C69 THE PAST, PRESENT AND FUTURE OF NEUROIMAGING IN ALS/MND
TURNER MR
University of Oxford, Oxford, UK
Email address for correspondence: [email protected]
Keywords: magnetic resonance imaging, positron emission tomography, biomarker
History may judge the development of neuroimaging as transformational in clinical neuroscience, bringing the post-mortem neuropathological insights of pioneers like Lockhart Clarke and Charcot to the in vivo domain. Whilst MRI retains an important role in the exclusion of alternative pathology, advanced applications now provide a parallel role as a source of diagnostic and potentially monitoring biomarkers in ALS (1). In addition, neuroimaging continues to provide important clues to pathogenic mechanisms:
Positron emission tomography (PET) studies of cerebral blood flow and metabolism pioneered the concept of ALS as a multiple system disorder (2).
Ligand PET revealed cerebral microglial activation in vivo (3), underpinning in vitro data supporting the pathogenic theme of neuroinflammation in ALS (4). Emerging rodent MRI studies mark an era of molecular imaging, with ‘smart’ contrast agents targeting surrogate markers of neuroinflammation that may offer therapeutic strategies in human ALS.
The marked and similar regional reductions of serotonin (5-HT) 1A receptor binding seen in PET studies of non-demented ALS patients (5) and pure frontotemporal dementia (6) may warrant reappraisal in light of the subsequent emergence of a unifying histopathological marker, namely TDP-43.
Flumazenil PET as a surrogate for loss of GABA-ergic function supports the concept of ALS as fundamentally involving a ‘failure of cortical inhibition’ (7), and so possibly as an ‘interneuronopathy’ by implication. Developments in computational neuroscience and biostatistics mean that combined structural and functional cerebral connectivity can now be studied non-invasively using MRI. With the addition of high-field magnetic resonance spectroscopy, there is potential to test the hypothesis of imbalance between inhibitory and excitatory neuronal activity in ALS, with potential for improved therapeutic strategies. Connectivity studies in pre-symptomatic carriers of ALS-related gene mutations might reveal an inherently vulnerable motor network, with implications for identifying the larger at-risk population that will be essential to any longer-term aspiration for primary prevention of the sporadic disorder.
MRI is a largely non-invasive, ubiquitous but expensive technology. Whether it can deliver, at routine clinical scanner field strengths, on the promise of a biomarker sensitive enough in the context of a therapeutic trial is being tested through emerging international collaboration (8). MRI may ultimately be only one part of a multimodal biomarker panel that includes biofluid and neurophysiological measurements. However it looks certain to continue to make important contributions to understanding in vivo disease mechanisms.
References
- Turner MR, Modo M. Exp Op Med Diag 2010;PM: 21516259.
- Kew JJ, et al. Brain 1993;PM:8513396.
- Turner MR, et al. Neurobiol Dis 2004;PM:15056468.
- Philips T, Robberecht W. Lancet Neurol 2011;PM: 21349440.
- Turner MR, et al. Brain 2005;PM:15689356.
- Lanctot KL, et al. Psychiatry Res 2007;PM:17976961.
- Turner MR, et al. Brain 2005;PM:15843422.
- Turner MR, et al. Lancet Neurology 2011;PM:21511189.
C70 MAGNETIC RESONANCE MICROIMAGING OF THE SPINAL CORD IN THE SOD1 MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS DETECTS MOTOR NERVE ROOT DEGENERATION
BUTLER T1, COWIN G1, KURNIAWAN N1, WATSON C2, WALLACE R1
1The University of Queensland, Brisbane, Australia, 2Curtin University, Perth, Australia
Email address for correspondence: [email protected]
Keywords: MRI, SOD1 mouse, spinal cord imaging
Current imaging studies in ALS have concentrated on areas of the brain and spinal cord that contain mixed populations of sensory and motor neurons. In this study, ex vivo magnetic resonance microimaging (MRM) was used to separate motor and sensory components by visualizing individual dorsal and ventral roots in fixed spinal cords. MRM at 15 μm in plane resolution enabled the axons of pure populations of sensory and motor neurons to be measured in the lumbar region of the SOD1 mouse model of ALS. MRM signal intensity increased by 38.3% (p < 0.05) exclusively in the ventral motor nerve roots of the lumbar spinal cord of ALS-affected SOD1 mice compared to wildtype littermates. The hyperintensity was therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibres were unchanged. Significant decreases in ventral nerve root volume were also detected in the SOD1 mice, which correlated with the axonal degeneration observed by microscopy. These results demonstrate the usefulness of MRM in visualising the ultrastructure of the mouse spinal cord. The detailed 3D anatomy allowed the processes of pure populations of sensory and motor neurons to be compared. This has been the first study to use MRM in the mouse spinal cord to detect nerve root volume loss. In the future, these MRM techniques may translate to the study of human ALS patients.
C71 MRI EVIDENCE OF DISEASE IN PRE-SYMPTOMATIC SOD1 + INDIVIDUALS AT RISK FOR DEVELOPING FAMILIAL ALS
NAIR G2, WUU J1, GRONKA S1, WALKER M1, CAREW J3, BENATAR M1
1University of Miami, Miami, FL, USA, 2Emory University, Atlanta, GA, USA, 3Carolinas Healthcare, Charlotte, NC, USA
Email address for correspondence: [email protected]
Keywords: MRS, DTI, pre-symptomatic
Background: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a pre-manifest period during which neurodegeneration precedes the appearance of clinical manifestations. Evidence to support this hypothesis derives primarily from the SOD1 mouse model of ALS but also from preliminary data in a small number of healthy individuals carrying a mutation in the SOD1 gene and at risk for developing ALS.
Methods: The Pre-familial ALS (Pre-fALS) study is an ongoing prospective observational study of people who are at risk for developing familial ALS; participants are recruited from amongst healthy relatives of patients with fALS due to mutations in known susceptibility genes such as SOD1, TDP43 and FUS. Study participants are seen at least annually and undergo multi-modal (clinical, electrophysiological, imaging and “wet”) biomarker studies. All pre-symptomatic subjects have no clinical manifestations of disease, normal forced vital capacity, and normal electromyographic examination. Age-matched, healthy gene negative subjects and patients with ALS (either familial or sporadic) were recruited as “comparison” populations. Diffusion tensor imaging of the brain and cervical spinal cord, as well as magnetic resonance spectroscopy (MRS) of the cervical spinal cord, were performed as described elsewhere (1,2).
Results: DTI data are currently being analyzed. Here we present the results of 1H-MRS of the cervical spine performed on 29 healthy controls, 24 pre-symptomatic SOD1 + volunteers, and 23 ALS patients. Compared to controls, NAA/Cr and NAA/Myo ratios are reduced in both SOD1 + subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and ALS patients (41.2%, p < 0.001 and 24.0%, p = 0.01). Myo/Cr is reduced (10.3%, p = 0.02) in SOD1 + subjects compared to controls, but no difference was observed between ALS and controls. By contrast, compared to controls, NAA/Cho is reduced in ALS patients (24.0%, p = 0.002), but not in pre-symptomatic SOD1 + subjects.
Conclusions: Changes in neurometabolite ratios in the cervical spinal cord (i.e. reductions in NAA/Cr and NAA/Myo) are evident in pre-symptomatic SOD1 + people in advance of symptoms as well as clinical and electromyographic signs of disease. These cross-sectional neurometabolic findings resemble those observed in patients with clinically apparent ALS; they suggest that neurometabolic changes occur early in the course of the disease process. These findings await confirmation from longitudinal imaging data collected as part of the Pre-fALS study.
References
- Amyotroph Laterl Scler 2010 Dec 14 (Epub ahead of print).
- Neuroimage 2010;53(2):576–83.
C72 IN VIVO NEUROPATHOLOGY OF ALS: MULTIMODAL MRI REVEALS EXTENSIVE CENTRAL AND FRONTOTEMPORAL WHITE MATTER DAMAGE
HARTUNG V1, TIETZ F1, PENZLIN S1, PRELL T1, BOKEMEYER M2, ILSE B1, RAGOSCHKE-SCHUMM A2, WITTE OW1, GROSSKREUTZ J1
1Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany, 2Section of Neuroradiology, IDIR, Jena University Hospital, Jena, Germany
Email address for correspondence: [email protected]
Keywords: multimodal MRI, diagnosis, biomarker
Background: Visualizing the subtle neuron damage of ALS in MRI has recently been facilitated by computerized statistical image analysis methods. Voxel-based morphometry (VBM), diffusion tensor imaging (DTI) and resting state functional MRI (rsfMRI) have reported consistent changes in ALS; data on magnetization transfer imaging (MTI) and susceptibility weighted imaging (SWI) are controversial. Yet few multimodal MRI data are available which enable neuropathological in vivo studies using the different sequences to display several ALS related damage mechanisms simultaneously.
Objectives: To extract typical patterns of ALS damage in VBM, DTI, MTI, rsfMRI and SWI in a group of well characterized ALS patients without manifest dementia; to identify areas of concurrent or alternative MRI damage signature; and to define a set of ALS signature areas for future MRI diagnosis of ALS.
Methods: We investigated ALS related brain damage in 38 ALS patients (age 62.5 + -10.1 yrs, 23 male) with an average ALSFRS-R of 36.8 + -6.9, and 37 healthy, age and sex matched volunteers, using a Siemens Sonata 1.5T scanner. For every patient and volunteer MMSE, FAB, EQ-5D and SF36 scores were obtained. We used MATLAB R2009b (TheMathworks,Natick,USA) as mathematical framework, SPM8 (Wellcome Trust Centre for Neuroimaging, UCL, London, UK), the VBM8 toolbox (Christian Gaser), and FSL/Freesurfer software for preprocessing raw data and assessing results. For white matter analysis we altered the classical VBM approach to spatially normalized, bias corrected T1-contrasted images for SPM-like group comparisons.
Results: Using VBM on grey matter, volume reduction was seen in central areas and frontal areas concurrent with known changes. White matter changes, however, were extensive in custom-masked datasets with a typical frontotemporal distribution, along the subcentral matter and the corticospinal tracts, which was confirmed in diffusion based datasets. These displayed different areas of damage in CST, subcortical central and frontal white matter depending on the DTI parameter analyzed, and may differentiate between early, partly functional, and late, structural damage. RsfMRI confirmed alterations of in particular the motor resting state network. SWI and MRI confirmed substructural damage in the same areas as T1 white matter images indicating macromolecular alterations.
Discussion and conclusion: VBM still produces inconstant results in the grey matter of ALS patients, possibly due to large interindividual variability. In contrast, white matter space is less variable between subjects, and ALS typical changes were seen in a large array of MRI sequences which may in part display different degrees of damage, and possibly different pathophysiological processes. Consistent changes across sequences were seen in the corticospinal tract, the central corpus callosum and the frontal white matter. These should be used as landmarks for ALS single subject multimodal MRI which in the future should provide valid diagnostic and biomarker information.
C73 A LONGITUDINAL 4 TESLA MRI STUDY OF THE ANTERIOR CINGULATE
WOOLLEY S1, ZHANG Y2, SCHUFF N2, LAXAMANA J2, MOORE D1, WEINER M3, KATZ J1
1Forbes Norris ALS Center, San Francisco, CA, USA, 2VA Medical Center/UCSF, San Francisco, CA, USA, 3Center for Imaging of Neurodegenerative Disease, San Francisco, CA, USA
Email address for correspondence: [email protected]
Keywords: anterior cingulate, fluency, MRI
Background: Abnormalities in the anterior cingulate have been identified in multiple ALS studies (1,2) and correlate with cognitive deficits. A recent 4 Tesla study (3) in non-demented ALS patients also found a correlation between anterior cingulate abnormalities and behavioral signs of apathy. No ALS imaging studies, however, have attempted to measure these changes longitudinally to determine how or when they develop.
Objectives: To investigate longitudinal MRI changes, focusing on the anterior cingulate cortex as the primary region of interest (ROI).
Methods: We analyzed longitudinal scans from seventeen ALS patients. Baseline and follow-up T1-weighted images and DTI were scanned at 4.0-Tesla (Bruker/Siemens). Grey matter volume and white matter FA were measured in similar anatomical regions (ROI), and annual change and change rates were calculated. Differences between baseline and follow-up measurements were assessed using a paired-sample t-test and a linear mixed-effects model, with significance set at p < 0.05. Apathy was assessed at both time points using the Frontal Systems Behaviour Scale (FrSBe) and verbal fluency, a focused measure of cognition, was assessed using the Delis Kaplan Executive Functions System (DKEFS).
Results: The mean age of the cohort was 59 years with mean duration between scans of 7.4 months (range 5–11). Significant FA changes were noted in multiple anterior cingulate regions using DTI (most significant left caudal anterior cingulate, p = 0.003, paired t-test).Using a linear mixed-effect model that controls for variance in age and scan duration, we found gray matter volume changes in the left caudal anterior cingulate which trended towards significance (p = 0.09) but no significant DTI findings remained. No significant declines in apathy were noted between the time points, and practice effects were suggested for phonemic fluency. When contrasting semantic fluency (Category Fluency) scores with semantic set shifting (Category Switching) scores, we observed a nonsignificant decline over time. Correlation between this fluency contrast score and FA values in the most anterior section of the right cingulate gyrus trended towards significance (p = 0.061).
Discussion and conclusions: Subtle MRI changes in the anterior cingulate may occur in non-demented ALS patients over a relatively short time period, even though significant clinical changes were not seen and would not be expected during this time frame. These longitudinal findings lend information to earlier work where we identified abnormalities in the right anterior cingulate at baseline. In the current analysis, anterior cingulate changes were primarily left-sided. Future studies require a control group for deeper comparisons.
References
- Strong M, Grace G, Orange J, et al. Neurology 1999;53:1665–70.
- Abrahams S, Goldstein, LH, Simmons A, et al. Brain 2004; 1507–17.
- Woolley SC, Zhang Y, Schuff, N, et al. ALS 2011;12:52–8.