Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients.

OBJECTIVES: Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics). METHODS: In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed. RESULTS: Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration. CONCLUSIONS: Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.

Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology.

Diffusion tensor imaging can identify amyotrophic lateral sclerosis-associated patterns of brain alterations at the group level. Recently, a neuropathological staging system for amyotrophic lateral sclerosis has shown that amyotrophic lateral sclerosis may disseminate in a sequential regional pattern during four disease stages. The objective of the present study was to apply a new methodological diffusion tensor imaging-based approach to automatically analyse in vivo the fibre tracts that are prone to be involved at each neuropathological stage of amyotrophic lateral sclerosis. Two data samples, consisting of 130 diffusion tensor imaging data sets acquired at 1.5 T from 78 patients with amyotrophic lateral sclerosis and 52 control subjects; and 55 diffusion-tensor imaging data sets at 3.0 T from 33 patients with amyotrophic lateral sclerosis and 22 control subjects, were analysed by a tract of interest-based fibre tracking approach to analyse five tracts that become involved during the course of amyotrophic lateral sclerosis: the corticospinal tract (stage 1); the corticorubral and the corticopontine tracts (stage 2); the corticostriatal pathway (stage 3); the proximal portion of the perforant path (stage 4); and two reference pathways. The statistical analyses of tracts of interest showed differences between patients with amyotrophic lateral sclerosis and control subjects for all tracts. The significance level of the comparisons at the group level was lower, the higher the disease stage with corresponding involved fibre tracts. Both the clinical phenotype as assessed by the amyotrophic lateral sclerosis functional rating scale-revised and disease duration correlated significantly with the resulting staging scheme. In summary, the tract of interest-based technique allowed for individual analysis of predefined tract structures, thus making it possible to image in vivo the disease stages in amyotrophic lateral sclerosis. This approach can be used not only for individual clinical work-up purposes, but enlarges the spectrum of potential non-invasive surrogate markers as a neuroimaging-based read-out for amyotrophic lateral sclerosis studies within a clinical context.

Cognitive and behavioral impairments in German and Chinese ALS populations - a post-hoc comparison of national study data.

This study aimed to clarify whether differences between German and Chinese studies using the standardized Edinburgh Cognitive and Behavioural ALS Screen (ECAS), might be explained by differences in translated versions of ECAS, by patient demographic or clinical characteristics or by population-specific factors. Comparisons were performed on data from two previous studies in Germany and China. We found except for spelling task (p = 0.05), no differences between control groups of two countries were detected after adjusting for demographics. In contrast, differences were observed in scores on total ECAS, ALS-specific function such as different executive functions (all p < 0.01) and language (p = 0.02), even after correcting for demographic and clinical variables. Chinese ALS cohort performed worse in executive subfunction scores for sentence completion, alternation, social cognition, digit span and language comprehension; they performed better in spelling. Chinese ALS cohort more frequently exhibited disinhibition (p = 0.02), whereas German cohort more frequently exhibited loss of sympathy (p = 0.01) and stereotyped behavior (p = 0.03). Chinese and German ALS cohorts showed a distinctly different pattern in executive and language function. Most of the differences might be related to distinct differences between populations as only spelling might be affected by different language versions of ECAS. Socio-cultural factors might explain behavioral profile differences.

Moral judgment in patients with behavioral variant of frontotemporal dementia and amyotrophic lateral sclerosis: no impairment of the moral position, but rather its execution.

OBJECTIVE: To investigate moral judgment competence in patients with the behavioral variant frontotemporal dementia (bvFTD) compared to amyotrophic lateral sclerosis (ALS) and controls. METHODS: N = 12 bvFTD, N = 22 ALS patients and N = 19 neurological unimpaired controls were examined. In the 'Moral Competence Test' (MCT), participants had to evaluate two moral dilemmas by predefined arguments to measure the consistency of their moral judgments. The 'Ethics Position Questionnaire' (EPQ) addresses whether individuals prefer binding ethical standards, the Idler Index of Religiosity (IIR) measures the level of religiosity. Cognition was assessed with the CERAD-plus. RESULTS: BvFTD and ALS patients exhibited a similar moral position as healthy controls but a significantly lower judgment consistency in the MCT. MCT performance was independent from general cognitive functioning and not associated with moral orientation and religiosity. CONCLUSIONS: Our findings indicate that not the moral position itself seems to be impaired in patients with bvFTD, but rather their competence to transfer it into situational decisions. The fact that ALS patients have similar problems in applying moral principles in a consistent manner might indicate a deficit in execution of moral judgment, and this is in line with studies suggesting a damage of specific cerebral structures.

Functional reorganization during cognitive function tasks in patients with amyotrophic lateral sclerosis.

Cognitive deficits, especially in the domains of social cognition and executive function including verbal fluency, are common in amyotrophic lateral sclerosis (ALS) patients. There is yet sparse understanding of pathogenesis of the underlying, possibly adaptive, cortical patterns. To address this issue, 65 patients with ALS and 33 age-, gender- and education-matched healthy controls were tested on cognitive and behavioral deficits with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Using functional magnetic resonance imaging (fMRI), cortical activity during social cognition and executive function tasks (theory of mind, verbal fluency, alternation) adapted from the ECAS was determined in a 3 Tesla scanner. Compared to healthy controls, ALS patients performed worse in the ECAS overall (p < 0.001) and in all of its subdomains (p < 0.02), except memory. Imaging revealed altered cortical activation during all tasks, with patients consistently showing a hyperactivation in relevant brain areas compared to healthy controls. Additionally, cognitively high performing ALS patients consistently exhibited more activation in frontal brain areas than low performing patients and behaviorally unimpaired patients presented with more neuronal activity in orbitofrontal areas than behaviorally impaired patients. In conclusion, hyperactivation in fMRI cognitive tasks seems to represent an early adaptive process to overcome neuronal cell loss in relevant brain areas. The hereby presented cortical pattern change might suggest that, once this loss passes a critical threshold and no cortical buffering is possible, clinical representation of cognitive and behavioral impairment evolves. Future studies might shed light on the pattern of cortical pattern change in the course of ALS.

Cognitive phenotypes of sequential staging in amyotrophic lateral sclerosis.

Sequential spread of TDP-43 load in the brain may be a pathological characteristic of amyotrophic lateral sclerosis (ALS). Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) based marker of this pathological feature. Cognitive deficits known to be present in a subset of ALS patients might act as an additional in vivo clinical marker of disease spread. N = 139 patients with ALS were tested with the Edinburgh Cognitive and Behavioural ALS screen (ECAS) in addition to DTI brain measures of pathological spread. Executive function, memory and disinhibited behaviour were selected for Cognitive-Staging criteria, as these cognitive functions are attributed to cerebral areas analogous to the pattern of MRI markers of TDP-43 pathology. ROC curve analyses were performed to define cut-off scores for cognitive stages 2 (executive function), stage 3 (disinhibited behaviour) and stage 4 (memory), and staging was performed according to the cognitive profile subsequently. Associations of Cognitive-Staging (stage 2-4) and MRI-Staging measures were determined. In total, 77 patients (55%) performed below ROC cut-off scores in either executive function or memory or both and/or were reported to have disinhibited behaviour which permitted Cognitive-Staging. The cognitive profile of patients with discrete MRI stages 2-4 correlated significantly with DTI parameters. For those patients with cognitive impairment, there was a high congruency between MRI and Cognitive-Staging with high specificity and sensitivity of executive functions for MRI stage 2, disinhibited behaviour for MRI stage 3 and moderate of memory for MRI stage 4. Cognitive impairment follows specific patterns in ALS and these patterns can be used for Cognitive-Staging with a high specificity compared to MRI-Staging. For the individual, cognitive screening is a fast and easy to apply measurement of cerebral function giving valuable information in a clinical context.

Therapeutic decisions in ALS patients: cross-cultural differences and clinical implications.

OBJECTIVE: Quantitative analysis of decision-making on therapeutic options in different sociocultural context in amyotrophic lateral sclerosis (ALS). METHODS: ALS patients (n = 244) were consecutively recruited in Germany (n = 83), Poland (n = 83), and Sweden (n = 78) in a prospective cross-cultural study ( www.NEEDSinALS.com ). They were interviewed on preferences for therapeutic techniques including invasive (IV) and non-invasive ventilation (NIV), as well as percutaneous endoscopic gastrostomy (PEG) and on hypothetical termination of these using quantitative questions. Using standardized questionnaires, religiousness, personal values, quality of life, and depressiveness were assessed. RESULTS: NIV was most frequently used in Germany and PEG in Sweden. Swedish patients were most liberal on initiation and termination of PEG, NIV and IV. Polish patients were mostly undecided and were least likely to consider discontinuing supportive management. Current use was partly associated with age, gender and state of physical function; also, financial support explained some variance. Future preferences on therapeutic options from the patient's perspective were also closely associated with cultural factors. The more oriented towards traditional and conservative values, the less likely patients were to decide for invasive therapeutic devices (IV, PEG), the least likely to have ideations to discontinue any device and the more likely to have an undecided attitude. CONCLUSIONS: Current use of therapeutic options is determined by medical condition in analogy to clinical guidelines. For future considerations, other factors such as cultural background are crucial, yielding hurdles to be regarded in the implementation of advanced directives in a multicultural environment.

Experience matters: neurologists' perspectives on ALS patients' well-being.

Despite the fatal outcome and progressive loss of physical functioning in amyotrophic lateral sclerosis (ALS), many patients maintain contentment in life. It has been shown that non-professionals tend to underestimate the well-being of patients with ALS, but professionals' perspective is yet to be studied. In total, 105 neurologists with varying degrees of experience with ALS were included in an anonymous survey. They were asked to estimate the quality of life and depressiveness of ALS patients with artificial ventilation and nutrition. Physicians' estimations were compared with previously reported subjective ratings of ALS patients with life-prolonging measures. Neurologists with significant experience on ALS and palliative care were able to accurately estimate depressiveness and quality of life of ALS patients with life-prolonging measures. Less experienced neurologists' estimation differed more from patients' reports. Of all life-prolonging measures neurologists regarded invasive ventilation as the measure associated with lowest quality of life and highest depressiveness of the patients. Experienced neurologists as well as neurologists with experience in palliative care are able to better empathize with patients with a fatal illness such as ALS and support important decision processes.

A first approach to a neuropsychological screening tool using eye-tracking for bedside cognitive testing based on the Edinburgh Cognitive and Behavioural ALS Screen.

OBJECTIVE: Reliable assessment of cognitive functions is a challenging task in amyotrophic lateral sclerosis (ALS) patients unable to speak and write. We therefore present an eye-tracking based neuropsychological screening tool based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a standard screening tool for cognitive deficits in ALS. METHODS: In total, 46 ALS patients and 50 healthy controls matched for age, gender and education were tested with an oculomotor based and a standard paper-and-pencil version of the ECAS. RESULTS: Significant correlation between both versions was observed for ALS patients and healthy controls in the ECAS total score and in all of its ALS-specific domains (all r > 0.3; all p < 0.05). The eye-tracking version of the ECAS reliably distinguished between ALS patients and healthy controls in the ECAS total score (p < 0.05). Also, cognitively impaired and non-impaired patients could be reliably distinguished with a specificity of 95%. CONCLUSION: This study provides first evidence that the eye-tracking based ECAS version is a promising approach for assessing cognitive deficits in ALS patients who are unable to speak or write.

Age and education-matched cut-off scores for the revised German/Swiss-German version of ECAS.

The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) has been developed to assess cognition and behaviour in patients with amyotrophic lateral sclerosis (ALS). Cognitive impairments of ALS-specific and ALS-non-specific functions can be determined using cut-off scores based on performance of healthy subjects. However, detailed analyses show that older healthy subjects perform worse than younger ones, whereas highly-educated individuals perform better than those with lower education levels. As a consequence, this study presents new age and education matched cut-off scores for the revised German/Swiss-German version of the ECAS based on the performance of 86 healthy subjects.

The Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen: a cross-sectional comparison of established screening tools in a German-Swiss population.

The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) has recently been developed as a fast and easy cognitive screening tool specifically designed for patients with motor impairments in routine clinical use. The German/Swiss-German version of the ECAS was validated in a German-Swiss consortium. One hundred and thirty-six non-demented ALS patients and 160 healthy controls were included in the study. In addition, the Frontal Assessment Battery (FAB), Montreal Cognitive Assessment (MoCA) and Consortium to Establish a Registry for Alzheimer's Disease plus Scale (CERAD plus) were administered to subgroups of patients. Results showed that administration of ECAS was fast (mean 24 min). Similar to the population in the UK version, ALS patients performed significantly worse in the ALS-specific functions (p < 0.001), specifically in the domain of language (p < 0.001), verbal fluency (p = 0.005) and executive functions (p = 0.02), but not for the non-ALS-specific functions. Carers reported behavioural abnormalities in about 30% and psychotic symptoms in 6% of the patients. Compared to ECAS, FAB, MoCA and CERAD were more generic and performance was not adjusted to motor speed. We conclude that the German/Swiss-German version of the ECAS is a fast and easy to administer cognitive screening instrument sensitive for ALS-specific dysfunctions and behaviour change.