Berry Kremer

Reliability and Validity of the international cooperative ataxia rating scale: A study in 156 spinocerebellar ataxia patients

To evaluate the efficacy of treatments in spinocerebellar ataxias (SCAs), appropriate clinical scales are required. This study evaluated metric properties of the International Cooperative Ataxia Rating Scale (ICARS) in 156 SCA patients and 8 controls. ICARS was found to be a reliable scale satisfying accepted criteria for interrater reliability, test–retest reliability, and internal consistency. Although validity testing was limited, we found evidence of validity of ICARS when ataxia disease stages and Barthel index were used as external criteria. On the other hand, our study revealed two major problems associated with the use of ICARS. First, the redundant and overlapping nature of several items gave rise to a considerable number of contradictory ratings. Second, a factorial analysis showed that the rating results were determined by four different factors that did not coincide with the ICARS subscales, thus questioning the justification of ICARS subscore analysis in clinical trials.

No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial.

Background The objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimers disease (AD). Methodology/Principal Findings This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinicians Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8±7.6), than in the placebo group (9.3±10.0). This difference (1.5 points; CI −4.5–7.5) was not statistically significant, and neither were any of the secondary outcome measures. Conclusions/Significance The results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD. Trial Registration ClinicalTrials.gov NCT00432081

Expression pattern of apoptosis-related markers in Huntington's disease

Inappropriate apoptosis has been implicated in the mechanism of neuronal death in Huntington’s disease (HD). In this study, we report the expression of apoptotic markers in HD caudate nucleus (grades 1–4) and compare this with controls without neurological disease. Terminal transferase-mediated biotinylated-UTP nick end-labeling (TUNEL)-positive cells were detected in both control and HD brains. However, typical apoptotic cells were present only in HD, especially in grade 3 and 4 specimens. Expression of the pro-apoptotic protein Bax was increased in HD brains compared to controls, demonstrating a cytoplasmic expression pattern in predominantly shrunken and dark neurons, which were most frequently seen in grades 2 and 3. Control brains displayed weak perinuclear expression of the anti-apoptotic protein Bcl-2, whereas in HD brains Bcl-2 immunoreactivity was markedly enhanced, especially in severely affected grade 4 brains, and was observed in both healthy neurons and dark neurons. Caspase-3, an executioner protease, was only found in four HD brains of different grades and was not expressed in controls. A strong neuronal and glial expression of poly(ADP-ribose) polymerase (PARP)-immunoreactivity was observed in HD brains. These data strongly suggest the involvement of apoptosis in HD. The exact apoptotic pathway occurring in HD neurodegeneration remains yet unclear. However, the presence of late apoptotic events, such as enhanced PARP expression and many TUNEL-positive cells accompanied with weak caspase-3 immunoreactivity in severely affected HD brains, suggests that caspase-mediated neuronal death only plays a minor role in HD.

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1–3), speech (item 4) and the limb kinetic subscore (items 5–8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose–finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

Autosomal recessive cerebellar ataxias: the current state of affairs

Among the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, and the genetic heterogeneity often complicate the clinical management of such patients. Despite the steady increase in newly discovered ARCA genes, many patients with a putative ARCA cannot be genotyped yet, proving that more genes must be involved. This review presents an updated overview of the various ARCAs. The clinical and genetic characteristics of those forms with a known molecular genetic defect are discussed, along with the emerging insights in the underlying pathophysiological mechanisms.

Self-rated health status in spinocerebellar ataxia—Results from a European multicenter study†

Patient‐based measures of subjective health status are increasingly used as outcome measures in interventional trials. We aimed to determine the variability and predictors of subjective health ratings in a possible target group for future interventions: the spinocerebellar ataxias (SCAs). A consecutive sample of 526 patients with otherwise unexplained progressive ataxia and genetic diagnoses of SCA1 (117), SCA2 (163), SCA3 (139), and SCA6 (107) were enrolled at 18 European referral centers. Subjective health status was assessed with a generic measure of health related quality of life, the EQ‐5D (Euroqol) questionnaire. In addition, we performed a neurological examination and a screening questionnaire for affective disorders (patient health questionnaire). Patient‐reported health status was compromised in patients of all genotypes (EQ‐5D visual analogue scale (EQ‐VAS) mean 61.45 ± 20.8). Specifically, problems were reported in the dimensions of mobility (86.9% of patients), usual activities (68%), pain/discomfort (49.4%), depression/anxiety (46.4%), and self care (38.2%). Multivariate analysis revealed three independent predictors of subjective health status: ataxia severity, extent of noncerebellar involvement, and the presence of depressive syndrome. This model explained 30.5% of EQ‐VAS variance in the whole sample and might be extrapolated to other SCA genotypes.

The mitochondrial toxin 3-nitropropionic acid induces differential expression patterns of apoptosis-related markers in rat striatum.

The mitochondrial toxin 3‐nitropropionic acid (3‐NP) causes selective striatal lesions in rats and serves as an experimental model for the neurodegenerative disorder Huntingtons disease (HD). Apoptotic cell death has been implicated for the neuronal degeneration that occurs in HD brains. The present study was designed to investigate whether the 3‐NP‐induced cell death in rats involves apoptosis and an altered expression of Bcl‐2 family proteins. Systemic administration of 3‐NP via subcutaneous Alzet pumps resulted in lesions of variable severity with neuronal loss and gliosis in the striatum. Using the terminal transferase‐mediated biotinylated‐UTP nick end‐labelling (TUNEL) of DNA, TUNEL‐positive cells exhibiting typical apoptotic morphology were detected only in the striatum of rats with a severe lesion. Furthermore, the neuronal expression of the pro‐apoptotic protein Bax was strongly increased in the core of the severe lesion. Expression of the anti‐apoptotic marker Bcl‐2 was unchanged in this location, but was enhanced in the margins of the lesions. A moderately increased expression of both Bax and Bcl‐2 was observed in dark neurones in the mild lesion and in the subtle lesion. The presence of nuclear DNA fragmentation, strong granular Bax expression and an increased Bax/Bcl‐2 ratio in the centre of severe lesions suggests the occurrence of apoptotic cell death following 3‐NP administration. In contrast, the dark compromised neurones observed in 3‐NP‐treated animals revealed an equally enhanced expression of both Bax and Bcl‐2, but lacked TUNEL‐labelling, and are therefore not apoptotic.

Guanidinoacetate methyltransferase (GAMT) deficiency diagnosed by proton NMR spectroscopy of body fluids

In patients with guanidinoacetate methyltransferase (GAMT) deficiency several parameters may point towards the diagnosis of GAMT deficiency. These include the low levels of creatine and creatinine in urine, the high concentration of guanidinoacetic acid (GAA) in urine and the low levels of creatine and creatinine in the cerebrospinal fluid (CSF). In this study, body fluids from 10 GAMT deficient patients were analysed using 1H NMR spectroscopy. The urine 1D 1H NMR spectra of all the patients showed a doublet resonance at 3.98 ppm (pH 2.50) derived from GAA present in high concentration. For this compound, a good recovery and good correlation was found between an LC‐MS/MS method and 1H NMR spectroscopy. In CSF NMR spectra of these patients, the singlet resonances of creatine and creatinine (3.05 and 3.13 ppm, respectively) were absent (normally always present in 1H NMR spectra of CSF). Due to overlap by other resonances, the doublet of GAA could not be observed. Our data demonstrate that 1H NMR spectroscopy of urine and CSF can be used to diagnose patients with GAMT deficiency. Copyright

3-Nitropropionic acid induces cell death and mitochondrial dysfunction in rat corticostriatal slice cultures.

Exposure of organotypic rat corticostriatal slice cultures to the mitochondrial toxin 3-nitropropionic acid (3-NP) resulted in concentration-dependent loss of cresylviolet-stained cells and increase of lactate dehydrogenase and lactate efflux into the culture medium, indicators for cell death and metabolic activity in the slices, respectively. The involvement of apoptosis in these slices was suggested by using the terminal transferase-mediated biotinylated-UTP nick end-labeling (TUNEL) technique, and immunohistochemistry for the apoptosis-related markers Bax and Bcl-2. In 3-NP-exposed slices, TUNEL-positive cells were observed in both the striatum and the cortex but in different forms: striatal neurons were either diffusely stained or showed nuclear fragmentation, cortical neurons only exhibiting nuclear fragmentation. In 3-NP-exposed slices, the pro-apoptotic protein Bax was abundantly expressed, whereas the anti-apoptotic protein Bcl-2 was not expressed in striatal neurons. We suggest that both apoptosis and necrosis are involved in the 3-NP-treated slices, apoptosis as well as necrosis in the striatum and apoptosis in the cortex.

Differential gene expression in human brain pericytes induced by amyloid-beta protein.

Cerebral amyloid angiopathy is one of the characteristics of Alzheimers disease (AD) and this accumulation of fibrillar amyloid‐β (Αβ) in the vascular wall is accompanied by marked vascular damage. In vitro, Aβ1−40 carrying the ‘Dutch’ mutation (DAβ1−40) induces degeneration of cultured human brain pericytes (HBP). To identify possible intracellular mediators of Aβ‐induced cell death, a comparative cDNA expression array was performed to detect differential gene expression of Aβ‐treated vs. untreated HBP. Messenger RNA expression of cyclin D1, integrin β4, defender against cell death‐1, neuroleukin, thymosin β10, and integrin α5 were increased in DAβ1−40‐treated HBP, whereas insulin‐like growth factor binding protein‐2 mRNA expression was decreased. Corresponding protein expression was investigated in AD and control brains to explore a potential role for these proteins in pathological lesions of the AD brain. Cyclin D1 expression was increased in cerebral amyloid angiopathy and cells in a perivascular position, suggesting that the cell cycle may be disturbed during Aβ‐mediated degeneration of cerebrovascular cells. Moreover, cyclin D1 expression, but also that of integrin β4, defender against cell death‐1, neuroleukin and thymosin β10 was found in a subset of senile plaques, suggesting a role for these proteins in the pathogenesis of senile plaques.