Hereditary Spastic Paraplegia: Beyond Clinical Phenotypes toward a Unified Pattern of Central Nervous System Damage

Scarlato, Marina; Spinelli, Edoardo Gioele; Canu, Elisa; Benedetti, Sara; Bassi, Maria Teresa; Casali, Carlo; Sessa, Maria; Copetti, Massimiliano; Pagani, Elisabetta; Comı, Gıancarlo; Ferrari, Maurizio; Falini, Andrea; Filippi, Massimo

doi:10.1148/radiol.14141715

Cited by 36 publications

(41 citation statements)

References 39 publications

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“…However, given the small size of our sample, such conclusion needs to be confirmed. Nevertheless, this reflects the rarity of these conditions, and it is in line with previous neuroimaging studies in these patients [ 17 , 40 , 41 ].…”

Section: Discussionsupporting

confidence: 89%

Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks

et al. 2019

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Aim Our aim was to describe the rearrangements of the brain activity related to genetic mutations in the SPAST gene. Methods Ten SPG4 patients and ten controls underwent a 5 min resting state magnetoencephalography recording and neurological examination. A beamformer algorithm reconstructed the activity of 90 brain areas. The phase lag index was used to estimate synchrony between brain areas. The minimum spanning tree was used to estimate topological metrics such as the leaf fraction (a measure of network integration) and the degree divergence (a measure of the resilience of the network against pathological events). The betweenness centrality (a measure to estimate the centrality of the brain areas) was used to estimate the centrality of each brain area. Results Our results showed topological rearrangements in the beta band. Specifically, the degree divergence was lower in patients as compared to controls and this parameter related to clinical disability. No differences appeared in leaf fraction nor in betweenness centrality. Conclusion Mutations in the SPAST gene are related to a reorganization of the brain topology.

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Section: Discussionsupporting

confidence: 89%

Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks

et al. 2019

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“…We found no correlation between the severity or duration of the disease and the degree of spinal cord atrophy, as reported by others in distinct subtypes of hereditary spastic paraplegias (Hedera et al, 2005;Agosta et al, 2015). Moreover, as in an earlier study of patients with adrenomyeloneuropathy (Dubey et al, 2005), we found no correlation between disease severity and DTI-derived measures along the corticospinal tract in the brain.…”

Section: Discussionsupporting

confidence: 76%

“…Quantitative MRI has been largely used for identifying, characterizing and quantifying structural changes of the brain in many neurological diseases, including hereditary neurodegenerative diseases and hereditary spastic paraplegias (Mascalchi et al, 2004;Rosas et al, 2006;Agosta et al, 2015). Moreover, quantitative MRI-derived measures of the brain might reveal longitudinal changes that make them attractive as surrogate outcome measures (Harrison et al, 2011;Poudel et al, 2015), despite their external validity is still a matter of concern (Rothwell, 2005).…”

Section: Introductionmentioning

confidence: 99%

Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy:in vivoassessment of structural changes

Castellano

Papinutto

Cadioli

et al. 2016

Brain

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Adrenomyeloneuropathy is the late-onset form of X-linked adrenoleukodystrophy, and is considered the most frequent metabolic hereditary spastic paraplegia. In adrenomyeloneuropathy the spinal cord is the main site of pathology. Differently from quantitative magnetic resonance imaging of the brain, little is known about the feasibility and utility of advanced neuroimaging in quantifying the spinal cord abnormalities in hereditary diseases. Moreover, little is known about the subtle pathological changes that can characterize the brain of adrenomyeloneuropathy subjects in the early stages of the disease. We performed a cross-sectional study on 13 patients with adrenomyeloneuropathy and 12 age-matched healthy control subjects who underwent quantitative magnetic resonance imaging to assess the structural changes of the upper spinal cord and brain. Total cord areas from C2-3 to T2-3 level were measured, and diffusion tensor imaging metrics, i.e. fractional anisotropy, mean, axial and radial diffusivity values were calculated in both grey and white matter of spinal cord. In the brain, grey matter regions were parcellated with Freesurfer and average volume and thickness, and mean diffusivity and fractional anisotropy from co-registered diffusion maps were calculated in each region. Brain white matter diffusion tensor imaging metrics were assessed using whole-brain tract-based spatial statistics, and tractography-based analysis on corticospinal tracts. Correlations among clinical, structural and diffusion tensor imaging measures were calculated. In patients total cord area was reduced by 26.3% to 40.2% at all tested levels (P < 0.0001). A mean 16% reduction of spinal cord white matter fractional anisotropy (P ≤ 0.0003) with a concomitant 9.7% axial diffusivity reduction (P < 0.009) and 34.5% radial diffusivity increase (P < 0.009) was observed, suggesting co-presence of axonal degeneration and demyelination. Brain tract-based spatial statistics showed a marked reduction of fractional anisotropy, increase of radial diffusivity (P < 0.001) and no axial diffusivity changes in several white matter tracts, including corticospinal tracts and optic radiations, indicating predominant demyelination. Tractography-based analysis confirmed the results within corticospinal tracts. No significant cortical volume and thickness reduction or grey matter diffusion tensor imaging values alterations were observed in patients. A correlation between radial diffusivity and disease duration along the corticospinal tracts (r = 0.806, P < 0.01) was found. In conclusion, in adrenomyeloneuropathy patients quantitative magnetic resonance imaging-derived measures identify and quantify structural changes in the upper spinal cord and brain which agree with the expected histopathology, and suggest that the disease could be primarily caused by a demyelination rather than a primitive axonal damage. The results of this study may also encourage the employment of quantitative magnetic resonance imaging in other hereditary diseases with spinal cord involvement.

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“…The common DTI indices are: fractional anisotropy, a measure of sensitivity to changes in orientation of axons along the tracts; mean diffusivity, a measure of magnitude of water diffusion and the presence of obstacles to diffusion [14,15], and radial diffusion, used to differentiate axonal injury from demyelination [13]. The most common radiological changes in a variety of HSP gene mutations are alterations in the corticospinal tract (70% of all studies, 71% of SPAST studies) and corpus callosum (80% of all studies, 86% of SPAST studies) [16,17,18,19,20,21,22,23,24,25]. Loss or damage to axons in the corticospinal tract are consistent with the motor symptoms of the disease, although white matter disturbances are not confined to the corticospinal tract and corpus callosum with involvement at the whole brain level, frontal and temporal lobes, cerebellum, and other regions.…”

Section: Radiology Of Hspmentioning

confidence: 99%

“…These changes are consistent with widely distributed axonal damage in the white matter of the brain, including the corticospinal tract, which contains the axons of the motor neurons projecting to the lower motor neurons in the distal spinal cord, whose degeneration is responsible for the clinical manifestations of HSP. There is evidence for correlation between radiological findings and disease severity and duration [16,17,19,24]. Future clinical investigations could consider examining late-stage SPAST HSP patients for evidence of non-motor manifestations that are seen in patients with other HSP mutations [27].…”

Section: Radiology Of Hspmentioning

confidence: 99%

Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

2018

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Hereditary spastic paraplegia is an inherited, progressive paralysis of the lower limbs first described by Adolph Strümpell in 1883 with a further detailed description of the disease by Maurice Lorrain in 1888. Today, more than 100 years after the first case of HSP was described, we still do not know how mutations in HSP genes lead to degeneration of the corticospinal motor neurons. This review describes how patient-derived stem cells contribute to understanding the disease mechanism at the cellular level and use this for discovery of potential new therapeutics, focusing on SPAST mutations, the most common cause of HSP.

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Hereditary Spastic Paraplegia: Beyond Clinical Phenotypes toward a Unified Pattern of Central Nervous System Damage

Cited by 36 publications

References 39 publications

Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks

Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks

Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy:in vivoassessment of structural changes

Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

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