Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several classes of medications have been used to treat generalized anxiety disorders (GAD). Antidepressants are useful for chronic subpanic anxiety and anxiety associated with depression. Benzodiazepines are generally safe, but recent research suggests that the incidence of chronic abstinence syndromes may be higher than has been suspected. This class of medications is best used for circumscribed periods of time. Because buspirone has no significant interactions, it does not prevent benzodiazepine withdrawal and cannot be directly substituted for this class of medications. beta-Blockers are used when cardiovascular symptoms and tremor are prominent, for stage fright (propranolol) and possibly for social phobia (atenolol). Antihistamines have been used for elderly patients and for those with a history of substance abuse. Neuroleptics should only be prescribed for anxiety associated with psychosis, psychotic and possibly severe depression, and borderline personality disorder. Drug treatment of GAD should be used as part of a comprehensive treatment plan that includes assessment for medical illnesses that can aggravate anxiety, withdrawal of all unnecessary medications (especially CNS depressants) and caffeine, structured relaxation techniques, evaluation of the specific type of anxiety, and psychotherapy.
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PMID:Generalized anxiety disorder: new concepts and psychopharmacologic therapies. 196 48

Generalized anxiety disorder is a syndrome characterized by excessive anxiety or apprehension concerning two or more of life's circumstances. Presenting signs and symptoms often include somatic complaints, such as tremor, dyspnea, palpitations, lightheadedness and nausea. Treatment includes supportive psychotherapy and antianxiety drugs, primarily benzodiazepines. In some cases, antidepressants may prove beneficial.
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PMID:Generalized anxiety disorder. 264 85

The optimal time for treating congenital hydrocephalus is still unknown. The following study tries to answer this question by shunting hydrocephalic rats around the 10th day of life when the brain development corresponds to that of humans at birth. The animals were allocated to 4 groups: normal, hydrocephalic, normal sham-operated and hydrocephalic-shunted rats (groups 1-4). Body weight and neurological development was tested every 2nd-3rd day. X-rays of the skull were performed in groups 2, 3 and 4 at 10 days and in all at 20 days. In groups 2 and 4 0.1 ml lohexolum was instilled into the lateral ventricle at 10 days and in all at 20 days. X-rays were used to calculate the volume of the neurocranium and to identify ventriculomegaly and its grade (1-3). The x-rays and shunting were performed under general anesthesia, the latter using Kausch's technique. At 20 days of age the animals were sacrificed, the homogenized brain tissue was used to measure Protein, DNA, GAD and CNP by photometry, fluorometry and enzymatically. Time-course of neurological development in group 1: The locomotor patterns were attained gradually up to the ability to hold on to a bar. In group 2 there were larger variations and holding on to a bar was possible only in 6/13. In addition, a distinct tremor was observed in 34%. In group 4 holding on to a bar was possible in all, tremor was observed in 20% of examinations and diminishing following surgery. The volume of the neurocranium in groups 2 and 4 was significantly larger than in groups 3 at 10 days; and in group 2 significantly larger than in groups 1, 3 and 4 at 20 days. In group 4 the ventriculomegaly was distinctly reduced in 7 and remained the same in 1. Protein was significantly lower in group 4. DNA was the same in all groups. GAD was the lowest and the CNP significantly low in group 2. The study shows that an effective shunt may reverse the progressive clinical, radiological and neurochemical changes of hydrocephalus, and that surgery must not be performed necessarily earlier (e.g. prenatally in humans).
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PMID:Clinical, gross morphological and neurochemical follow-up in normal, hydrocephalic and hydrocephalic-shunted rats. 982 33

This gene transfer experiment is the first Parkinson's Disease (PD) protocol to be submitted to the Recombinant DNA Advisory Committee. The principal investigators have uniquely focused their careers on both pre-clinical work on gene transfer in the brain and clinical expertise in management and surgical treatment of patients with PD. They have extensively used rodent models of PD for proof-of-principle experiments on the utility of different vector systems. PD is an excellent target for gene therapy, because it is a complex acquired disease of unknown etiology (apart from some rare familial cases) yet it is characterized by a specific neuroanatomical pathology, the degeneration of dopamine neurons of the substantia nigra (SN) with loss of dopamine input to the striatum. This pathology results in focal changes in the function of several deep brain nuclei, which have been well-characterized in humans and animal models and which account for many of the motor symptoms of PD. Our original approaches, largely to validate in vivo gene transfer in the brain, were designed to facilitate dopamine transmission in the striatum using an AAV vector expressing dopamine-synthetic enzymes. Although these confirmed the safety and potential efficacy of AAV, complex patient responses to dopamine augmenting medication as well as poor results and complications of human transplant studies suggested that this would be a difficult and potentially dangerous clinical strategy using current approaches. Subsequently, we and others investigated the use of growth factors, including GDNF. These showed some encouraging effects on dopamine neuron survival and regeneration in both rodent and primate models; however, uncertain consequences of long-term growth factor expression and question regarding timing of therapy in the disease course must be resolved before any clinical study can be contemplated. We now propose to infuse into the subthalamic nucleus (STN) recombinant AAV vectors expressing the two isoforms of the enzyme glutamic acid decarboxylase (GAD-65 and GAD-67), which synthesizes the major inhibitory neurotransmitter in the brain, GABA. The STN is a very small nucleus (140 cubic mm or 0.02% of the total brain volume, consisting of approximately 300,000 neurons) which is disinhibited in PD, leading to pathological excitation of its targets, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr). Increased GPi/SNpr outflow is believed responsible for many of the cardinal symptoms of PD, i.e., tremor, rigidity, bradykinesia, and gait disturbance. A large amount of data based on lesioning, electrical stimulation, and local drug infusion studies with GABA-agonists in human PD patients have reinforced this circuit model of PD and the central role of the STN. Moreover, the closest conventional surgical intervention to our proposal, deep brain stimulation (DBS) of the STN, has shown remarkable efficacy in even late stage PD, unlike the early failures associated with recombinant GDNF infusion or cell transplantation approaches in PD. We believe that our gene transfer strategy will not only palliate symptoms by inhibiting STN activity, as with DBS, but we also have evidence that the vector converts excitatory STN projections to inhibitory projections. This additional dampening of outflow GPi/SNpr outflow may provide an additional advantage over DBS. Moreover, of perhaps the greatest interest, our preclinical data suggests that this strategy may also be neuroprotective, so this therapy may slow the degeneration of dopaminergic neurons. We will use both GAD isoforms since both are typically expressed in inhibitory neurons in the brain, and our data suggest that the combination of both isoforms is likely to be most beneficial. Our preclinical data includes three model systems: (1) old, chronically lesioned parkinsonian rats in which intraSTN GAD gene transfer results not only in improvement in both drug-induced asymmetrical behavior (apomorphine symmetrical rotations), but also in spontaneous behaviors. In our second model, GAD gene transfer precedes the generation of a dopamine lesion. Here GAD gene transfer showed remarkable neuroprotection. Finally, we carried out a study where GAD-65 and GAD-67 were used separately in monkeys that were resistant to MPTP lesioning and hence showed minimal symptomatology. Nevertheless GAD gene transfer showed no adverse effects and small improvements in both Parkinson rating scales and activity measures were obtained. In the proposed clinical trial, all patients will have met criteria for and will have given consent for STN DBS elective surgery. Twenty patients will all receive DBS electrodes, but in addition they will be randomized into two groups, to receive either a solution containing rAAV-GAD, or a solution which consists just of the vector vehicle, physiological saline. Patients, care providers, and physicians will be blind as to which solution any one patient receives. All patients, regardless of group, will agree to not have the DBS activated until the completion and unblinding of the study. Patients will be assessed with a core clinical assessment program modeled on the CAPSIT, and in addition will also undergo a preop and several postop PET scans. At the conclusion of the study, if any patient with sufficient symptomatic improvement will be offered DBS removal if they so desire. Any patients with no benefit will simply have their stimulators activated, which would normally be appropriate therapy for them and which requires no additional operations. If any unforeseen symptoms occur from STN production of GABA, this might be controlled by blocking STN GABA release with DBS, or STN lesioning could be performed using the DBS electrode. Again, this treatment would not subject the patient to additional invasive brain surgery. The trial described here reflects an evolution in our thinking about the best strategy to make a positive impact in Parkinson Disease by minimizing risk and maximizing potential benefit. To our knowledge, this proposal represents the first truly blinded, completely controlled gene or cell therapy study in the brain, which still provides the patient with the same surgical procedure which they would normally receive and should not subject the patient to additional surgical procedures regardless of the success or failure of the study. This study first and foremost aims to maximally serve the safety interests of the individual patient while simultaneously serving the public interest in rigorously determining in a scientific fashion if gene therapy can be effective to any degree in treating Parkinson's disease.
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PMID:Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. 1152 46

Myoclonus dystonia syndrome is a childhood onset hyperkinetic movement disorder characterized by predominant alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. Previous studies have suggested that patients with SGCE mutations may have an increased rate of psychiatric disorders. We established a cohort of patients with myoclonus dystonia syndrome and SGCE mutations to determine the extent to which psychiatric disorders form part of the disease phenotype. In all, 89 patients with clinically suspected myoclonus dystonia syndrome were recruited from the UK and Ireland. SGCE was analysed using direct sequencing and for copy number variants. In those patients where no mutation was found TOR1A (GAG deletion), GCH1, THAP1 and NKX2-1 were also sequenced. SGCE mutation positive cases were systematically assessed using standardized psychiatric interviews and questionnaires and compared with a disability-matched control group of patients with alcohol responsive tremor. Nineteen (21%) probands had a SGCE mutation, five of which were novel. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-compulsive disorder was eight times more likely (P < 0.001) in mutation positive cases, compulsivity being the predominant feature (P < 0.001). Generalized anxiety disorder (P = 0.003) and alcohol dependence (P = 0.02) were five times more likely in mutation positive cases than tremor controls. SGCE mutations are associated with a specific psychiatric phenotype consisting of compulsivity, anxiety and alcoholism in addition to the characteristic motor phenotype. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms.
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PMID:SGCE mutations cause psychiatric disorders: clinical and genetic characterization. 2336 3

OBJECTIVEDeep brain stimulation (DBS) is an effective therapy for movement disorders such as idiopathic Parkinson's disease (PD) and essential tremor (ET). However, some patients who demonstrate benefit on objective motor function tests do not experience postoperative improvement in depression or anxiety, 2 important components of quality of life (QOL). Thus, to examine other possible explanations for the lack of a post-DBS correlation between improved objective motor function and decreased depression or anxiety, the authors investigated whether patient perceptions of motor symptom severity might contribute to disease-associated depression and anxiety.METHODSThe authors performed a retrospective chart review of PD and ET patients who had undergone DBS at the Cleveland Clinic in the period from 2009 to 2013. Patient demographics, diagnosis (PD, ET), motor symptom severity, and QOL measures (Primary Care Evaluation of Mental Disorders 9-item Patient Health Questionnaire [PHQ-9] for depression, Generalized Anxiety Disorder 7-item Scale [GAD-7], and patient-assessed tremor scores) were collected at 4 time points: preoperatively, postoperatively, 1-year follow-up, and 2-year follow-up. Multivariable prediction models with solutions for fixed effects were constructed to assess the correlation of predictor variables with PHQ-9 and GAD-7 scores. Predictor variables included age, sex, visit time, diagnosis (PD vs ET), patient-assessed tremor, physician-reported tremor, Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score, and patient-assessed tremor over time.RESULTSSeventy PD patients and 17 ET patients were included in this analysis. Mean postoperative and 1-year follow-up UPDRS-III and physician-reported tremor scores were significantly decreased compared with preoperative scores (p < 0.0001). Two-year follow-up physician-reported tremor was also significantly decreased from preoperative scores (p < 0.0001). Only a diagnosis of PD (p = 0.0047) and the patient-assessed tremor rating (p < 0.0001) were significantly predictive of depression. A greater time since surgery, in general, significantly decreased anxiety scores (p < 0.0001) except when a worsening of patient-assessed tremor was reported over the same time period (p < 0.0013).CONCLUSIONSPatient-assessed tremor severity alone was predictive of depression in PD and ET following DBS. This finding suggests that a patient's perception of illness plays a greater role in depression than objective physical disability regardless of the time since surgical intervention. In addition, while anxiety may be attenuated by DBS, patient-assessed return of tremor over time can increase anxiety, highlighting the importance of long-term follow-up for behavioral health features in chronic neurological disorders. Together, these data suggest that the patient experience of motor symptoms plays a role in depression and anxiety-a finding that warrants consideration when evaluating, treating, and following movement disorder patients who are candidates for DBS.
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PMID:Prediction of depression and anxiety via patient-assessed tremor severity, not physician-reported motor symptom severity, in patients with Parkinson's disease or essential tremor who have undergone deep brain stimulation. 2947 81