The blood-brain barrier and folate deficiency.

Twenty-three patients (average age: 63.2 +/- 14.9 (x +/- SEM) ranging from 28 to 83 yr) with low or borderline cerebrospinal fluid (CSF) folate and low serum underwent two lumbar punctures, i.e., before and after 3 wk of folate therapy. The rise in CSF folate content in the whole group after the replacement therapy was significant by both the Lactobacillus casei and radioisotope methods of folate determination. In patients with folate-responsive neurological disorders, the rise of CSF values after replacement therapy was definitely higher than in the group of patients in whom folate deficiency was not related to the actual clinical picture. Contrary to previous statements, the present study revealed that there is not an absolute blood-brain barrier for folate because the lower the CSF folate level was, the more rapid and spectacular the increase in CSF folate after replacement therapy was found.

Visual memory deficits after damage to the anterior commissure and right fornix.

A 47-year-old right-handed woman suffered an accidental dural perforation in the course of intranasal drainage of a right-sided sphenoid mucocele. Radiological examination revealed a small hematoma involving the anterior commissure, the right foramen of Monro, and the right fornix, resulting in severe anterograde amnesia for visual stimuli. Visual retention disturbances were manifested by a loss of the ability to conjure up new visual images, loss of topographical memory, and the cessation of dreaming. Dissociation was striking between severe deficits on tests exploring anterograde visual memory, revisualization, visuospatial organization, construction abilities, and normal or mildly impaired performance on tests implying verbal material and verbal memory. In agreement with experimental findings, it is postulated that combined damage to the anterior commissure and fornix on the right side could cause severe deficits in visual retention in humans.

Can we treat respiratory failure in Friedreich ataxia?

BACKGROUND: Neurochemical disorders associated with spinocerebellar ataxias are multiple. OBJECTIVE: To use replacement and neuroprotective therapy in a case of severe respiratory failure in Friedreich ataxia. PATIENT AND TREATMENT: A 44-year-old man with severe Friedreich ataxia displayed arduous periodic breathing associated with minor desaturation as well as obstructive or mixed apneas associated with severe desaturation during the night. He was given oxitriptan (5-hydroxy-L-tryptophan) (1500 mg/d), thiamine hydrochloride (100 mg/d), and amantadine hydrochloride (100 mg/d). The first sleep study was conducted during the night before treatment, whereas the second was performed during the night after 9 months of treatment. RESULTS: After treatment, striking clinical improvement of spastic dysphonia was accompanied by significant diminution in the time spent in periodic breathing and in the number of obstructive and mixed apneas during the night. Controlled studies are needed.

Polyneuropathy and folate deficiency.

We studied five patients (two men and three women, age between 58 and 76 years) with clinical and electrophysiological signs of polyneuropathy. Routine neurological, hematological, and gastroenterological studies as well as procedures to test fat malabsorption were performed. Folate determinations were done using both radioactive and Lactobacillus casei methods. Two patients displayed the signs of subacute combined degeneration of the spinal cord with polyneuropathy, while three had only signs of neuropathy. All had low serum folate concentration, long-standing gastrointestinal disease, and deficient folate intake. The D-xylose absorption test gave values in all patients, while none displayed the classical malabsorption syndrome. The patients had substantial improvement or recovered (according to clinical and electrophysiological measurements) after periods ranging from 9 to 39 months of folate therapy. Such acquired folate-responsive polyneuropathy has two principal characteristics: mixed sensorimotor with mainly sensory deficits, and involvement of one or both of the lower extremities much more extensively than the upper extremities.

Reversible chronic cerebellar ataxia after phenytoin intoxication: possible role of cerebellum in cognitive thought.

Reversible chronic cerebellar ataxia followed phenytoin treatment in two epileptic women. Cerebellar ataxia in both patients and axonal polyneuropathy in one patient were improved after administration of thiamine alone or with folate. In one patient, some specific behavioral functions improved. However, recovery could have been spontaneous.

Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients.

The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.

Regional distribution of the 5-HT innervation in the brain of normal and lurcher mice as revealed by [3H]citalopram quantitative autoradiography.

The neurological cerebellar mutant lurcher is characterized by a primary degeneration of Purkinje cells as well as retrograde secondary partial degeneration of cerebellar granule cells and inferior olivary neurons. Since serotonin (5-HT) has been implicated in the modulation of excitatory amino acid systems of the cerebellum, the 5-HT innervation of the normal and lurcher mice was examined by quantifying uptake sites using [3H]citalopram autoradiography, and by biochemical assays of the indoles 5-HT, 5-hydroxy-L-tryptophan and 5-hydroxyindole-3-acetic acid using high-performance liquid chromatography. Comparable results were found between [3H]citalopram binding and 5-HT tissue concentrations in different brain regions. The highest [3H]citaslopram labelling was observed in defined structures of the mesencephalic and upper pontine regions, in limbic strutures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling of uptake sites was documented in cerebellum and brainstem reticular formation. In lurcher mutants, the histology confirmed cell degeneration and the reduction in width, leading to 65%, 45% and 25% atrophies of total cerebellum, deep nuclei and inferior olivary nucleus, respectively. The [3H]citalopram labelling corrected for surface loss was 45% and 20% higher to cerebellar deep nuclei and red nucleus, respectively, but remained unchanged in the cerebellar cortex and inferior olivary nucleus. Moreover, higher labelling was found in nucleus raphe dorsalis, ventral tegmental area, inferior colliculus, locus coeruleus, pontine central grey and anterior thalamic nuclei, areas known to be part of cerebellar afferent and efferent systems. The present results indicate that in such pathological conditions as described for the lurcher mutant, the 5-HT system may modulate motor function not only at the level of the cerebellum, but also in other forebrain structures functionally related to the motor system.

Regional distribution of 5-HT transporters in the brain of wild type and 'Purkinje cell degeneration' mutant mice: a quantitative autoradiographic study with [3H]citalopram.

The neurological mutant 'Purkinje cell degeneration' (pcd) is characterized by a primary degeneration of Purkinje cells, as well as by retrograde and secondary partial degeneration of cerebellar granule cells and inferior olivary neurons, and can be considered as an animal model of human degenerative ataxias. The serotonin (5-HT) innervation was examined in wild type and pcd mice, by quantifying 5-HT uptake sites, or transporters, using [3H]citalopram binding autoradiography. In both wild type and pcd mutants, the highest densities of 5-HT transporters were in mesencephalic and rostral pontine regions, in limbic structures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling was found in cerebellum and brainstem reticular formation. In pcd mice, although [3H]citalopram labelling was higher in cerebellar cortex and deep cerebellar nuclei, when binding densities were corrected for surface area, the up-regulation of 5-HT transporters was present only in deep cerebellar nuclei. Also, higher labelling was found in nuclei raphe dorsalis and medialis, in ventral divisions of rostral neostriatum, caudal neostriatum, rostral globus pallidus, posteromedial amygdaloid nucleus, septum, olfactory tubercles, vertical limb of Broca's diagonal band, periventricular, latero-ventral and medio-ventral thalamic nuclei, medial geniculate nucleus, anterior hypothalamus and entorhinal cortex. The results indicate a relative integrity of the 5-HT innervation, but with a reorganization of serotoninergic terminals in the cerebellum, in particular in the deep cerebellar nuclei. This suggests that in progressive cerebellar degeneration, as found in the pcd mutant, the modified 5-HT system may still participate in motor functions by exerting an overall modulation of excitatory amino acid neurotransmission, but the availability of 5-HT may be altered in defined brain targets, as is the case for other spontaneous cerebellar mutants, in particular for the 'Lurcher' mutant mouse, a model of human olivopontocerebellar atrophy.

Spontaneous alternation and habituation in a t-maze in nervous mutant mice.

Nervous mutant mice have a selective degeneration of Purkinje cells and deep cerebellar nuclei. In comparison with littermate controls, nervous mutant mice did not alternate spontaneously in a successive trial procedure (six consecutive trials per day) and did not habituate in a restricted part of a t-maze in a 4-min session. These data indicate that the cerebellum may have a role in spatial learning.

Subsensitivity to muscimol-induced catalepsy after long-term administration of phenytoin in rats.

Male albino rats were injected with 25 mg/kg of phenytoin (PHT) every day for 20 consecutive days and were tested on days 21 and 28 for their response to 1 or 2 mg/kg of muscimol, a GABA receptor agonist. Rats treated with PHT showed a decreased responsiveness to muscimol-induced catalepsy (2 mg/kg) on day 21 but not on day 28. Acutely administered PHT, on the contrary, had a tendency to potentiate muscimol-induced catalepsy. Muscimol-induced catalepsy was not antagonized by acute treatment with bicuculline (0.5-2.0 mg/kg). It is proposed that withdrawal after long-term administration of PHT reduces the sensitivity of a GABA receptor site not sensitive to bicuculline.

Amantadine and ketamine-induced improvement of motor coordination in lurcher mutant mice.

The effects of amantadine and ketamine were compared to a placebo in a coat-hanger test on lurcher mutant mice. This test measures motor coordination and is dependent on cerebellar functioning. Both drugs improved motor coordination of the cerebellar mutants in that the time taken to reach the side-bar according to a 2 paw criterion was decreased during the drugged condition in comparison to the non-drugged condition. This result indicates that NMDA receptor antagonists may improve motor coordination in animals with cerebellar disease.

The effects of chronic dietary phenytoin on 5-HT and 5-HIAA levels in rats.

Rats were given, by means of the diet, phenytoin (PHT) every day for either 4 (400-800 mg/kg) or 14 (400 mg/kg) weeks. Serum values of PHT in both cases were in the pharmacological range (10-15 microg/ml). An increase in brain 5-HIAA levels was noted after 4 but not 14 weeks of PHT administration. There was no change in brain 5-HT levels. In accordance with results in epileptic patients, it appears that under some circumstances, PHT can increase 5-HIAA levels, but the mechanism of this action is unknown.

Distribution of dopamine transporters in basal ganglia of cerebellar ataxic mice by [125I]RTI-121 quantitative autoradiography.

Dopamine (DA) uptake sites, or transporters, were examined with [125I]RTI-121 in mutant mice that exhibit motor control deficits, namely weaver, lurcher and dystonia musculorum. In lurcher mice, the distribution of [125I]RTI-121 binding was similar to controls, except for a decrease in the subthalamic nucleus. For dystonia musculorum mice, the labelling presented no differences between controls and mutants, except for decreases in the dorsal half of caudal neostriatum and in the ventral tegmental area. Moreover, in this mutant the left rostral neostriatum DA transporters were reduced, when compared to the right counterpart. In weaver heterozygote (wv/+) mice, the distribution and density gradients of [125I]RTI-121 labelling were similar as in their controls, except in caudal neostriatum, where binding was slightly higher. In contrast, the weaver homozygote (wv/wv) showed important decreases in labelling of the dorsal quadrant of rostral neostriatum as well as of the dorsal half of caudal neostriatum, where the reductions of binding densities were of 65% to 70%, respectively. There were also slight decreases in [125I]RTI-121 binding in olfactory tubercles as well as in subthalamic nucleus, but only in wv/wv mice. In substantia nigra pars compacta and ventral tegmental area of wv/wv mice the labelling was lower; however, while the 60% decrease in labelling in substantia nigra was highly significant, the 30% reduction in ventral tegmental area did not attain statistical significance. In summary, in the ataxic neurological mutant mice studied, important reductions of DA transporters were documented only for the weaver mice, the cerebellar mutant presenting, besides its cerebellar pathology, a known degeneration of mesencephalic dopaminergic neurons. The results rule out major alterations of the central DA systems in lurcher and dystonia musculorum, and are compatible with the hypothesis that the dopaminergic abnormalities of weaver mutants are not secondary to cerebellar atrophy, but may be a direct consequence of the abnormal weaver gene expressed by DA neurons leading to their apoptotic death.

Exploration and habituation in nervous mutant mice.

Nervous mutant mice have selective damage to deep cerebellar nuclei and Purkinje cells. Compared to normal littermate controls, nervous mutant mice did not show habituation of a hole poke response to a large hole. The nervous mutants showed both signs of increased contact with a novel stimulus (number of rearing responses) and decreased exploration (number of hole pokes in small holes). Results are discussed in terms of a similarity between the behavioral effects of cerebellar damage and hippocampal damage.

Spontaneous alternation and exploration in weaver mutant mice.

Weaver mutant mice engaged less in motor activity and hole poking. Weaver mice alternated spontaneously in a 4-trial but not a 2-trial test. These results are similar to those of a previous study with staggerer mutants, in that both are less active. However, weaver mutants are less affected in the spontaneous alternation measure.

Spontaneous alternation and exploration in staggerer mutant mice.

Staggerer mutant mice were found to be less active in terms of motor activity in a maze, hole poking and rearing. Staggerer mutant mice also showed a lack of spontaneous alternation in both 2-trial and 4-trial tests. A lack of spontaneous alternation in this mutant may be due to a deficit in response inhibition or in spatial orientation, similar to that of animals with limbic lesions.

Navigational deficits in weaver mutant mice.

Weaver mutant mice have selective degeneration of cerebellar granule cells. In comparison to normal mice, the weaver mutants made more errors and took a longer time to reach a platform in a water-maze. Results are discussed in terms of a role for the cerebellum in spatial orientation.

Exploration of a hole-board matrix in nervous mutant mice.

Nervous mutant mice and normal littermate controls explored a 4 X 4 hole matrix for 3 consecutive days. No difference was found between the groups for the following measures: total number of hole visits, visits to the center holes, and visits to contiguous holes or different holes. However, nervous mutants persevered more in visiting the same hole than controls. These results are discussed in terms of a possible role for the cerebellum in spatial working memory, similar to that suggested for the hippocampus.

Chronic phenytoin and the stereotyped motor response induced by 5-methoxy-N,N-dimethyltryptamine in rats.

Male Sprague-Dawley rats were injected with phenytoin (PHT) once a day for 20 consecutive days and then tested as to their response to 5-methoxy-N,N-dimethyltryptamine (5-MDMT), a 5-hydroxytryptamine (5-HT) agonist, at 1 and 3 mg/kg on days 21 and 28. It was found that long-term PHT administration decreased the intensity of a stereotyped motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (1.7, 3.2 mg/kg). It is suggested that PHT increases the functional availability of 5-HT before its receptors, and thereby causes 5-HT receptor subsensitivity.

Spontaneous alternation and habituation in Purkinje cell degeneration mutant mice.

Purkinje cell degeneration (pcd) mutant mice were found to be as active as normal mice in a T-maze. The pcd mutants, contrary to normal mice, did not alternate spontaneously in either a 2-trial or a 4-trial test. Results are discussed in terms of a role for the cerebellum in behavioral inhibition and visuo-spatial organization.