J. A. Molina

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.

Cerebrospinal fluid levels of transition metals in patients with Alzheimer's disease

Summary. We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 26 patients patients with Alzheimers disease (AD) without major clinical signs of undernutrition, and 28 matched controls. CSF zinc levels were significantly decreased in AD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between AD-patient and control groups. These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. Because serum zinc levels were normal, the possibility that low CSF zinc levels were due to a deficiency of dietary intake seems unlikely. However, it is possible that they might be related to the interaction of beta-amyloid and/or amyloid precursor protein with zinc, that could result in a depletion of zinc levels.

Long-term prognosis of ischemic stroke in young adults. Study of 272 cases.

BackgroundThere have been few studies of the long-term prognosis of young adults with ischemic stroke. The present study aimed to evaluate the long-term clinical outcome in a large series of young adults with ischemic stroke admitted to a tertiary medical center over the last 27 years, and to identify possible predictors for mortality, stroke recurrence and poor functional recovery.MethodsWe retrospectively reviewed 272 young adults (15–45 years) with a first-ever ischemic stroke admitted to the Neurology Department of University Hospital “12 de Octubre” between 1974 and 2001. Follow-up assessments were performed by review of medical records and telephone interviews.ResultsNine patients (3 %) died as the result of their initial stroke and follow-up information about the status of 23 (8%) patients was not available. The remaining 240 patients (89%) were followed. Two hundred and ten of them (88%) were alive with a mean follow-up of 12.3 years and 30 (12%) died during follow-up. The average annual mortality rate was 1.4%, being notably higher during the first (4.9%) than in the subsequent years (0.9 %) after the initial stroke. Ninety per cent of the followed patients were independent and 53% returned to work, although adjustments were necessary for 23% of them. The annual stroke recurrence rate during the first year was 3.6% dropping to 1.7 % in subsequent years. Age over 35 years, male gender, the presence of cardiovascular risk factors and large-artery atherosclerosis in the carotid territory were predictors of negative long-term outcome after the initial stroke.ConclusionsThe long-term prognosis for the ischemic stroke in the young is better than in the elderly, but the risk of mortality in young adults with ischemic stroke is much higher than in the general population of the same age. A bad prognosis is associated with an atherosclerotic risk profile, with a higher mortality and recurrent stroke rates and poorer functional recovery. The main functional limitation in the young survivors of their initial ischemic stroke occurs in work activity, since most patients are independent but almost half of them do not return to work.

Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease.

Summary. We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 37 patients with Parkinsons disease (PD) and 37 matched controls. The CSF levels of zinc were significantly decreased in PD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between PD-patient and control groups.There was no influence of antiparkinsonian therapy on CSF levels of none of these transition metals. These values were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group, with the exception of CSF copper levels with the duration of the disease (r = 0.38, p < 0.05). These results suggest that low CSF zinc concentrations might be related with the risk for PD, although they could be related with oxidative stress processes.

Megalin mediates the transport of leptin across the blood-CSF barrier

Leptin, a peptide hormone secreted by adipose tissue, exhibits a large range of central and peripheral actions. It has been proposed that the participation of leptin in diseases such as obesity is due to, at least in part, its impaired transport across the blood-brain barrier (BBB). Since, the mechanisms by which brain takes up leptin remain unclear, we set out to study how leptin may cross the BBB. We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans. We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium. Indeed, the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimers disease was correlated with poor entry of leptin into the brain. Moreover, amyloid beta (Abeta) deposits of choroid plexus could be disturbing megalin function. The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain.

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.

Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer's disease

SummaryWe compared CSF and serum levels, and the CSF/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 44 apparently well-nourished patients with Alzheimers disease (AD) and 37 matched controls. CSF and serum vitamin E levels were correlated, both in AD patients and in controls. The mean CSF and serum vitamin E levels were significantly lower in AD patients, and the CSF/serum ratio of AD patients did not differ significantly between the 2 study groups. CSF vitamin E levels did not correlate with age, age at onset, duration of the disease and score of the Minimental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that low CSF and serum vitamin E concentrations in AD patients could be related with a deficiency of dietary intake of vitamin E.

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

Summary. We measured the CSF and plasma levels of glutamate, glutamine, aspartate (only in plasma), asparagine, glutamine, glycine and GABA in 37 patients with Alzheimers disease and in 32 matched controls. We used an ion-exchange chromatography method. When compared to controls, AD patients had higher CSF glutamate and glycine levels, higher plasma levels of aspartate and glycine, and lower plasma levels of asparagine and GABA. When expressed relative to CSF proteins, CSF levels of glutamate and glycine remained higher, and CSF asparagine levels were lower in AD patients than in controls. The CSF levels of the amino acids measured were not correlated with the clinical features of AD with the exception of plasma GABA levels with duration of the disease. Our results might suggest a possible pathogenetic role of neurotransmitter amino acids in AD.

The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer's disease.

Cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in Alzheimers disease (AD). Vascular endothelial growth factor (VEGF), an angiogenic protein with important neurotrophic and neuroprotective actions, is under investigation as a therapeutic agent for the treatment of neurodegenerative disorders. The aim of this study was to generate encapsulated VEGF-secreting cells and implant them in a transgenic mouse model of AD, the double mutant amyloid precursor protein/presenilin 1 (APP/Ps1) mice, which shows a disturbed vessel homeostasis. We report that, after implantation of VEGF microcapsules, brain Abeta burden, hyperphosphorylated-tau and cognitive impairment attenuated in APP/Ps1 mice. Based on the neurovascular hypothesis, our findings suggest a new potential therapeutic approach that could be developed for AD, to enhance Abeta clearance and neurovascular repair, and to protect the cognitive behavior. Stereologically-implanted encapsulated VEGF-secreting cells could offer an alternative strategy in the treatment of AD.

Symptomatic orthostatic tremor in pontine lesions

Orthostatic tremor (OT) is a rare movement disorder that consists of involuntary shaking of the legs and trunk present only on standing. Although the origin and the mechanism of this condition are not well understood, the neurophysiologic abnormalities and PET studies suggest a central origin. We describe the clinical and radiologic features of two patients with symptomatic OT and associated pontine lesions, and conclude that OT may arise from dysfunction of the cerebellum or related pontine structures.