Amide signal intensities may be reduced in the motor cortex and the corticospinal tract of ALS patients.

OBJECTIVES: The aim of the study is to assess amide concentration changes in ALS patients compared with healthy controls by using quantitative amide proton transfer (APT) and multiparameter magnetic resonance imaging, and testing its correlation with clinical scores. METHODS: Sixteen ALS patients and sixteen healthy controls were recruited as part of the Canadian ALS Neuroimaging Consortium, and multimodal magnetic resonance imaging was performed at 3 T, including APT and diffusion imaging. Lorentz fitting was used to quantify the amide effect. Clinical disability was evaluated using the revised ALS functional rating scale (ALSFRS-R), and its correlation with image characteristics was assessed. The diagnostic performance of different imaging parameters was evaluated with receiver operating characteristic analysis. RESULTS: Our results showed that the amide peak was significantly different between the motor cortex and other gray matter territories within the brain of ALS patients (p < 0.001). Compared with controls, amide signal intensities in ALS were significantly reduced in the motor cortex (p < 0.001) and corticospinal tract (p = 0.046), while abnormalities were not detected using routine imaging methods. There was no significant correlation between amide and ALSFRS-R score. The diagnostic accuracy of the amide peak was superior to that of diffusion imaging. CONCLUSIONS: This study demonstrated changes of amide signal intensities in the motor cortex and corticospinal tract of ALS patients. KEY POINTS: • The neurodegenerative disease amyotrophic lateral sclerosis (ALS) has a lack of objective imaging indicators for diagnosis and assessment. • Analysis of amide proton transfer imaging revealed changes in the motor cortex and corticospinal tract of ALS patients that were not visible on standard magnetic resonance imaging. • The diagnostic accuracy of the amide peak was superior to that of diffusion imaging.

Neuroanatomical associations of the Edinburgh cognitive and Behavioural ALS screen (ECAS).

Cognitive impairment is now recognized in a subset of patients with amyotrophic lateral sclerosis (ALS). The objective of the study was to identify group differences and neuroanatomical correlates of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in participants ALS. Fifty-three ALS patients and 43 healthy controls recruited as a part of our multicentre study (CALSNIC) were administered the ECAS and underwent an MRI scan. Voxel-based morphometry and tract based spatial statistics (TBSS) was performed to identify structural changes and associations with impaired ECAS scores. Lower performance in the ECAS verbal fluency and executive domains were noted in ALS patients as compared to controls (p < 0.01). Extensive white matter degeneration was noted in the corticospinal tract in all ALS patients, while ALS patients with impaired verbal fluency or executive domains (ALS-exi, n = 22), displayed additional degeneration in the corpus callosum, cingulum and superior longitudinal fasciculus as compared to controls (p < 0.05, TFCE corrected). Mild grey matter changes and associations with ECAS verbal fluency or executive performance were noted at lenient statistical thresholds (p < 0.001, uncorrected). Executive impairment was detected using the ECAS in our multicentre sample of Canadian ALS patients. White matter degeneration in motor regions was revealed in ALS patients with extensive spread to frontal regions in the ALS-exi sub-group. Mild associations between ECAS verbal fluency, executive function scores and MRI metrics suggest that reduced performance may be associated with widespread structural integrity.

Cerebral degeneration in amyotrophic lateral sclerosis: A prospective multicenter magnetic resonance spectroscopy study.

BACKGROUND: We investigated cerebral degeneration and neurochemistry in patients with amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS). METHODS: We prospectively studied 65 patients and 43 age-matched healthy controls. Participants were recruited from 4 centers as part of a study in the Canadian ALS Neuroimaging Consortium. All participants underwent single-voxel proton MRS using a protocol standardized across all sites. Metabolites reflecting neuronal integrity (total N-acetyl aspartyl moieties [tNAA]) and gliosis (myo-inositol [Ino]), as well as creatine (Cr) and choline (Cho), were quantified in the midline motor cortex and midline prefrontal cortex. Comparisons were made between patients with ALS and healthy controls. Metabolites were correlated with clinical measures of upper motor neuron dysfunction, disease progression rate, and cognitive performance. RESULTS: In the motor cortex, tNAA/Cr, tNAA/Cho, and tNAA/Ino ratios were reduced in the ALS group compared with controls. Group differences in tNAA/Cr and tNAA/Cho in the prefrontal cortex displayed reduced ratios in ALS patients; however, these were not statistically significant. Reduced motor cortex ratios were associated with slower foot tapping rate, whereas only motor tNAA/Ino was associated with finger tapping rate. Disease progression rate was associated with motor tNAA/Cho. Verbal fluency, semantic fluency, and digit span forwards and backwards were associated with prefrontal tNAA/Cr. CONCLUSIONS: This study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.

Corticospinal tract degeneration in ALS unmasked in T1-weighted images using texture analysis.

The purpose of this study was to investigate whether textures computed from T1-weighted (T1W) images of the corticospinal tract (CST) in amyotrophic lateral sclerosis (ALS) are associated with degenerative changes evaluated by diffusion tensor imaging (DTI). Nineteen patients with ALS and 14 controls were prospectively recruited and underwent T1W and diffusion-weighted magnetic resonance imaging. Three-dimensional texture maps were computed from T1W images and correlated with the DTI metrics within the CST. Significantly correlated textures were selected and compared within the CST for group differences between patients and controls using voxel-wise analysis. Textures were correlated with the patients' clinical upper motor neuron (UMN) signs and their diagnostic accuracy was evaluated. Voxel-wise analysis of textures and their diagnostic performance were then assessed in an independent cohort with 26 patients and 13 controls. Results showed that textures autocorrelation, energy, and inverse difference normalized significantly correlated with DTI metrics (p < .05) and these textures were selected for further analyses. The textures demonstrated significant voxel-wise differences between patients and controls in the centrum semiovale and the posterior limb of the internal capsule bilaterally (p < .05). Autocorrelation and energy significantly correlated with UMN burden in patients (p < .05) and classified patients and controls with 97% accuracy (100% sensitivity, 92.9% specificity). In the independent cohort, the selected textures demonstrated similar regional differences between patients and controls and classified participants with 94.9% accuracy. These results provide evidence that T1-based textures are associated with degenerative changes in the CST.

Psychiatric co-morbidity and asthma: A pilot study utilizing a free use tool to improve asthma care.

PURPOSE: To assess the prevalence of co-morbid psychiatric disorders in asthmatic patients in a Western Canadian Regional Severe Asthma Center. METHODS: A prospective study was completed of patients evaluated through the Edmonton Regional Severe Asthma Clinic (ERSAC). A standardised evaluation, the Mini International Neuropsychiatric Interview (MINI) screen was used to identify possible psychiatric disorders. RESULTS: Twenty-four individuals with moderate to severe asthma, who presented for treatment at ERSAC, were recruited and underwent assessment with the MINI screen. The average patient age was 48 years (range 18-81 years). Nine patients were male and fifteen were female. Twenty subjects (83%) screened positive for a possible psychiatric co-morbidity using the MINI screen. The most common psychiatric co-morbidities identified were post-traumatic stress disorder (50% of the sampled population), depressive episode or persistent depressive disorder (42%), substance/alcohol abuse (33%), generalized anxiety disorder (335), manic episode (25%), agoraphobia (21%), panic disorder (21%) and obsessive-compulsive disorder (17%). Some individuals had more than one concomitant possible psychiatric co-morbidity identified by the MINI screen. CONCLUSIONS: Psychiatric co-morbidity was confirmed to be common in patients with moderate-severe asthma. In individuals with asthma, the MINI screen appeared to be a simple and useful clinical tool to screen for untreated/sub-optimally-managed psychiatric co-morbidities that may impact management.

Evaluating the cerebral correlates of survival in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate cerebral degenerative changes in ALS and their correlates with survival using 3D texture analysis. METHODS: A total of 157 participants were included in this analysis from four neuroimaging studies. Voxel-wise texture analysis on T1-weighted brain magnetic resonance images (MRIs) was conducted between patients and controls. Patients were divided into long- and short-survivors using the median survival of the cohort. Neuroanatomical differences between the two survival groups were also investigated. RESULTS: Whole-brain analysis revealed significant changes in image texture (FDR P < 0.05) bilaterally in the motor cortex, corticospinal tract (CST), insula, basal ganglia, hippocampus, and frontal regions including subcortical white matter. The texture of the CST correlated (P < 0.05) with finger- and foot-tapping rate, measures of upper motor neuron function. Patients with a survival below the media of 19.5 months demonstrated texture change (FDR P < 0.05) in the motor cortex, CST, basal ganglia, and the hippocampus, a distribution which corresponds to stage 4 of the distribution TDP-43 pathology in ALS. Patients with longer survival exhibited texture changes restricted to motor regions, including the motor cortex and the CST. INTERPRETATION: Widespread gray and white matter pathology is evident in ALS, as revealed by texture analysis of conventional T1-weighted MRI. Length of survival in patients with ALS is associated with the spatial extent of cerebral degeneration.

Texture Analysis to Detect Cerebral Degeneration in Amyotrophic Lateral Sclerosis.

BACKGROUND: Evidence of cerebral degeneration is not apparent on routine brain MRI in amyotrophic lateral sclerosis (ALS). Texture analysis can detect change in images based on the statistical properties of voxel intensities. Our objective was to test the utility of texture analysis in detecting cerebral degeneration in ALS. A secondary objective was to determine whether the performance of texture analysis is dependent on image resolution. METHODS: High-resolution (0.5×0.5 mm2 in-plane) coronal T2-weighted MRI of the brain were acquired from 12 patients with ALS and 19 healthy controls on a 4.7 Tesla MRI system. Image data sets at lower resolutions were created by down-sampling to 1×1, 2×2, 3×3, and 4×4 mm2. Texture features were extracted from a slice encompassing the corticospinal tract at the different resolutions and tested for their discriminatory power and correlations with clinical measures. Subjects were also classified by visual assessment by expert reviewers. RESULTS: Texture features were different between ALS patients and healthy controls at 1×1, 2×2, and 3×3 mm2 resolutions. Texture features correlated with measures of upper motor neuron function and disability. Optimal classification performance was achieved when best-performing texture features were combined with visual assessment at 2×2 mm2 resolution (0.851 area under the curve, 83% sensitivity, 79% specificity). CONCLUSIONS: Texture analysis can detect subtle abnormalities in MRI of ALS patients. The clinical yield of the method is dependent on image resolution. Texture analysis holds promise as a potential source of neuroimaging biomarkers in ALS.

Utility of the Addenbrooke's Cognitive Examination in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that primarily affects motor neurons. Cognitive changes are reported in 25%-50% of patients, secondary to frontotemporal involvement. The objective of this study was to evaluate the utility of a screening tool, the Addenbrooke's Cognitive Examination (ACE), in ALS patients. METHODS: In this retrospective cross-sectional study, performance on the ACE was compared between 55 ALS patients and 49 healthy controls. The validation of the ACE in ALS patients was explored using a neuropsychometric battery. Correlations between the ACE and clinical variables such as the ALS Functional Rating Scale-Revised (ALSFRS-R) and forced vital capacity were computed. RESULTS: A higher percentage of patients were below cut-off scores, although this remained non-significant between the patient and control groups. The ACE did not reveal significant differences between ALS patients and controls. The scores on the ACE displayed moderate correlations with our neuropsychometric battery for some domains, whereas others showed poor or no associations. Poor ACE Total was associated with lower ALSFRS-R and finger-tapping scores. CONCLUSIONS: Performance on the ACE was comparable between patients and controls. Associations with motor function pose a challenge to accurate interpretation of ACE performance. It is likely that patients with poor cognition have greater disability, or that poor ACE performance reflects reduced motor ability to perform the task. This raises concern for the utility of the ACE as a screening tool in ALS patients, especially since recent versions of the ACE continue to include motor-based tasks.

Hair product artifact in magnetic resonance imaging.

The presence of metallic compounds in facial cosmetics and permanent tattoos may affect the quality of magnetic resonance imaging. We report a case study describing a signal artifact due to the use of a leave-on powdered hair dye. On reviewing the ingredients of the product, it was found to contain several metallic compounds. In lieu of this observation, we suggest that MRI centers include the use of metal- or mineral-based facial cosmetics or hair products in their screening protocols.

White matter structural network abnormalities underlie executive dysfunction in amyotrophic lateral sclerosis.

Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract-based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain-specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co-localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249-1268, 2017. © 2016 Wiley Periodicals, Inc.

Investigating Default Mode and Sensorimotor Network Connectivity in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by degeneration of upper motor neurons (UMN) arising from the motor cortex in the brain and lower motor neurons (LMN) in the brainstem and spinal cord. Cerebral changes create differences in brain activity captured by functional magnetic resonance imaging (fMRI), including the spontaneous and simultaneous activity occurring between regions known as the resting state networks (RSNs). Progressive neurodegeneration as observed in ALS may lead to a disruption of RSNs which could provide insights into the disease process. Previous studies have reported conflicting findings of increased, decreased, or unaltered RSN functional connectivity in ALS and do not report the contribution of UMN changes to RSN connectivity. We aimed to bridge this gap by exploring two networks, the default mode network (DMN) and the sensorimotor network (SMN), in 21 ALS patients and 40 age-matched healthy volunteers. An UMN score dichotomized patients into UMN+ and UMN- groups. Subjects underwent resting state fMRI scan on a high field MRI operating at 4.7 tesla. The DMN and SMN changes between subject groups were compared. Correlations between connectivity and clinical measures such as the ALS Functional Rating Scale-Revised (ALSFRS-R), disease progression rate, symptom duration, UMN score and finger tapping were assessed. Significant group differences in resting state networks between patients and controls were absent, as was the dependence on degree of UMN burden. However, DMN connectivity was increased in patients with greater disability and faster progression rate, and SMN connectivity was reduced in those with greater motor impairment. These patterns of association are in line with literature supporting loss of inhibitory interneurons.

High prevalence of abnormal gastrointestinal permeability in moderate-severe asthma.

PURPOSE: Abnormal gastrointestinal permeability (GIP) has been implicated in a number of diseases, including chronic intestinal inflammatory disorders such as Crohn's as well as non-intestinal immunologic diseases such as diabetes and multiple sclerosis. Although evidence in the literature demonstrates mucosal abnormalities of the digestive barrier in asthma, previous studies have assessed only colonic permeability, while ignoring the mucosal-associated lymphoid tissue (MALT) rich areas of the small intestine. Alterations in GIP may lead to increased entry of allergenic proteins from the gut lumen into the systemic circulation, thus priming and activating the adaptive immune system and leading to inappropriate allergen sensitization and/or deregulated extra-intestinal inflammation. This study examines GIP in adults with moderate to severe asthma. METHODS: Patients ingested a mixed-sugar solution and urine was collected. GIP was assayed using high-performance liquid chromatography. Demographics, atopy (assessed by allergen skin testing) and sputum cell counts were also assessed. RESULTS: Fourteen patients with moderate to severe asthma were studied, half of whom were found to have abnormal GIP. Abnormal GIP did not correlate with sputum cell counts and there was no apparent association between atopy and intestinal permeability. CONCLUSION: This study demonstrated our ability to identify abnormal GIP in the MALT-rich, immunogenic small intestine of patients with asthma. The absence of a correlation between airway inflammation and increased GIP suggests that these two parameters are not causally linked, but rather define distinct entities that could separately or sequentially be involved with the development and propagation of asthma over time.

Fragrance materials in asthma: a pilot study using a surrogate aerosol product.

OBJECTIVE: Many household products contain fragrances. Little is known about exposure to fragrances on human health, particularly within the airways. This study aimed to evaluate how common household fragrance products (i.e. air fresheners, cleaning products) affect people with asthma, who frequently report sensitivity to these products. Many of these products have volatile organic compounds or semi-volatile organic compounds. This study evaluated nine fragrance materials in an aerosol formulation to assess effects on airway physiology, airway inflammation and symptom perception in normal controls and those with asthma. METHODS: The effects of fragrances were evaluated in people without asthma, people with mild asthma and people with moderate asthma in a four-way crossover placebo-controlled study. Subjects were exposed twice to a fragranced aerosol and twice to a placebo aerosol (15 and 30 min each). Subjects completed a questionnaire for 29 symptoms during and up to 3 h after each exposure scenario. Spirometry was performed prior to and 3 h post-exposure; sputum induction was conducted 3 h post-exposure. RESULTS: Nasal symptoms showed the greatest frequency of response in all three subject groups, and moderate asthmatics reported the greatest symptom severity and symptom types. No significant differences were noted in physiology or cellular inflammation. CONCLUSION: A trend for increased symptoms was noted in moderate asthmatics, suggesting that asthma severity may play a factor in fragrance sensitivity.