Biomedical subjects

J S Perlmutter

Publications and source records attributed to J S Perlmutter.

At least 19 recordsLinked to original sources

PubMed2006

Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Disease Susceptibility↗

PubMed2006

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced acute transient dystonia in monkeys associated with low striatal dopamine.

Unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in baboons produces transient contralateral dystonia lasting 2-3 weeks followed by chronic hemiparkinsonism. We now extend this model to Macaca nemestrina and Macaca fascicularis. MPTP was infused unilaterally into the internal carotid artery of two M. nemestrina and 11 M. fascicularis. Effects were assessed with blinded clinical ratings of dystonia and Parkinsonism; [18F]-6-fluoro-DOPA (FDOPA) positron emission tomography; and postmortem measurements of striatal dopamine content. In two M. nemestrina, MPTP 0.4 mg/kg intracarotid produced acute dystonia within 24 h then chronic Parkinsonism starting 3 weeks later. In three M. fascicularis, MPTP 0.4 mg/kg produced acute dystonia within 3-8 h but two others died from large hemispheric infarcts within 1 day. A much lower dose, MPTP 0.1 mg/kg produced no clinical manifestations (n=1), whereas MPTP 0.25 mg/kg produced consistent transient dystonia and ipsiversive turning within 1-3 days followed by chronic Parkinsonism at 3 weeks (n=5). One week after MPTP, striatal FDOPA uptake decreased an average of 69% in M. nemestrina (0.4 mg/kg); and decreased an average of 70+/-21% in M. fascicularis (0.25 mg/kg). Striatal dopamine was reduced an average 66% in the first day (n=2) during acute dystonia, 98% at 3 days (n=1) and 99%+/-2.3% at 2-4 months (n=5). M. nemestrina had a clinical response similar to baboons whereas M. fascicularis seemed more sensitive to MPTP. These findings extend the model of MPTP-induced transient dystonia followed by chronic hemiparkinsonism to M. nemestrina and M. fascicularis and demonstrate that the early dystonic phase is accompanied by striatal dopamine deficiency.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2005

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Age of Onset↗

PubMed2005

Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders.

OBJECTIVE: To estimate the prevalence of parkinsonism in welders in Alabama and to compare this prevalence with that in a general population sample. METHODS: The authors screened 1,423 welders from Alabama who were referred for medical-legal evaluation for Parkinson disease (PD). Standardized videotaped assessments using the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) were obtained. Patients provided information regarding exposure to welding fumes and job titles. Job titles were matched with Department of Labor Standard Occupational Codes (SOCs). Diagnoses were assigned based on quantitative criteria for the diagnosis of PD using two thresholds for diagnosis. With use of the number of active welders in this screening with parkinsonism as the numerator and the age-adjusted number of welders in each SOC as the denominator, the prevalence of parkinsonism in Alabama welders was estimated using conservative assumptions and compared with general population data from Copiah County, MS. RESULTS: With use of conservative and liberal case definitions of parkinsonism, the estimated prevalence of parkinsonism among active male welders age 40 to 69 statewide was 977 to 1,336 cases/100,000 population. The prevalence of parkinsonism was higher among welders vs age-standardized data for the general population (prevalence ratio = 10.19, 95% CI 4.43 to 23.43). CONCLUSION: The estimated prevalence of parkinsonism was higher within a sample of male Alabama welders vs the general population of male residents of Copiah County, MS.

Adult↗

PubMed2005

Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

Aged↗

PubMed2004

Stimulation of STN impairs aspects of cognitive control in PD.

OBJECTIVE: To test the hypothesis that subthalamic nucleus (STN) stimulation in Parkinson disease (PD) patients affects working memory and response inhibition performance, particularly under conditions of high demand on cognitive control. METHODS: To test this hypothesis, spatial working memory (spatial delayed response [SDR]) and response inhibition (Go-No-Go [GNG]) tasks requiring varying levels of cognitive control were administered to patients with PD with previously implanted bilateral STN stimulators (n = 24). Patients did not take PD medications overnight. Data were collected while bilateral stimulators were on and off, counterbalancing the order across subjects. RESULTS: On the SDR task, STN stimulation decreased patients' working memory performance under a high but not low memory load condition (effect of stimulator condition on high load only and condition x load interaction, p < 0.05). On the GNG task, STN stimulation reduced discriminability on a high but not medium inhibition condition (effect of stimulator condition on high inhibition level only, p = 0.05; condition x inhibition level interaction, p = 0.07). CONCLUSION: STN stimulation reduces working memory and response inhibition performance under conditions of greater challenge to cognitive control despite significant improvement of motor function.

Cognition Disorders↗

PubMed2004

Association of variations in monoamine oxidases A and B with Parkinson's disease subgroups.

Idiopathic Parkinson's disease (PD) is an age dependent, neurodegenerative disorder and is predominantly a sporadic disease. A minority of patients has a positive family history for PD and the majority of those families exhibit a complex mode of inheritance. The monoamine oxidases A and B (MAO-A and -B) genes, which are involved in serotonin and dopamine metabolism, are possible candidate genes for susceptibility to PD. Previous association studies of MAO-A and -B in PD have been inconclusive. To determine the role of MAO-A and -B in the development of PD, we screened a sample of 96 patients with familial PD, 164 with sporadic PD, and 180 matched normal controls with dinucleotide repeat markers in these genes. MAO-A and -B gene polymorphisms were strongly associated with total PD (p < 0.00001), familial PD (p < 0.00001), and sporadic PD (p < 0.00001). There were no significant differences between familial or sporadic PD with age of onset younger than 50 years compared to those with age of onset older than 51 years for both MAO-A and -B genes. There was no linkage disequilibrium between these genes in male PD and control groups. The frequency of common haplotypes from MAO-A and -B was different in PD and control group (p = 0.02). Our data indicate that MAO-A and -B may play a role in susceptibility to PD in our sample.

Age of Onset↗

PubMed2004

Pathophysiology of parkinsonism due to hydrocephalus.

We report a patient with hydrocephalus who developed levodopa responsive parkinsonism and severe bradyphrenia associated with shunt malfunction and revision. Magnetic resonance imaging revealed periaqueductal edema involving medial substantia nigra. [18F]dopa positron emission tomography demonstrated reduced uptake in the caudate and putamen with relative sparing of the posterior putamen. Hydrocephalus associated with shunt malfunction can cause a distinct parkinsonian syndrome with greater dysfunction of projections from the medial substantia nigra to anterior striatum than in idiopathic Parkinson's disease.

Adult↗

PubMed2003

A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study.

OBJECTIVE: To identify a haplotype influencing onset age for Parkinson's disease (PD) in the PARK3 region on chromosome 2p13. METHODS: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. RESULTS: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP-rs2421095, rs1876487, rs1561244-revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005). CONCLUSIONS: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Adolescent↗

PubMed2003

Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD.

OBJECTIVE: To assess whether subthalamic nuclei (STN) stimulation's primary mechanism of action is to drive or inhibit output neurons. METHODS: Cerebral blood flow responses to STN stimulation were measured using PET in 13 patients with Parkinson disease. Patients were scanned with stimulators off and on (six scans each condition). Clinical ratings, EMG, and videotaping of movements were obtained at each scan. Scans with observable tremor or movement were eliminated from analysis. Brain regions where STN stimulation significantly altered blood flow were identified. RESULTS: STN stimulation increased blood flow in midbrain (including STN), globus pallidus, and thalamus, primarily on the left side, but reduced blood flow bilaterally in frontal, parietal, and temporal cortex. CONCLUSIONS: These data suggest that STN stimulation increases firing of STN output neurons, which increases inhibition of thalamocortical projections, ultimately decreasing blood flow in cortical targets. STN stimulation appears to drive, rather than inhibit, STN output neurons.

Action Potentials↗

PubMed2003

Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease.

OBJECTIVES: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa. METHODS: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. RESULTS: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. CONCLUSIONS: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.

Administration, Oral↗

PubMed2002

Ptosis as a remote effect of therapeutic botulinum toxin B injection.

The authors report a patient with cervical dystonia, previously treated with botulinum toxin A (BTX-A), who developed bilateral ptosis and difficulty with accommodation only after botulinum toxin B (BTX-B). High-frequency repetitive nerve stimulation of the abductor digiti minimi demonstrated a 34% increment in compound muscle action potential. No increment in 20 people injected with BTX-A and no cases of ptosis in a chart review of 1,606 BTX-A injections for cervical dystonia were found. The authors conclude that systemic spread of BTX-B can cause symptomatic involvement of autonomic neurons.

Adult↗

PubMed2002

Blood flow responses to deep brain stimulation of thalamus.

BACKGROUND AND OBJECTIVE: Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM) provides remarkable relief of tremor in the limbs contralateral to the side of the brain stimulated. The benefits have been sufficiently dramatic that this is now an accepted clinical treatment of essential as well as other forms of tremor. Despite this clinical benefit, the mechanism of action of DBS remains unknown. In this investigation, we sought to determine the effects of VIM DBS on neuronal function. METHODS: The authors used PET measurements of qualitative regional cerebral blood flow in patients with essential tremor to determine the effects of DBS in the left VIM. Each subject had four to six scans with the arms at rest and DBS turned either on or off during alternate scans. Continuous physiologic monitoring revealed no tremor during any of the scans. The PET images from each subject were aligned, averaged, and coregistered to a standard image oriented in stereotactic space. RESULTS: The authors used subtraction image analysis with statistical parametric mapping methods and a restricted volume search to identify a significantly increased flow response at the site of stimulation in thalamus. An exploratory analysis revealed increased flow in ipsilateral supplementary motor area, a region that receives afferents from VIM. CONCLUSIONS: The increased blood flow at terminal fields of thalamocortical projections suggests that DBS stimulates and does not inactivate projection neurons in VIM thalamus.

Aged↗

PubMed2002

A multi-incident, Old-Order Amish family with PD.

BACKGROUND: PD is largely a sporadic condition of unknown etiology, but specific inherited mutations are a cause of PD. OBJECTIVE: To describe a large, multi-incident Amish pedigree with PD. METHODS: Case ascertainment, calculation of population prevalence, and calculation of kinship coefficients (a measure of relatedness between two individuals) for affecteds and subjects in a large kindred with PD were conducted. Sequencing of genes with known mutations sufficient to cause PD and marker-by-marker haplotype analysis in chromosomal regions flanking previously described genes with known mutations were performed. RESULTS: The authors have examined 113 members of this pedigree and classified 67 as normal (no evidence of PD), 17 as clinically definite PD, 6 as clinically probable PD, and 23 as clinically possible PD. The mean age at onset of the clinically definite subjects was 56.7 years. The phenotype in this family is typical of idiopathic PD, including rest tremor, rigidity, bradykinesia, postural instability, and response to levodopa. In addition, dementia occurred in six of the clinically definite subjects, and many subjects experienced levodopa-related motor complications including wearing off and dopa-induced dyskinesias. In the index Amish community, a minimum prevalence of PD in the population 40 years and older of 552/100,000 was calculated. The mean kinship coefficient in the subjects with PD and those with PD by history (0.036) was higher (p = 0.007) than in a group of age-matched normal Amish control subjects (0.016), providing evidence that PD is inherited in this family. Sequence analysis did not detect any mutations in known PD genes. No single haplotype cosegregates with the disease in any of the chromosomal regions previously found to be linked to PD, and no marker in these regions exhibits increased homozygosity among definite PD cases. CONCLUSIONS: PD in this community is more common than in the general population, and this increased prevalence may be due in part to a novel gene(s).

Adult↗

PubMed2002

Thalamic stimulation reduces essential tremor but not the delayed antagonist muscle timing.

BACKGROUND: Electrical stimulation of the thalamus dramatically reduces essential tremor (ET). It has been hypothesized that the cerebellum and inferior olive are involved in the generation of ET, and thalamic stimulation is presumed to dampen ET through interactions with cerebellar output to the thalamus. Evidence suggests that abnormal timing of agonist and antagonist muscle responses contribute to cerebellar tremor (CbT); however, this relationship has not been investigated for ET. The mechanisms of the tremor and improvement are unknown. OBJECTIVE: To measure the effect of ventral intermediate thalamic stimulation in controlling the ET response to sudden stretch of an agonist muscle and to determine whether, in ET, the timing relationships between the initial agonist and antagonist electromyography (EMG) responses show abnormalities similar to those seen in CbT. METHODS: The authors studied ET subjects (with implanted thalamic stimulators turned off and on) and normal controls as they responded to mechanical torque pulses given at the wrist joint. The wrist joint angle, wrist agonist, and antagonist EMG were recorded. RESULTS: Like CbT, patients with ET showed delayed onsets of antagonist EMG and excessive rebound. Thalamic stimulation reduced the tremor but did not alter the antagonist delay or the rebound. CONCLUSIONS: In ET, antagonist muscle responses to a torque pulse are similar to that in CbT. However, benefit from thalamic stimulation did not alter these EMG responses; therefore, suppression of tremor must be caused by mechanisms other than the re-establishment of normal agonist-antagonist timing.

Aged↗

PubMed2001

Welding-related parkinsonism: clinical features, treatment, and pathophysiology.

OBJECTIVE: To determine whether welding-related parkinsonism differs from idiopathic PD. BACKGROUND: Welding is considered a cause of parkinsonism, but little information is available about the clinical features exhibited by patients or whether this is a distinct disorder. METHODS: The authors performed a case-control study that compared the clinical features of 15 career welders, who were ascertained through an academic movement disorders center and compared to two control groups with idiopathic PD. One control group was ascertained sequentially to compare the frequency of clinical features, and the second control group was sex- and age-matched to compare the frequency of motor fluctuations. RESULTS: Welders were exposed to a mean of 47,144 welding hours. Welders had a younger age at onset (46 years) of PD compared with sequentially ascertained controls (63 years; p < 0.0001). There was no difference in frequency of tremor, bradykinesia, rigidity, asymmetric onset, postural instability, family history, clinical depression, dementia, or drug-induced psychosis between the welders and the two control groups. All treated welders responded to levodopa. Motor fluctuations and dyskinesias occurred at a similar frequency in welders and the two control groups. PET with 6-[18F]fluorodopa obtained in two of the welders showed findings typical of idiopathic PD, with greatest loss in posterior putamen. CONCLUSIONS: Parkinsonism in welders is distinguished clinically only by age at onset, suggesting welding may be a risk factor for PD. These preliminary data cannot exclude a genetic contribution to susceptibility in these exposed individuals.

Adult↗

PubMed2001

Late-onset neurodegeneration with brain iron accumulation type 1: expanding the clinical spectrum.

We report on two patients with pathologically proven neurodegeneration with brain iron accumulation type 1 (NBIA-1) with late onset and atypical presentations. One patient experienced gradual onset of shuffling gait, rigidity, bradykinesia, and increasing postural instability at age 85 years. He died a few weeks after developing acute hemiballismus at age 90 years. Histopathology revealed marked neuronal loss in the internal segment of the globus pallidum, astrocytosis, axonal spheroids, and extensive iron deposition consistent with NBIA-1. No additional lesions were found to explain the hemiballismus. The second patient experienced fulminant dementia evolving to total disability and death within 2 months. Autopsy showed typical NBIA-1 pathology. We conclude that NBIA-1 pathology can develop at any age, and that the phenotype should be expanded to include late-onset parkinsonism. The relationship to hemiballismus and adult-onset dementia is less clear.

Age of Onset↗

PubMed2001

Template images for nonhuman primate neuroimaging: 1. Baboon.

Coregistration of functional brain images across many subjects offers several experimental advantages and is widely used for studies in humans. Voxel-based coregistration methods require a high-quality 3-D template image, preferably one that corresponds to a published atlas. Template images are available for human, but we could not find an appropriate template for neuroimaging studies in baboon. Here we describe the formation of a T1-weighted structural MR template image and a PET blood flow template, derived from 9 and 7 baboons, respectively. Custom software aligns individual MR images to the MRI template; human supervision is needed only to initially estimate any gross rotational misalignment. In these aligned individual images, internal subcortical fiducial points correspond closely to a photomicrographic baboon atlas with an average error of 1.53 mm. Cortical test points showed a mean error of 1.99 mm compared to the mean location for each point. Alignment of individual PET blood flow images directly to the PET template was compared to a two-step alignment process via each subject's MR image. The two transformations were identical within 0.41 mm, 0.54 degrees, and 1.0% (translation, rotation, and linear stretch; mean). These quantities provide a check on the validity of the alignment software as well as of the template images. The baboon structural MR and blood flow PET templates are available on the Internet (purl.org/net/kbmd/b2k) and can be used as targets for any image registration software.

Animals↗