Susanne Abdulla

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

Abstract 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 Alzheimers 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.

Basal ganglia pathology in ALS is associated with neuropsychological deficits

Objectives: To evaluate basal ganglia changes along the amyotrophic lateral sclerosis (ALS)–ALS–frontotemporal dementia (FTD) continuum using multiple, complementary imaging techniques. Methods: Sixty-seven C9orf72-negative patients with ALS and 39 healthy controls were included in a cross-sectional quantitative MRI study. Seven patients with ALS met criteria for comorbid behavioral variant FTD (ALS-FTD), 18 patients met the Strong criteria for cognitive and/or behavioral impairment (ALS-Plus), and 42 patients had no cognitive impairment (ALS-Nci). Volumetric, shape, and density analyses were performed for the thalamus, amygdala, nucleus accumbens, hippocampus, caudate nucleus, pallidum, and putamen. Results: Significant basal ganglia volume differences were identified between the study groups. Shape analysis revealed distinct atrophy patterns in the amygdala in patients with ALS-Nci and in the hippocampus in patients with ALS-Plus in comparison with controls. Patients with ALS-FTD exhibited pathologic changes in the bilateral thalami, putamina, pallida, hippocampi, caudate, and accumbens nuclei in comparison with all other study groups. A preferential vulnerability has been identified within basal ganglia subregions, which connect directly to key cortical sites of ALS pathology. While the anatomical patterns were analogous, the degree of volumetric, shape, and density changes confirmed incremental pathology through the spectrum of ALS-Nci, ALS-Plus, to ALS-FTD. Performance on verbal memory tests correlated with hippocampal volumes, and accumbens nuclei volumes showed a negative correlation with apathy scores. Conclusions: We demonstrate correlations between basal ganglia measures and structure-specific neuropsychological performance and a gradient of incremental basal ganglia pathology across the ALS–ALS-FTD spectrum, suggesting that the degree of subcortical gray matter pathology in C9orf72-negative ALS is closely associated with neuropsychological changes.

Hippocampal degeneration in patients with amyotrophic lateral sclerosis.

There is increasing appreciation of non-motor system involvement in amyotrophic lateral sclerosis (ALS), although its full extent and clinical significance remains to be established. This study tested the hypothesis that memory impairment in patients with ALS is related to hippocampal degeneration. Consecutive patients with ALS (58) and 29 matched controls participated in standardized neuropsychological assessment and magnetic resonance imaging. Patients with ALS performed worse in global cognitive functioning and executive and verbal memory tests (p < 0.05). The hippocampus was manually segmented in each hemisphere, and volumes were calculated with correction for intracranial volume. Analysis of covariance, controlled for the effect of age and education years, showed significantly smaller hippocampal volume on the right (p = 0.004) in patients with ALS. Verbal memory test performance correlated with the left hippocampal volume in patients with ALS (p < 0.05), although there was no significant correlation with tests of executive function and clinical variables underscoring the specificity of the present findings. Hippocampal volume loss and its correlation with the severity of verbal memory impairment highlight significant hippocampal involvement which can occur as a non-motor deficit in patients with ALS.

Memory deficits in amyotrophic lateral sclerosis are not exclusively caused by executive dysfunction: a comparative neuropsychological study of amnestic mild cognitive impairment.

BackgroundRecent work suggests that ALS and frontotemporal dementia can occur together and share at least in part the same underlying pathophysiology. However, it is unclear at present whether memory deficits in ALS stem from a temporal lobe dysfunction, or are rather driven by frontal executive dysfunction. In this study we sought to investigate the nature of memory deficits by analyzing the neuropsychological performance of 40 ALS patients in comparison to 39 amnestic mild cognitive impairment (aMCI) patients and 40 healthy controls (HC). The neuropsychological battery tested for impairment in executive functions, as well as memory and visuo-spatial skills, the results of which were compared across study groups. In addition, we calculated composite scores for memory (learning, recall, recognition) and executive functions (verbal fluency, cognitive flexibility, working memory). We hypothesized that the nature of memory impairment in ALS will be different from those exhibited by aMCI patients.ResultsPatient groups exhibited significant differences in their type of memory deficit, with the ALS group showing impairment only in recognition, whereas aMCI patients showed short and delayed recall performance deficits as well as reduced short-term capacity. Regression analysis revealed a significant impact of executive function on memory performance exclusively for the ALS group, accounting for one fifth of their memory performance. Interestingly, merging all sub scores into a single memory and an executive function score obscured these differences.ConclusionThe presented results indicate that the interpretation of neuropsychological scores needs to take the distinct cognitive profiles in ALS and aMCI into consideration. Importantly, the observed memory deficits in ALS were distinctly different from those observed in aMCI and can be explained only to some extent in the context of comorbid (coexisting) executive dysfunction. These findings highlight the qualitative differences in temporal lobe dysfunction between ALS and aMCI patients, and support temporal lobe dysfunction as a mechanism underlying the distinct cognitive impairments observed in ALS.

Structural and diffusion imaging versus clinical assessment to monitor amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects upper and lower motor neurons. Observational and intervention studies can be tracked using clinical measures such as the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) but for a complete understanding of disease progression, objective in vivo biomarkers of both central and peripheral motor pathway pathology are highly desirable. The aim of this study was to determine the utility of structural and diffusion imaging as central nervous system biomarkers compared to the standard clinical measure, ALSFRS-R, to track longitudinal evolution using three time-point measurements. N = 34 patients with ALS were scanned and clinically assessed three times at a mean of three month time intervals. The MRI biomarkers were structural T1-weighted volumes for cortical thickness measurement as well as deep grey matter volumetry, voxel-based morphometry and diffusion tensor imaging (DTI). Cortical thickness focused specifically on the precentral gyrus while quantitative DTI biomarkers focused on the corticospinal tracts. The evolution of imaging biomarkers and ALSFRS-R scores over time were analysed using a mixed effects model that accounted for the scanning interval as a fixed effect variable, and, the initial measurements and time from onset as random variables. The mixed effects model showed a significant decrease in the ALSFRS-R score, (p < 0.0001, and an annual rate of change (AROC) of − 7.3 points). Similarly, fractional anisotropy of the corticospinal tract showed a significant decrease (p = 0.009, AROC = − 0.0066) that, in turn, was driven by a significant increase in radial diffusivity combined with a trend to decrease in axial diffusivity. No significant change in cortical thickness of the precentral gyrus was found (p > 0.5). In addition, deep grey matter volumetry and voxel-based morphometry also identified no significant changes. Furthermore, the availability of three time points was able to indicate that there was a linear progression in both clinical and fractional anisotropy measures adding to the validity of these results. The results indicate that DTI is clearly a superior imaging marker compared to atrophy for tracking the evolution of the disease and can act as a central nervous biomarker in longitudinal studies. It remains, however, less sensitive than the ALSFRS-R score for monitoring decline over time.

Peripheral nerve ultrasound in amyotrophic lateral sclerosis phenotypes

Introduction: In this study we sought to determine the cross‐sectional area (CSA) of peripheral nerves in patients with distinct subtypes of amyotrophic lateral sclerosis (ALS). Methods: Ulnar and median nerve ultrasound was performed in 78 ALS patients [classic, n = 21; upper motor neuron dominant (UMND), n = 14; lower motor neuron dominant (LMND), n = 20; bulbar, n = 15; primary lateral sclerosis (PLS), n = 8] and 18 matched healthy controls. Results: Compared with controls, ALS patients had significant, distally pronounced reductions of ulnar CSA (forearm/wrist level) across all disease groups, except for PLS. Median nerve CSA (forearm/wrist level) did not differ between controls and ALS. Conclusion: Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications. Muscle Nerve 51:669–675, 2015

Interaction of physical function, quality of life and depression in Amyotrophic lateral sclerosis: characterization of a large patient cohort

BackgroundDue to lack of any curative therapy for ALS, symptomatic treatment and maintenance of quality of life (QoL) is very important. We aimed to characterize the affected domains of QoL in ALS patients and to identify factors which are associated with reduced QoL and increased depression.Methods159 ALS patients answered standardized questionnaires (Beck Depression Inventory-II, SF-36 Health Survey questionnaire, revised ALS functional rating scale). Multiple regression analysis was used to identify correlations between clinical features of ALS patients and depression/QoL scores. In addition, QoL data from ALS patients were compared to age-matched reference values representing the German normal population.ResultsQoL of ALS patients was reduced in nearly all SF-36-categories. Progression of physical impairment was positively correlated with depression but reduced QoL scores only in items directly related to physical function. However, QoL was considerably influenced by depression, independently from physical impairment. Regarding distinct patient characteristics one of the most interesting findings was that increasing age was correlated with significantly worse QoL results regarding social functioning.ConclusionsDepressive symptoms had a strong influence on QoL, hence their detection and treatment is of particular importance. Different domains of QoL are differently affected in subgroups of ALS patients. Being aware of these differences can be valuable for both ALS professional and family caregivers and physicians.

Central white matter degeneration in bulbar- and limb-onset amyotrophic lateral sclerosis

Previous studies using diffusion tensor imaging (DTI) have examined for differences between bulbar- and limb-onset amyotrophic lateral sclerosis (ALS). Findings between studies have been markedly inconsistent, though possibly as a consequence of poor matching for confounding variables. To address this problem, this study contrasted the DTI profiles of limb-onset (ALS-L) and bulbar-onset (ALS-B) in groups that were tightly matched for the potential confounding effects of power, age, cognitive impairment and motor dysfunction. 14 ALS-L and 14 ALS-B patients were selected from a large prospective study so as to be matched on clinical and demographic features. All subjects, including 29 controls, underwent neuropsychological and neurological assessment. Tract-based spatial statistics and region of interest techniques were used to analyse fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (λ1). Extensive bilateral FA and RD changes along the corticospinal tract were found in ALS-B compared to controls, p (corrected) <0.05; a similar distribution was seen for ALS-L at a less stringent statistical threshold. ROI analyses also showed more significant changes in ALS-B than ALS-L when each was compared to controls; for FA, MD and RD the changes reached statistical significance in the direct contrast between the two patient groups. With careful matching for confounding factors, the results suggest that ALS-B is associated with greater central white matter degeneration than ALS-L, possibly contributing to the known worse prognosis of ALS-B. The study, however, found no evidence that the spatial distribution of white matter degeneration differs between these groups.

Quantifying disease progression in amyotrophic lateral sclerosis using peripheral nerve sonography

Introduction: In this study we investigated whether peripheral nerve sonography could be used as a biomarker to monitor disease progression in amyotrophic lateral sclerosis (ALS). Methods: In 37 patients, ulnar and median nerve cross‐sectional area (CSA) was determined in at least 2 ultrasound sessions; mean follow‐up was 14.5 months. Linear mixed‐effects models were conducted to analyze time effects on CSA. Results: Ulnar nerve CSA declined significantly at a monthly rate of –0.04 mm2 (forearm) and –0.05 mm2 (wrist); the decrease was more pronounced when baseline CSA was greater. To detect a 50% treatment effect on ulnar nerve CSA, 332 patients would need to be entered in a hypothetical randomized, controlled clinical trial. Time had no significant impact on median nerve CSA. Conclusions: Distal ulnar nerve ultrasound may be a useful biomarker to monitor disease progression in ALS, especially as hypothetical treatment effects on CSA seem to be detectable in manageable cohort sizes. Muscle Nerve 54: 391–397, 2016

Executive Dysfunctions and Event-Related Brain Potentials in Patients with Amyotrophic Lateral Sclerosis.

A growing body of evidence implies psychological disturbances in amyotrophic lateral sclerosis (ALS). Specifically, executive dysfunctions occur in up to 50% of ALS patients. The recently shown presence of cytoplasmic aggregates (TDP-43) in ALS patients and in patients with behavioral variants of frontotemporal dementia suggests that these two disease entities form the extremes of a spectrum. The present study aimed at investigating behavioral and electrophysiological indices of conflict processing in patients with ALS. A non-verbal variant of the flanker task demanded two-choice responses to target stimuli that were surrounded by flanker stimuli which either primed the correct response or the alternative response (the latter case representing the conflict situation). Behavioral performance, event-related potentials (ERP), and lateralized readiness potentials (LRP) were analyzed in 21 ALS patients and 20 controls. In addition, relations between these measures and executive dysfunctions were examined. ALS patients performed the flanker task normally, indicating preserved conflict processing. In similar vein, ERP and LRP indices of conflict processing did not differ between groups. However, ALS patients showed enhanced posterior negative ERP waveform deflections, possibly indicating increased modulation of visual processing by frontoparietal networks in ALS. We also found that the presence of executive dysfunctions was associated with more error-prone behavior and enhanced LRP amplitudes in ALS patients, pointing to a prefrontal pathogenesis of executive dysfunctions and to a potential link between prefrontal and motor cortical functional dysregulation in ALS, respectively.