Ana S. Costa

Biological and clinical characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data.

BACKGROUND Friedreichs ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreichs ataxia database registry. METHODS Within the European Friedreichs Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreichs ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and secondary outcome measures were the Inventory of Non-Ataxia Signs (INAS), the performance-based coordination test Spinocerebellar Ataxia Functional Index (SCAFI), the neurocognitive phonemic verbal fluency test, and two quality-of-life measures: the activities of daily living (ADL) part of the Friedreichs Ataxia Rating Scale and EQ-5D. The Friedreichs ataxia cohort was subdivided into three groups: early disease onset (≤14 years), intermediate onset (15-24 years), and late onset (≥25 years), which were compared for clinical characteristics and outcome measures. We used linear regression analysis to estimate the annual decline of clinical outcome measures based on disease duration. This study is registered with ClinicalTrials.gov, number NCT02069509. FINDINGS We enrolled 592 patients with genetically confirmed Friedreichs ataxia between Sept 15, 2010, and April 30, 2013, at 11 sites in seven European countries. Age of disease onset was inversely correlated with the number of GAA repeats in the frataxin (FXN) gene: every 100 GAA repeats on the smaller repeat allele was associated with a 2·3 year (SE 0·2) earlier onset. Regression analyses showed significant estimated annual worsening of SARA (regression coefficient 0·86 points [SE 0·05], INAS (0·14 points [0·01]), SCAFI Z scores (-0·09 [0·01]), verbal fluency (-0·34 words [0·07]), and ADL (0·64 points [0·04]) during the first 25 years of disease; the regression slope for health-related quality-of-life state from EQ-5D was not significant (-0·33 points [0·18]). For SARA, the predicted annual rate of worsening was significantly higher in early-onset patients (n=354; 1·04 points [0·13]) and intermediate-onset patients (n=137; 1·17 points [0·22]) than in late-onset patients (n=100; 0·56 points [0·10]). INTERPRETATION The results of this cross-sectional baseline analysis of the EFACTS cohort suggest that earlier disease onset is associated with larger numbers of GAA repeats and more rapid disease progression. The differential estimated progression of ataxia symptoms related to age of onset have implications for the design of clinical trials in Friedreichs ataxia, for which SARA might be the most suitable measure to monitor disease progression. FUNDING European Commission.

Genotype-specific patterns of atrophy progression are more sensitive than clinical decline in SCA1, SCA3 and SCA6

Spinocerebellar ataxias are dominantly inherited disorders that are associated with progressive brain degeneration, mainly affecting the cerebellum and brainstem. As part of the multicentre European integrated project on spinocerebellar ataxias study, 37 patients with spinocerebellar ataxia-1, 19 with spinocerebellar ataxia-3 and seven with spinocerebellar ataxia-6 were clinically examined and underwent magnetic resonance imaging at baseline and after a 2-year follow-up. All patients were compared with age-matched and gender-matched healthy control subjects. Magnetic resonance imaging analysis included three-dimensional volumetry and observer-independent longitudinal voxel-based morphometry. Volumetry revealed loss of brainstem, cerebellar and basal ganglia volume in all genotypes. Most sensitive to change was the pontine volume in spinocerebellar ataxia-1, striatal volume in spinocerebellar ataxia-3 and caudate volume in spinocerebellar ataxia-6. Sensitivity to change, as measured by standard response mean, of the respective MRI measures was greater than that of the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia. Longitudinal voxel-based morphometry revealed greatest grey matter loss in the cerebellum and brainstem in spinocerebellar ataxia-1, in the putamen and pallidum in spinocerebellar ataxia-3 and in the cerebellum, thalamus, putamen and pallidum in spinocerebellar ataxia-6. There was a mild correlation between CAG repeat length and volume loss of the bilateral cerebellum and the pons in spinocerebellar ataxia-1. Quantitative volumetry and voxel-based morphometry imaging demonstrated genotype-specific patterns of atrophy progression in spinocerebellar ataxias-1, 3 and 6, and they showed a high sensitivity to detect change that was superior to clinical scales. These structural magnetic resonance imaging findings have the potential to serve as surrogate markers, which might help to delineate quantifiable endpoints and non-invasive methods for rapid and reliable data acquisition, encouraging their use in clinical trials.

Alternate-Form Reliability of the Montreal Cognitive Assessment Screening Test in a Clinical Setting

Aims: The Montreal Cognitive Assessment (MoCA) has gained recognition for its validity in detecting cognitive impairment in several clinical populations. For serial assessments, alternate forms are needed to overcome possible practice effects. Our objective was to investigate the reliability of two German MoCA alternate forms for longitudinal assessment applications. Methods: The original and one of two alternate forms of the MoCA were administered within a 60-min interval of a clinical interview in a counterbalanced order to 100 healthy elderly controls, 30 patients with mild cognitive impairment (MCI) and 30 patients with Alzheimer’s disease (AD). The diagnosis of the majority of patients was supported by in vivo AD pathology biomarkers. Results: There was a strong correlation between the alternate forms and the original MoCA in all groups, but particularly in the clinical samples. Total mean scores did not differ significantly between the MoCA versions, even taking into account the presentation order. As in previous studies, age and education influenced performance in the MoCA. The same pattern of group differences (controls > MCI > AD) was observed for each of the versions. Conclusion: All three forms can be reliably and interchangeably used in serial cognitive assessment, confirming the MoCA’s applicability in research and clinical longitudinal approaches.

The Montreal Cognitive Assessment (MoCA) - A Sensitive Screening Instrument for Detecting Cognitive Impairment in Chronic Hemodialysis Patients

Background Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) therapy have an increased risk of developing cognitive impairment and dementia, which are known relevant factors in disease prognosis and therapeutic success, but still lack adequate screening in clinical routine. We evaluated the Montreal Cognitive Assessment (MoCA) for suitability in assessing cognitive performance in HD patients in comparison to the commonly used Mini-Mental State Examination (MMSE) and a detailed neuropsychological test battery, used as gold standard. Methods 43 HD patients and 42 healthy controls with an average age of 58 years, were assessed with the MoCA, the MMSE and a detailed neuropsychological test battery, covering the domains of memory, attention, language, visuospatial and executive functions. Composite scores were created for comparison of cognitive domains and test results were analyzed using Spearmans correlation and linear regression. Cognitive dysfunction was defined using z-score values and predictive values were calculated. Sensitivity and specificity of the MoCA were determined using receiver operating characteristic (ROC) analysis. Results HD patients performed worse in all cognitive domains, especially in memory recall and executive functions. The MoCA correlated well with the detailed test battery and identified patients with cognitive impairment with a sensitivity of 76.7% and specificity of 78.6% for a cut-off value of ≤24 out of 30 points. In the detailed assessment executive functions accounted significantly for performance in the MoCA. The MMSE only discriminated weakly between groups. Conclusions The MoCA represents a suitable cognitive screening tool for hemodialysis patients, demonstrating good sensitivity and specificity levels, and covering executive functions, which appear to play an important role in cognitive performance of HD patients.

Clinical Predictors of Individual Cognitive Fluctuations in Patients Undergoing Hemodialysis

BACKGROUND Cognitive impairment in hemodialysis (HD) patients is frequent and mediated by several factors. It is unclear which patients are more susceptible to cognitive variations around the dialysis cycle and which clinical factors may play a mediator role. We aimed to answer these issues by investigating intraindividual changes within the dialysis cycle. STUDY DESIGN Cross-sectional observational study with repeated measures. SETTING & PARTICIPANTS 47 HD patients and 40 controls without kidney disease, both without history of neurologic disease. PREDICTORS Dialysis vintage, disease duration, vascular risk factors, comorbidity index score, intradialytic weight change, frequency of hypotensive episodes, and biochemical levels (hemoglobin, leukocytes, urea, creatinine, sodium, and potassium). Covariates included demographics (age, education, and sex). OUTCOMES & MEASUREMENTS Significant individual deterioration in attention and executive functions (phasic and intrinsic alertness, Stroop test, and Trail Making Test) after dialysis, as measured by a regression-based reliable change method. Regression models were used to identify clinical predictors of individual cognitive decline after dialysis. RESULTS After dialysis, patients primarily showed prolonged reaction times and psychomotor slowing. However, individual-based analyses revealed that fluctuations in attention and executive functions were present in only a minority of patients. Significant individual fluctuations on particular attention and executive tasks were associated moderately with intradialytic hypotensive episodes, as well as with psychoactive medication, and were predicted weakly by blood leukocyte count, sodium level, dialysis vintage, and volume. LIMITATIONS Small sample size; patient group younger and healthier than the overall HD population, limiting generalizability. CONCLUSIONS Only a minority of patients exhibit significant individual cognitive fluctuations, predominantly showing deterioration after dialysis in attention and executive functions. Susceptibility to such fluctuations was predicted in part by both HD-dependent and -independent factors.

Parkinson’s Disease and Dementia: A Longitudinal Study (DEMPARK)

Background: Parkinson’s disease (PD) is a progressive neurodegenerative motor disorder. However, non-motor complications frequently alter the course of the disease. A particularly disabling non-motor symptom is dementia. Methods/Design: The study is designed as a multicentre prospective, observational cohort study of about 700 PD patients aged 45–80 years with or without dementia and PD-mild cognitive impairment (MCI). The patients will be recruited in eight specialized movement disorder clinics and will be followed for 36 months. Information about the patients’ functional status will be assessed at baseline and 6-/12- month intervals. In addition, 120 patients with dementia with Lewy bodies (DLB) will be included. Well-established standardized questionnaires/tests will be applied for detailed neuropsychological assessment. In addition, patients will be asked to participate in modules including volumetric MRI, genetic parameters, and neuropsychology to detect risk factors, early diagnostic biomarkers and predictors for dementia in PD. Results: The study included 604 PD patients by March 2011; 56.3% were classified as having PD alone, with 30.6% of patients suffering from PD-MCI and 13.1% from PD with dementia. The mean age of the cohort was 68.6 ± 7.9 years, with a mean disease duration of 6.8 ± 5.4 years. There was a preponderance of patients in the earlier Hoehn and Yahr stages. Conclusion: The main aim of the study is to characterize the natural progression of cognitive impairment in PD and to identify factors which contribute to the evolution and/or progression of the cognitive impairment. To accomplish this aim we established a large cohort of PD patients without cognitive dysfunction, PD patients with MCI, and PD patients with dementia, to characterize these patients in a standardized manner, using imaging (serial structural MRI), genetic and proteomic methods in order to improve our understanding of the course of the PD process and the development of cognitive dysfunction and dementia in this disease. The inclusion of the DLB patients will start in the second quarter of 2011 in the BMBF-funded follow-up project LANDSCAPE.

Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study

Friedreichs ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico‐cerebellar dysfunctions underlying executive functioning in individuals with FRDA.

Evidence of the Sensitivity of the MoCA Alternate Forms in Monitoring Cognitive Change in Early Alzheimer's Disease

Background/Aims: There is an increasing interest in using the Montreal Cognitive Assessment (MoCA) test as a monitoring tool in Alzheimers disease (AD) in both research and clinical settings. Our aim was to investigate the utility of alternate forms of the MoCA in detecting cognitive deterioration in a sample of early AD patients followed longitudinally in an outpatient memory clinic. Method: Twenty-five patients with early-stage AD (prodromal or mild dementia) were administered the original version and one of two previously validated alternate forms of the MoCA within an interval of about 1 year. The decline over time and the rate of change of the MoCA were compared to the total score of a standardized neuropsychological assessment battery (Consortium to Establish a Registry of Alzheimers Disease; CERAD-Plus). Responsiveness to change was determined by calculating standard response means and the respective effect sizes. Results: Sixty percent of the sample showed a clinical decline on the clinical dementia rating (CDR) scale. There was significant deterioration in the MoCA and CERAD total scores. Conclusion: The results demonstrate that the MoCA is capable of detecting change over time and seems to be a valid tool with small to moderate sensitivity for monitoring cognitive change in early AD.

Increased Cerebral Water Content in Hemodialysis Patients

Little information is available on the impact of hemodialysis on cerebral water homeostasis and its distribution in chronic kidney disease. We used a neuropsychological test battery, structural magnetic resonance imaging (MRI) and a novel technique for quantitative measurement of localized water content using 3T MRI to investigate ten hemodialysis patients (HD) on a dialysis-free day and after hemodialysis (2.4±2.2 hours), and a matched healthy control group with the same time interval. Neuropsychological testing revealed mainly attentional and executive cognitive dysfunction in HD. Voxel-based-morphometry showed only marginal alterations in the right inferior medial temporal lobe white matter in HD compared to controls. Marked increases in global brain water content were found in the white matter, specifically in parietal areas, in HD patients compared to controls. Although the global water content in the gray matter did not differ between the two groups, regional increases of brain water content in particular in parieto-temporal gray matter areas were observed in HD patients. No relevant brain hydration changes were revealed before and after hemodialysis. Whereas longer duration of dialysis vintage was associated with increased water content in parieto-temporal-occipital regions, lower intradialytic weight changes were negatively correlated with brain water content in these areas in HD patients. Worse cognitive performance on an attention task correlated with increased hydration in frontal white matter. In conclusion, long-term HD is associated with altered brain tissue water homeostasis mainly in parietal white matter regions, whereas the attentional domain in the cognitive dysfunction profile in HD could be linked to increased frontal white matter water content.

Acknowledgement to the Reviewers

The editor-in-chief extends her appreciation to the editorial board members and to all ad hoc reviewers whose comments and criticisms ensure the timeliness and quality of the papers published in this journal. We are especially grateful to those members of the editorial board who, after serving for many years, have retired from the board, and we look forward to the new colleagues who will join us. Finally, we thank all of you, authors and contributors, who give this journal the international standing in the research into dementing disorders that it enjoys.