Impaired implicit learning and feedback processing after stroke.

The ability to learn is assumed to support successful recovery and rehabilitation therapy after stroke. Hence, learning impairments may reduce the recovery potential. Here, the hypothesis is tested that stroke survivors have deficits in feedback-driven implicit learning. Stroke survivors (n=30) and healthy age-matched control subjects (n=21) learned a probabilistic classification task with brain activation measured using functional magnetic resonance imaging in a subset of these individuals (17 stroke and 10 controls). Stroke subjects learned slower than controls to classify cues. After being rewarded with a smiley face, they were less likely to give the same response when the cue was repeated. Stroke subjects showed reduced brain activation in putamen, pallidum, thalamus, frontal and prefrontal cortices and cerebellum when compared with controls. Lesion analysis identified those stroke survivors as learning-impaired who had lesions in frontal areas, putamen, thalamus, caudate and insula. Lesion laterality had no effect on learning efficacy or brain activation. These findings suggest that stroke survivors have deficits in reinforcement learning that may be related to dysfunctional processing of feedback-based decision-making, reward signals and working memory.

Risk of osteoporotic fractures following stroke in older persons.

UNLABELLED: The aim of this study was to explore the increased risk of stroke survivors to different sustained osteoporotic fractures. We used hospital data and data on functional impairment. We found a higher risk in stroke survivors without functional impairment with the risk higher for lower than for upper extremity fractures. INTRODUCTION: Stroke survivors are at high risk of osteoporotic fractures due to frequent falls and an increased risk to develop osteoporosis. Data on their relative risk to sustain other than hip fractures is limited. Furthermore, the role of severe functional impairment on their fracture risk has not been considered yet. The aim of this study was to determine the relative risk of stroke survivors to sustain different osteoporotic fractures with regard to the presence of severe functional impairment. METHODS: Data from 2004 to 2009 of more than 1.2 million individuals aged 65 years or older and insured at a large German health insurance company were used for the analyses. Incident stroke and fractures were obtained from hospital diagnoses. Analyses were stratified by gender and information on severe functional impairment. Persons without preceding incident stroke were used as the reference group. Multistate models were used to estimate hazard ratios. RESULTS: Stroke survivors had a higher risk for fractures. However, a strong effect modification by functional impairment was apparent. Stroke survivors with functional impairment had no significantly increased risk for any fractures site compared to the corresponding reference group with functional impairment. In contrast, stroke survivors without functional impairment had a clearly and significantly increased fracture risk for most fracture sites. In these persons, the relative fracture risk for fractures of the lower extremities was higher than for fractures of the upper extremities. CONCLUSION: To evaluate the relative risk of stroke survivors for osteoporotic fractures, functional status appears to be a relevant parameter.

Prospective analysis of falls in dominant ataxias.

In a previous retrospective study, we demonstrated that falls are common and often injurious in dominant spinocerebellar ataxias (SCAs) and that nonataxia features play an important role in these falls. Retrospective surveys are plagued by recall bias for the presence and details of prior falls. We therefore sought to corroborate and extend these retrospective findings by means of a prospective extension of this fall study. 113 patients with SCA1, SCA2, SCA3 or SCA6, recruited from the EuroSCA natural history study, were asked to keep a fall diary in between their annual visits to the participating centres. Additionally, patients completed a detailed questionnaire about the first three falls, to identify specific fall circumstances. Relevant disease characteristics were retrieved from the EuroSCA registry. 84.1% of patients reported at least one fall during a time period of 12 months. Fall-related injuries were common and their frequency increased with that of falls. The presence of nonataxia symptoms was associated with a higher fall frequency. This study confirms that falls are a frequent and serious complication of SCA, and that the presence of nonataxia symptoms is an important etiological factor in its occurrence.

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study.

OBJECTIVE: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits. METHODS: As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. RESULTS: The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females. CONCLUSIONS: Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.

Valsalva manoeuvre in patients with different Parkinsonian disorders.

The valsalva manoeuvre (VM), used as an autonomic function test, can detect sympathetic and/or parasympathetic autonomic dysfunction. This study investigated the value of VM in patients with different Parkinsonian syndromes (PS). We continuously recorded blood pressure, ECG and respiration among 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (PD) and in 27 healthy subjects matched in age and sex (Con). VM was performed in addition to metronomic breathing and tilt-table testing. VM could not be analysed in 26% of the ES patients. Valsalva ratio (VR), as a parameter of cardiovagal function, was pathologically decreased in all patient groups. Valsalva ratio (VR) was not able to discriminate parasympathetic dysfunction between patients and controls as well as E/I ratio of metronomic breathing. As a parameter of sympathetic dysfunction during VM, the physiological increase of blood pressure was more often missing during phase IV than phase II especially in PD and MSA patients. Correlation with orthostatic hypotension during tilt-table testing was only moderate. Although VM can demonstrate sympathetic and parasympathetic autonomic dysfunction, we cannot recommend VM as a first line autonomic test in PS patients. Metronomic breathing and tilt-table test seem more capable as parasympathetic resp. and sympathetic function tests to identify cardiovascular abnormalities in PS patients.

Baroreflex sensitivity and power spectral analysis in different extrapyramidal syndromes.

Cardiac autonomic abnormalities have been described in Parkinson's disease and other extrapyramidal syndromes. To investigate baroreflex sensitivity as an important risk marker of cardiovascular mortality in patients with Parkinson's disease and other extrapyramidal syndromes. We recorded continuously blood pressure, ECG and respiration in 35 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 46 patients with idiopathic Parkinson's disease (PD) and in 27 corresponding healthy subjects (Con). Recordings of 2 min at rest were used to calculate baroreflex and spectral analysis of heart rate and systolic blood pressure. Resting baroreflex sensitivity (BRS) was significantly lower in the MSA and the PSP group but not in the PD group in comparison to the Con group. With increasing Hoehn & Yahr stage, BRS significantly decreased in all patient groups. In spectral analysis, all patient groups had a significantly lower relative low frequency (LF)-band power than the healthy controls. Patients with extrapyramidal disorders frequently demonstrate pathologically decreased BRS values and abnormalities of spectral analysis. This may have fundamental impact on the cardiovascular prognosis of patients with extrapyramidal disease.

SCA Functional Index: a useful compound performance measure for spinocerebellar ataxia.

OBJECTIVE: To evaluate the usefulness of functional measures in patients with spinocerebellar ataxia (SCA). METHODS: We assessed three functional measures-8 m walking time (8MW), 9-hole peg test (9HPT), and PATA repetition rate-in 412 patients with autosomal dominant SCA (genotypes 1, 2, 3, and 6) in a multicenter trial. RESULTS: While PATA rate was normally distributed (mean/median 21.7/20.5 per 10 s), the performance times for 8MW (mean/median 10.8/7.5 s) or 9HPT (mean/median 47.2/35.0 s in dominant, 52.2/37.9 s in nondominant hand) were markedly skewed. Possible learning effects were small and likely clinically irrelevant. A composite functional index (SCAFI) was formed after appropriate transformation of subtest results. The Z-scores of each subtest correlated well with the Scale for the Assessment and Rating of Ataxia (SARA), the Unified Huntington's disease Rating Scale functional assessment, and disease duration. Correlations for SCAFI with each of these parameters were stronger (Pearson r = -0.441 to -0.869) than for each subtest alone. Furthermore, SCAFI showed a linear decline over the whole range of disease severity, while 9HPT and 8MW had floor effects with respect to SARA. Analysis of possible confounders showed no effect of genotype or study site and only minor effects of age for 8MW. CONCLUSION: The proposed functional measures and their composite SCAFI have favorable properties to assess patients with spinocerebellar ataxia.

Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.

Scale for the assessment and rating of ataxia: development of a new clinical scale.

OBJECTIVE: To develop a reliable and valid clinical scale measuring the severity of ataxia. METHODS: The authors devised the Scale for the Assessment and Rating of Ataxia (SARA) and tested it in two trials of 167 and 119 patients with spinocerebellar ataxia. RESULTS: The mean time to administer SARA in patients was 14.2 +/- 7.5 minutes (range 5 to 40). Interrater reliability was high, with an intraclass coefficient (ICC) of 0.98. Test-retest reliability was high with an ICC of 0.90. Internal consistency was high as indicated by Cronbach's alpha of 0.94. Factorial analysis revealed that the rating results were determined by a single factor. SARA ratings showed a linear relation to global assessments using a visual analogue scale, suggesting linearity of the scale (p < 0.0001, r(2) = 0.98). SARA score increased with the disease stage (p < 0.001) and was closely correlated with the Barthel Index (r = -0.80, p < 0.001) and part IV (functional assessment) of the Unified Huntington's Disease Rating Scale (UHDRS-IV) (r = -0.89, p < 0.0001), whereas it had only a weak correlation with disease duration (r = 0.34, p < 0.0002). CONCLUSIONS: The Scale for the Assessment and Rating of Ataxia is a reliable and valid measure of ataxia, making it an appropriate primary outcome measure for clinical trials.

Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred.

The authors report a German family with autosomal dominant cerebellar ataxia tightly linked to the spinocerebellar ataxia type 5 (SCA5) locus (multipoint lod score 5.76). The phenotype is characterized by a purely cerebellar syndrome with a downbeat nystagmus occurring prior to the development of other features. Imaging studies demonstrated cortical cerebellar atrophy. Progression is slow even in patients with a disease onset during the second decade. The age at onset varies from 15 to 50 years.

MRI-based volumetric differentiation of sporadic cerebellar ataxia.

The term idiopathic cerebellar ataxia (IDCA) designates a variety of cerebellar syndromes that may present with a purely cerebellar syndrome (IDCA-C) or with additional extracerebellar features (IDCA-P). Multiple system atrophy is also a sporadic neurodegenerative disorder of unknown origin that may cause prominent cerebellar symptoms (MSA-C). The final neuropathological answer to the question whether IDCA-P and MSA-C represent different varieties of one disease or two distinct entities is still lacking. Three-dimensional MRI-based volumetry allows morphological investigations intra vitam. Volumetric analysis of cerebellum, brainstem and basal ganglia was therefore performed in 46 patients with sporadic cerebellar ataxia and 16 age-matched healthy controls. Patients with dementia were excluded from the study since cognitive impairment is an exclusion criterion for the diagnosis of MSA. Cerebellar patients were clinically divided into two groups: 33 patients with multiple system atrophy with prominent cerebellar symptoms (MSA-C) and 13 patients with extracerebellar features not corresponding to MSA-C (IDCA-P). There was evidence for substantial cerebellar atrophy in both cerebellar groups while additional brainstem atrophy was significantly more pronounced in MSA-C patients. Absolute caudate and putamen atrophy was found to be restricted to single MSA-C individuals while group comparisons of mean volumes did not yield significant differences from controls. Based on the volumetric data, diagnosis could be correctly predicted in 94% of control, 82% of MSA-C and 100% of IDCA-P individuals. The finding of specific imaging characteristics strengthens (i) the value of MRI volumetry in separating MSA-C from other types of sporadic cerebellar ataxia, and (ii) the hypothesis of two independent neurodegenerative disorders in MSA-C and IDCA-P.

The cerebellum and cognition. Intellectual function in spinocerebellar ataxia type 6 (SCA6).

The aim of this study was to assess cognitive function in patients with spinocerebellar ataxia type 6 (SCA6), an autosomal-dominantly inherited disease leading to a progressive cerebellar syndrome. In contrast to other SCA types, the pathological changes are mostly restricted to the cerebellum. Cognitive function was studied in 12 patients with genetically confirmed SCA6 (mean duration of disease: 9.2 +/- 11.6 years) and 12 age- and IQ-matched controls using a test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive function. While none of the SCA6 subjects had features of general intellectual impairment, only mild deficits in single subtests especially in fronto-executive tasks were observed, but without reaching statistical significance. Thus the current findings do not demonstrate severe cognitive dysfunction in SCA6.

Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3.

Cognitive impairment was studied in distinct types of spinocerebellar ataxia (SCA): eleven SCA1, 14 SCA2, and 11 SCA3 individuals and 8 age- and IQ- matched controls. All were submitted to a neuropsychological test battery that comprised tests for IQ, attention, executive function, verbal and visuospatial memory. Executive dysfunction was prominent in SCA1 as compared with controls and all other SCA types. Mild deficits of verbal memory were present in SCA1, SCA2 and SCA3. The neuropathological pattern in different SCA types suggests that these cognitive deficits are not likely to be contingent upon cerebellar degeneration but to result from disruption of a cerebrocerebellar circuitry presumably at the pontine level.

Executive dysfunction in spinocerebellar ataxia type 1.

Fourteen patients with spinocerebellar ataxia 1 (SCA1) and 11 controls with similar mean age and IQ estimates were submitted to a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory as well as executive functions. Neuropsychological assessment yielded verbal memory and executive dysfunction while tests of visuospatial memory and attention were not significantly impaired in SCA1 as compared to controls. Test performance was neither related to the repeat length, the age of onset nor the disease duration. The profile of cognitive impairment in SCA1 with prominent executive dysfunction corresponds to the concept of "frontal-subcortical" dementia that is likely to be contingent upon disruption of a cerebrocerebellar circuitry that consists of afferent and efferent connections between the prefrontal cortex and the cerebellum.

Cognitive deficits in spinocerebellar ataxia 2.

This is one of the first studies assessing the pattern of cognitive impairment in spinocerebellar ataxia 2 (SCA2). Cognitive function was studied in 17 patients with genetically confirmed SCA2 and 15 age- and IQ- matched controls using a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive functions. Twenty-five percent of the SCA2 subjects showed evidence of dementia. Even in non-demented SCA2 subjects, there was evidence of verbal memory and executive dysfunction. Tests of visuospatial memory and attention were not significantly impaired in the non-demented group compared with controls. There was no relationship between test performance and motor disability, repeat length or age of onset, while disease duration was shown to be inversely correlated with two tests reflecting the progression of cognitive deficits during the course of the disease. Intellectual impairment should therefore not be interpreted as a secondary effect of progressive motor disability, but represents an important and independent part of the SCA2 phenotype.