Dorothée Lulé

Global brain atrophy and corticospinal tract alterations in ALS, as investigated by voxel‐based morphometry of 3‐D MRI

In ALS, advanced magnetic resonance imaging (MRI) techniques are increasingly used to investigate the underlying pathology. In this study, the technique of voxel‐based morphometry (VBM) was applied to 3‐D MRI data in ALS patients to localize regional grey and white matter changes. Twenty‐two ALS patients (mean age 58±9 years) with clinically definite ALS by revised El Escorial criteria were studied. None of the patients had any signs of associated frontotemporal dementia. High‐resolution 3‐D MRI data sets of the whole brain, collected on a 1.5 T scanner, were analysed by statistical parametric mapping (SPM) and VBM in comparison to an age‐matched normal data base consisting of 22 healthy volunteers (mean age 59±11 years), for grey matter and white matter segments separately. Global brain atrophy was assessed by calculation of brain parenchymal fractions (BPF). In ALS patients, BPF were significantly reduced compared to controls (p = 0.0003), indicating global brain atrophy. Regional decreases of grey matter density were found in the ALS patients at corrected p<0.01 in the right‐hemispheric primary motor cortex (area of the highest Z‐score) and in the left medial frontal gyrus. Furthermore, regional white matter alterations were observed along the corticospinal tracts bilaterally and in multiple smaller areas including corpus callosum, cerebellum, frontal and occipital subcortical regions. Besides considerable global atrophy in ALS, the topography of ALS‐associated cerebral morphological changes could be mapped using VBM, in particular white matter signal changes along the bilateral corticospinal tracts, but also in extra‐motor areas. VBM might be a potential tool to visualize disease progression in future longitudinal studies.

Neuroimaging in amyotrophic lateral sclerosis

The catastrophic system failure in amyotrophic lateral sclerosis is characterized by progressive neurodegeneration within the corticospinal tracts, brainstem nuclei and spinal cord anterior horns, with an extra-motor pathology that has overlap with frontotemporal dementia. The development of computed tomography and, even more so, MRI has brought insights into neurological disease, previously only available through post-mortem study. Although largely research-based, radionuclide imaging has continued to provide mechanistic insights into neurodegenerative disorders. The evolution of MRI to use advanced sequences highly sensitive to cortical and white matter structure, parenchymal metabolites and blood flow, many of which are now applicable to the spinal cord as well as the brain, make it a uniquely valuable tool for the study of a multisystem disorder such as amyotrophic lateral sclerosis. This comprehensive review considers the full range of neuroimaging techniques applied to amyotrophic lateral sclerosis over the last 25 years, the biomarkers they have revealed and future developments.

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.

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.

Emotional responding in amyotrophic lateral sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal disease, leaving the patient in a partially or completely deafferented state. In an explorative study, we investigated responses to visual socio–emotional stimuli in ALS patients. Pictures from the International Affective Picture System (IAPS) were verbally judged by 12 moderately affected ALS patients with a spinal onset and a slow progression and 18 age–matched controls, and data were compared with psychophysiological responses. Verbal emotional judgments of patients were more positive than ratings of controls. Regarding arousal, patients neutralized extreme pictures, in that they rated calm pictures as more exciting than controls and exciting pictures as more calm. These changes of emotional processing were unrelated to depression or frontal lobe dysfunction. There were no major differences between patients and controls concerning physiological responses to emotional stimuli. We conclude that emotional responses of ALS patients tend to be altered towards positive valence and towards a more balanced arousal state in early stages of the disease. These findings contradict assumptions of a generally negative impact of the disease on the emotional disposition and may indicate compensatory cognitive or neuroplastic changes.

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.

Neuroimaging of multimodal sensory stimulation in amyotrophic lateral sclerosis

Aim Structural and functional imaging techniques were combined to investigate sensory system function in amyotrophic lateral sclerosis (ALS). Methods Functional MRI (fMRI) was used to investigate cortical activity during visual, auditory and somatosensory stimulation in 14 ALS patients and 18 control subjects. Changes in amplitude, latency and duration of the blood oxygen level dependent response were modelled. Furthermore, diffusion tensor imaging was used to investigate changes in white matter networks. Results During visual stimulation, fMRI demonstrated a decreased response in secondary visual areas in ALS, possibly related to demyelination of sensory nerve fibres. Increasing brain activity in associative cortices was linked to a decrease in physical functioning and might represent a compensatory process. Additionally, reduced white matter functioning became evident for fibres projecting to the extrastriate visual cortex. For auditory stimulation, a delayed response in secondary auditory areas probably linked to prolonged nerve conductance time and an altered cortical pattern in areas involved in target processing/detection became evident in ALS patients. Structural white matter changes in the primary and secondary auditory cortices were observed. For somatosensory stimulation, a prolonged/reduced response in sensory integration areas of the parietal lobe was observed, perhaps linked to the reduced visceral inflow due to immobility. Conclusion Multiparametric MRI suggests a progressive functional deficit in secondary/higher order sensory processing areas in ALS, probably associated with reduction of re-afferent information flow due to progressive immobility. The changes described might also represent an expression of the disease process itself. Evidence for compensatory processes in multimodal associative cortices was found.

Depression and Quality of Life in Patients With Amyotrophic Lateral Sclerosis

INTRODUCTION There is increasing debate on the issue of whether to facilitate the end-of-life decisions of severely disabled patients with diseases such as amyotrophic lateral sclerosis (ALS). Our two studies were intended to explore the emotional state and quality of life of patients with ALS. METHODS Two studies were performed to investigate depression and the quality of life in ALS patients: one was a longitudinal study, the other a comparison of ALS patients to normal control subjects. RESULTS These studies found no correlation between physical disability in ALS and either depression or the quality of life. The severity of depression was found to be inversely related to educational status. In ALS patients the quality of life was comparable with healthy controls. DISCUSSION The rationale for not providing life-sustaining treatment to severely disabled patients is that a poor quality of life is expected after such treatment. Our studies have shown, however, that ALS patients can experience a satisfactory quality of life without depressive manifestations even if they are severely physically impaired, including in the terminal phase.

Cortical plasticity in amyotrophic lateral sclerosis: motor imagery and function.

Background. Cortical networks underlying motor imagery are functionally close to motor performance networks and can be activated by patients with severe motor disabilities. Objective. The aim of the study was to examine the longitudinal effect of progressive motoneuron degeneration on cortical representation of motor imagery and function in amyotrophic lateral sclerosis. Methods. The authors studied 14 amyotrophic lateral sclerosis patients and 15 healthy controls and a subgroup of 11 patients and 14 controls after 6 months with a grip force paradigm comprising imagery and execution tasks using functional magnetic resonance imaging. Results. Motor imagery activated similar neural networks as motor execution in amyotrophic lateral sclerosis patients and healthy subjects in the primary motor (BA 4), premotor, and supplementary motor (BA 6) cortex. Amyotrophic lateral sclerosis patients presented a stronger response within premotor and primary motor areas for imagery and execution compared to controls. After 6 months, these differences persisted with additional activity in the precentral gyrus in patients as well as in a frontoparietal network for motor imagery, in which activity increased with impairment. Conclusion. The findings suggest an ongoing compensatory process within the higher order motor-processing system of amyotrophic lateral sclerosis patients, probably to overcome loss of function in primary motor and motor imagery-specific networks. The increased activity in precentral and frontoparietal networks in motor imagery might be used to control brain-computer interfaces to drive communication and limb prosthetic devices in patients with loss of motor control such as severely disabled amyotrophic lateral sclerosis patients in a locked-in-like state.

NEK1 mutations in familial amyotrophic lateral sclerosis

Sir, Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by adult-onset loss of motor neurons. Five to 10% of all ALS cases are familial ALS. To date, more than 20 genes have been implicated in causing familial ALS, with the discovery of mutations in CHCHD10 (Bannwarth et al. , 2014) and TBK1 (Cirulli et al. , 2015; Freischmidt et al. , 2015) representing the latest examples for monogenic causes of ALS. Most recently, whole exome sequencing of ALS patients suggested an association of heterozygous loss-of-function mutations in NEK1 with ALS. However, this observation was made in a cohort of mostly sporadic patients, and the result was only significant in a combined analysis of the discovery and the replication cohort (Cirulli et al. , 2015), making further validation essential. To assess the association between NEK1 variants and familial ALS we analysed whole exome sequence data of 265 familial ALS index patients and 827 control individuals. A subset of these exome sequence data has recently led to the discovery of mutations in TBK1 as a cause for ALS in an exome-wide mutational burden analysis (Freischmidt et al. , 2015). The patients with familial ALS were selected from families with two or more affected individuals from European countries (Germany, Sweden, Finland, Denmark, Switzerland, and Portugal) following a negative screen for SOD1 and C9orf72 mutations as described previously (Freischmidt et al. , 2015). In-house control exomes ( n = 827) from Germany were used to compare the variant burden in NEK1 . All ALS patients were diagnosed according to the EFNS Consensus criteria (Andersen et al. , 2012). Control subjects were comprised of healthy parents of children with various diseases, healthy control tissues of individuals with tumour diseases and 200 individuals of the KORA study. With informed written consent and approval by …