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Biomedical subjects

John G Nutt

Publications and source records attributed to John G Nutt.

At least 19 recordsLinked to original sources
PubMed2007

Joubert syndrome surviving to adulthood associated with a progressive movement disorder.

A 48-year-old man presented with a progressive gait disorder. He had longstanding ataxia, oculomotor apraxia, motor delay, and cognitive impairment, diagnosed as cerebral palsy. Physical examination revealed ataxia, oculomotor apraxia, extrapyramidal signs, and a wide-based, shuffling gait. Magnetic resonance imaging showed vermian aplasia, consistent with Joubert syndrome. Positron emission tomography scan revealed normal fluorodopa uptake, but elevated raclopride binding, compatible with dopamine deficiency. This case demonstrates that a patient with Joubert syndrome may survive into adulthood and present as a chronic neurologic disorder with subacute extrapyramidal signs.

Age Factors↗
PubMed2007

Continuous dopaminergic stimulation: Is it the answer to the motor complications of Levodopa?

Continuous dopaminergic stimulation (CDS) is a treatment strategy hypothesized to avoid or reduce the motor complications of long-term levodopa therapy, motor fluctuations, and dyskinesia, by preventing or reversing sensitization induced by pulsatile dopaminergic stimulation. The CDS hypothesis is itself based on several hypotheses. First, tonic dopaminergic stimulation is physiological. Second, sensitization is undesirable and should be reversed. Third, reduction of off time and dyskinesia can be induced simultaneously. Finally, clinical studies substantiate the CDS hypothesis. The evidence for these hypotheses is reviewed, and the need for randomized clinical trials that rigorously test the CDS hypothesis is emphasized.

Animals↗
PubMed2006

LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago.

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic determinant of Parkinson disease (PD) identified to date. It accounts for 1%-7% of PD in patients of European origin and 20%-40% in Ashkenazi Jews and North African Arabs with PD. Previous studies concluded that patients from these populations all shared a common Middle Eastern founder who lived in the 13th century. We tested this hypothesis by genotyping 25 microsatellite and single-nucleotide-polymorphism markers in 22 families with G2019S and observed two distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in three European American families. Using a maximum-likelihood method, we estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Our data suggest two separate founding events for G2019S in these populations, beginning at a time that coincides with the Jewish Diasporas.

Africa, Northern↗
PubMed2006

An alternative clinical postural stability test for patients with Parkinson's disease.

We compared the sensitivity and consistency of a new Push and Release Test versus the Pull Test (item 30 of the Unified Parkinson's Disease Rating Scale; UPDRS) as clinical measures of postural stability. Subjects with Parkinson's disease and age-matched control subjects participated in 3 protocols investigating: (1) the sensitivity and specificity of the two tests related to the subjects' balance confidence, as measured by the Activities-specific Balance Confidence (ABC) scale, (2) the inter-rater reliability of the two tests, and (3) the consistency of the perturbation forces applied to the subjects by each balance test. As a test for concurrent validity, the balance tests were also compared with the subjects' retrospective reports of fall frequency. Compared with the Pull Test, the Push and Release Test was more sensitive to subjects with low balance confidence, but less specific for subjects with high balance confidence. The inter-rater correlations were higher with the Push and Release Test. Examiners applied more consistent perturbation forces to the subjects with the Push and Release Test than with the Pull Test. The Push and Release Test correlated better with self-reported falls. Therefore, the Push and Release Test provided a more sensitive and consistent test of postural stability than the Pull Test.

Adult↗
PubMed2006

Disease progression and pharmacodynamics in Parkinson disease - evidence for functional protection with levodopa and other treatments.

We have modelled the Unified Parkinson's Disease Rating Scale (UPDRS) scores collected in 800 subjects followed for 8 years. Newly diagnosed and previously untreated subjects were initially randomized to treatment with placebo, deprenyl, tocopherol or both and, when clinical disability required, received one or more dopaminergic agents (levodopa (carbidopa/levodopa), bromocriptine, or pergolide). Using models for disease progression and pharmacodynamic models for drug effects we have characterized the changes in UPDRS over time to determine the influence of the various drug treatments. We have confirmed and quantitated the relative symptomatic benefits of the dopaminergic agents and provide model-based evidence for slowing of disease progression.

Algorithms↗
PubMed2006

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

OBJECTIVE: Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). METHODS: Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake. RESULTS: At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). INTERPRETATION: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

Adult↗
PubMed2006

Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics.

The G2019S mutation in the LRRK2 gene is reportedly a common cause of familial Parkinson's disease (PD) and may also have a significant role in nonfamilial PD. The objective of this study was to assess mutation carrier frequency in PD patients from movement disorder clinics in the United States, stratified by family history, age at onset, and geography; to determine carrier frequency in a large and well-characterized control population; to examine segregation of mutation in families of patients; and to correlate genotype with clinical phenotype. One thousand four hundred twenty-five unrelated PD patients from movement disorder clinics in Oregon, Washington, and New York and 1,647 unrelated controls were studied. The G2019S mutation was detected using a TaqMan assay and verified by sequencing. Eighteen of 1,425 patients and one of 1,647 controls had the mutation. Carrier frequency (+/- 2SE) in patients was 0.013 +/- 0.006 overall, 0.030 +/- 0.019 in familial PD, 0.007 +/- 0.005 in nonfamilial PD, 0.016 +/- 0.013 in early-onset PD, and 0.012 +/- 0.007 in late-onset PD. Geographic differences were insignificant. Age at onset of mutation carriers ranged from 28 to 71 years. Mutation carriers were clinically indistinguishable from idiopathic PD. LRRK2 G2019S is the single most common pathogenic mutation linked to neurodegenerative disease to date.

Adolescent↗
PubMed2006

OFF-off rebound dyskinesia in subthalamic nucleus deep brain stimulation of Parkinson's disease.

A 61-year-old man with Parkinson's disease (PD), motor fluctuations, and dyskinesias underwent bilateral implantation of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN). One month after surgery, DBS was optimized to bilateral monopolar settings at the most proximal electrode just superior to the STN, which improved motor fluctuations and dyskinesias. At several postoperative evaluations off medications overnight, both stimulators were turned off and within 60 seconds he developed severe dyskinesias. When the stimulators were turned back on, the dyskinesias soon resolved. This article is a first report of a unique pattern of rebound-type dyskinesia that occurred in the off medication state produced by stopping STN DBS.

Antiparkinson Agents↗
PubMed2006

Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.

BACKGROUND: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

Aged↗
PubMed2005

Can stooped posture explain multidirectional postural instability in patients with Parkinson's disease?

To determine the effects of the stooped posture of patients with Parkinson's disease (PD) on postural stability, we compared the kinetic, kinematic, and electromyographic responses of seven subjects with PD and 11 control subjects to eight directions of surface translations. Control subjects were studied in an upright posture and in a stooped posture that mimicked the posture of the PD subjects. When control subjects adopted a stooped posture, peak center of pressure displacements slowed and decreased, reducing stability margins toward values observed in PD subjects. Stooped control subjects, however, responded to translations with large joint angle displacements, whereas PD subjects exhibited small joint angle displacements. Stooping in control subjects did not lead to abnormally directed horizontal forces under each foot or antagonistic muscle co-activation at the hip and trunk, as seen in PD subjects. Upright and stooped control subjects never fell during the trials, whereas PD subjects fell in 16% of the trials. We conclude that stooped posture is a destabilizing posture, but it does not account for abnormal postural responses in PD.

Aged↗
PubMed2005

Short-term paroxetine treatment does not alter the motor response to levodopa in PD.

The authors examined the motor effects of 2 weeks of paroxetine, a serotonin reuptake inhibitor (SSRI), and placebo on responses to 2-hour levodopa infusions in 14 subjects with Parkinson disease. Paroxetine did not affect tapping scores or dyskinesia. Baseline walking speed (preinfusion) increased on paroxetine, often associated with an increased subjective perception of worsened balance.

Accidental Falls↗
PubMed2005

Parkin mutation dosage and the phenomenon of anticipation: a molecular genetic study of familial parkinsonism.

BACKGROUND: parkin mutations are a common cause of parkinsonism. Possessing two parkin mutations leads to early-onset parkinsonism, while having one mutation may predispose to late-onset disease. This dosage pattern suggests that some parkin families should exhibit intergenerational variation in age at onset resembling anticipation. A subset of familial PD exhibits anticipation, the cause of which is unknown. The aim of this study was to determine if anticipation was due to parkin mutation dosage. METHODS: We studied 19 kindreds that had early-onset parkinsonism in the offspring generation, late-onset parkinsonism in the parent generation, and > or = 20 years of anticipation. We also studied 28 early-onset parkinsonism cases without anticipation. Patients were diagnosed by neurologists at a movement disorder clinic. parkin analysis included sequencing and dosage analysis of all 12 exons. RESULTS: Only one of 19 cases had compound parkin mutations, but contrary to our postulate, the affected relative with late-onset parkinsonism did not have a parkin mutation. In effect, none of the anticipation cases could be attributed to parkin. In contrast, 21% of early-onset parkinsonism patients without anticipation had parkin mutations. CONCLUSION: Anticipation is not linked to parkin, and may signify a distinct disease entity.

Adult↗
PubMed2005

Importance of within subject variation in levodopa pharmacokinetics: a 4 year cohort study in Parkinson's disease.

The purpose of the study was to describe the population pharmacokinetics of levodopa in patients with Parkinson's disease studied in 5 trials (10 occasions) over 4 years. Twenty previously untreated Parkinsonian patients were investigated. Each trial consisted of a 2-hr IV infusion of levodopa (1 mg/kg/h) with concomitant oral carbidopa given on two occasions separated by 72 hr with no levodopa in between. This trial design was repeated at 6, 12, 24 and 48 months. A two-compartment pharmacokinetic model with central volume (V1), peripheral volume (V2), clearance (CL) and inter-compartmental clearance (CL(ic)) was used to fit plasma levodopa concentrations. The model accounted for levodopa dosing prior to each trial and endogenous levodopa synthesis. Population parameter estimates (geometric mean) and population parameter variability (PPV; SD of normal distribution) were V1 11.4 l/70 kg (0.44), CL 30.9 l/h/70 kg (0.25), V2 27.3 l/70 kg (0.27), and CL(ic) 34.6 l/h/70 kg (0.48). PPV was partitioned into between subject variability (BSV) which was 0.12 V1, 0.13 CL, 0.15 V(2), 0.28 CL(ic), within trial variability (WTV) which was 0.16 V1, 0.13 CL, 0.08 V2, 0.18 CL(ic) and between trial variability (BTV) which was 0.40 V1, 0.17 CL, 0.21 V2, 0.34 CL(ic.) Neither structural nor random levodopa pharmacokinetic parameters were associated with the time course of development of fluctuation in motor response. Variability in levodopa pharmacokinetic parameters (particularly V1) may result in variability in plasma levodopa concentrations that could contribute to fluctuations in motor response.

Administration, Oral↗
PubMed2005

Pharmacokinetic and pharmacodynamic changes during the first four years of levodopa treatment in Parkinson's disease.

The purpose of this analysis is to describe how levodopa pharmacokinetic and pharmacodynamic parameters change over the first 4 years of long-term levodopa treatment in patients with Parkinson's disease. Twenty previously untreated Parkinsonian patients were admitted to the general clinical research center (GCRC) for 4 days at the beginning of long-term levodopa therapy and 6, 12, 24 and 48 months later. On each GCRC admission, patients received a 2 hr IV infusion of levodopa on day 1 and day 4 with no oral levodopa between the infusions. After the first GCRC admission patients were treated with oral levodopa dosed for optimal control of Parkinsonism. Motor function was measured by finger tapping rate. A pharmacokinetic-pharmacodynamic model incorporating 3 effect compartments was used to fit the individual plasma levodopa concentrations and tapping rates. Motor function before the first levodopa infusion (E0(1)) improved over the first 20 months and subsequently returned to the initial baseline at the start of the study. A similar pattern was seen in motor function before the second infusion (E0(2)) after the 3 days levodopa withdrawal, with a decline predicted to fall below the initial baseline at the start of the study by 6 years. Eight patients showed an increase in maximum tapping rate with levodopa (E(max)) approaching a steady state after 16 months. Ten patients showed an increase in E(max) with a peak at 31 months. One patient showed a linear decrease and another patient did not change over the 48 months. Longitudinal progress models were used to describe the time course of pharmacokinetic and pharmacodynamic parameters over 4 years. Peak treatment benefit, defined as the difference between E(max) and E0(1) or E0(2) (D(max)1 or D(max)2), increased with time particularly after the 3-day levodopa withdrawal. Deterioration of pre-dose motor function (E0) as disease progresses coupled with a greater amplitude of response due to levodopa (D(max)) could be a key factor contributing to motor fluctuations associated with long-term levodopa treatment.

Administration, Oral↗
PubMed2005

Direction-specific postural instability in subjects with Parkinson's disease.

The purpose of this study was to determine whether and why subjects with Parkinson's disease (PD) have greater instability in response to specific directions of perturbations than do age-matched control subjects and how instability is affected by stance width. This study compared postural responses to 8 directions of surface translations in PD subjects and age-matched control subjects while standing in a narrow and wide stance. PD subjects were tested in their practical OFF state. A postural stability margin was quantified as the difference between peak center of pressure (CoP) and peak center of mass (CoM) displacement in response to surface translations. The control subjects maintained a consistent stability margin across directions of translations and for both narrow and wide stance by modifying rate of rise of CoP responses. PD subjects had smaller than normal postural stability margins in all directions, but, especially for backwards sway in both stance widths and for lateral sway in narrow stance width. The reduced stability margin in PD subjects was due to a slower rise and smaller peak of CoP in the PD subjects than in control subjects. Lateral postural stability was compromised in PD subjects by lack of trunk flexibility and backwards postural stability was compromised by lack of knee flexion, resulting in excessive displacements of the body CoM. Stability margins in PD subjects were related to their response on the pull test in the Unified Parkinson's Disease Rating Scale. Thus, PD patients have directionally specific postural instability due to an ineffective stiffening response and inability to modify their postural responses for changing postural demands related to direction of perturbation and initial stance posture. These results suggest that the basal ganglia, in addition to regulating muscle tone and energizing postural muscle activation, also are critical for adapting postural response patterns for specific biomechanical conditions.

Aged↗