Metabolic abnormality in the cerebellum in patients with essential tremor: a proton magnetic resonance spectroscopic imaging study

Louis, Elan D.; Shungu, Dikoma C.; Chan, Stephen; Mao, Xiangling; Jurewicz, Eva C.; Watner, Dryden

doi:10.1016/s0304-3940(02)00966-7

Cited by 169 publications

(133 citation statements)

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“…Linkage in the presence of association was positively demonstrated by the use of the Transmission Disequilibrium Test (TDT) in families with both parents available and at least one heterozygous parent (families 2,9,12,14,19,21) or the Sib-TDT (S-TDT) in other informative sibships (families 7,8,15,17,18,25,26,28,30) (18). TDT 2 value was 7.364 (P ϭ 0.0067), and S-TDT zЈ score was 4.306 (P Ͻ 0.00001).…”

Section: Resultsmentioning

confidence: 99%

“…Largest DRD3 densities occur in the basal ganglia, but cerebellum also expresses DRD3 at a lower density (15). In the rat cerebellum, DRD3 is present in Purkinje cells (16), and cerebellum has been implicated in the pathogenesis of ET (17). The DRD3 gene is located on chromosome 3q13.3 between markers D3S1278 and D3S1267, which gave highest logarithm of odds (LOD) scores at the ETM1 locus (6).…”

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confidence: 99%

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A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Jeanneteau

Funalot

Jankovic

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

175

120

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Familial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D 3 receptor gene (DRD3), localized on 3q13.3, is associated and cosegregates with familial ET in 23 out of 30 French families. Sequencing revealed no other nonsynonymous variants in the DRD3-coding sequence and in the first 871 bp of the 5 flanking region. Moreover, Gly-9 homozygous patients presented with more severe and͞or earlier onset forms of the disease than heterozygotes. A replication study comparing 276 patients with ET and 184 normal controls confirmed the association of the Gly-9 variant with risk and age-at-onset of ET. In human embryonic kidney (HEK) 293-transfected cells, the Gly-9 variant did not differ from the Ser-9 variant with respect to glycosylation and to anterograde and retrograde trafficking, but dopamine had an affinity that was four to five times higher. With the Gly-9 variant, the dopamine-mediated cAMP response was increased, and the mitogen-associated protein kinase (MAPK) signal was prolonged, as compared with the Ser-9 variant. The gain-of-function produced by the Gly-9 variant may explain why drugs active against tremor in Parkinson's disease (PD) are usually not effective in the treatment of ET and suggests that DRD3 partial agonists or antagonists should be considered as novel therapeutic options for patients with ET.dopamine receptor ͉ gain-of-function ͉ gene dosage ͉ movement disorder ͉ polymorphism

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Jeanneteau

Funalot

Jankovic

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

175

120

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“…Also, underlying brain changes are similar. Changes, including neuronal loss, have been shown to occur in the ET cerebellum (Axelrad JE, 2007 In Press; Louis et al, 2002a;Louis et al, 2004;Louis et al, 2006a;Louis et al, 2006b;Pagan et al, 2003;Shill H, 2007). Similarly, β-carboline alkaloids produce toxic damage with significant loss of cerebellar Purkinje cells (Du et al, 1997;Milner et al, 1995;O'Hearn and Molliver, 1997;Robertson, 1980;Sinton et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Louis

2008

NeuroToxicology

127

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Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3 ± 15.5 vs. 65.5 ± 14.2 years, p = 0.94). Mean log blood harmane concentration was ∼50% higher in cases than controls (0.50 ± 0.54 g -10 /ml vs. 0.35 ± 0.62 g -10 /ml, p = 0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR adjusted 1.56, 95% CI 1.01 -2.42, p = 0.04), and odds of ET was 1.90 (95% CI 1.07 -3.39, p = 0.029) in the highest vs. lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53 ± 0.57 g -10 /ml), intermediate in cases with sporadic ET (0.43 ± 0.45 g -10 /ml) and lowest in controls (0.35 ± 0.62 g -10 /ml) (test for trend, p = 0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

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“…Moreover, an autopsy study of humans with chronic organic lead exposure revealed severe destruction of cerebellar Purkinje cells (Valpey et al 1978). Multiple lines of evidence suggest that the cerebellum is involved in ET, including imaging studies [positron emission tomography (Wills et al 1994), functional magnetic resonance imaging (Bucher et al 1997), and magnetic resonance spectroscopic imaging (Louis et al 2002a)], clinical studies and electrophysiologic studies Gironell et al 2000;Stolze et al 2000), and case reports (Dupuis et al 1989). Unfortunately, there have been few postmortem studies of ET; several studies revealed loss of cerebellar Purkinje cells, but without control brains for comparison, these results are difficult to interpret (Louis 2001).…”

Section: Discussionmentioning

confidence: 99%

“…As such, ET is one of the most common neurologic diseases. The pathogenesis of this progressive ) and often disabling (Louis et al 2001a) disease is poorly understood, although there is evidence of cerebellar involvement (Bucher et al 1997;Louis et al 2002a;Wills et al 1994). There is no cure for ET, and there has been no attempt to favorably modulate or halt its progression with neuroprotective therapy.…”

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confidence: 99%

Association between essential tremor and blood lead concentration.

Louis

Jurewicz

Applegate

et al. 2003

Environ Health Perspect

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Lead is a ubiquitous toxicant that causes tremor and cerebellar damage. Essential tremor (ET) is a highly prevalent neurologic disease associated with cerebellar involvement. Although environmental toxicants may play a role in ET etiology and their identification is a critical step in disease prevention, these toxicants have received little attention. Our objective was to test the hypothesis that ET is associated with lead exposure. Therefore, blood lead (BPb) concentrations were measured and a lifetime occupational history was assessed in ET patients and in controls. We frequency matched 100 ET patients and 143 controls on age, sex, and ethnicity. BPb concentrations were analyzed using graphite furnace atomic absorption spectrophotometry. A lifetime occupational history was reviewed by an industrial hygienist. BPb concentrations were higher in ET patients than in controls (mean +/- SD, 3.3 +/- 2.4 and 2.6 +/- 1.6 microg/dL, respectively; median, 2.7 and 2.3 microg/dL; p = 0.038). In a logistic regression model, BPb concentration was associated with diagnosis [control vs. ET patient, odds ratio (OR) per unit increase = 1.21; 95% confidence interval (CI), 1.05-1.39; p = 0.007]. BPb concentration was associated with diagnosis (OR per unit increase = 1.19; 95% CI, 1.03-1.37; p = 0.02) after adjusting for potential confounders. Prevalence of lifetime occupational lead exposure was similar in ET patients and controls. We report an association between BPb concentration and ET. Determining whether this association is due to increased exposure to lead or a difference in lead kinetics in ET patients requires further investigation.

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Metabolic abnormality in the cerebellum in patients with essential tremor: a proton magnetic resonance spectroscopic imaging study

Cited by 169 publications

References 16 publications

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Association between essential tremor and blood lead concentration.

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Metabolic abnormality in the cerebellum in patients with essential tremor: a proton magnetic resonance spectroscopic imaging study

Cited by 169 publications

References 16 publications

A functional variant of the dopamine D 3 receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D 3 receptor is associated with risk and age-at-onset of essential tremor

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Association between essential tremor and blood lead concentration.

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A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor