M I Botez

Université de Montréal, Montréal, Quebec, Canada

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Publications (89)352.27 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Thirty-two OPCA patients without cortical atrophy were studied. In addition to inspection of films by a neuroradiologist (i.e. “subjective” assessment), five neuroradiological measures were used, namely, the estimation of brainstem ratio, midbrain ratio, fourth ventricular ratio, brachium pontis ratio and bicaudate ratio. The patients were divided into two groups: one with mild and the other with moderate-severe atrophies. The neuropsychological assessment measures were: global memory quotient, verbal learning capacities, recall and recognition, attention, abstract thinking, visuo-spatial and visuo-constructive functioning. Three conclusions emerged: (i) cognitive disturbances in OPCA are related to the degree of cerebellar damage; (ii) these findings are consistent with the concept of anatomic and metabolic neocerebellar → basal ganglia → associative cerebral cortex loops; and (iii) it appears that the role of the neocerebellum in cognition is not exclusive because some other structures (fastigius, vermis) and the fastigial → limbic loops seem to be involved.
    European Journal of Neurology 01/2011; 3(2):89 - 97. · 4.16 Impact Factor
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    ABSTRACT: We report a case study of a frontal and parietal lobe syndrome with memory loss after unilateral left-sided cerebellar damage caused by a stroke in a patient with right cerebellar unusual developmental agenesis. The syndrome consisted of severe deficits in planning an organized sequence of events, in visuo-constructive abilities and inappropriate jocularity. These changes are ascribed in part to cerebellar-pontine lesions with resulting frontal lobe diaschisis as documented by single-photon emission computed tomography in the absence of morphological damage to the neocortex.
    European Journal of Neurology 08/2001; 8(4):347-53. · 4.16 Impact Factor
  • Source
    M I Botez, S N Young
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    ABSTRACT: The aims of the present study were: i) to measure levels of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA) and precursor tryptophan, as well as the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and thiamine in the cerebrospinal fluid (CSF) of patients with Friedreich's ataxia (FA), olivopontocerebellar atrophy (OPCA), and the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSAC), as compared with sex- and age-matched control subjects. CSF amine related compound levels and thiamine results were compared in 40 FA, 44 OPCA and nine ARSAC patients with those of 94 sex- and age-matched subjects. Neuroimaging (CT scans and single photon emission computed tomographies i.e. SPECT) were carried out in all patients and controls. Genetic studies were conducted on OPCA patients. CSF amine related compounds were measured by high performance liquid chromatography, whereas CSF thiamine levels were measured by a microbiological method. FA patients had significantly lower CSF HVA, 5HIAA and thiamine values than control patients and a trend for lower MHPG levels. In OPCA patients, CSF HVA, MHPG and thiamine values were markedly lower whereas CSF 5HIAA values showed only a trend towards lower levels; in ARSAC patients only thiamine and HVA CSF values were lower than those in control subjects. After presenting the relationships between neurochemical findings on one side, the degree of ataxia, the degree of cerebellar atrophy and the SPECT findings on the other, the authors concluded that replacement and neuroprotective clinical trials in these patients would have to include two or three drugs because the neurotransmitter deficiencies are multiple.
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 06/2001; 28(2):134-40. · 1.33 Impact Factor
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    ABSTRACT: The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways that lead to ataxia. To investigate possible changes in the central serotonin system of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-tryptamine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain regions and the spinal cord of wild type and dt(J)/dt(J) mutant mice. Also, 5-HT transporters were quantified by [(3)H]citalopram autoradiography in 72 brain regions, subregions, and nuclei, and the 5-HT innervation visualized by immunocytochemistry throughout the brain and spinal cord. In all brain regions measured for indoleamine content, there were no significant differences between the two genotypes. In the spinal cord, an increased tissue concentration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytryptophol (+21%), and 5-hydroxytryptophan (+45%) in dt(J)/dt(J) actually corresponded to the same total amount of each of these indoleamines in the entire spinal cord, when taking into account its reduced size in the mutants. Quantification of the binding to 5-HT transporters showed increases in the medial geniculate nucleus (+14%), medial (+24%) and lateral (+18%) hypothalamus, interpeduncular (+13%), vestibular (+22%), and deep cerebellar nuclei (+37%) of dt(J)/dt mice, and decreases in the ventral tegmental area (-13%), median and linear raphe nuclei (-20%), as well as in the solitary complex (-35%). There were no apparent differences in the distribution of 5-HT-immunostained fibers in these and other regions of brain and in the spinal cord of dt(J)/dt(J) compared to wild type mice. The bulk of these results indicates a relative sparing of the central 5-HT system in the dt(J)/dt(J) mice, even though alterations in 5-HT transporters could justify attempts at improving the sensorimotor dysfunction by administration of serotoninergic agents in these mice.
    Synapse 10/2000; 37(3):179-93. · 2.31 Impact Factor
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    ABSTRACT: The autosomal recessive mutation dystonia musculorum (dtJ/dtJ) causes degenerative alterations of peripheral and central sensory pathways that lead to ataxia. To investigate possible changes in the central serotonin system of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-tryptamine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain regions and the spinal cord of wild type and dtJ/dtJ mutant mice. Also, 5-HT transporters were quantified by [3H]citalopram autoradiography in 72 brain regions, subregions, and nuclei, and the 5-HT innervation visualized by immunocytochemistry throughout the brain and spinal cord. In all brain regions measured for indoleamine content, there were no significant differences between the two genotypes. In the spinal cord, an increased tissue concentration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytryptophol (+21%), and 5-hydroxytryptophan (+45%) in dtJ/dtJ actually corresponded to the same total amount of each of these indoleamines in the entire spinal cord, when taking into account its reduced size in the mutants. Quantification of the binding to 5-HT transporters showed increases in the medial geniculate nucleus (+14%), medial (+24%) and lateral (+18%) hypothalamus, interpeduncular (+13%), vestibular (+22%), and deep cerebellar nuclei (+37%) of dtJ/dt mice, and decreases in the ventral tegmental area (−13%), median and linear raphe nuclei (−20%), as well as in the solitary complex (−35%). There were no apparent differences in the distribution of 5-HT-immunostained fibers in these and other regions of brain and in the spinal cord of dtJ/dtJ compared to wild type mice. The bulk of these results indicates a relative sparing of the central 5-HT system in the dtJ/dtJ mice, even though alterations in 5-HT transporters could justify attempts at improving the sensorimotor dysfunction by administration of serotoninergic agents in these mice. Synapse 37:179–193, 2000. © 2000 Wiley-Liss, Inc.
    Synapse 06/2000; 37(3):179 - 193. · 2.31 Impact Factor
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    ABSTRACT: The efficacy of amantadine, a dopamine-releasing agent and antagonist of the N-methyl-D-aspartate glutamate receptor, was evaluated in patients with olivopontocerebellar atrophy. By contrast to an untreated control group whose terminal performance deteriorated on 8 of 8 measurements of reaction time and movement time, patients treated with amantadine for a mean duration of over 40 months had improved performances in 1 of 4 reaction time measurements and in 3 of 4 movement time measurements and remained stable on the others. These results demonstrate long-term benefits of amantadine in olivopontocerebellar atrophy-induced deficits of movement initiation and movement completion.
    European Neurology 02/1999; 41(4):212-5. · 1.50 Impact Factor
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    ABSTRACT: The Lurcher (Lc/+) mutant mouse is characterized by a considerable atrophy of the cerebellum due to a massive loss of cerebellar Purkinje and granule cells, as well as of neurons from the inferior olivary nucleus. In this study the effects of a therapeutic combination of amantadine, thiamine and L-tryptophan on the serotonin (5-HT) innervation was assessed in Lurcher mice by autoradiography, using [3H]citalopram to label 5-HT transporters. In wild type mice as well as in both saline-treated and drug-treated Lurcher mutants, [3H]citalopram binding remained unchanged in forebrain and brainstem regions. In the cerebellum, labelling of deep cerebellar nuclei (CBnuc) was about twofold higher than in the cortex (CBctx). In saline-treated Lurcher mutants compared to wild type mice, the densities of [3H]citalopram were 98% higher in CBctx, and 180% higher in CBnuc. In CBctx of drug-treated Lurcher mutants, transporter densities were 89% higher than in the wild type, but did not differ from the saline-treated Lurcher. In the CBnuc of the drug-treated Lurcher mutants, [3H]citalopram binding was 50% higher than in the saline-treated Lurcher group, and 320% higher than in wild type mice. The results show that 5-HT transporters, already upregulated in the CBnuc of Lurcher mutant mice, can be further increased by a pharmacological treatment, possibly altering the availability of 5-HT in some of its target areas.
    Brain Research Bulletin 02/1999; 48(2):195-201. · 2.94 Impact Factor
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    ABSTRACT: Actual therapeutic assays in spinocerebellar ataxias, i.e. in Friedreich's ataxia (FA) and olivopontocerebellar atrophy (OPCA) are discussed in relation to (i) the serotoninergic theory; (ii) the excitotoxic action of glutamate; and (iii) cerebrospinal fluid thiamine deficiency in ataxic patients. Data from the literature show that neurochemical deficiencies arising from cerebellar damage in both FA and OPCA patients are multiple. Assays of replacement and neuroprotective therapeutics with a single drug have produced controversial data or mildly effective results. Consequently, it is hypothesized that a drug cocktail, i.e. L-5-hydroxytryptophan, thiamine and amantadine hydrochloride, would be more beneficial. This cocktail proved to be useful in open studies, improving respiratory disorders in FA patients. More powerful inhibitors of N-methyl-D aspartate receptor channels should be tried initially in animal experiments.
    Medical Hypotheses 12/1998; 51(5):381-4. · 1.18 Impact Factor
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    ABSTRACT: 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.
    Journal of Chemical Neuroanatomy 10/1998; 15(3):155-71. · 2.48 Impact Factor
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    ABSTRACT: Lurcher mutant mice are characterized by massive degeneration of the cerebellum, including Purkinje cells and granule cells, as well as for the loss of neurons from the inferior olive. Concentrations of dopamine and two of its metabolites and of several amino acid neurotransmitters were determined in the cerebellum and in other brain regions of these mutants. By comparison to wild-type mice of the same background strain, glutamate and taurine concentrations were reduced in the Lurcher cerebellum. No decrease was found for aspartate, gamma-aminobutyric acid (GABA), glycine, as well as dopamine and its metabolites. Moreover, no neurochemical alterations occurred in the brain stem, thalamus, or neostriatum of Lurcher mutants. A selective reduction of glutamate concentration was found in the hippocampus, while all amino acids measured were decreased in the entorhinal-piriform areas. These results indicate region-selective reductions of neurotransmitter concentrations in a mouse mutant with a defined cerebellar cortical pathology.
    Brain Research Bulletin 04/1998; 45(5):489-93. · 2.94 Impact Factor
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    ABSTRACT: 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.
    Neurochemistry International 02/1998; 32(1):61-8. · 2.66 Impact Factor
  • Neuropsychologie clinique et neurologie du comportement, 2nd edited by MI Botez, 12/1997; Presses de l'Université de Montréal and Masson., ISBN: 978-2225850097
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    ABSTRACT: Neurochemical disorders associated with spinocerebellar ataxias are multiple. 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. 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.
    JAMA Neurology 09/1997; 54(8):1030-3. · 7.58 Impact Factor
  • Journal of The Neurological Sciences - J NEUROL SCI. 01/1997; 150.
  • Journal of The Neurological Sciences - J NEUROL SCI. 01/1997; 150.
  • T Botez-Marquard, M I Botez
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    ABSTRACT: This chapter deals with neuropsychological disturbances in patients with bilateral cerebellar damage (BCD), i.e., epileptic patients chronically receiving phenytoin, patients with olivopontocerebellar atrophy (OPCA), and Friedreich's ataxia (FA) versus those with unilateral cerebellar damage (UCD), i.e., patients with cerebellar strokes. BCD patients showed: (i) impaired executive functions in planning and programming of daily activities, elaborating and using structures, and difficulty in abstract thinking, functions that are related to cerebello-frontal loops; (ii) deficits in visuospatial organization for a concrete task and deficient visual-spatial working memory, functions related to cerebello-parietal loops; (iii) lower general intellectual abilities than controls (especially those with OPCA); (iv) difficulties with memory retrieval, diminished global memory quotient, and reduced spatial working memory ability; and (v) slower speed of information processing, as measured by simple and multiple choice reaction time (RT). In UCD patients, neuropsychological and neurobehavioral abilities were deficient for 2-5 months; after this time period, their performances returned to normal. In both BCD and UCD patients, single photon emission computed tomography (SPECT) studies showed different degrees of "reverse" cerebellar-->basal ganglia-->frontoparietal diaschisis which may underlie permanent or transitory neuropsychological deficits. The relationships among neuropsychological findings, SPECT studies, and chemical neuroanatomy are discussed.
    International Review of Neurobiology 01/1997; 41:387-410. · 2.46 Impact Factor
  • Journal of The Neurological Sciences - J NEUROL SCI. 01/1997; 150.
  • Source
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    ABSTRACT: A group of 27 patients with Friedreich's ataxia and another group of 30 patients with olivopontocerebellar atrophies were each randomly divided into two subgroups, one receiving placebo and the other amantadine hydrochloride (AH; 200 mg daily) for three to four months. The effect of double blind treatment was evaluated by simple visual and auditory reaction time (RT) and movement time (MT) for both right and left hands. The subgroup with olivopontocerebellar atrophies receiving AH showed significant improvement on seven out of eight variables studied by analysis of covariance. In patients with Friedreich's ataxia, improvement was definitely less. Treatment remained contraindicated for those with cardiomyopathies or drug intolerance. The rationale of AH use in heredodegenerative ataxias can be explained by its replacement effect (dopamine release) and by direct involvement of N-methyl-D-aspartate (NMDA) in glutamate mediated neurotoxicity in cerebellar granular cells; memantine, an AH analogue, is a potent blocker of NMDA receptors.
    Journal of Neurology Neurosurgery & Psychiatry 10/1996; 61(3):259-64. · 4.92 Impact Factor
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    ABSTRACT: 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.
    Journal of Chemical Neuroanatomy 05/1996; 10(2):157-71. · 2.48 Impact Factor
  • Chapter: Cerebellum.
    The Blackwell dictionary of neuropsychology, 2nd edited by J. Graham Beaumont, Marcus J. Rogers, Pamela Keneal, 01/1996: pages 194-209; Blackwell., ISBN: 978-0631178965

Publication Stats

1k Citations
352.27 Total Impact Points

Institutions

  • 1988–2011
    • Université de Montréal
      • • Faculty of Medicine
      • • Center for Mathematical Research
      • • Department of Radiology, Radiation Oncology and Nuclear Medicine
      • • Department of Physiology
      • • Department of Medicine
      Montréal, Quebec, Canada
  • 1990–1998
    • Université du Québec à Montréal
      • • Department of Sociology
      • • Department of Psychology
      Montréal, Quebec, Canada
  • 1984–1997
    • Hotel Dieu Hospital
      Kingston, Ontario, Canada
  • 1982–1989
    • McGill University
      • Department of Medicine
      Montréal, Quebec, Canada
  • 1985
    • Instituto de Investigación Clínica de Occidente
      Zapopan, Jalisco, Mexico
  • 1982–1985
    • Montreal Heart Institute
      Montréal, Quebec, Canada