Oscillating central motor networks in pathological tremors and voluntary movements. What makes the difference?

Parkinsonian tremor (PD), essential tremor (ET) and voluntarily mimicked tremor represent fundamentally different motor phenomena, yet, magnetoencephalographic and imaging data suggest their origin in the same motor centers of the brain. Using EEG-EMG coherence and coherent source analysis we found a different pattern of corticomuscular delays, time courses and central representations for the basic and double tremor frequencies typical for PD suggesting a wider range defective oscillatory activity. For the basic tremor frequency similar central representations in primary sensorimotor, prefrontal/premotor and diencephalic (e.g. thalamic) areas were reproduced for all three tremors. But renormalized partial directed coherence of the spatially filtered (source) signals revealed a mainly unidirectional flow of information from the diencephalon to cortex in voluntary tremor, e.g. a thalamocortical relay, as opposed to a bidirectional subcortico-cortical flow in PD and ET promoting uncontrollable, e.g. thalamocortical, loop oscillations. Our results help to understand why pathological tremors although originating from the physiological motor network are not under voluntary control and they may contribute to the solution of the puzzle why high frequency thalamic stimulation has a selective effect on pathological tremor leaving voluntary movement performance almost unaltered.

Loss of breast epithelial marker hCLCA2 promotes epithelial-to-mesenchymal transition and indicates higher risk of metastasis.

Transition between epithelial and mesenchymal states is a feature of both normal development and tumor progression. We report that expression of chloride channel accessory protein hCLCA2 is a characteristic of epithelial differentiation in the immortalized MCF10A and HMLE models, while induction of epithelial-to-mesenchymal transition by cell dilution, TGFß or mesenchymal transcription factors sharply reduces hCLCA2 levels. Attenuation of hCLCA2 expression by lentiviral small hairpin RNA caused cell overgrowth and focus formation, enhanced migration and invasion, and increased mammosphere formation in methylcellulose. These changes were accompanied by downregulation of E-cadherin and upregulation of mesenchymal markers such as vimentin and fibronectin. Moreover, hCLCA2 expression is greatly downregulated in breast cancer cells with a mesenchymal or claudin-low profile. These observations suggest that loss of hCLCA2 may promote metastasis. We find that higher-than-median expression of hCLCA2 is associated with a one-third lower rate of metastasis over an 18-year period among breast cancer patients compared with lower-than-median (n=344, unfiltered for subtype). Thus, hCLCA2 is required for epithelial differentiation, and its loss during tumor progression contributes to metastasis. Overexpression of hCLCA2 has been reported to inhibit cell proliferation and is accompanied by increases in chloride current at the plasma membrane and reduced intracellular pH (pHi). We found that knockdown cells have sharply reduced chloride current and higher pHi, both characteristics of tumor cells. These results suggest a mechanism for the effects on differentiation. Loss of hCLCA2 may allow escape from pHi homeostatic mechanisms, permitting the higher intracellular and lower extracellular pH that are characteristic of aggressive tumor cells.

Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology.

BACKGROUND: This evidence-based guideline is an update of the 2005 American Academy of Neurology practice parameter on the treatment of essential tremor (ET). METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 2004 and April 2010. RESULTS AND RECOMMENDATIONS: Conclusions and recommendations for the use of propranolol, primidone (Level A, established as effective); alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate (Level B, probably effective); nadolol, nimodipine, clonazepam, botulinum toxin A, deep brain stimulation, thalamotomy (Level C, possibly effective); and gamma knife thalamotomy (Level U, insufficient evidence) are unchanged from the previous guideline. Changes to conclusions and recommendations from the previous guideline include the following: 1) levetiracetam and 3,4-diaminopyridine probably do not reduce limb tremor in ET and should not be considered (Level B); 2) flunarizine possibly has no effect in treating limb tremor in ET and may not be considered (Level C); and 3) there is insufficient evidence to support or refute the use of pregabalin, zonisamide, or clozapine as treatment for ET (Level U).

Gait and dementia: moving beyond the notion of gait apraxia.

Highest level gait disorders are produced by pathology in one or more structures in the cortical-basal ganglia-thalamocortical loop, which plays an important role in producing movements and postural synergies that meet personal desires and environmental constraints. Virtually all patients with dementia have pathology in one or more components of this loop, so highest level gait disorders are common in patients with dementia. The terminology surrounding these gait disorders is unnecessarily complex and too heavily influenced by the controversial concept of gait apraxia. Straightforward descriptive diagnostic criteria are needed. To this end, four core clinical features of highest level gait disorders are proposed: 1) inappropriate (counterproductive) or bizarre limb movement, postural synergies, and interaction with the environment, 2) qualitatively variable performance, influenced greatly by the environment and emotion, 3) hesitation and freezing, and 4) absent or inappropriate (counterproductive) rescue reactions. These core features follow logically from the physiology of the cortical-basal ganglia-thalamocortical loop and should be regarded as signs of pathology in this loop. A clinical rating scale based on these features should be developed to facilitate clinical diagnosis and clinicopathological correlation, while avoiding the ambiguities and controversies of gait apraxia.

Topiramate in essential tremor: a double-blind, placebo-controlled trial.

BACKGROUND: Essential tremor is most prevalent and most disabling in older patients. Additional therapies are required for patients with an inadequate response or intolerable side effects. In small trials, topiramate appeared to be beneficial in essential tremor. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-design trial, patients with moderate to severe essential tremor of the upper limbs were randomized to 24 weeks of treatment with placebo or topiramate (target dose, 400 mg/day) as monotherapy or as an adjunct to one antitremor medication. The primary efficacy variable was the final visit tremor score based on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: The intent-to-treat population was 208 patients (topiramate, 108; placebo, 100). The final visit score (last observation carried forward) was lower in the topiramate group than with placebo (p < 0.001). Mean percentage improvement in overall TRS scores was 29% with topiramate at a mean final dose of 292 mg/day and 16% with placebo (p < 0.001). Topiramate was associated with greater improvement in function and disability (p = 0.001). A between-group difference (p < 0.001) was observed at the first on-treatment visit at 4 weeks when the target topiramate dose was 100 mg/day (mean achieved dose, 62 +/- 9 mg/day). The most common treatment-limiting adverse events in topiramate-treated patients were paresthesia (5%), nausea (3%), concentration/attention difficulty (3%), and somnolence (3%). Adverse events were treatment limiting in 31.9% of topiramate patients and 9.5% of placebo patients. CONCLUSIONS: Topiramate was effective in the treatment of moderate to severe essential tremor. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking.

Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology.

BACKGROUND: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use. METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. RESULTS AND CONCLUSIONS: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET.

Tumor suppression by a proapoptotic calcium-activated chloride channel in mammary epithelium.

Little is known of the roles played by ion channels in cancer. Here we describe a pair of closely related calcium-activated chloride channels whose differential regulation in normal, apoptotic, and transformed mouse cells suggests that channel function is proapoptotic and antineoplastic. While mCLCA1 predominates over mCLCA2 under normal physiological conditions, this relationship is reversed by apoptotic stress both in developing mammary gland and in cultured HC11 mammary epithelial cells. Consistent with an apoptosis-promoting role, splicing of mCLCA2 is disrupted in apoptosis-resistant tumor cell lines and in HC11 cells selected for resistance to detachment-induced apoptosis (anoikis). Unexpectedly, mCLCA1 message is also down-regulated in these cells by at least 30-fold. These results suggest that both genes antagonize survival of mammary tumor cells by sensitizing them to anoikis. When MCF7 or HEK293 tumor cells were transfected with plasmids encoding either mCLCA1 or mCLCA2, colony formation was greatly reduced relative to a vector-transfected control, demonstrating that calcium-sensitive chloride channel (CLCA) expression is deleterious to tumor cell survival. Furthermore, mammary epithelial cells overexpressing mCLCA2 had twice the rate of apoptosis of normal cells when subjected to serum starvation and formed multinuclear giants at a high frequency in normal culture, suggesting that mCLCA2 can promote either apoptosis or senescence.

Genetic heterogeneity in autosomal dominant essential tremor.

PURPOSE: To perform linkage analysis of candidate loci in a large Midwestern family with autosomal dominant essential tremor. METHODS: Thirty-eight members of a six-generation family were evaluated for essential tremor using consensus criteria. Linkage analysis was performed with microsatellite markers reported for three genetic loci associated with familial essential tremor. RESULTS: Patients exhibited a combination of postural and kinetic tremor involving primarily the arms and hands, with a mean age of onset of 31 years. Genetic studies excluded linkage to ETM1 and ETM2 loci, as well as a candidate locus for parkinsonism and postural tremor on chromosome 4p. CONCLUSION: Familial essential tremor is a common hereditary movement disorder demonstrating phenotypic variability and genetic heterogeneity.

The breast cancer beta 4 integrin and endothelial human CLCA2 mediate lung metastasis.

Adhesion of blood-borne cancer cells to the endothelium is a critical determinant of organ-specific metastasis. Here we show that colonization of the lungs by human breast cancer cells is correlated with cell surface expression of the alpha(6)beta(4) integrin and adhesion to human CLCA2 (hCLCA2), a Ca(2+)-sensitive chloride channel protein that is expressed on the endothelial cell luminal surface of pulmonary arteries, arterioles, and venules. Tumor cell adhesion to endothelial hCLCA2 is mediated by the beta(4) integrin, establishing for the first time a cell-cell adhesion property for this integrin that involves an entirely new adhesion partner. This adhesion is augmented by an increased surface expression of the alpha(6)beta(4) integrin in breast cancer cells selected in vivo for enhanced lung colonization but abolished by the specific cleavage of the beta(4) integrin with matrilysin. beta(4) integrin/hCLCA2 adhesion-blocking antibodies directed against either of the two interacting adhesion molecules inhibit lung colonization, while overexpression of the beta(4) integrin in a model murine tumor cell line of modest lung colonization potential significantly increases the lung metastatic performance. Our data clearly show that the beta(4)/hCLCA2 adhesion is critical for lung metastasis, yet expression of the beta(4) integrin in many benign breast tumors shows that this integrin is insufficient to bestow metastatic competence on cells that lack invasiveness and other established properties of metastatic cells.

Pentagon copying is more impaired in dementia with Lewy bodies than in Alzheimer's disease.

OBJECTIVES: In many cases the clinical differentiation of patients with dementia with Lewy bodies (DLB) from those with Alzheimer's disease (AD) has been difficult. Because many neuropsychological studies have reported greater visuospatial/constructional impairment in DLB than in AD, it was determined whether accuracy in copying the interlocking pentagons item on the mini mental state examination (MMSE) may be helpful in distinguishing patients with DLB from those with AD relatively early in the course of the dementia. METHODS: All cases of neuropathologically proved DLB and AD in the Center for Alzheimer Disease and Related Disorders brain bank were retrospectively reviewed, and the first available MMSE for each was retrieved. Only patients with MMSE scores > or = 13 were included, indicating mild to moderate dementia. The patients' copies of the interlocking pentagons were analyzed and graded as acceptable or unacceptable according to the original instructions for grading the MMSE. RESULTS: Seventeen patients with DLB and 27 patients with AD were identified for whom MMSE with copies of the interlocking pentagons were available. Two patients with DLB (MMSEs 22 and 27) drew the pentagons acceptably, by contrast with 16 of the patients with AD (MMSEs 13-28). An unacceptable copy was associated with DLB with a sensitivity of 88% and a specificity of 59% (p = 0.002). CONCLUSIONS: For patients with MMSE scores > or = 13, an inability to accurately copy the pentagons suggests that the diagnosis is more likely DLB than AD. The results confirm the work of others on visuospatial/constructional impairment in DLB and indicate that this feature may be helpful in its diagnosis.

Ca(2+)-activated Cl(-) channels: a newly emerging anion transport family.

A new family of chloride transport proteins has recently emerged. These proteins have extensive homology to a protein previously isolated from bovine tracheal epithelium that acts as a Ca(2+)-sensitive Cl(-) channel (CaCC) when heterologously expressed or when reconstituted into planar lipid bilayers. Several new members of this family have been identified in human, murine, and bovine epithelia, in addition to some other tissues, and are associated with Ca(2+)-sensitive conductive chloride transport when heterologously expressed in Xenopus oocytes or HEK 293 cells. The expressed current is also sensitive to inhibitors such as DIDS and niflumic acid. In addition, at least one family member acts as an endothelial cell adhesion molecule. This emerging family may underlie the Ca(2+)-mediated Cl(-) conductance responsible for rescue of the cystic fibrosis (CF) knockout mouse from significant airway disease.

Molecular characteristics and functional diversity of CLCA family members.

1. In the present brief review, we describe some of the molecular and functional characteristics of a novel mammalian family of putative Ca2+-activated chloride channels (CLCA). 2. So far, two bovine (bCLC1; bCLCA2 (Lu-ECAM-1)), three mouse (mCLCA1; mCLCA2; mCLCA3) and four human (hCLCA1; hCLCA2; hCLCA3; hCLCA4) CLCA family members have been cloned. Each CLCA exhibits a distinct, often overlapping, tissue expression pattern. 3. With the exception of the truncated secreted hCLCA3, all CLCA proteins are synthesized as an approximately 125 kDa precursor transmembrane glycoprotein that is rapidly cleaved into 90 and 35 kDa subunits. 4. The CLCA proteins expressed on the luminal surface of lung vascular endothelia (bCLCA2; mCLCA1; hCLCA2) serve as adhesion molecules for lung metastatic cancer cells, mediating vascular arrest and lung colonization. 5. Expression of hCLCA2 in normal mammary epithelium is consistently lost in human breast cancer and in all tumorigenic breast cancer cell lines. Re-expression of hCLCA2 in human breast cancer cells abrogates invasiveness of Matrigel (BD Biosciences-Labware, Bedford, MA, USA) in vitro and tumorigenicity in nude mice, implying that hCLCA2 acts as a tumour suppressor in breast cancer.

Essential tremor frequency decreases with time.

OBJECTIVE: To quantify the extent to which tremor frequency changes with time in patients with essential tremor. BACKGROUND: Tremor frequency tends to be lower in older patients. The author's previous study of 18 patients with essential tremor produced evidence that tremor frequency decreases slowly over a period of 4 to 8 years. A decrement in frequency will increase tremor amplitude because there is less attenuation of lower-frequency tremor by the low-pass filtering properties of muscle and limb mechanics. METHODS: Nineteen women and 25 men with essential tremor and no other neurologic conditions were followed for 4 years. Accelerometry and surface electromyography (EMG) were used to measure hand tremor and motor unit entrainment in the extensor carpi radialis brevis every 2 years. Tremor frequency was computed from the spectral peak in the rectified filtered EMG spectrum under the condition of 300-gram loading. RESULTS: The patients' mean +/- SD age was 68.0+/-9.95 years. The mean tremor frequency at baseline was 5.79+/-1.32 Hz. The mean decrement in tremor frequency over 4 years was 0.332 Hz (95% CI = 0.141 to 0.523) and was 0.270 Hz (95% CI = 0.122 to 0.418) when a 61-year-old outlier patient was excluded. Tremor frequency and patient age were linearly related: frequency = -0.061(age) + 9. 94 (r = 0.459; p<0.002). CONCLUSIONS: The frequency of essential tremor decreases by approximately 0.06 to 0.08 Hz/year. This decrement in frequency is consistent with the linear relationship between age and tremor frequency.

Diagnostic criteria for essential tremor and differential diagnosis.

Classic essential tremor (ET) is a condition in which the upper limbs (approximately 95% of patients) and, less commonly, the head (approximately 34%), face (approximately 5%), voice (approximately 12%), trunk (approximately 5%), and lower limbs (approximately 20%) exhibit a mixed postural and kinetic tremor without other neurologic abnormalities. Most patients with ET probably inherit the disease through an autosomal dominant gene, but the true ratio of hereditary versus sporadic ET is unknown. Isolated focal, position-specific, and task-specific tremors are probably not ET in most patients and are often due to subtle dystonia. Unilateral tremor, gait disturbance, rigidity, bradykinesia, rest tremor, and rapid onset of symptoms are indications of other tremorogenic disorders.

The pathophysiology of essential tremor.

The pathophysiologic abnormalities that underlie essential tremor (ET) are difficult to decipher because autopsy studies reveal no gross or microscopic abnormalities. Electrophysiologic studies are consistent with a central source of tremorogenic oscillation. The inferior olive and cerebellum are implicated by PET studies. Harmaline tremor in animals shares many features with ET, and the inferior olive has been identified as the source of oscillation in this animal model. Therefore, a disturbance of olivocerebellar rhythmicity is at present the most popular hypothesis for the etiology of ET. Although electrophysiologic tests are available that are helpful in the diagnosis of ET, a gold-standard test or biologic marker for ET is still lacking.

Pushing and pulling with the upper extremities while standing: the effects of mild Alzheimer dementia and Parkinson's disease.

Eleven patients with mild dementia of Alzheimer type, 12 patients with mild to moderate Parkinson disease, and 27 control subjects of comparable age, education, and gender pushed or pulled on a rigid horizontal bar while maintaining stable erect stance. A target window (target force +/-10% maximum force) and a bar force cursor were displayed on a video screen, and subjects were asked to place the bar force cursor within the target window as quickly and as accurately as possible holding the target window for at least 1 sec. The target forces were 50% and 75% maximum force for each person, and three 4.0-sec push trials and three 4.0-sec pull trials were performed for each target force. Moments of force (torque), body motion, and extremity electromyography were measured with a computerized motion analysis system. The patients with Alzheimer's disease had only slightly lower Mini Mental State Examination (MMSE) scores (mean +/- standard deviation [SD] = 25.0 +/- 2.3) than the patients with Parkinson's disease (28.8 +/- 1.5) and control subjects (28.7 +/- 1.3). The patients with Alzheimer's disease had upper limb reaction times (0.827 +/- 0.399 sec) that were greater than those of the patients with Parkinson's disease (0.672 +/- 0.315 sec) and control subjects (0.606 +/- 0.263 sec). Furthermore, the patients with Alzheimer's disease achieved the designated target in only 46.2% of trials, which was comparable to the performance of the patients with Parkinson's disease (55.6%) but inferior to the control subjects (80.6%). Movement times did not differ significantly. The patients and control subjects initiated movement with comparable anticipatory postural activity in the lower limbs. The poor success rates of the patients with Alzheimer's disease and the patients with Parkinson's disease were attributable to inadequate visually guided adjustments in force after the initial movement began. This difficulty in making quick motor adjustments may be relevant to the tendency of patients with Alzheimer's disease to fall.