CSF neurofilament light chain reflects corticospinal tract degeneration in ALS

Objective: Diffusion tensor imaging (DTI) is sensitive to white matter tract pathology. A core signature involving the corticospinal tracts (CSTs) has been identified in amyotrophic lateral sclerosis (ALS). Raised neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) is thought to reflect axonal damage in a range of neurological disorders. The relationship between these two measures was explored. Methods: CSF and serum NfL concentrations and DTI acquired at 3 Tesla on the same day were obtained from ALS patients (n = 25 CSF, 40 serum) and healthy, age-similar controls (n = 17 CSF, 25 serum). Within-group correlations between NfL and DTI measures of microstructural integrity in major white matter tracts (CSTs, superior longitudinal fasciculi [SLF], and corpus callosum) were performed using tract-based spatial statistics. Results: NfL levels were higher in patients compared to controls. CSF levels correlated with clinical upper motor neuron burden and rate of disease progression. Higher NfL levels were significantly associated with lower DTI fractional anisotropy and increased radial diffusivity in the CSTs of ALS patients, but not in controls. Interpretation: Elevated CSF and serum NfL is, in part, a result of CST degeneration in ALS. This highlights the wider potential for combining neurochemical and neuroimaging-based biomarkers in neurological disease.The project was funded by The Motor Neurone Disease Association (Malaspina/ Apr13/6097), Barts and The London Charities (468/1714). The Oxford MND Centre (M. R. T., K. T.) receives funding from the Motor Neurone Disease Association U. K. M. R. T. is funded by the Medical Research Council & Motor Neurone Disease Association Lady Edith Wolfson Fellowship (G0701923 and MR/K01014X/1), and E. G. through the PROMISES project award to M. R. T. by the Thierry Latran Foundation. J. K. is funded by an ECTRIMS Research Fellowship Programme and by the Research Funds of the University of Basel, Switzerland

Comprehensive morphometry of subcortical grey matter structures in early-stage Parkinson's disease

Previous imaging studies that investigated morphometric group differences of subcortical regions outside the substantia nigra between non-demented Parkinson's patients and controls either did not find any significant differences, or reported contradictory results. Here, we performed a comprehensive morphometric analysis of 20 cognitively normal, early-stage PD patients and 19 matched control subjects. In addition to relatively standard analyses of whole-brain grey matter volume and overall regional volumes, we examined subtle localized surface shape differences in striatal and limbic grey matter structures and tested their utility as a diagnostic marker. Voxel-based morphometry and volumetric comparisons did not reveal significant group differences. Shape analysis, on the other hand, demonstrated significant between-group shape differences for the right pallidum. Careful diffusion tractography analysis showed that the affected parts of the pallidum are connected subcortically with the subthalamic nucleus, the pedunculopontine nucleus, and the thalamus and cortically with the frontal lobe. Additionally, microstructural measurements along these pathways, but not along other pallidal connections, were significantly different between the two groups. Vertex-wise linear discriminant analysis, however, revealed limited accuracy of pallidal shape for the discrimination between patients and controls. We conclude that localized disease-related changes in the right pallidum in early Parkinson's disease, undetectable using standard voxel-based morphometry or volumetry, are evident using sensitive shape analysis. However, the subtle nature of these changes makes it unlikely that shape analysis alone will be useful for early diagnosis. © 2013 Wiley Periodicals, Inc

Comprehensive morphometry of subcortical grey matter structures in early-stage Parkinson's disease

Previous imaging studies that investigated morphometric group differences of subcortical regions outside the substantia nigra between non-demented Parkinson's patients and controls either did not find any significant differences, or reported contradictory results. Here, we performed a comprehensive morphometric analysis of 20 cognitively normal, early-stage PD patients and 19 matched control subjects. In addition to relatively standard analyses of whole-brain grey matter volume and overall regional volumes, we examined subtle localized surface shape differences in striatal and limbic grey matter structures and tested their utility as a diagnostic marker. Voxel-based morphometry and volumetric comparisons did not reveal significant group differences. Shape analysis, on the other hand, demonstrated significant between-group shape differences for the right pallidum. Careful diffusion tractography analysis showed that the affected parts of the pallidum are connected subcortically with the subthalamic nucleus, the pedunculopontine nucleus, and the thalamus and cortically with the frontal lobe. Additionally, microstructural measurements along these pathways, but not along other pallidal connections, were significantly different between the two groups. Vertex-wise linear discriminant analysis, however, revealed limited accuracy of pallidal shape for the discrimination between patients and controls. We conclude that localized disease-related changes in the right pallidum in early Parkinson's disease, undetectable using standard voxel-based morphometry or volumetry, are evident using sensitive shape analysis. However, the subtle nature of these changes makes it unlikely that shape analysis alone will be useful for early diagnosis. © 2013 Wiley Periodicals, Inc

Regional thalamic MRI as a marker of widespread cortical pathology and progressive frontotemporal involvement in amyotrophic lateral sclerosis

Background The thalamus is a major neural hub, with selective connections to virtually all cortical regions of the brain. The multisystem neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) has pathogenic overlap with frontotemporal dementia, and objective in vivo markers of extra-motor pathological spread are lacking. To better consider the role of the thalamus in neurodegeneration, the present study assessed the integrity of the thalamus and its connectivity to major cortical regions of the brain in a longitudinal manner. Methods Diffusion-based MRI tractography was used to parcellate the thalamus into distinct regions based on structural thalamo-cortical connectivity in 20 patients with ALS, half of whom were scanned at two time points, and 31 matched controls scanned on a single occasion. Results At baseline, widespread diffusivity alterations in motor- and extramotor-associated thalamic parcellations were detectable. Longitudinal decline selectively affected thalamic regions associated with frontal and temporal lobe connectivity. Diffusivity measures were significantly correlated with clinical measures of disease burden. Progression of functional disability, as indicated by change on the ALS functional rating scale, was associated with longitudinal change in mean diffusivity of the right frontal lobe thalamic parcellation (r=0.59, p=0.05). Conclusions Regional thalamic connectivity changes mirror the progressive frontotemporal cortical involvement associated with the motor functional decline in ALS. Longitudinal MRI thalamic parcellation has potential as a non-invasive surrogate marker of cortical dysfunction in ALS

Regional thalamic MRI as a marker of widespread cortical pathology and progressive frontotemporal involvement in amyotrophic lateral sclerosis

Background The thalamus is a major neural hub, with selective connections to virtually all cortical regions of the brain. The multisystem neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) has pathogenic overlap with frontotemporal dementia, and objective in vivo markers of extra-motor pathological spread are lacking. To better consider the role of the thalamus in neurodegeneration, the present study assessed the integrity of the thalamus and its connectivity to major cortical regions of the brain in a longitudinal manner. Methods Diffusion-based MRI tractography was used to parcellate the thalamus into distinct regions based on structural thalamo-cortical connectivity in 20 patients with ALS, half of whom were scanned at two time points, and 31 matched controls scanned on a single occasion. Results At baseline, widespread diffusivity alterations in motor- and extramotor-associated thalamic parcellations were detectable. Longitudinal decline selectively affected thalamic regions associated with frontal and temporal lobe connectivity. Diffusivity measures were significantly correlated with clinical measures of disease burden. Progression of functional disability, as indicated by change on the ALS functional rating scale, was associated with longitudinal change in mean diffusivity of the right frontal lobe thalamic parcellation (r=0.59, p=0.05). Conclusions Regional thalamic connectivity changes mirror the progressive frontotemporal cortical involvement associated with the motor functional decline in ALS. Longitudinal MRI thalamic parcellation has potential as a non-invasive surrogate marker of cortical dysfunction in ALS

Neuroimaging endpoints in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative, clinically heterogeneous syndrome pathologically overlapping with frontotemporal dementia. To date, therapeutic trials in animal models have not been able to predict treatment response in humans, and the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), which is based on coarse disability measures, remains the gold standard measure of disease progression. Advances in neuroimaging have enabled mapping of functional, structural and molecular aspects of ALS pathology, and these objective measures may be uniquely sensitive to the detection of propagation of pathology in vivo. Abnormalities are detectable before clinical symptoms develop, offering the potential for neuroprotective intervention in familial cases. Although promising neuroimaging biomarker candidates for diagnosis, prognosis and disease progression have emerged, these have been from the study of necessarily select patient cohorts identified in specialized referral centres. Further multi-centre research is now needed to establish their validity as therapeutic outcome measures

Investigation of urinary storage symptoms in Parkinson's disease utilizing structural MRI techniques

BACKGROUND:Lower urinary tract symptoms occur in 27% to 86% of patients with Parkinson's disease (PD), however, the mechanisms responsible for bladder dysfunction are not fully understood. This study utilized magnetic resonance imaging (MRI) to test the hypothesis that key brainstem bladder control areas (including the pontine micturition center and the pontine continence center (PCC) and their links with the basal ganglia are important in the development of urinary storage symptoms in PD. METHODS:Seventeen patients with PD completed a "bladder symptom questionnaire" and underwent diffusion-weighted MRI (1.5 T). Storage symptom severity and MRI measures of white matter microstructural integrity were correlated using tract-based spatial statistics. RESULTS:Mean diffusivity in the ventral brainstem correlated significantly with the bladder symptom severity in areas close to the predicted anatomical co-ordinates of the PCC. Tracts seeded from these regions passed via areas involved in pelvic floor musculature control and urinary voiding including the cerebellum, pallidum, and precentral gyrus. CONCLUSION:We used diffusion-weighted MRI to investigate the role of the brainstem and its structural connections in the development of urinary storage symptoms in PD. Our data suggest that the brainstem degenerative change in the vicinity of the PCC may be implicated in the pathogenesis of storage symptoms in these patients

Neuroimaging endpoints in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative, clinically heterogeneous syndrome pathologically overlapping with frontotemporal dementia. To date, therapeutic trials in animal models have not been able to predict treatment response in humans, and the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), which is based on coarse disability measures, remains the gold standard measure of disease progression. Advances in neuroimaging have enabled mapping of functional, structural and molecular aspects of ALS pathology, and these objective measures may be uniquely sensitive to the detection of propagation of pathology in vivo. Abnormalities are detectable before clinical symptoms develop, offering the potential for neuroprotective intervention in familial cases. Although promising neuroimaging biomarker candidates for diagnosis, prognosis and disease progression have emerged, these have been from the study of necessarily select patient cohorts identified in specialized referral centres. Further multi-centre research is now needed to establish their validity as therapeutic outcome measures