Structural imaging differences and longitudinal changes in primary lateral sclerosis and amyotrophic lateral sclerosis.
ABSTRACT: Magnetic resonance imaging measures have been proposed as objective markers to study upper motor neuron loss in motor neuron disorders. Cross-sectional studies have identified imaging differences between groups of healthy controls and patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS) that correlate with disease severity, but it is not known whether imaging measures change as disease progresses. Additionally, whether imaging measures change in a similar fashion with disease progression in PLS and ALS is unclear. To address these questions, clinical and imaging evaluations were first carried out in a prospective cross-sectional study of 23 ALS and 22 PLS patients with similar motor impairment and 19 age-matched healthy controls. Clinical evaluations consisted of a neurological examination, the ALS Functional rating scale-revised, and measures of finger tapping, gait, and timed speech. Age and ALSFRS score were not different, but PLS patients had longer duration of symptoms. Imaging measures examined were cortical thickness, regional brain volumes, and diffusion tensor imaging of the corticospinal tract and callosum. Imaging measures that differed from controls in a cross-sectional vertex-wise analysis were used as regions of interest for longitudinal analysis, which was carried out in 9 of the ALS patients (interval 1.26 ± 0.72 years) and 12 PLS patients (interval 2.08 ± 0.93 years). In the cross-sectional study both groups had areas of cortical thinning, which was more extensive in motor regions in PLS patients. At follow-up, clinical measures declined more in ALS than PLS patients. Cortical thinning and grey matter volume loss of the precentral gyri progressed over the follow-up interval. Fractional anisotropy of the corticospinal tracts remained stable, but the cross-sectional area declined in ALS patients. Changes in clinical measures correlated with changes in precentral cortical thickness and grey matter volume. The rate of cortical thinning was greater in ALS patients with shorter disease durations, suggesting that thickness decreases in a non-linear fashion. Thus, cortical thickness changes are a potential imaging marker for disease progression in individual patients, but the magnitude of change likely depends on disease duration and progression rate. Differences between PLS and ALS patients in the magnitude of thinning in cross-sectional studies are likely to reflect longer disease duration. We conclude that there is an evolution of structural imaging changes with disease progression in motor neuron disorders. Some changes, such as diffusion properties of the corticospinal tract, occur early while cortical thinning and volume loss occur later.
Project description:BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease characterized by both upper and lower motor neuron degeneration. While neuroimaging studies of the brain can detect upper motor neuron degeneration, these brain MRI scans also include the upper part of the cervical spinal cord, which offers the possibility to expand the focus also towards lower motor neuron degeneration. Here, we set out to investigate cross-sectional and longitudinal disease effects in the upper cervical spinal cord in patients with ALS, progressive muscular atrophy (PMA: primarily lower motor neuron involvement) and primary lateral sclerosis (PLS: primarily upper motor neuron involvement), and their relation to disease severity and grey and white matter brain measurements. METHODS:We enrolled 108 ALS patients without C9orf72 repeat expansion (ALS C9-), 26 ALS patients with C9orf72 repeat expansion (ALS C9+), 28 PLS patients, 56 PMA patients and 114 controls. During up to five visits, longitudinal T1-weighted brain MRI data were acquired and used to segment the upper cervical spinal cord (UCSC, up to C3) and individual cervical segments (C1 to C4) to calculate cross-sectional areas (CSA). Using linear (mixed-effects) models, the CSA differences were assessed between groups and correlated with disease severity. Furthermore, a relationship between CSA and brain measurements was examined in terms of cortical thickness of the precentral gyrus and white matter integrity of the corticospinal tract. RESULTS:Compared to controls, CSAs at baseline showed significantly thinner UCSC in all groups in the MND spectrum. Over time, ALS C9- patients demonstrated significant thinning of the UCSC and, more specifically, of segment C3 compared to controls. Progressive thinning over time was also observed in C1 of PMA patients, while ALS C9+ and PLS patients did not show any longitudinal changes. Longitudinal spinal cord measurements showed a significant relationship with disease severity and we found a significant correlation between spinal cord and motor cortex thickness or corticospinal tract integrity for PLS and PMA, but not for ALS patients. DISCUSSION:Our findings demonstrate atrophy of the upper cervical spinal cord in the motor neuron disease spectrum, which was progressive over time for all but PLS patients. Cervical spinal cord imaging in ALS seems to capture different disease effects than brain neuroimaging. Atrophy of the cervical spinal cord is therefore a promising additional biomarker for both diagnosis and disease progression and could help in the monitoring of treatment effects in future clinical trials.
Project description:BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by motor neuron degeneration. How this disease affects the central motor network is largely unknown. Here, we combined for the first time structural and functional imaging measures on the motor network in patients with ALS and healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: Structural measures included whole brain cortical thickness and diffusion tensor imaging (DTI) of crucial motor tracts. These structural measures were combined with functional connectivity analysis of the motor network based on resting state fMRI. Focal cortical thinning was observed in the primary motor area in patients with ALS compared to controls and was found to correlate with disease progression. DTI revealed reduced FA values in the corpus callosum and in the rostral part of the corticospinal tract. Overall functional organisation of the motor network was unchanged in patients with ALS compared to healthy controls, however the level of functional connectedness was significantly correlated with disease progression rate. Patients with increased connectedness appear to have a more progressive disease course. CONCLUSIONS/SIGNIFICANCE: We demonstrate structural motor network deterioration in ALS with preserved functional connectivity measures. The positive correlation between functional connectedness of the motor network and disease progression rate could suggest spread of disease along functional connections of the motor network.
Project description:OBJECTIVE:The clinical diagnosis of primary lateral sclerosis can only be made after upper motor neuron symptoms have progressed for several years without developing lower motor neuron signs. The goal of the study was to identify neuroimaging changes that occur early in primary lateral sclerosis, prior to clinical diagnosis. METHODS:MRI scans were obtained on 13 patients with adult-onset progressive spasticity for five years or less who were followed longitudinally to confirm a clinical diagnosis of primary lateral sclerosis. Resting state functional MRI, diffusion tensor imaging, and anatomical images were obtained. These "pre-PLS" patients were compared to 18 patients with longstanding, established primary lateral sclerosis and 28 controls. RESULTS:Pre-PLS patients had a marked reduction in seed-based resting-state motor network connectivity compared to the controls and patients with longstanding disease. White matter regions with reduced fractional anisotropy were similar in the two patient groups compared to the controls. Patients with longstanding disease had cortical thinning of the precentral gyrus. A slight thinning of the right precentral gyrus was detected in initial pre-PLS patients' scans. Follow-up scans in eight pre-PLS patients 1-2 years later showed increasing motor connectivity, thinning of the precentral gyrus, and no change in diffusion measures of the corticospinal tract or callosal motor region. CONCLUSIONS:Loss of motor functional connectivity is an early imaging marker in primary lateral sclerosis. This differs from literature descriptions of amyotrophic lateral sclerosis, warranting further studies to test whether resting-state functional MRI can differentiate between amyotrophic lateral sclerosis and primary lateral sclerosis at early disease stages.
Project description:OBJECTIVE:To characterize [11 C]-PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). We have previously shown increased [11 C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray versus white matter distribution of [11 C]-PBR28 uptake in a larger cohort of patients with ALS and PLS. METHODS:Eighty-five participants including 53 with ALS, 11 with PLS, and 21 healthy controls underwent integrated [11 C]-PBR28 PET-magnetic resonance brain imaging. Patients were clinically assessed using the Upper Motor Neuron Burden (UMNB) and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). [11 C]-PBR28 uptake was quantified as standardized uptake value ratio (SUVR) and compared between groups. Cortical thickness and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. [11 C]-PBR28 uptake and ALSFRS-R were compared longitudinally over 6 months in 10 ALS individuals. RESULTS:Whole brain voxelwise, surface-based, and region of interest analyses revealed increased [11 C]-PBR28 uptake in the precentral and paracentral gyri in ALS, and in the subcortical white matter for the same regions in PLS, compared to controls. The increase in [11 C]-PBR28 uptake colocalized and correlated with cortical thinning, reduced fractional anisotropy, and increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in [11 C]-PBR28 uptake over 6 months despite clinical progression. INTERPRETATION:Glial activation measured by in vivo [11 C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. Ann Neurol 2018;83:1186-1197.
Project description:OBJECTIVE:In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. METHODS:Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [11C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [11C]-PBR28 uptake. RESULTS:In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [11C]-PBR28 binding in the left motor cortex was correlated with FA (r = -0.68, p < 0.05) and cortical thickness (r = -0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = -0.77, p < 0.05), and cortical thickness (r = -0.75, p < 0.05) in the motor cortex. CONCLUSIONS:Increased uptake of the glial marker [11C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS.
Project description:Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations across its clinical phenotypes. Ventricular enlargement can be measured over a 6-month time frame, and appears to be faster in patients with cognitive impairment.
Project description:A standardised imaging protocol was implemented to evaluate disease burden in specific thalamic and amygdalar nuclei in 133 carefully phenotyped and genotyped motor neuron disease patients. "Switchboard malfunction in motor neuron diseases: selective pathology of thalamic nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis"  "Amygdala pathology in amyotrophic lateral sclerosis and primary lateral sclerosis"  Raw volumetric data, group comparisons, effect sizes and percentage change are presented. Both ALS and PLS patients exhibited focal thalamus atrophy in ventral lateral and ventral anterior regions revealing extrapyramidal motor degeneration. Reduced accessory basal nucleus and cortical nucleus volumes were noted in the amygdala of C9orf72 negative ALS patients compared to healthy controls. ALS patients carrying the GGGGCC hexanucleotide repeats in C9orf72 exhibited preferential pathology in the mediodorsal-paratenial-reuniens thalamic nuclei and in the lateral nucleus and cortico-amygdaloid transition area of the amygdala. Considerable thalamic atrophy was observed in the sensory nuclei and lateral geniculate region of PLS patients. Our data demonstrate genotype-specific patterns of thalamus and amygdala involvement in ALS and a distinct disease-burden pattern in PLS. The dataset may be utilised for validation purposes, meta-analyses and the interpretation of thalamic and amygdalar profiles from other ALS genotypes.
Project description:INTRODUCTION:Discrepancies between diffusion tensor imaging (DTI) findings and functional rating scales in amyotrophic lateral sclerosis (ALS) may be due to symptom heterogeneity, particularly coexisting cognitive-behavioural dysfunction affecting non-motor regions of the brain. Carriers of expansion mutations in the C9orf72 gene, whose motor and cognitive-behavioural symptoms span a range from ALS to frontotemporal dementia, present an opportunity to evaluate the relationship between symptom heterogeneity and DTI changes. METHODS:Twenty-eight C9orf72 mutation carriers with varied cognitive and motor symptoms underwent clinical evaluation and DTI imaging. Twenty returned for two or more follow-up evaluations. Each evaluation included motor, executive and behavioural scales and disease staging using the King's college staging system. RESULTS:Widespread reduction of white matter integrity occurred in C9orf72 mutation carriers compared with 28 controls. The ALS Functional Rating Scale (ALSFRS-R) and King's stage correlated with DTI measures of the corticospinal tract and mid-callosum. Cognitive and behavioural scores correlated with diffusion measures of frontal white matter. King's stage, but not ALSFRS-R, correlated with anterior callosum DTI measures. Over a 6-month follow-up, DTI changes spread from anterior to posterior, and from deep to superficial subcortical white matter. In C9orf72 carriers with ALS or ALS-FTD, changes in corticospinal tractography measures correlated with changes in ALSFRS-R. CONCLUSION:Discrepancies between DTI findings and clinical measures of disease severity in ALS may partly be accounted for by cognitive-behavioural deficits affecting extramotor white matter tracts. Both ALSFRS-R and King's stage correlated with corticospinal DTI measures. Group-level DTI changes could be detected over 6 months.
Project description:<h4>Objective</h4>While the hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract in combination with lower motor neuron degeneration, the clinical involvement of both compartments is characteristically variable and the site of onset debated. We sought to establish whether there is a consistent signature of cerebral white matter abnormalities in heterogeneous ALS cases.<h4>Methods</h4>In this observational study, diffusion tensor imaging was applied in a whole-brain analysis of 24 heterogeneous patients with ALS and well-matched healthy controls. Tract-based spatial statistics were used, with optimized voxel-based morphometry of T1 images to determine any associated gray matter involvement.<h4>Results</h4>A consistent reduction in fractional anisotropy was demonstrated in the corpus callosum of the ALS group, extending rostrally and bilaterally to the region of the primary motor cortices, independent of the degree of clinical upper motor neuron involvement. Matched regional radial diffusivity increase supported the concept of anterograde degeneration of callosal fibers observed pathologically. Gray matter reductions were observed bilaterally in primary motor and supplementary motor regions, and also in the anterior cingulate and temporal lobe regions. A post hoc group comparison model incorporating significant values for fractional anisotropy, radial diffusivity, and gray matter was 92% sensitive, 88% specific, with an accuracy of 90%.<h4>Conclusion</h4>Callosal involvement is a consistent feature of ALS, independent of clinical upper motor neuron involvement, and may reflect independent bilateral cortical involvement or interhemispheric spread of pathology. The predominantly rostral corticospinal tract involvement further supports the concept of independent cortical degeneration even in those patients with ALS with predominantly lower motor neuron involvement clinically.