Cerebral Atrophy in Amyotrophic Lateral Sclerosis Parallels the Pathological Distribution of TDP43

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a preferential involvement of both upper and lower motor neurons. Evidence from neuroimaging and post-mortem studies confirms additional involvement of brain regions extending beyond the motor cortex. The aim of this study was to assess the extent of cerebral disease in ALS cross-sectionally and longitudinally, and to compare the findings with a recently proposed disease-staging model of ALS pathology. Deformation-based morphometry (DBM) was used to identify the patterns of brain atrophy associated with ALS and to assess their relationship with clinical symptoms. Longitudinal T1-weighted MRI data and clinical measures were acquired at baseline, 4 months, and 8 months, from 66 ALS patients and 43 age-matched controls who participated in the Canadian ALS Neuroimaging Consortium (CALSNIC) study. Whole brain voxel-wise mixed-effects modelling analysis showed extensive atrophy patterns differentiating ALS patients from the normal controls. Cerebral atrophy was present in the motor cortex and corticospinal tract, involving both GM and WM, and to a lesser extent in non-motor regions. More specifically, the results showed significant bilateral atrophy in the motor cortex, the corticospinal tract including the internal capsule and brainstem, with an overall pattern of ventricular enlargement; along with significant progressive longitudinal atrophy in the precentral gyrus, frontal and parietal white matter, accompanied by ventricular and sulcal enlargement. Atrophy in the precentral gyrus was significantly associated with greater disability as quantified with the ALS Functional Rating Scale-Revised (ALSFRS-R) (p<0.0001). The pattern of atrophy observed using DBM was consistent with the Brettschneider’s four stage pathological model of the disease. Deformation based morphometry provides a sensitive indicator of atrophy in ALS, and has potential as a biomarker of disease burden, in both gray and white matter.

Cerebral atrophy in amyotrophic lateral sclerosis parallels the pathological distribution of TDP43

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by a preferential involvement of both upper and lower motor neurons. Evidence from neuroimaging and post-mortem studies confirms additional involvement of brain regions extending beyond the motor cortex. The aim of this study was to assess the extent of cerebral disease in amyotrophic lateral sclerosis cross-sectionally and longitudinally and to compare the findings with a recently proposed disease-staging model of amyotrophic lateral sclerosis pathology. Deformation-based morphometry was used to identify the patterns of brain atrophy associated with amyotrophic lateral sclerosis and to assess their relationship with clinical symptoms. Longitudinal T1-weighted MRI data and clinical measures were acquired at baseline, 4 months and 8 months, from 66 patients and 43 age-matched controls who participated in the Canadian Amyotrophic Lateral Sclerosis Neuroimaging Consortium study. Whole brain voxel-wise mixed-effects modelling analysis showed extensive atrophy patterns differentiating patients from the normal controls. Cerebral atrophy was present in the motor cortex and corticospinal tract, involving both grey matter and white matter, and to a lesser extent in non-motor regions. More specifically, the results showed significant bilateral atrophy in the motor cortex and corticospinal tract (including the internal capsule and brainstem) and ventricular enlargement, along with significant longitudinal atrophy in precentral gyrus, frontal and parietal white matter, accompanied by ventricular and sulcal enlargement. Atrophy in the precentral gyrus was significantly associated with greater disability as quantified with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (P &lt; 0.0001). The pattern of atrophy observed using deformation-based morphometry was consistent with the Brettschneider’s four-stage pathological model of the disease. Deformation-based morphometry provides a sensitive indicator of atrophy in Amyotrophic lateral sclerosis and has potential as a biomarker of disease burden, in both grey matter and white matter.

Data-driven algorithm for the diagnosis of behavioral variant frontotemporal dementia

INTRODUCTIONBrain structural imaging is paramount for the diagnosis of behavioral variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis.METHODSA total of 515 subjects from two different bvFTD databases (training and validation cohorts) were included to perform voxel-wise deformation-based morphometry analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from morphometric differences in isolation and together with bedside cognitive scores.RESULTSAverage ten-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In a separate validation cohort of genetically confirmed bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added cognitive scores.DISCUSSIONThe random forest classifier developed can accurately predict bvFTD at the individual subject level.

DEFORMATION BASED MORPHOMETRY STUDY OF LONGITUDINAL MRI CHANGES IN BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA

ABSTRACTObjectiveTo objectively quantify how cerebral volume loss could assist with clinical diagnosis and clinical trial design in the behavioural variant of frontotemporal dementia (bvFTD).MethodsWe applied deformation-based morphometric analyses with robust registration to precisely quantify the magnitude and pattern of atrophy in patients with bvFTD as compared to cognitively normal controls (CNCs), to assess the progression of atrophy over one year follow up and to generate clinical trial sample size estimates to detect differences for the structures most sensitive to change. This study included 203 subjects - 70 bvFTD and 133 CNCs - with a total of 482 timepoints from the Frontotemporal Lobar Degeneration Neuroimaging Initiative.ResultsDeformation based morphometry (DBM) revealed significant atrophy in the frontal lobes, insula, medial and anterior temporal regions bilaterally in bvFTD subjects compared to controls with outstanding subcortical involvement. We provide detailed information on regional changes per year. In both cross-sectional analysis and over a one-year follow-up period, ventricle expansion was the most prominent differentiator of bvFTD from controls and a sensitive marker of disease progression.ConclusionsAutomated measurement of ventricular expansion is a sensitive and reliable marker of disease progression in bvFTD to be used in clinical trials for potential disease modifying drugs, as well as possibly to implement in clinical practice. Ventricular expansion measured with DBM provides the lowest published estimated sample size for clinical trial design to detect significant differences over one and two years.

C.03 Deformation-based morphometry analysis of longitudinal low-grade glioma growth

Background: Diffuse low-grade gliomas (LGGs) are primary brain tumours with infiltrative, anisotropic growth related to surrounding white and grey matter structures. Deformation-based morphometry (DBM) is a simple and objective image analysis method that can identify areas of local volume change over time. In this study, we illustrate the use of DBM to study the local expansion patterns of LGGs monitored by serial magnetic resonance imaging (MRI). Methods: We developed an image processing pipeline optimized for the study of LGG growth involving the fusion of follow-up MRIs for a given patient into an average template space using nonlinear registration. The displacement maps derived from nonlinear registration were converted to Jacobian maps, which estimate local tissue expansion and contraction over time. Results: Our results demonstrate that neoplastic growth occurs primarily around the edges of the tumour while the lesion core and areas adjacent to obstacles, such as the skull, show no significant expansion. Regions of normal brain tissue surrounding the lesion show slight contraction over time, representing compression due to mass effect of the tumour. Conclusions: DBM is a useful tool to understand the long-term clinical course of individual tumours and identify areas of rapid growth, which may explain the current presentation and/or predict future symptoms.

Neurologic Examination Findings Associated With Small Cerebellar Volumes After Prematurity

To help clinicians understand what to expect from small cerebellar volumes after prematurity, this study aims to characterize the specific impacts of small cerebellar volumes on the infant neurologic examination. A prospective cohort of preterm newborns (<32 weeks’ gestational age) had brain magnetic resonance imaging (MRI) studies at term-equivalent age. Cerebellar volumes were compared with neurologic examination findings in follow-up, adjusting for severity of intraventricular hemorrhage, white matter injury, and cerebellar hemorrhage. Deformation-based analyses delineated regional morphometric differences in the cerebellum associated with these findings. Of 119 infants with MRI scans, 109 (92%) had follow-up at 19.0±1.7 months corrected age. Smaller cerebellar volume at term was associated with increased odds of truncal hypotonia, postural instability on standing, and patellar hyperreflexia ( P < .03). Small cerebellar volume defined as <19 cm3 by 40 weeks was associated with 7.5-fold increased odds of truncal hypotonia ( P < .001), 8.9-fold odds postural instability ( P < .001), and 9.7-fold odds of patellar hyperreflexia ( P < .001). Voxel-based deformation-based morphometry showed postural instability associated with paravermian regions. Small cerebellar volume is associated with specific abnormalities on neurologic examination by 18 months of age, including truncal tone, reflexes, and postural stability.

Clinical, imaging genetics and deformation based morphometry study of longitudinal changes after surgery for intractable aggressive behaviour

ABSTRACTIntractable aggressive behaviour is a devastating behavioural disorder that reach 30% of psychiatric aggressive patients. Neuromodulatory surgeries may be treatment alternatives to reduce suffering. We investigated the outcomes of bilateral amygdala radiofrequency ablation in four patients with intractable aggressive behaviour (life-threatening-self-injury and social aggression) by studying whole brain magnetic resonance imaging and clinical data. Post-surgery assessments revealed decreases in aggression and agitation and improvements in quality of life. Aggressive behaviour was positively correlated with serum testosterone levels and the testosterone/cortisol ratio in males. No clinically significant side effects were observed. Imaging analyses revealed preoperative amygdala volumes within normal range and confirmed appropriate lesion locations. Reduction in aggressiveness were accompanied by volumetric reduction in brain areas associated with aggressive behaviour (express genes related to aggressive behaviour), and increases in regions related to somatosensation. These findings further elucidates the neurocircuitry of aggression and suggests novel neuromodulation targets.