6 research outputs found
Pathological Crying and Laughing in Motor Neuron Disease: Pathobiology, Screening, Intervention
Pathological crying and laughing (PCL) has significant quality-of-life implications in amyotrophic lateral sclerosis (ALS); it can provoke restrictive life-style modifications and lead to social isolation. Despite its high prevalence and quality of life implications, it remains surprisingly understudied. Divergent pathophysiological models have been proposed, centered on corticobulbar tract degeneration, prefrontal cortex pathology, sensory deafferentation, and impaired cerebellar gate-control mechanisms. Quantitative MRI techniques and symptom-specific clinical instruments offer unprecedented opportunities to elucidate the anatomical underpinnings of PCL pathogenesis. Emerging neuroimaging studies of ALS support the role of cortico–pontine–cerebellar network dysfunction in context-inappropriate emotional responses. The characterization of PCL-associated pathophysiological processes is indispensable for the development of effective pharmacological therapies
Tracking a Fast-Moving Disease: Longitudinal Markers, Monitoring, and Clinical Trial Endpoints in ALS
Amyotrophic lateral sclerosis (ALS) encompasses a heterogeneous group of phenotypes with different progression rates, varying degree of extra-motor involvement and divergent progression patterns. The natural history of ALS is increasingly evaluated by large, multi-time point longitudinal studies, many of which now incorporate presymptomatic and post-mortem assessments. These studies not only have the potential to characterize patterns of anatomical propagation, molecular mechanisms of disease spread, but also to identify pragmatic monitoring markers. Sensitive markers of progressive neurodegenerative change are indispensable for clinical trials and individualized patient care. Biofluid markers, neuroimaging indices, electrophysiological markers, rating scales, questionnaires, and other disease-specific instruments have divergent sensitivity profiles. The discussion of candidate monitoring markers in ALS has a dual academic and clinical relevance, and is particularly timely given the increasing number of pharmacological trials. The objective of this paper is to provide a comprehensive and critical review of longitudinal studies in ALS, focusing on the sensitivity profile of established and emerging monitoring markers
Occulomotor Neural Integrator Dysfunction in Multiple Sclerosis: Insights From Neuroimaging
Background: Magnetic resonance imaging is a key diagnostic and monitoring tool in multiple Sclerosis (MS). While the substrates of motor and neuropsychological symptoms in MS have been extensively investigated, nystagmus-associated imaging signatures are relatively under studied. Accordingly, the objective of this study is the comprehensive characterisation of cortical, subcortical, and brainstem involvement in a cohort of MS patients with gaze-evoked nystagmus.Methods: Patients were recruited from a specialist MS clinic and underwent multimodal neuroimaging including high-resolution structural and diffusion tensor data acquisitions. Morphometric analyses were carried out to evaluate patterns of cortical, subcortical, brainstem, and cerebellar gray matter pathology. Volumetric analyses were also performed to further characterize subcortical gray matter degeneration. White matter integrity was evaluated using axial-, mean-, and radial diffusivity as well as fractional anisotropy.Results: Whole-brain morphometry highlighted considerable brainstem and cerebellar gray matter atrophy, and the tract-wise evaluation of white matter metrics revealed widespread pathology in frontotemporal and parietal regions. Nystagmus-associated gray matter degeneration was identified in medial cerebellar, posterior medullar, central pontine, and superior collicular regions. Volume reductions were identified in the putamen, thalamus and hippocampus.Conclusions: Multiple sclerosis is associated with widespread gray matter pathology which is not limited to cortical regions but involves striatal, thalamic, cerebellar, and hippocampal foci. The imaging signature of gaze-evoked nystagmus in MS confirms the degeneration of key structures of the neural integrator network
Genotype-associated cerebellar profiles in ALS: focal cerebellar pathology and cerebro-cerebellar connectivity alterations
Objective Cerebellar disease burden and cerebro-cerebellar connectivity
alterations are poorly characterised in amyotrophic lateral sclerosis
(ALS) despite the likely contribution of cerebellar pathology to the
clinical heterogeneity of the condition. Methods A prospective imaging
study has been undertaken with 271 participants to systematically
evaluate cerebellar grey and white matter alterations, cerebellar
peduncle integrity and cerebro-cerebellar connectivity in ALS.
Participants were stratified into four groups: (1) patients testing
positive for GGGGCC repeat expansions in C9orf72, (2) patients carrying
an intermediate-length repeat expansion in ATXN2, (3) patients without
established ALS-associated mutations and (4) healthy controls.
Additionally, the cerebellar profile of a single patient with ALS who
had an ATXN2 allele length of 62 was evaluated. Cortical thickness, grey
matter and white matter volumes were calculated in each cerebellar
lobule complemented by morphometric analyses to characterise
genotype-associated atrophy patterns. A Bayesian segmentation algorithm
was used for superior cerebellar peduncle volumetry. White matter
diffusivity parameters were appraised both within the cerebellum and in
the cerebellar peduncles. Cerebro-cerebellar connectivity was assessed
using deterministic tractography. Results Cerebellar pathology was
confined to lobules I-V of the anterior lobe in patients with sporadic
ALS in contrast to the considerable posterior lobe and vermis disease
burden identified in C9orf72 mutation carriers. Patients with
intermediate ATXN2 expansions did not exhibit significant cerebellar
pathology. Conclusions Focal rather than global cerebellar degeneration
characterises ALS. Pathognomonic ALS symptoms which are typically
attributed to other anatomical regions, such as dysarthria, dysphagia,
pseudobulbar affect, eye movement abnormalities and cognitive deficits,
may be modulated, exacerbated or partially driven by cerebellar changes
in ALS