Biomedical subjects

J P Hubble

Publications and source records attributed to J P Hubble.

At least 19 recordsLinked to original sources

PubMed2004

Apolipoprotein E controls the risk and age at onset of Parkinson disease.

BACKGROUND: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous studies seeking to establish such a link used case-control datasets and results have been inconsistent. OBJECTIVE: To investigate APOE's role in PD using family-based association analyses. METHODS: APOE functional polymorphisms were genotyped for 658 PD affected families, including 282 multiplex and 376 singleton families. The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of APOE on age at onset of PD. RESULTS: APOE was significantly associated with risk of developing PD. Stratified analysis revealed that APOE was most strongly associated with families with a positive PD family history (global p = 0.003). Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele decreases risk. We detected a positive association of APOE-3 (p = 0.019) and a negative association of APOE-4 (p = 0.015) with age at onset in PD. CONCLUSIONS: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.

Adult↗

PubMed2003

Vagus nerve stimulation for essential tremor: a pilot efficacy and safety trial.

OBJECTIVE: To assess the safety and efficacy of vagus nerve stimulation (VNS) for essential tremor (ET). METHODS: This was a pilot open-treatment trial at three centers, with masked videotape tremor assessments. Inclusion required a severity score of 3 or 4 on the Tremor Rating Scale (TRS) in one or both hands. At baseline, tremor was assessed with TRS and Unified Tremor Rating Assessment (UTRA), accelerometry, and a videotape protocol. The VNS device was implanted with leads placed around the left cervical vagus nerve. Stimulation was adjusted over 4 weeks before the repeat tremor assessments. Two raters masked to the study visit scored the videotapes. RESULTS: Nine subjects participated, with a mean age of 65 years and a mean age at onset of tremor of 24. Investigators rated hand tremor as mildly improved (TRS 2.3 +/- 0.7 during VNS vs 3.0 +/- 0.4 during baseline, p = 0.06). Accelerometry-measured total power improved 50.2 +/- 31.8% (p < 0.01). Videotape tremor scores were highly correlated between the masked raters and revealed no changes in tremor scores with treatment. VNS was well tolerated, with the most common adverse events being stimulation related. CONCLUSIONS: VNS was judged by investigators to mildly improve upper extremity tremor. This finding was not confirmed in videotape scoring by masked raters. VNS is not likely to have a clinically meaningful effect on ET.

Adolescent↗

PubMed2003

Genetic polymorphisms of the N-acetyltransferase genes and risk of Parkinson's disease.

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1 and NAT2. The authors examined NAT1 and NAT2 for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1 or NAT2 SNP or acetylation haplotype (N = 397 families, 1,580 individuals).

Aged↗

PubMed2001

Complete genomic screen in Parkinson disease: evidence for multiple genes.

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Adult↗

PubMed2001

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Age of Onset↗

PubMed2001

Genome-wide scan for Parkinson's disease: the GenePD Study.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Aged↗

PubMed2000

Test-retest reliability of an epidemiological instrument for Parkinson's disease.

Reliability testing was conducted on a survey instrument for a genetic epidemiological study of Parkinson's disease (PD). Information on demographics, medical history, places of residence, and occupations was collected. The instrument was administered to 11 pairs of siblings discordant for PD and then re-administered after 4 weeks. Twenty of 22 (91%) subjects completed and returned the retest questionnaire. Overall reliability of the instrument was acceptable (kappa = 0.88). This instrument could be used to elicit reliable information from similar profiled subjects in future investigations.

Aged↗

PubMed2000

Pre-clinical studies of pramipexole: clinical relevance.

This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal alpha2-adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have 'neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties.

Animals↗

PubMed2000

Time course of loss of clinical benefit following withdrawal of levodopa/carbidopa and bromocriptine in early Parkinson' s disease.

Putative neuroprotective agents for Parkinson's disease can be assessed in untreated patients using progression of clinical disability as an index of disease progression. To avoid the confound associated with symptomatic therapy, progression of the underlying disease can be assessed by evaluating the progression of clinical disability from an untreated baseline to a final visit following wash-out of symptomatic medication. In this type of analysis it is critical to use a washout of sufficient duration to ensure elimination of symptomatic effects. To assess the time course of resolution of symptomatic effects, we evaluated 31 patients at days 1, 8, and 15 following discontinuation of levodopa/carbidopa and bromocriptine. Mean total Unified Parkinson's Disease Rating Scale scores (+/- standard error) increased (worsened) by 7.4+/-1.5 from day 1 to day 15 (p <0.0001), 4.5+/-1.2 from day 1 to day 8 (p = 0.0009), and 2.9+/-1.0 from day 8 to day 15 (p = 0.01). We conclude that a wash-out of at least 2 weeks is required to eliminate the symptomatic effects of levodopa/carbidopa and bromocriptine in patients with early Parkinson's disease.

Aged↗

PubMed1999

Novel drugs for Parkinson's disease.

Treatment options in PD have expanded remarkably in the past several years. Three new drugs were approved for use in the United States just within the 9 months preceding the preparation of this article. Several new compounds are in the pipeline. Nevertheless, the unmet needs of PD patients are readily apparent in any busy clinical practice. These needs can be posed as three deceivingly simple questions: 1. When and how should L-dopa be started? Despite the fact that L-dopa remains the mainstay of PD therapy after 30 years' time, lacking is a fundamental understanding of proper usage and avoidance of long-term complications. 2. What can be done about cognitive decline and dementia in PD? The current answer is nothing. Efforts are just beginning to fill this large void in knowledge and provide adequate treatment for this disabling problem. 3. How can PD be prevented? This question cannot be answered because the cause of PD remains uncertain. The dearth of substantive information available on this topic is evidenced in this article. The bulk of text appears under the heading Symptomatic Treatments, whereas only a few speculative comments can be offered under the heading Preventive Treatments. The paramount need for expanded resources and dedicated efforts to identify the causes and devise preventions must be met if advances in the treatment of PD are to be made in the twenty-first century.

Antiparkinson Agents↗

PubMed1998

Double-blind controlled trial of gabapentin in essential tremor.

Gabapentin has been reported to be effective for essential tremor (ET) based on open-label trials. We studied gabapentin (1800 mg/day) and placebo in a double-blind crossover design in 20 ET patients. Eighteen patients completed the study and two patients dropped out as a result of adverse effects which resolved when the medication was discontinued. Tremor was assessed at baseline and after 2 weeks of gabapentin and placebo treatment. One patient was mildly improved and another was moderately improved with placebo. Similarly, one patient reported mild improvement and another patient had marked improvement with gabapentin. All the remaining patients either reported no change or were worse with both treatment arms. There was no significant difference for total tremor score, hand tremor score, handwriting scores, or pouring scores. Sickness Impact Profile scores were no different between placebo and gabapentin. Our results suggest that as an adjuvant therapy in ET, gabapentin has limited benefit.

Acetates↗

PubMed1998

Aging and the basal ganglia.

Age-related changes within the basal ganglia primarily affect the dopaminergic nigrostriatal pathway and related pigmented nuclei. These alterations resemble the pathologic changes of Parkinson's disease, but cell dropout is not as marked or uniquely selective in the aged brain. Histopathologic changes including interneuronal inclusion bodies are associated with aging, but the number and location of these suggest that this is a nonspecific phenomenon, not the harbinger of Parkinson's disease or other specific neuropathology. It appears that aging and Parkinson's disease result in similar brain cell degenerative processes, but the causes and specific triggering mechanisms for these changes are likely to be quite distinct.

Aged↗

PubMed1998

Gene-toxin interaction as a putative risk factor for Parkinson's disease with dementia.

We had previously examined environmental, sociodemographic and clinical variables as predictors for Parkinson's disease with dementia (PD + D) and found that lower educational attainment, greater motor impairment and advanced age at disease onset were more common in PD + D than in subjects with Parkinson's disease without dementia (PD-D). We now explore the hypothesis that genetic traits coupled with nongenetic factors may raise the risk of development of PD + D. The study cohort of 43 PD + D and 51 PD-D subjects was analyzed examining environmental, sociodemographic and clinical variables along with 3 candidate gene markers: poor debrisoquine metabolizer allele (CYP 2D6 29B+), monoamine oxidase B allele 1, and apolipoprotein E epsilon 4 allele. Variables were initially entered into a multivariate model singly. Again lower education, age at onset and motor impairment appeared as predictors of PD + D while other variables (including allele status) failed to emerge as significant individual risk factors for dementia. We then examined environmental and genetic variables analyzed in tandem to look for potential variable interactions. Subjects who had pesticide exposure and at least 1 copy of the CYP 2D6 29B+ allele had 83% predicted probability of PD + D (stepwise logistic regression model: p = 0.0491). This case-control study provides preliminary evidence that a gene-toxin interaction may play an etiological role in PD + D. Further assessment of the role of these putative risk factors in incident dementia in PD is indicated.

Aged↗

PubMed1997

Effects of thalamic deep brain stimulation based on tremor type and diagnosis.

It has been suggested that deep brain stimulation (DBS) is less effective in alleviating proximal than distal postural arm tremor reduction is said to be less in essential tremor (ET) than in Parkinson's disease (PD). We analyzed blinded rater's tremor scores and subjects' disability ratings at 3-month follow-up to examine the effects of DBS based on tremor type (rest, kinetic, distal postural, proximal postural) and diagnosis (ET, PD). An independent examiner provided tremor scores using randomized videotaped footage of 19 ET and 10 PD subjects at baseline and at follow-up with DBS "on." Subjects provided self-ratings of disability at baseline and at follow-up. Comparisons of baseline and follow-up tremor scores and disability ratings were made using the Mann-Whitney U and Wilcoxon rank sum W test; correlation analyses were performed using Spearman rank order correlation test. There were significant and essentially equal improvements in tremor scores of test, kinetic, distal postural, and proximal postural tremor at follow-up. Only one subject had no improvement in tremor. Tremor improved significantly and to the same extent in ET and PD subjects in each position except "at rest," which was most improved in PD (p = 0.0003). ET and PD subjects did not differ in the extent of disability improvement. Improved disability correlated only with improved postural tremor scores; proximal postural and distal postural (r = 0.41, p = 0.03; r = 0.47, p = 0.01). DBS is effective in alleviating tremor and disability in both ET and PD. Resting, kinetic, distal postural, and proximal postural tremor can be reduced to an equal degree. However, DBS produces the greatest improvement in disability in association with improved postural tremor in both ET and PD.

Adolescent↗

PubMed1997

Clinical expression of essential tremor: effects of gender and age.

Essential tremor (ET) is considered to be a monosymptomatic disorder consisting primarily of postural hand tremor. Nevertheless, clinical expression can vary based on the body region affected by tremor and the coexistence of other neurologic signs, such as tandem gait disturbance. We conducted a two-part study to test the hypothesis that variability in ET clinical expression is influenced by gender and age. In part 1, we examined a large ET clinical database (n = 450), comparing ratings of postural hand and head/voice tremor based on gender. Head/voice tremor was significantly more frequent and more severe among female ET patients; men had more severe postural hand tremor. In part 2, ET patients (n = 40) had significantly more missteps when tandem walking in comparison to age-matched controls. Poor tandem walk in ET cases was associated with more advanced age, but not gender, disease duration, or ratings of postural hand or head/voice tremor. We conclude that gender influences the body region most affected by ET possibly through the effects of the sex chromosomes or hormones. Ataxia (tandem gait difficulty) is common in ET and may be an accentuation of cerebellar dysfunction due to aging.

Age Distribution↗

PubMed1996

Early morning akinesia in Parkinson's disease: effect of standard carbidopa/levodopa and sustained-release carbidopa/levodopa.

We examined the effects of supplemental standard carbidopa/levodopa (Std-L) on early morning akinesia in patients with Parkinson's disease (PD) who were being treated with sustained-release carbidopa/levodopa (L-CR). We compared plasma dopa levels and clinical response in 15 PD patients after a dose of Std-L and L-CR (2 hours later) and after a dose of L-CR and placebo in a double-blind, placebo-controlled, crossover study. Plasma dopa levels, total motor score, walking time, and finger tapping time were assessed every 15 minutes for the first 2 hours and then every 30 minutes for the next 3 hours. The time of onset in clinical benefit was significantly earlier with Std-L (47 minutes, range 15 to 75 minutes) as the first dose as compared with L-CR (58 minutes, range 30 to 105 minutes). Similarly, there was a significant difference in the peak plasma dopa levels (Cmax) and the time to reach peak plasma dopa levels (Tmax) with administration of Std-L (Tmax 36 minutes; Cmax 1,501 micrograms/ml) as compared with L-CR (Tmax 111 minutes, Cmax 1,260 micrograms/ml). There was no significant difference in dyskinesias between the two treatment arms. An initial morning dose of Std-L alleviates the problem of delayed-onset clinical response that commonly occurs with L-CR.

Aged↗

PubMed1996

Deep brain stimulation for essential tremor.

We examined the effects and safety of deep brain stimulation (DBS) as a treatment for essential tremor (ET). Ten ET patients with disabling medication-refractory tremor underwent stereotactic implantation of a DBS lead in the left Vim thalamic nucleus and completed a 6-month follow-up. The Clinical Tremor Rating Scale and disability assessments were performed at baseline, 1-, 3-, and 6-month follow-up. There were significant improvements in dressing, drinking, eating, bathing, and handwriting as reported by the subjects. Tremor severity, writing, pouring, and spiral and line drawing were significantly improved as rated by the examiner. Improvements persisted through the 6-month follow-up period. Although global disability significantly lessened in the group as a whole, one subject with hand-finger tremor accentuated by writing had no change in disability status. In this 6-month open-label study, DBS was effective and safe in reducing tremor and functional disability in ET.

Aged↗

PubMed1996

Normal distribution of apolipoprotein E alleles in progressive supranuclear palsy.

Apolipoprotein E (Apo E) genotype is a genetic risk factor influencing the development of Alzheimer's disease (AD). Progressive supranuclear palsy (PSP), like AD, is a dementing illness with neurofibrillary tangles. We determined the frequencies of Apo E alleles in 52 PSP patients and 52 age- and gender-matched controls. The distribution of Apo E allele frequencies and genotypes showed no difference between PSP and controls. Apo E allele status does not influence the development of PSP.

Aged↗