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Biomedical subjects

J G Nutt

Publications and source records attributed to J G Nutt.

At least 19 recordsLinked to original sources
PubMed2006

Multiple balance tests improve the assessment of postural stability in subjects with Parkinson's disease.

OBJECTIVES: Clinicians often base the implementation of therapies on the presence of postural instability in subjects with Parkinson's disease (PD). These decisions are frequently based on the pull test from the Unified Parkinson's Disease Rating Scale (UPDRS). We sought to determine whether combining the pull test, the one-leg stance test, the functional reach test, and UPDRS items 27-29 (arise from chair, posture, and gait) predicts balance confidence and falling better than any test alone. METHODS: The study included 67 subjects with PD. Subjects performed the one-leg stance test, the functional reach test, and the UPDRS motor exam. Subjects also responded to the Activities-specific Balance Confidence (ABC) scale and reported how many times they fell during the previous year. Regression models determined the combination of tests that optimally predicted mean ABC scores or categorised fall frequency. RESULTS: When all tests were included in a stepwise linear regression, only gait (UPDRS item 29), the pull test (UPDRS item 30), and the one-leg stance test, in combination, represented significant predictor variables for mean ABC scores (r2 = 0.51). A multinomial logistic regression model including the one-leg stance test and gait represented the model with the fewest significant predictor variables that correctly identified the most subjects as fallers or non-fallers (85% of subjects were correctly identified). CONCLUSIONS: Multiple balance tests (including the one-leg stance test, and the gait and pull test items of the UPDRS) that assess different types of postural stress provide an optimal assessment of postural stability in subjects with PD.

Accidental Falls↗
PubMed2004

parkin mutation analysis in clinic patients with early-onset Parkinson [corrected] disease.

parkin Mutations are the most common identified cause of Parkinson's disease (PD). It has been suggested that patients with young-onset PD be screened for parkin mutations as a part of their clinical work-up. The aim of this study was to assess parkin mutation frequency in a clinical setting, correlate genotype with phenotype, and evaluate the current justification for clinical parkin testing. Patients were selected from a movement disorder clinic based on diagnosis of PD and onset age </=40 years. parkin was genotyped by sequence and dosage analysis for all 12 exons. Key relatives and controls were screened for identified mutations. Mutations were found in 7/39 patients. Two patients were compound heterozygous; five were heterozygous. Mutations included deletions in exons 2, 3, and 8, duplications in exons 2-4, and 9, and P437L substitution. Seventy-eight percent of mutations were deletions/multiplications. A novel substitution (R402W) was found in one patient and in one control. None of the point mutations found in patients were detected in 96 controls. parkin phenotypes were consistent with idiopathic PD. In conclusion, parkin mutations are common in the clinic setting: 10% of PD patients had early-onset and 18% of them had parkin mutations. However, if parkin is recessive, only 5% of early-onset cases who had compound mutations could be attributed to this locus. Mutation frequency was 0.12 (95% CI 0.04-0.19). parkin cases can present as typical idiopathic PD, distinguishable only by molecular testing. Seventy percent of parkin cases were heterozygous. It is unclear whether heterozygous mutations are pathogenic. parkin-based diagnosis and counseling require a better understanding of the mode of inheritance, penetrance, and carrier frequencies.

Adolescent↗
PubMed2003

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD.

OBJECTIVE: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. BACKGROUND: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. METHODS: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. RESULTS: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. CONCLUSIONS: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

Adult↗
PubMed2001

Interactions between deep brain stimulation and levodopa in Parkinson's disease.

OBJECTIVE: To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS. BACKGROUND: Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown. METHODS: Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores. RESULTS: DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia. CONCLUSION: DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.

Adult↗
PubMed2001

DBS and diathermy interaction induces severe CNS damage.

Pulse-modulated radiofrequency diathermy treatment to the maxilla produced permanent diencephalic and brainstem lesions and a vegetative state in a patient with PD with implanted subthalamic electrodes for deep brain stimulation.

Aged↗
PubMed2001

Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease.

BACKGROUND: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. OBJECTIVE: To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. METHODS: We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. RESULTS: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. CONCLUSION: Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.

Adult↗
PubMed2001

Response to levodopa treatment in dopa-responsive dystonia.

BACKGROUND: Dopa-responsive dystonia (DRD) is similar to Parkinson disease in that both disorders have impaired dopamine synthesis and respond to levodopa treatment. Dopa-responsive dystonia differs in that dopamine storage is intact in contrast to Parkinson disease in which it is markedly reduced. OBJECTIVE: To examine the short- and long-duration responses to levodopa dosing in subjects with DRD. METHODS: The response to brief infusions of levodopa was examined in 4 subjects with DRD and the effects of withdrawal of levodopa for 3 to 7 days studied in the 3 subjects receiving long-term levodopa therapy. Motor function was measured with tapping speed, Unified Parkinson's Disease Rating Scale motor score, and global dystonia score. RESULTS: The short-duration response to levodopa dosing seems to develop more slowly and persists longer in subjects with DRD than in subjects with Parkinson disease. Withdrawal of levodopa leads to a gradual decline in tapping speed and reemergence of dystonia over several days, similar to the rate of decay of motor function in Parkinson disease. The short- and long-duration responses were not clearly differentiated in DRD. CONCLUSIONS: This pilot study suggests that retained dopamine storage in DRD may prolong the short-duration response and blur the distinction of the short- and long-duration responses. The decline in motor function in DRD on withdrawal of long-term levodopa therapy resembles that in Parkinson disease, suggesting that a long-duration response, if it exists in DRD, is unrelated to dopamine storage.

Adult↗
PubMed2001

Motor fluctuations and dyskinesia in Parkinson's disease.

Motor fluctuations and dyskinesia are common complications of long-term levodopa therapy. The neural and molecular mechanisms underlying their development are partially understood. A variety of clinical strategies may reduce the unpredictability of motor fluctuations and reduce their impact. Prevention of these complications remains an elusive goal.

Antiparkinson Agents↗
PubMed2000

Apomorphine can sustain the long-duration response to L-DOPA in fluctuating PD.

The authors investigated the ability of daytime infusions of apomorphine, a D-1 and D-2 dopamine agonist, to sustain the long-duration response (LDR) in seven subjects with fluctuating PD in whom L-DOPA was discontinued for 3 days. Apomorphine maintained the LDR to the extent that it kept the subjects "on" during the day. This observation suggests that the LDR can be a postsynaptic effect, independent of dopamine storage.

Aged↗
PubMed2000

Determinants of tapping speed in normal control subjects and subjects with Parkinson's disease: differing effects of brief and continued practice.

BACKGROUND: Alternate tapping speed is widely used as a measure of bradykinesia in Parkinson's disease (PD). Tapping speed in normal control subjects and factors that might influence tapping speed have not been systematically examined. OBJECTIVE: To examine the effects of age, hand dominance, and gender on tapping speed in normal control subjects and to compare the effects of practice on tapping speed in normal and PD control subjects. METHODS: Tapping speed for three sequential trials in the dominant and nondominant hand was examined in 100 normal control subjects and 60 subjects with PD. The effect of hourly practice over 26 hours (19 trials) was investigated in 14 normal and 24 PD subjects. RESULTS: The speed with which normal subjects alternately tapped two counters was negatively correlated with age, was greater in the dominant hand, was not related to gender, and improved with short-term practice (three trials) and with continued practice over 26 hours. Parkinsonian subjects, in general, tapped more slowly than normal control subjects and more slowly in the more affected arm. Parkinsonian subjects benefited from short-term practice as much as normal control subjects but, unlike normal control subjects, did not improve with continued practice over 26 hours. CONCLUSIONS: Alternate tapping speed is influenced by age, hand dominance, Parkinson's disease, and practice. Subjects with PD do not benefit as much from continued practice as do normal subjects, suggesting some limitation or impairment of procedural (motor) learning in PD.

Adult↗
PubMed2000

Continuous dopamine-receptor stimulation in advanced Parkinson's disease.

Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of the motor fluctuations and dyskinesia that complicate long-term L-dopa therapy of Parkinson's disease. As a corollary to this hypothesis, continuous dopamine-receptor stimulation can avoid or reverse these complications. Such continuous stimulation is unlikely to mimic completely the normal function of the dopaminergic system, but should avoid the supra-physiological swings in extracellular dopamine that accompany intermittent L-dopa dosing. The concern is that this continuous stimulation might induce tolerance rather than sensitization to some effects of L-dopa. Open clinical trials support the value of continuous dopaminergic stimulation in Parkinson's disease with established motor complications, but rigorous studies, although experimentally difficult, are needed.

Antiparkinson Agents↗
PubMed2000

Levodopa motor complications in Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disorder with an average onset age of 60 years. In the United States, approximately one million persons suffer from PD, and there are 60,000 newly diagnosed cases every year. The estimated cost of PD to society is $27 billion per year. Based on United States Census Bureau projections, it is estimated that the frequency of PD will increase fourfold by the year 2040, making it an even larger burden on patients, their families and society.

Age of Onset↗
PubMed2000

Clinical pharmacology of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia (LID) is a major impediment to the successful therapy of Parkinson's disease. The development of LID is facilitated by dopaminergic denervation but may not require denervation. Repeated levodopa dosing is necessary to induce dyskinesia, implying the development of sensitization to levodopa. There is inconclusive evidence on whether repeated dosing lowers the threshold (shifts the levodopa-dyskinesia response curve to the left), increases the severity of dyskinesia (increases the maximum effect that is initially zero) or induces more complex changes in the dose-response curve. Once a patient develops LID, the severity of LID is not dose responsive, but the duration of dyskinesia is. Clinically, it is very difficult to separate the antiparkinsonian and dyskinetic effects of levodopa. Whether this separation is possible with more selective agonists with antiparkinsonian effects that are equipotent to levodopa is unknown. The fact that selective stimulation of the pallidum does not separate antiparkinsonian and dyskinetic actions implies that they are closely related anatomically and physiologically.

Dopamine Agents↗
PubMed2000

Effect of COMT inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients.

Catechol-O-methyl transferase (COMT) is one of the principal levodopa-metabolizing enzymes, particularly when aromatic amino acid decarboxylase (AAAD) is partially inhibited by carbidopa or benserazide. This paper examines the pharmacology of COMT inhibitors such as tolcapone and entacapone, and considers the effects of these drugs on the pharmacolinetics of levodopa. Both agents extend the elimination half-life and plasma area under the curve of levodopa without affecting the maximal plasma concentration of levodopa (Cmax) or the time until an oral dose of levodopa reaches its peak plasma concentration (Tmax). Clinically, these pharmacokinetic effects permit a reduction in the levodopa dose, an increase in "on" time and a decrease in "off" time in fluctuating PD patients. Motor benefits can also be seen in stable PD patients. COMT inhibitors are thus an alternative to increasing levodopa doses or adding dopamine agonists to reduce "off" time and enhance motor function in fluctuating PD patients.

Catechol O-Methyltransferase Inhibitors↗