(1)H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2.

BACKGROUND AND AIM: Friedreich's ataxia (FRDA) and ataxia with oculomotor apraxia type 2 (AOA2) are the two most frequent forms of autosomal recessive cerebellar ataxias. However, brain metabolism in these disorders is poorly characterized and biomarkers of the disease progression are lacking. We aimed at assessing the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases. METHODS: Short-echo, single-voxel proton ((1)H) magnetic resonance spectroscopy data were acquired from 8 volunteers with FRDA, 9 volunteers with AOA2, and 38 control volunteers at 4T. Disease severity was assessed by the Friedreich's Ataxia Rating Scale (FARS). RESULTS: Neuronal loss/dysfunction was indicated in the cerebellar vermis and hemispheres in both diseases by lower total N-acetylaspartate levels than controls. The putative gliosis marker myo-inositol was higher than controls in the vermis and pons in AOA2 and in the vermis in FRDA. Total creatine, another potential gliosis marker, was higher in the cerebellar hemispheres in FRDA relative to controls. Higher glutamine in FRDA and lower glutamate in AOA2 than controls were observed in the vermis, indicating different mechanisms possibly leading to altered glutamatergic neurotransmission. In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p<0.01). CONCLUSION: Distinct neurochemical patterns were observed in the two patient populations, warranting further studies with larger patient populations to determine if the alterations in metabolite levels observed here may be utilized to monitor disease progression and treatment.

Cerebrospinal fluid concentrations of idebenone in Friedreich ataxia patients.

We studied plasma and cerebrospinal fluid (CSF) concentrations of idebenone in five Friedreich ataxia patients on treatment with this antioxidant, and plasma and CSF ubiquinone-10 (Q (10)) concentrations in 15 controls. CSF idebenone concentrations were below the detection limit in 3 Friedreich ataxia patients and no association could be demonstrated between plasma and CSF idebenone values. Q (10) CSF concentrations (median: 2.25 nmol/L) were approximately 300 times lower than those of plasma (median: 0.77 micro mol/L). No correlation was observed between plasma and CSF Q (10) concentrations. A significantly positive correlation was observed between CSF total protein values (range 8.1 - 107.5 mg/dL; median: 29.5) and CSF Q (10) concentrations (Spearman test: r = 0.664; p = 0.01). Our findings suggest that less idebenone is distributed to the brain than to other tissues, although CSF does not appear to be an appropriate material for treatment monitoring of idebenone and other quinoid compounds.

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

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cerebrospinal fluid corticotropin-releasing hormone in neurodegenerative diseases: reduction in spinocerebellar degeneration.

Levels of corticotropin-releasing hormone (CRH) in cerebrospinal fluid (CSF) were examined in patients with spinocerebellar degeneration (SCD) including olivopontocerebellar atrophy (OPCA), dentatorubropallidoluysian atrophy (DRPLA) and Friedreich's ataxia, Parkinson's disease (PD) and senile dementia of the Alzheimer type (SDAT), and normal aged subjects. CRH concentrations in CSF were significantly reduced in SCD compared to SDAT, PD and CSF and normal aged subjects. It is likely that degeneration not only of the cerebral cortex and the limbic system but also of the subcortical structures such as the brainstem and the cerebellum alters levels of CRH in CSF. Together with the recent anatomical and physiological evidence, the results suggest pathophysiological relevance of CRH for the cerebellar symptoms in SCD.

Thiamine status in inherited degenerative ataxias.

Blood thiamine levels in ataxia patients were studied. No significant differences were found between 30 patients with Friedreich's ataxia and 29 patients with olivopontocerebellar atrophy (OPCA) compared with control subjects. Both OPCA and Friedreich's ataxia patients presented significantly lower cerebrospinal fluid thiamine levels than their controls (p less than 0.001 and p less than 0.04 respectively). These results, discussed in terms of the high degree of cerebellar atrophy on CT scans in OPCA v Friedreich's ataxia patients, seem to correlate with cerebellar thiamine turnover and content.

Treatment of heredo-degenerative ataxias with amantadine hydrochloride.

Amantadine hydrochloride (AH) was administered (200 mg/day) for more than three months to 17 patients with Friedreich's ataxia (FA) and to 12 patients with olivopontocerebellar atrophies (OPCA) in an open clinical trial. Reaction time (RT) and movement time (MT) with the right and left hand were measured before and after treatment. A striking improvement on both RT and MT was observed in the OPCA group (on seven out of eight measures), whereas in the FA patients improvement was seen only in two out of four MT measures with no improvement in RT. Both groups had low levels of homovanillic acid (HVA) in their cerebrospinal fluid before treatment, relative to their controls. However, improvement with AH was not related to HVA levels.

Cerebrospinal fluid GABA and homocarnosine concentrations in patients with Friedreich's ataxia, Parkinson's disease, and Huntington's chorea.

Free and total gamma-aminobutyric acid (GABA) and homocarnosine concentrations were measured in the lumbar cerebrospinal fluid (CSF) of patients with Friedreich's ataxia, Huntington's chorea, and Parkinson's disease (with and without levodopa treatment), and compared with those determined in control subjects. Values found in Friedreich's ataxia or Parkinson's disease were not significantly different from those in controls. Unexpectedly, in Huntington patients, known to have a characteristic decrease in GABA concentrations in specific brain areas, CSF concentrations of total GABA and homocarnosine were significantly higher, whereas free GABA was not different from controls. These findings indicate that the measurement of CSF GABA and homocarnosine in patients with CNS degenerative diseases should be interpreted cautiously.

Friedreich's ataxia in the south of Italy: a clinical and biochemical survey of 23 patients.

We report a clinical and biochemical survey of 23 patients with Friedreich's ataxia from southern Italy. They were studied clinically and by means of a clinical rating scale devised by us (Inherited Ataxias Clinical Rating Scale). Laboratory tests, based on the Quebec Cooperative Study, were also performed on our patients. No major clinical or biochemical differences were found between Italian and Canadian patients. Investigation of CSF monoamine metabolites showed that HVA decreased after probenecid and metoclopramide loading.

[Degenerative changes in cerebrospinal fluid electrophoresis recordings during spinocerebellar hereditary degenerative disorders. A study of 111 cases (author's transl)]. / Electrophorèse du liquide céphalo-rachidien au cours des hérédodégénérescences spino-cérébelleuses. Etude de 111 observations.

The authors describe the results of electrophoresis studies of 111 cerebrospinal fluids from 110 patients with various spinocerebellar degenerative diseases (58 cases of Friedreich's disease, 14 of Pierre-Marie's ataxia, 12 of Strumpell-Lorrain paraplegia, 23 cerebellar atrophies, and 4 cases of Roussy-Levy disease). The degenerative profile of the electrophoresis findings were characterized by an overall reduction in CSF proteins, an increase in pre-albumin, and a reduction in gammaglobulin, and this was noted in 82 cases (73.8 p. 100). Low levels (less than or equal to 0.17 g/l) of proteins were observed in 19 cases (17.1 p. 100), and increased pre-albumin in 43 cases (38.7 p. 100). Reduced gammaglobulin was present in 20 cases (18.0 p. 100), and the cerebrospinal fluid was normal in only 29 cases (26.1 p. 100). These modifications could result from a particular type of physiopathological process of cell degeneration in the nervous system.

Taurine in cerebrospinal fluid in Friedreich's ataxia.

In a previous study we reported low values of taurine and aspartic acid in the CSF of patients with Friedreich's ataxia, when the results were compared to the literature. Further studies have revealed that unforetold difficulties with the advertised methodology of sequential multi-sample amino acid analysis were responsible for low values in the determination of these two amino acids in the small volumes necessary for CSF. A corrected method is presented. With the latter method the differences disappear for CSF taurine and aspartic acid, but they remain valid for the previously reported blood and urine values in Friedreich's ataxia. GABA levels are also normal in Friedreich's ataxia CSF.

Protein patterns of cerebrospinal fluid in hereditary ataxias and hereditary spastic paraplegia.

The CSF findings in hereditary ataxias and allief disorders have hitherto mostly been reported as normal if one excludes Refsum's syndrome. The CSF-protein patterns found on isoelectric focusing and quantitative paper electrophoresis were studied in 12 patients with hereditary ataxias and hereditary spastic paraplegia. Using a recently-developed technique of isoelectric focusing of CSF-proteins in flat beds of polyacrylamide gel, the authors could show abnormal CSF-protein patterns in all but 1 of the present cases. The aberrant CSF-protein patterns found showed differences between the syndromes studied. Two unique patterns with conspicuous fractions in the acid range were observed in patients with Marie-Sanger-Brown's ataxia (mother and daughter) and Holmes' ataxia. A third CSF-protein pattern was found in a sibship with Friedreich's ataxia including a double fraction in the acid region (pI 5.9-6.1) in all 4 subjects and a highly alkaline fraction (HAF) with pI about 9.3, in 3 of them. Similar acid fractions (pI 5.9-6.1) were also detected in 3 of 4 patients with hereditary spastic paraplegia, a brother and sister showing a very similar CSF-protein pattern. Double fractions with pI 5.9-6.1 and/or HAF may also occur in other neurological diseases, mostly, however, associated with other distinctive features of their CSF-protein patterns. A possibility in the future of distinguishing hereditary CNS-diseases by examination of the CSF-protein pattern is suggested.