Félix Javier Jiménez-Jiménez

Drug-Induced Movement Disorders

SummaryParkinsonism, tremor, chorea-ballismus, dystonia, tardive dyskinesia, myoclonus, tics and akathisia can be induced by many drugs. The drugs that are most frequently implicated in movement disorders are antipsychotics, calcium antagonists, orthopramides and substituted benzamides (e.g. metoclopramide, sulpiride, clebopride, domperidone), CNS stimulants, antidepressants, anticonvulsants, antiparkinsonian drugs and lithium. It is possible for a single drug to induce 2 or more types of movement disorders in the same patient. Movement disorders are not always reversible after drug withdrawal.

Acoustic voice analysis in patients with Parkinson's disease treated with dopaminergic drugs

To quantify several acoustic features of the voice in patients with Parkinsons disease (PD), 41 patients and 28 age and sex-matched controls were studied. PD severity was assessed with the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr staging. The Computerized Speech Lab 4300 program (Kay Elemetrics) was used. Two seconds of a sustained /a/ and a sentence were captured with a microphone and laryngograph equipment. Measures included fundamental frequency (F0), frequency perturbation (jitter), intensity perturbation (shimmer), and harmonic/noise ratio (H/N) of the vowel /a/, and frequency and intensity variability of a sentence, phonational range, dynamic range at the natural frequency, maximum phonational time and s/z ratio. All subjects underwent indirect laryngoscopy and/or laryngeal fibroscopy. When compared with controls, PD patients showed higher jitter, lower H/N ratio, lower frequency and intensity variability of the sentence, and lower phonational range and reported a higher frequency of the presence of low voice-intensity, monopitch, voice arrests, and struggle. These features seem to be unaffected by the duration and severity of the disease.

Association between the oxidative polymorphism and early onset of Parkinson's disease

The frequency of five cytochrome P450IID6 allelic variants was studied in deoxyribonucleic acid from 123 patients with Parkinsons disease and 150 healthy volunteers. This was chieved by the use of mutation‐specific polymerase chain reaction and restriction fragment length polymorphism. The analyses of the CYP2D6 genotype revealed no evidence for a higher prevalence of poor metabolizers among patients with Parkinsons disease. However, increased frequency of patients with Parkinsons disease with the genotype CYP2D6wt/CYP2D6B was observed. This is attributable exclusively to subjects with early onset of the disease (28 to 49 years), with a relative risk ratio of 4.16 (95% confidence limits, 2.0 to 8.3; p < 0.0005). The subjects who had late‐onset Parkinsons disease (≥50 years) had genotypes and CYP2D6 allele frequencies similar to the healthy subjects. This indicates that the oxidative polymorphism is related to early‐onset but not to late‐onset Parkinsons disease. A different influence of CYP2D6 genotype on the risk of development of Parkinsons disease is observed in Spaniards, compared with previous findings in British subjects. These results suggest the combined effect of environmental toxins and CYP2D6 in the cause of Parkinsons disease.

The role of nitric oxide in neurodegeneration : Potential for pharmacological intervention

SummaryNitric oxide (NO) is involved in important physiological functions of the CNS, including neurotransmission, memory and synaptic plasticity. Depending on the redox state of NO, it can act as a neurotoxin or it can have a neuroprotective action. Data suggest that NO may have a role in the pathogenesis of neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease. Additionally, these data indicate that inhibitors of the NO-synthesising enzyme, NO synthase, may be useful as neuroprotective agents in these diseases. In animal models, NOS inhibitors have been shown to prevent the neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other dopaminergic toxins. However, the clinical effects of NOS inhibitors remain unknown.

Decreased cerebrospinal fluid levels of neutral and basic amino acids in patients with Parkinson's disease

We measured the CSF levels of 21, and the plasma levels of 26, amino acids in 31 patients with Parkinsons disease (PD) and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had lower CSF levels of taurine, alanine, valine, leucine, isoleucine, ethanolamine, citrulline, ornithine, lysine, histidine, arginine, and alpha-aminobutyric acid. PD patients not treated with levodopa or with dopamine agonists had higher CSF tyrosine and phenylalanine levels than those not treated with these drugs and also than controls. PD patients had higher plasma levels of phosphoserine, threonine, methionine, tyrosine, sarcosine and alpha-aminoadipic acid, and lower plasma levels of valine, leucine, and tryptophan, than controls. The CSF/plasma ratio of many of these amino acids was significantly lower in PD patients than those of controls, suggesting that PD patients might have a dysfunction in the transport of neutral and basic amino acids across the blood-brain barrier.

Parkinsonism associated with calcium channel blockers : a prospective follow-up study

Parkinsonism is a well-known side effect of some calcium channel blockers (CCB). Its long-term evolution, however, is unknown. To clarify this issue, we performed a prospective follow-up study involving 32 patients diagnosed with CCB-induced parkinsonism. After the baseline examination, the CCB were discontinued and serial evaluations were carried out according to the same protocol. Despite a global improvement, cognitive and mood disturbances subsided slowly, and tremor persisted in most patients. After 18 months of CCB withdrawal, 44% of patients had depression, 88% had tremor, and 33% still had criteria for diagnosis of parkinsonism. During the survey, only three patients were found to be fully recovered. The improvement of some clinical symptoms was related to age: Patients younger than 73 years recovered better than older patients did. Our data indicate that CCB-induced parkinsonism is not the benign condition previously thought, and suggest an age-related prognosis of this entity.

Acoustic voice analysis in patients with essential tremor

To quantify several acoustic features of the voice in patients with essential tremor (ET), 28 patients and 28 age- and sex-matched controls were studied. ET severity was assessed with the rating scale for tremor of Fahn, Tolosa, and Marín. The Computerized Speech Lab 4300 program (Kay Elemetrics) was used. Two-second samples of a sustained /a/ and a sentence were captured with a microphone and laryngograph equipment. Measures included fundamental frequency (F0), frequency perturbation (jitter, Koike algorithm), intensity perturbation (shimmer, Horii algorithm), and harmonic-to-noise ratio (H/N, Yumoto algorithm) of the vowel /a/, and the frequency and intensity variability of the sentence, phonational range, and dynamic range at the natural frequency, maximum phonational time, and s/z ratio. All subjects underwent indirect laryngoscopy and/or laryngeal fibroscopy. When compared with controls, ET patients showed higher jitter, lower H/N ratio (the last one only with laryngographic signal), of the vowel /a/, lower frequency variability in the microphonic signal, lower intensity variability in the laryngographic signal of the sentence, and significantly lower dynamic range at natural frequency of phonation. ET patients reported higher frequency of the presence of high voice intensity, tremor, and struggle. Several acoustic parameters were influenced by the severity of the disease, including shimmer, jitter, H/N ratio, frequency variability of the sentence, and s/z ratio, although neither of the acoustic analysis values or the phonetometric measurements were affected by the presence of voice tremor or by a successful pharmacological treatment of ET.

Serum levels of alpha‐tocopherol (vitamin E) in Parkinson's disease

To elucidate the possible role of vitamin E in the pathogenesis of Parkinsons disease (PD), we compared serum levels of alpha-tocopherol (vitamin E), measured by high-performance liquid chromatography, and the vitamin E/cholesterol ratio of 42 Parkinsons disease (PD) patients using their spouses as the control group. The serum levels of vitamin E did not differ significantly between the groups (13.84 ± 0.56 μg/ml for PU and 14.80 ± 0.57 μg/ml for controls), nor did the vitamin E/cholesterol ratio (0.64 ± 0.03 for both groups). There was no influence of antiparkinsonian therapy on vitamin E or the vitamin E/cholesterol ratio. Serum levels of the vitamin E and vitamin E/cholesterol ratio did not correlate with age age at onset, scores of the Unified Parkinsons Disease Rating Scale or the Hoehn and Yahr staging in the PD group. These results suggest that serum vitamin E concentrations do not play a role in the pathogenesis of PD.

Serum levels of zinc and copper in patients with Parkinson's disease

Several recent studies have shown decreased copper and increased zinc concentrations in the substantia nigra and increased copper concentrations in the cerebrospinal fluid of Parkinsons disease patients. To elucidate whether changes in serum levels of these trace elements may increase the risk of developing Parkinsons disease (PD), we assessed serum levels of zinc and copper by flame atomic absorption spectrophotometry, and albumin and ceruloplasmin, in 32 (Zn) and 39 PD patients (Cu), respectively, with their spouses as the control group. Serum zinc, albumin, copper and ceruloplasmin levels and the zinc/albumin and copper/ceruloplasmin ratios, did not differ significantly between the two groups and were not influenced by antiparkinsonian therapy in the PD patients. Serum zinc/albumin ratio (r = 0.43), ceruloplasmin (r = -0.36) and copper/ceruloplasmin ratio (r = 0.36) correlated significantly with age, but not with age of onset, duration of the disease, scores of the Unified Parkinsons Disease Rating Scale and Hoehn and Yahr staging in PD patients. These values did not correlate with age in the control group. These results suggest that serum levels of zinc and copper do not play any role as risk factors for PD.

Neurotransmitter amino acids in cerebrospinal fluid of patients with Parkinson's disease.

We measured the CSF and plasma levels of glutamate, glutamine, aspartate (only in plasma), asparagine, glutamine, glycine and GABA in 31 patients with Parkinsons disease and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had similar CSF levels of glutamate, glutamine, asparagine, and glycine higher CSF GABA levels higher plasma levels of glutamine, asparagine, and glycine, and lower plasma levels of aspartate. The CSF levels of the amino acids measured were not correlated with the clinical features of PD. Our results that CSF GABA levels are not decreased in PD as previously suggested.