.52; P = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (r = 0.50; P = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices. CONCLUSIONS: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.

Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson's disease.

Human retinal pigment epithelial (hRPE) cells are dopaminergic support cells in the neural retina. Stereotaxic intrastriatal implantation of hRPE cells attached to gelatin microcarriers (Spheramine) in rodent and non-human primate models of Parkinson's disease (PD) produces long term amelioration of motor and behavioral deficits, with histological and PET evidence of cell survival without immunosuppression. Long-term safety in cynomologous monkeys has also been demonstrated. Six H&Y stage III/IV PD patients were enrolled in a one-year, open-label, single center study to evaluate the safety and efficacy of Spheramine (approximately 325,000 cells) implanted in the most affected post-commissural putamen. All patients tolerated the implantation of Spheramine well and demonstrated improvement. At 6, 9, and 12 months post-operatively, the mean UPDRS-Motor score "off", the primary outcome measure, improved 33%, (n = 6), 42% (n = 6), and 48% (n = 3), respectively. No "off-state" dyskinesias have been observed. Based on these preliminary results, Spheramine appears to show promise in treating late stage PD patients.

Complications of gamma knife surgery for Parkinson disease.

BACKGROUND: Many medical centers throughout the world offer radiosurgery with the gamma knife (GK) for pallidotomy and thalamotomy as a safe and effective alternative to radiofrequency ablative surgery and deep brain stimulation for Parkinson disease (PD). The reported incidence of significant complications varies considerably, and the long-term complication rate remains unknown. DESIGN: We describe 8 patients seen during an 8-month period referred for complications of GK surgery for PD. RESULTS: Of the 8 patients, 1 died as a result of complications, including dysphagia and aspiration pneumonia. Other complications included hemiplegia, homonymous visual field deficit, hand weakness, dysarthria, hypophonia, aphasia, arm and face numbness, and pseudobulbar laughter. In all patients, lesions were significantly off target. CONCLUSIONS: The 8 patients with PD seen in referral at our center for complications of GK surgery highlight a spectrum of potential problems associated with this procedure. These include lesion accuracy and size and the delayed development of neurological complications secondary to radiation necrosis. Gamma knife surgery may have a higher complication rate than has been previously appreciated due to delayed onset and underreporting. We believe that the risk-benefit ratio of the GK will require further scrutiny when considering pallidotomy or thalamotomy in patients with PD. Physicians using this technique should carefully follow up patients postoperatively for delayed complications, and fully inform patients of these potential risks.

Corticobasal degeneration.

Corticobasal degeneration (CBG) is an increasingly recognized neurodegenerative disease with both motor and cognitive dysfunction. The diagnosis is probably underestimated because of the heterogeneity of clinical features, overlap with symptoms, and pathologic findings of other neurodegenerative diseases. The most characteristic initial motor symptoms are akinesia, rigidity, and apraxia. Dystonia and alien limb phenomena are frequently observed. There is often a parkinsonian picture with failure or lack of efficacy of dopaminergic medical therapy. Cognitive decline, prompting the diagnosis of dementia, may be the most common presentation of CBD that is misdiagnosed. Pathology is characterized by an asymmetric frontoparietal neuronal loss and gliosis with ballooned, achromatic cortical neurons, nigral degeneration, and variable subcortical involvement. Neuroimaging and electrophysiologic studies may help with the diagnosis but are not specific. Treatment is primarily symptomatic and minimally effective, especially after the first several years of symptoms. CBD should be considered in the differential diagnosis of patients with motor and cognitive dysfunction presenting with cortical and subcortical features. Further studies to elucidate molecular abnormalities and biological markers associated with CBD are needed to improve clinical diagnosis and treatment of patients with this disorder.

Trans-spliced leader addition to mRNAs in a cnidarian.

A search of databases with the sequence from the 5' untranslated region of a Hydra cDNA clone encoding a receptor protein-tyrosine kinase revealed that a number of Hydra cDNAs contain one of two different sequences at their 5' ends. This finding suggested the possibility that mRNAs in Hydra receive leader sequences by trans-splicing. This hypothesis was confirmed by the finding that the leader sequences are transcribed as parts of small RNAs encoded by genes located in the 5S rRNA clusters of Hydra. The two spliced leader (SL) RNAs (SL-A and -B) contain splice donor dinucleotides at the predicted positions, and genes that receive SLs contain splice acceptor dinucleotides at the predicted positions. Both of the SL RNAs are bound by antibody against trimethylguanosine, suggesting that they contain a trimethylguanosine cap. The predicted secondary structures of the Hydra SL RNAs show significant differences from the structures predicted for the SLs of other organisms. Messenger RNAs have been identified that can receive either SL-A or -B, although the impact of the two different SLs on the function of the mRNA is unknown. The presence and features of SL addition in the phylum Cnidaria raise interesting questions regarding the evolution of this process.

Expression of a novel receptor tyrosine kinase gene and a paired-like homeobox gene provides evidence of differences in patterning at the oral and aboral ends of hydra.

Axial patterning of the aboral end of the hydra body column was examined using expression data from two genes. One, shin guard, is a novel receptor protein-tyrosine kinase gene expressed in the ectoderm of the peduncle, the end of the body column adjacent to the basal disk. The other gene, manacle, is a paired-like homeobox gene expressed in differentiating basal disk ectoderm. During regeneration of the aboral end, expression of manacle precedes that of shin guard. This result is consistent with a requirement for induction of peduncle tissue by basal disk tissue. Our data contrast with data on regeneration of the oral end. During oral end regeneration, markers for tissue of the tentacles, which lie below the extreme oral end (the hypostome), are detected first. Later, markers for the hypostome itself appear at the regenerating tip, with tentacle markers displaced to the region below. Additional evidence that tissue can form basal disk without passing through a stage as peduncle tissue comes from LiCl-induced formation of patches of ectopic basal disk tissue. While manacle is ectopically expressed during formation of basal disk patches, shin guard is not. The genes examined also provide new information on development of the aboral end in buds. Although adult hydra are radially symmetrical, expression of both genes in the bud's aboral end is initially asymmetrical, appearing first on the side of the bud closest to the parent's basal disk. The asymmetry can be explained by differences in positional information in the body column tissue that evaginates to form a bud. As predicted by this hypothesis, grafts reversing the orientation of evaginating body column tissue also reverse the orientation of asymmetrical gene expression.

Appearance and disappearance of Syk family protein-tyrosine kinase genes during metazoan evolution.

Syk family protein-tyrosine kinases are essential components of immunoreceptor signaling in mammalian lymphocytes. The absence of Syk genes from the Caenorhabditis elegans genome suggests that this kinase family is of recent evolutionary origin. Surprisingly, we have found that Hydra vulgaris, a member of the early diverging animal phylum Cnidaria, contains a gene encoding a Syk kinase. Phylogenetic analysis indicates that a single Syk family gene was present in animals prior to the gene duplication that gave rise to Syk and ZAP-70, the two mammalian Syk family genes. C. elegans also lacks a Shark protein-tyrosine kinase gene, which we show is a member of a sister group to the Syk family. We conclude that both Syk and Shark genes were lost from the genome of an ancestor of C. elegans. This natural gene knockout result indicates that neither Syk nor Shark kinases are essential for processes held in common between the nematode and other metazoans. The Hydra Syk gene is expressed in epithelial cells, a site consistent with a role for Hydra Syk in recognition of foreign cells.

The level of expression of a protein kinase C gene may be an important component of the patterning process in Hydra.

Several studies have provided strong, but indirect evidence that signalling through pathways involving protein kinase C (PKC) plays an important role in morphogenesis and patterning in Hydra. We have cloned a gene (HvPKC2) from Hydra vulgaris which encodes a member of the nPKC subfamily. In adult polyps, HvPKC2 is expressed at high levels in two locations, the endoderm of the foot and the endoderm of the hypostomal tip. Increased expression of HvPKC2 is an early event during head and foot regeneration, with the rise in expression being restricted to the endodermal cells underlying the regenerating ends. No upregulation is observed if regenerates are cut too close to the head to form a foot. Elevated expression of HvPKC2 is also observed in the endoderm underlying lithium-induced ectopic feet. A dynamic and complex pattern of expression is seen in developing buds. Regeneration of either head or foot is accompanied by an increase in the amount of PKC in both soluble and particulate fractions. An increase in the fraction of PKC activity which is membrane-bound is specifically associated with head regeneration. Taken together these data suggest that patterning of the head and foot in Hydra is controlled in part by the level of HvPKC2 expression, whilst head formation is accompanied by an in vivo activation of both calcium-dependent and independent PKC isoforms.