GABAergic dysfunction in essential tremor: an 11C-flumazenil PET study.
ABSTRACT Essential tremor is the most common movement disorder, but the underlying pathophysiology is not well understood. A primary overactivity of cerebellothalamic output pathways is the most conspicuous finding, as indicated by animal and human studies. It has been argued that this overactivity may be due to impaired central inhibition, and converging evidence points toward a potential role of gamma-aminobutyric acid (GABA) dysfunction in tremor generation.
Using (11)C-flumazenil and PET, we calculated the distribution volume, an index of availability of benzodiazepine receptor sites of the GABA(A) complex, in a group of 8 patients with bilateral essential tremor, as compared with 11 healthy controls.
Significant increases in binding of (11)C-flumazenil at the benzodiazepine receptor site of the GABA(A) receptor in the cerebellum, the ventrolateral thalamus, and the lateral premotor cortex were identified in the essential tremor group.
Essential tremor is associated with reduced GABAergic function and increased availability of benzodiazepine receptor sites in brain regions implicated specifically in tremor genesis. This finding is thought to reflect overactivity of cerebellothalamic circuits and, hence, lends support to the "GABA hypothesis" of essential tremor.
- SourceAvailable from: Juan D Gispert
Dataset: GABA-PET-Tremor published paper
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ABSTRACT: Essential tremor is the most common movement disorder in adults, but its exact etiology and pathophysiology are still not fully understood. There is some consensus, however, about the involvement of the cerebellum and accumulating evidence points towards a dysfunction of the gabaergic system. We hypothesize that the serotonin neurotransmission system may also play a role as it does in tremor in Parkinson disease. This study aimed to investigate the association between the severity of tremor symptoms and the gabaergic and serotoninergic neurotransmission systems in essential tremor. We measured the tremor clinical rating scale score and acquired DASB and Flumazenil PET scans in 10 patients who presented with essential tremor at different stages of clinical severity. Statistically significant correlations were sought between the scale scores and parametric binding potential images. The correlation analysis of cerebellar Flumazenil uptake and tremor clinical rating scale scores reached statistical significance (R2 = 0.423, p = 0.041), whereas no association was detected in the DASB scans. The severity of tremor correlated with the abnormalities found in GABA receptor binding, suggesting a primary gabaergic deficiency or a functional abnormality at the level of GABA(A) receptor subtypes. These results may assist in the rational development of new pharmacological treatments for essential tremor.Parkinsonism & Related Disorders 05/2012; 18(7):876-80. DOI:10.1016/j.parkreldis.2012.04.024 · 4.13 Impact Factor
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ABSTRACT: The development of new treatments for essential tremor, the most frequent movement disorder, is limited by a poor understanding of its pathophysiology and the relative paucity of clinicopathological studies. Here, we report a post-mortem decrease in GABA(A) (35% reduction) and GABA(B) (22-31% reduction) receptors in the dentate nucleus of the cerebellum from individuals with essential tremor, compared with controls or individuals with Parkinson's disease, as assessed by receptor-binding autoradiography. Concentrations of GABA(B) receptors in the dentate nucleus were inversely correlated with the duration of essential tremor symptoms (r(2) = 0.44, P < 0.05), suggesting that the loss of GABA(B) receptors follows the progression of the disease. In situ hybridization experiments also revealed a diminution of GABA(B(1a+b)) receptor messenger RNA in essential tremor (↓27%). In contrast, no significant changes of GABA(A) and GABA(B) receptors (protein and messenger RNA), GluN2B receptors, cytochrome oxidase-1 or GABA concentrations were detected in molecular or granular layers of the cerebellar cortex. It is proposed that a decrease in GABA receptors in the dentate nucleus results in disinhibition of cerebellar pacemaker output activity, propagating along the cerebello-thalamo-cortical pathways to generate tremors. Correction of such defective cerebellar GABAergic drive could have a therapeutic effect in essential tremor.Brain 11/2011; 135(Pt 1):105-16. DOI:10.1093/brain/awr301 · 10.23 Impact Factor