Olivopontocerebellar Atrophy Patients Research Articles

Cerebellar activation during ataxic gait in olivopontocerebellar atrophy: a PET study.

To investigate the possible abnormal regional brain metabolism during ataxic gait in olivopontocerebellar atrophy (OPCA), and to evaluate the response of the cerebellar subregions to instability during bipedal gait. On 9 patients with OPCA in early phase and on 10 age-matched normal subjects, we performed positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) under two different conditions: supine resting and 30 min treadmill walking. Both in normals and in patients with OPCA, the FDG uptake in the walking state (Uwalk) was significantly greater than that in the resting state (Urest) in the pyramis, declive-folium-tuber and culmen of the cerebellar vermis, and in the thalamus. In the patients, the Uwalk was also significantly greater than the Urest in the posterior lobe of cerebellar hemisphere and in the pons and midbrain. In the pyramis, the activation ratio (= Uwalk/Urest) of the patients was significantly lower than that of the normals. We considered that these findings reflect the pathophysiology of ataxic gait in OPCA patients and the compensatory mechanism for the instability during ataxic gait.

Glutamate and GABA levels in CSF from patients affected by dementia and olivo-ponto-cerebellar atrophy.

The modifications in the CSF content of glutamate and GABA in patients afflicted with primary degenerative dementia (PDD) and olivo-ponto-cerebellar atrophy (OPCA) have been evaluated. Control subjects (with disk herniation) were also included in the study. The amino-acids assays were carried out utilizing enzymatic-bioluminescence technique. GABA levels in controls were 803 +/- 98 (n = 7) and in demented patients 702 +/- 98 (n = 7) pmol/ml. Glutamate levels were 2067 +/- 244 (n = 10) in controls, 1190 +/- 81 (n = 16) pmol/ml (vs controls p less than 0.01) in demented patients, and 1116 +/- 146 (vs controls p less than 0.01) in OPCA patients. These results suggest that CSF glutamate levels in severely demented patients might be a result of generalized neuronal loss in the brain with a reactive gliosis.

Autonomic nervous evaluation in the early stages of olivopontocerebellar atrophy

The clinical significance of evaluating autonomic nervous system functions in the early stages of olivopontocerebellar atrophy (OPCA) has been investigated in 13 OPCA out-patients (7 males and 6 females, mean age: 51.0 years). We have employed measurements of blood pressure, plasma norepinephrine (NE), CVR-R, low-frequency power/high-frequency power ratio (L/ H), high-frequency power (HF) score and heart rate (HR) monitoring using Holter ECG recording for evaluation of CVR-R. We have also carried out urodynamic examinations, focusing on the possible existence of bladder dysfunction. Although no significant changes were noted between control and OPCA groups concerning HR, CVR-R, L/ H, plasma levels of norepinephrine and systolic blood pressure, HF (high-frequency power) (ms 2), especially at night time, invariably showed a significant decline in OPCA groups. All OPCA patients who showed a decreased circadian HF also exhibited a tendency towards urinary bladder dysfunction. The present results appear to relate to disorder of the parasympathetic autonomic nervous system and neuromuscular dysfunction in the lower urinary tract. In conclusion, HRV (heart rate variability) analysis is a useful and safe tool and a keen predictor for evaluating functional states of autonomic nervous activity, especially in the early stages of OPCA. This study has also suggested the possible efficacy of urodynamic measurements in OPCA patients as an indicator of neuromuscular dysfunction in the lower urinary tract and of parasympathetic malfunction.

ADC mapping of neurodegeneration in the brainstem and cerebellum of patients with progressive ataxias

Analysis of the apparent diffusion coefficient (ADC) maps derived from diffusion-weighted MR imaging is emerging as a reproducible, sensitive, and quantitative tool to evaluate brain damage in diseases of the white and gray matter. To explore the potentials of ADC maps analysis in degenerative ataxias, we examined 28 patients and 26 age-matched controls with T1, T2, and diffusion ( b values 0–1000 along the three main body axes)-weighted MR images. Twenty-four patients had inherited genetically proven diseases including spinocerebellar ataxia type 1 (SCA1) ( n = 9), spinocerebellar ataxia type 2 (SCA2) ( n = 8), and Friedreich's ataxia (FA) ( n = 7), whereas four patients had sporadic adult onset pure cerebellar ataxia (three idiopathic, one gluten intolerance). Area and linear measurements of the CNS structures contained in the posterior cranial fossa (PCF) preliminary enabled classification of the patients in the three morphological categories reflecting the gross pathology findings, namely olivopontocerebellar atrophy (OPCA) ( n = 10: six SCA2 and four SCA1), spinal atrophy (SA) ( n = 7: all FA), and cortical cerebellar atrophy (CCA) ( n = 4: three idiopathic and one gluten intolerance). Seven patients with SCA1 ( n = 5) or SCA2 ( n = 2) had morphologic changes reminiscent of OPCA, but their values were still in the lower normal range and were classified as undefined. Mean diffusivity ( D̄) maps of the entire brain were generated and D̄ was measured with regions of interest (ROI) in the medulla, pons, middle cerebellar peduncles, and the peridentate white matter. Moreover, after exclusion of the skull with manual segmentation and of the CSF with application of a threshold value, histograms were obtained for D̄ of the brainstem and cerebellum and for D̄ of the cerebral hemispheres. As compared to controls, a ( P < 0.001) increase of D̄ was observed in the medulla, middle cerebellar peduncles, and peridentate white matter in OPCA and undefined patients groups who had also significantly increased values of the 25th and 50th percentiles in the brainstem and cerebellum D̄ histogram. In CCA ( P = 0.01), an increase of the 25th and 50th percentile of the D̄ value was observed in the brainstem and cerebellum histograms. The SA group showed ( P < 0.001) an increased D̄ in the medulla only. A correlation between clinical severity as assessed with the Inherited Ataxias Clinical Rating Scale (IACRS) and the 50th percentile of the D̄ value in the brainstem and cerebellum histogram ( r = 0.69) was observed in patients with SCA1 or SCA2. Diffusion MR imaging reveals variable patterns of increase of D̄ in the brainstem, cerebellum, and cerebral hemispheres in degenerative ataxias that match the known distribution of the neuropathological changes.

Characteristic MRI findings in multiple system atrophy: comparison of the three subtypes

We reviewed MRI findings in 29 patients with probable multiple system atrophy (MSA) to see whether there were common and or less common neuroradiological findings in the various clinical subtypes. We divided the patients into three clinical subtypes according to initial and predominant symptoms: 14 with olivopontocerebellar atrophy (OPCA), eight with the Shy-Drager syndrome (SDS) and seven with striatonigral degeneration (SND). The patients showed atrophy of the brain stem and cerebellum, high signal on T2-weighted images of the base of the pons and middle cerebellar peduncles, high and low signal on T2-weighted images of the putamen and atrophy of frontal and parietal lobes. The degree of atrophy of the middle cerebellar peduncle and cerebellum was greater in OPCA patients and a high-signal lateral rim to the putamen more frequent in SND. However, all findings were observed in all subtypes, and the degrees of atrophy of the putamen and pons and the frequency of high signal in the base of the pons were similar in the subtypes. We also found atrophy of the cerebral hemispheres, especially the frontal and parietal lobes, but its degree was not significantly different in the various subtypes. Our findings suggest that, although MSA can be divided clinically into three subtypes, most of the features on MRI are common and overlap in the subtypes, independently of the clinical presentation.

Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias.

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.

Oxidative injury is present in Purkinje cells in patients with olivopontocerebellar atrophy

To verify the presence of lipid peroxidation products in spinocerebellar degeneration (SCD), the cerebella from eight patients with olivopontocerebellar atrophy (OPCA) and six non-OPCA patients were immunohistochemically investigated with 4-hydroxy-2-nonenal (HNE) antibody. On average, 84.6% of Purkinje cells were positively or strongly positively immunostained in OPCA patients while only 15.5% were positive in non-OPCA patients. Other cells in the molecular and granular layers showed no obvious immunoreactivity. These data suggest that a lipid peroxidation product is present in Purkinje cells of OPCA patients and that oxidative stress may play an important role in the degeneration process of SCD.

The treatment of spinocerebellar ataxias: facts and hypotheses

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.

No association between apolipoprotein E alleles and olivopontocerebellar atrophy.

Apolipoprotein E (apo E) epsilon4 is a risk factor for sporadic and late-onset familial Alzheimer's disease, but it is not well known whether the apo E is associated with spinocerebellar degeneration. We studied the frequency of apo E allele in 59 olivopontocerebellar atrophy (OPCA) patients, including 13 pathologically confirmed cases. The distribution of the apo E allele frequency did not differ between OPCA patients and controls. Apo E allele does not influence the development of OPCA.

Psychological Factors and Pet Measured Glucose Metabolism in Olivopontocerebellar Atrophy

We compared 29 olivopontocerebellar atrophy (OPCA) patients on psychiatric rating scales, cognitive tests, and positron emission tomography to 12 normal volunteers with similar age and sex distributions. The patients were generally comparable to normals in cognitive function, but poorer on psychomotor tasks. They had significantly different scores on formal self-report scales than the normals, indicating a greater degree of self-complaint. Analyses of the components of self-complaint suggested that illness-related concerns accounted for most of the differences between the groups. The magnitude of self-complaint was significantly and specifically correlated with the level of glucose metabolism in the frontal cerebral cortex of OPCA patients. These results may be attributed to a combination of biological and experiential factors. The level of patient complaint may be influenced by organic brain dysfunction reflected in metabolism and emotional disturbance, whereas the content of complaint may be specific to the individual's situational experience.

A comparison of cerebral blood flow and glucose metabolism in olivopontocerebellar atrophy using PET.

In sporadic cases of olivopontocerebellar atrophy (OPCA), to determine whether local cerebral blood flow (lCBF) is reduced, whether lCBF is coupled to local cerebral metabolic rate for glucose (lCMRglc), and whether lCBF measurements are potentially useful in diagnosing OPCA. Positron emission tomography was used with [15O]H2O to measure lCBF and with [18F]fluorodeoxyglucose to measure lCMRglc in 17 patients with OPCA and 21 normal control subjects. In OPCA patients, lCBF was significantly decreased in the cerebellum, but not in the cerebral cortex, basal ganglia, thalamus, or brainstem. In the same patients, lCMRglc was significantly decreased in the cerebellum and brainstem, where the largest changes were observed, and also in the cerebral cortex, basal ganglia, and thalamus. The ratio of lCBF to lCMRglc, an indicator of the coupling of blood flow to metabolism, was similar in OPCA patients and normal subjects for all regions except the brainstem, where the ratio was marginally decreased in OPCA patients. Using logistic discriminant analysis to assess the ability of lCBF and lCMRglc to differentiate OPCA patients from normal subjects, we found the cross-validated sensitivity of absolute lCMRglc as a predictor of OPCA was 82% with a corresponding specificity of 71%; the sensitivity of absolute lCBF was 71% and the specificity 76%. In sporadic cases of OPCA, lCBF is reduced in the cerebellum, CBF remains coupled to lCMRglc, and the lCBF pattern is a useful predictor of the diagnosis.

Striatal 18F-Dopa uptake and brain glucose metabolism by PET in patients with syndrome of progressive ataxia

Striatal 18F-Dopa uptake and brain glucose metabolism were studied by PET with 6- l-[ 18F]fluorodopa and [ 18F]fluorodeoxyglucose in 11 patients with syndrome of progressive ataxia. Five of the 11 patients were diagnosed as having cerebellar cortical degeneration (CCD), including 3 with late cerebellar cortical atrophy and 2 with Holmes type hereditary ataxia while 6 demonstrated olivopontocerebellar atrophy (OPCA). The caudate and putaminal 18F-Dopa uptake ratios to the occipital cortex in CCD showed no significant difference from those in the controls. On the other hand, those with OPCA decreased as compared to the controls. In addition, the cerebellar glucose metabolism in CCD decreased as compared to the controls, while that in the brainstem showed no significant decrease from the controls. The glucose metabolic rates both in the cerebellar hemisphere and in the brainstem in the OPCA patients decreased compared to the controls. The cerebral cortical, striatal and thalamic glucose metabolisms were normal in both the CCD and OPCA in groups. The appearance of a decreased glucose metabolism in the cerebellum is considered to be relevant in the genesis of cerebellar ataxia, even though their underlying diseases were different from each other. The differences in the glucose metabolism of the brainstem and in the nigrostriatal presynaptic dopaminergic function between CCD and OPCA as assessed by PET may be caused by differences in the pathophysiological mechanism between CCD and OPCA, and those differences appear to be useful when making a differential diagnosis of CCD and OPCA.

Decreased insulin-like growth factor I-mediated protein tyrosine phosphorylation in human olivopontocerebellar atrophy and lurcher mutant mouse

We examined insulin-like growth factor I (IGF-I)-dependent phosphorylation and protein tyrosine kinase (PTK) activity in cerebellar cortex of normal humans, patients with olivopontocerebellar atrophy (OPCA) (“C” kindred) and in lurcher mutant mouse, a suggested animal model for OPCA. PTK activity and IGF-I-dependent protein tyrosine phosphorylation was significantly reduced in cerebellar cortex of human OPCA patients as compared to the normal controls. Immunoblot analysis also demonstrated a decrease in cerebellar 80 kDa phosphotyrosine protein in these patients. By autoradiography, IGF-I receptors were localized in the molecular layer of 30-day-old control and lurcher mutant mice cerebella. However, the lurcher mutant mice showed a decrease in [ 125I]-IGF-I binding in the molecular layer as compared to the littermate controls. The IGF-I receptor autophosphorylation was also markedly reduced in 15-day- and 22-day-old lurcher cerebella. These results suggest that the process of cerebellar degeneration in human OPCA and lurcher mutant mouse may be associated with altered IGF-I receptor binding and protein tyrosine phosphorylation.

Phospholipid metabolite levels are altered in cerebral cortex of patients with dominantly inherited olivopontocerebellar atrophy

We measured metabolic precursors and breakdown products of phosphatidylcholine (choline, glycerophosphocholine (GPC)) and phosphatidylethanolamine (ethanolamine, glycerophosphoethanolamine (GPE)) as well as the amino acid serine, a precursor of phosphatidylserine, in four morphologically unaffected cerebral cortical areas obtained at autopsy from 14 patients with dominantly inherited olivopontocerebellar atrophy (OPCA) and 13 controls matched for age and postmortem interval. As compared with the controls, mean GPE levels were elevated by 49 57% in frontal and parietal cortices of OPCA brains whereas concentrations of ethanolamine were significantly reduced in temporal, occipital and parietal cortex (−40 to −50%). This resulted in increased GPE ethanolamine ratios (+80 to +146%). GPC levels were significantly increased (by 53%) in the frontal cortex of OPCA patients relative to controls. Free serine levels were reduced by 20 to 28% in frontal, parietal, temporal, and occipital cortices. These abnormalities in phospholipid metabolite levels in OPCA resemble those seen in Alzheimer's disease, although the changes in GPC are less pronounced. These changes in phospholipid metabolism in OPCA cerebral cortex, a brain area spared from neurodegenerative changes, points to generalized disturbances in cellular membrane function in this disease.

Radiologic correlates of reaction time measurements in olivopontocerebellar atrophy.

We measured simple visual and auditory reaction time (RT) and movement time (MT) in 32 patients with olivopontocerebellar atrophy (OPCA) in comparison to 32 control subjects. In addition, we followed 2 approaches to radiologic assessment by computed tomographic scans: subjective (by inspection of films) and objective (by measurement of 4 radiologic ratios at the level of the posterior fossa and 1 ratio at the supratentorial level). All OPCA patients had various degrees of cerebellar atrophy and lengthened RT and MT in comparison to their controls. There were no significant differences in RT and MT performances in patients with mild-moderate versus those with severe cerebellar atrophy as assessed by inspection of their films. OPCA patients with severe versus mild-moderate atrophy evaluated by 3 measures, i.e., brainstem, brachium pontis and fourth ventricle ratios, presented few significantly lengthened RT and MT performances. In contrast, patients with severe atrophy revealed by the midbrain ratio had significantly lengthened RT and MT performances compared to those with mild-moderate atrophy assessed by this ratio on 7 of 8 measures; the 8th measure showed a borderline significant difference. This could be explained by the fact that atrophy at the midbrain level is the only one which involves dopaminergic, noradrenergic and glutamatergic structures and pathways.

Normal serotonin but elevated 5-hydroxyindoleacetic acid concentration in cerebellar cortex of patients with dominantly-inherited olivopontocerebellar atrophy

Beas-Zarate and coworkers (Eur. J. Pharmacol., 198 (1991) 7–14) recently reported markedly reduced concentration of presynaptic serotonin neurotransmitter markers in cerebellum of rodents which had suffered destruction of the inferior olivary-cerebellar (climbing fibre) projections by the neurotoxin 3-acetylpyridine; these experimental animal data suggested that serotonin might be one of the neurotransmitters released by climbing fibres. We measured the concentration of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in autopsied cerebellar cortex of 14 patients with dominantly-inherited olivopontocerebellar atrophy (OPCA) who all had near-total degeneration of the inferior olivary climbing fibres. As compared with the controls, mean concentration of serotonin in cerebellar cortex of the OPCA patients was normal whereas 5-HIAA levels (+79%, P<0.02) and ‘turnover’ ratio 5-HIAA/serotonin (+148%, P<0.05), on average, were significantly elevated. These data do not support the notion that serotonin is a predominant neurotransmitter of the human climbing fibre. However, the markedly elevated serotonin turnover ratio suggests the possibility of increased serotonergic neuronal activity, which might alter, and perhaps improve, the functioning of the preserved cerebellar cortical neurones in OPCA.

Continuous subcutaneous lisuride infusion in OPCA.

Four patients with sporadic olivopontocerebellar atrophy (OPCA) and severe signs of Parkinsonism received continuous subcutaneous lisuride infusion via a small external pump. All 4 patients benefitted from this treatment: 3 showed an overall improvement in motor performance, in 1 patient mainly dysphagia and dysarthria improved. Therapeutic benefit lasted for at least 6 months of follow up. With a daily dose of 1.0 mg subcutaneous lisuride, treatment limitations were reached in the form of dysphagia, probably due to oropharyngeal dystonia. Subcutaneous lisuride infusion should be taken into consideration in OPCA patients with signs of Parkinsonism if oral dopaminergic treatment has failed earlier on.

Selective delayed alternation deficits in dominantly inherited olivopontocerebellar atrophy

In order to characterize more completely the nature of the frontal lobe-type cognitive changes in patients with dominantly inherited olivopontocerebellar atrophy (OPCA) we administered two tasks sensitive to frontal system dysfunction, delayed alternation (DA) and delayed response (DR), to 12 patients from one OPCA family. Affected members from this family have previously been shown to have a marked and widespread cerebral (including frontal) cortical cholinergic reduction as severe as that observed in Alzheimer's disease. Performance on DA, but not on DR, was significantly impaired in the OPCA patients compared to that in the controls. We suggest that the DA deficits in OPCA could be a consequence of a loss of cholinergic innervation to orbitofrontal or possibly temporal cortical areas and/or damage to the integrity of the cerebellofrontal neuronal connections.

Decreased binding of 3H-glutamate in olivopontocerebellar atrophy patients and in Lurcher mutant mouse brain

Decreased binding of 3H-glutamate in olivopontocerebellar atrophy patients and in Lurcher mutant mouse brain

Dominantly inherited olivopontocerebellar atrophy from eastern Cuba: Clinical, neuropathological, and biochemical findings

A form of dominantly inherited olivopontocerebellar atrophy (OPCA) occurs commonly in persons of Spanish ancestry in northeastern Cuba. Its prevalence in the Province of Holguin is 41 per 100 000, a figure much higher than that found in western Cuba or in other parts of the world. The high prevalence is probably the result of a founder effect, but might be due to an interaction between a mutant gene and an unidentified environmental neurotoxin. We describe the clinical features of this disorder, and the neuropathological abnormalities in 7 autopsied patients. In addition, we report biochemical findings in plasma, cerebrospinal fluid (CSF) and urine obtained from 10 living OPCA patients. Quantitation of amino acids in fasting plasma showed a number of differences between the Cuban patients and healthy Canadian controls, but these are likely to have been caused by dietary differences. Amino acid concentrations in the CSF of the Cuban OPCA patients were similar to those of healthy Cuban controls, except for a decreased concentration of ethanolamine. Mean concentrations of dopamine metabolites were significantly low in the CSF of the OPCA patients, corresponding to neuronal depletion observed in the substantia nigra of autopsied cases. Examination of the patients' urines provided no evidence that either cyanide or 3-acetylpyridine is involved in causing this form of OPCA.