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Biomedical subjects

John Nutt

Publications and source records attributed to John Nutt.

15 recordsLinked to original sources
PubMed2007

Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients.

OBJECTIVE: Homozygous or compound heterozygous parkin mutations cause juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with typical Parkinson's disease (PD), but it is unclear whether a single "mutation" in a patient is related to disease or is coincidental, because the mutation frequency in control subjects is unknown. We present a comprehensive sequence analysis of parkin in control subjects. METHODS: A total of 302 patients and 301 control subjects were sequenced, and findings were replicated in 1,260 additional patients and 1,657 control subjects. RESULTS: Thirty-four variants were detected, of which 21 were novel; 12 were polymorphisms and 22 were rare variants. Patients and control subjects did not differ in the frequency, type, or functional location of the variants. Even P437L, a common mutation thought to be pathogenic, was present in unaffected control subjects. INTERPRETATION: parkin point mutations are not exclusive to PD. The mere presence of a single point mutation in a patient, in the absence of a second mutation, should not be taken as a cause of disease unless corroborated by family data and functional studies. This study does not support the notion that heterozygous parkin sequence variants (mutations or polymorphisms) are risk factors for PD. Whether heterozygous dosage anomalies are associated with PD remains to be determined.

Adult↗
PubMed2006

Postural muscle tone in the body axis of healthy humans.

Across the entire human body, postural tone might play its most critical role in the body's axis because the axis joins the four limbs and head into a single functioning unit during complex motor tasks as well as in static postures. Although postural tone is commonly viewed as low-level, tonic motor activity, we hypothesized that postural tone is both tonically and dynamically regulated in the human axis even during quiet stance. Our results describe the vertical distribution of postural muscle tone in the neck, trunk, and hips of standing human adults. Each subject stood blindfolded on a platform that axially rotated the neck, trunk, or pelvis at 1 degrees /s and +/-10 degrees relative to the neutral position (i.e., facing forward). The measured resistance to axial rotation was highest in the trunk and lowest in the neck and was characterized by several nonlinear features including short-range stiffness and hysteresis. In half of the subjects, axial muscle activity was relatively constant during axial rotation, and in the other half, muscle activity was modulated by lengthening and shortening reactions, i.e., decreasing activity in lengthening muscles and increasing activity in shortening muscles, respectively. Axial resistance to rotation was reduced in subjects whose muscle activity was modulated. The results indicate that axial tone is modulated sensitively and dynamically, this control originates, at least in part, from tonic lengthening and shortening reactions, and a similar type of control appears to exist for postural tone in the proximal muscles of the arm.

Adult↗
PubMed2006

A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations.

BACKGROUND: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. OBJECTIVE: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. DESIGN: A double-blind, randomized, comparative clinical trial. SETTING: Forty-four sites in the United States and Canada. PATIENTS: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. INTERVENTION: Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. MAIN OUTCOME MEASURE: Change from baseline in total daily TTON as measured using home diaries. RESULTS: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. CONCLUSION: Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.

Aged↗
PubMed2006

Validity and utility of a LRRK2 G2019S mutation test for the diagnosis of Parkinson's disease.

The G2019S mutation in the LRRK2 gene, the most common known cause of Parkinson's disease (PD), will soon be widely available as a molecular clinical test for PD. The objective of this study was to assess performance characteristics of G2019S as a clinical test for PD in the setting of typical movement disorder clinics in the United States. Subjects included 1,518 sequentially recruited PD patients from seven movement disorder clinics in the United States, and 1,733 unaffected subjects. All 3,251 subjects were genotyped for the G2019S mutation using a TaqMan assay, and mutations were verified by direct sequencing. Test validity estimates were calculated using standard methods. A total of 20/1518 patients and 1/1733 controls carried the G2019S mutation. Specificity was 99.9% (95% CI, 99.6-100%), sensitivity was 1.3% (0.8-2.1%), and the positive likelihood ratio was 22.8. A positive family history of PD increased the positive likelihood ratio to 82.5. Information on gender, age at disease onset, or age at testing did not improve test performance. The gene test was highly accurate in classifying mutation carriers as PD, but it performed poorly in predicting the phenotype of non-mutation carriers. A G2019S molecular test for PD would be highly specific, technically simple, and inexpensive. Test interpretation is straightforward when used for diagnosis of symptomatic individuals, but is more complex for risk assessment and predictive testing in asymptomatic individuals. Test results can have psychological, social, and economical ramifications; thus, proper counseling is essential.

Adolescent↗
PubMed2006

Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders.

Biomarkers are needed to assist in the diagnosis and medical management of various neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy body (DLB). We have employed a multiplex quantitative proteomics method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), in conjunction with multidimensional chromatography, followed by tandem mass spectrometry (MS/MS), to simultaneously measure relative changes in the proteome of cerebrospinal fluid (CSF) obtained from patients with AD, PD, and DLB compared to healthy controls. The diagnosis of AD and DLB was confirmed by autopsy, whereas the diagnosis of PD was based on clinical criteria. The proteomic findings showed quantitative changes in AD, PD, and DLB as compared to controls; among more than 1,500 identified CSF proteins, 136, 72, and 101 of the proteins displayed quantitative changes unique to AD, PD, and DLB, respectively. Eight unique proteins were confirmed by Western blot analysis, and the sensitivity at 95% specificity was calculated for each marker alone and in combination. Several panels of unique makers were capable of distinguishing AD, PD and DLB patients from each other as well as from controls with high sensitivity at 95% specificity. Although these preliminary findings must be validated in a larger and different population of patients, they suggest that a roster of proteins may be generated and developed into specific biomarkers that could eventually assist in clinical diagnosis and monitoring disease progression of AD, PD and DLB.

Alzheimer Disease↗
PubMed2005

Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.

Age Factors↗
PubMed2004

Abnormal force patterns for multidirectional postural responses in patients with Parkinson's disease.

This study tests the hypothesis that the basal ganglia are involved in optimizing postural responses for changes in perturbation direction and stance width. We compared the patterns of horizontal and vertical ground reactive forces under each leg in response to eight directions of surface translation in Parkinson's disease (PD) subjects and age-matched control subjects standing with both narrow and wide stance. Although passive reactive forces were larger, active forces were weaker and in abnormal directions for subjects with PD. Unlike the control subjects, who corrected their postural equilibrium in response to lateral and diagonal-lateral perturbations primarily with their loaded limbs, the PD subjects used both legs more symmetrically to recover equilibrium. PD subjects also did not change the magnitude or direction of reactive forces when initial stance width changed. These results support the hypothesis that the basal ganglia are important for optimizing automatic postural response patterns for changes in perturbation direction and for initial stance conditions.

Aged↗
PubMed2003

SCA2 may present as levodopa-responsive parkinsonism.

Some kindreds with familial parkinsonism exhibit genetic anticipation, suggesting possible involvement of trinucleotide repeat expansion. Recent reports have shown trinucleotide repeat expansions in the spinocerebellar ataxia 2 (SCA2) gene in patients with levodopa-responsive parkinsonism. We tested 136 unrelated patients with familial parkinsonism for SCA2 mutations. Two probands had borderline mutations; the rest were normal. ( or=36 is pathogenic). The expanded allele segregated with neurological signs in one kindred. The absence of borderline mutations in the normal population, and the co-segregation of the expanded allele with neurological signs in one kindred suggest that SCA2 mutations may be responsible for a subset of familial parkinsonism.

Adult↗
PubMed2003

Levodopa improves physical fatigue in Parkinson's disease: a double-blind, placebo-controlled, crossover study.

We quantitatively investigated the effect of carbidopa/levodopa (25/100) on physical fatigue during finger tapping and force generation in a double-blind, placebo-controlled crossover study. Parkinson's disease (PD) subjects were randomly assigned to carbidopa/levodopa or placebo for Visit 1 or 2 and participated in the following two studies: (1) Finger tapping. Twenty-five PD patients used their index fingers to strike two keys 20 cm apart on a musical instrument digital interface (MIDI) keyboard. The slopes of the regression line of dwell time and movement time were used to assess the rate of fatigue development. (2) Force generation. Twelve PD patients contracted the wrist extensors maximally to obtain a baseline maximum voluntary contraction (BMVC) force. Then they repetitively contracted the wrist extensors at 50% of the BMVC for 7 seconds and rested for 3 seconds. An interval maximum voluntary contraction (IMVC) was measured every three repetitions. Fatigue was defined as an IMVC of less than 60% of the BMVC. The slope of the regression line of IMVC was used to assess the rate of force decline. These two studies were repeated 1 hour after carbidopa/levodopa (25/100) or placebo. Subjects filled out the Multidimensional Fatigue Inventory (MFI) at the beginning of the first visit. Results showed that the slope of dwell time decreased with levodopa but not with placebo (P = 0.004). The rate of force decline also decreased with levodopa but not with placebo (P = 0.01). The subscores in the dimension of physical fatigue in the MFI did not correlate with the rate changes in dwell time or the rate changes in force decline. We concluded that (1) levodopa improves physical fatigue in finger tapping and force generation, (2) physical fatigue in Parkinson's disease is at least partially related to dopamine deficiency, and (3) the MFI measures different aspects of physical fatigue compared with those measured by finger tapping and force generation.

Aged↗
PubMed2003

Levodopa normalizes exercise related cortico-motoneuron excitability abnormalities in Parkinson's disease.

OBJECTIVES: To measure exercise induced changes in cortico-motoneuron excitability in Parkinson's disease (PD) before and after levodopa. METHODS: Transcranial magnetic stimulation was delivered at 10% above resting motor threshold in 9 PD and 8 control subjects. Each subject performed repetitive isometric wrist extension at 50% of the baseline maximal voluntary contraction (MVC) for 30s with 3s rest between extensions until fatigued, defined as the inability to generate force at more than 25% of the baseline MVC. We recorded motor evoked potentials (MEPs) from the resting extensor carpi radialis muscle before (baseline), during, and after fatiguing exercise. Baseline electromyographic activity was closely monitored. We compared absolute MEP amplitudes between PD and controls, before and after levodopa, during baseline, exercise, and recovery periods. We correlated absolute MEP amplitudes with an objective measure of fatigability. RESULTS: PD subjects in the "off" state had increased absolute MEP amplitudes compared with controls. The effect was present in all 3 exercise periods. These differences disappeared after levodopa. Post-exercise facilitation was clear for PD subjects before and after levodopa, but post-exercise depression was not significant. Absolute MEP amplitude showed negative correlation with objective fatigability for PD subjects before levodopa. CONCLUSIONS: Levodopa normalized the increased cortico-motoneuron excitability in PD patients before, during, and after fatiguing exercise. SIGNIFICANCE: This study demonstrated the abnormal cortico-motoneuron excitability associated with motor fatigue in PD.

Aged↗
PubMed2002

Age at onset of Parkinson disease and apolipoprotein E genotypes.

Several lines of evidence suggest that the variable age at onset of Parkinson disease (PD) is likely influenced by genes. The apolipoprotein E (APOE) gene is associated with onset of Alzheimer disease, and possibly other neurodegenerative disorders. APOE has been investigated in relation to onset of PD, but results have been inconsistent. The aim of the present study was to determine if APOE genotypes are associated with onset age of PD, using a patient population large enough to assure sufficient power. We studied 521 unrelated Caucasian patients with idiopathic PD from movement disorder clinics in Oregon and Washington. Genotyping and statistical analyses were carried out using standard methods. Age at onset of PD was significantly earlier in patients with the varepsilon3varepsilon4/varepsilon4varepsilon4 genotype than in patients with the varepsilon3varepsilon3 genotype (56.1 +/- 10.9 vs. 59.6 +/- 11.0, P = 0.003). The significantly earlier onset of PD was not influenced by the possible effects of recruitment site, family history and gender. The effect of the varepsilon2varepsilon3 genotype on onset of PD differed between the two recruitment sites. There was a trend for earlier onset of PD in varepsilon2varepsilon3 patients than in varepsilon3varepsilon3 patients only in the Oregon sample. In conclusion, APOE is associated with age at onset of PD.

Age of Onset↗
PubMed2002

Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.

BACKGROUND: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. OBJECTIVE: To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD. DESIGN: Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. SETTING: Academic movement disorders clinics. PATIENTS: Eighty subjects with early PD who did not require treatment for their disability. INTERVENTIONS: Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d. MAIN OUTCOME MEASURE: The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. RESULTS: The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04). CONCLUSIONS: Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.

Administration, Oral↗
PubMed2002

Familial aggregation of Parkinson disease: a comparative study of early-onset and late-onset disease.

CONTEXT: It is unclear whether late-onset Parkinson disease (PD), which is the most typical and most common form of the disease, has a familial component. Evidence for familial aggregation is key to whether research should focus on gene discovery or search for environmental factors. OBJECTIVE: To investigate familial aggregation of early-onset and late-onset PD separately. METHODS: Using survival methods, age-specific risk of PD was calculated and compared for 525 parents and siblings of 117 patients with early-onset PD, 1642 parents and siblings of 343 patients with late-onset PD, and 522 parents and siblings of 114 controls. The index patients were ascertained from a movement disorder clinic. Spouses and friends served as controls. RESULTS: Compared with the relatives of controls, age-specific risk of PD was increased 7.76-fold in the relatives of patients with early-onset disease (P<.001) and 2.95-fold in the relatives of those with late-onset disease (P =.02). CONCLUSIONS: Late-onset PD has a significant familial component. The magnitude of recurrence risk to relatives suggests a genetic etiology, without ruling out the possibility of a coexisting environmental component.

Adult↗