The extent of axonal loss in the long tracts in hereditary spastic paraplegia

Abstract

Hereditary spastic paraplegia (HSP) comprises a group of inherited neurodegenerative disorders with the shared characteristics of progressive weakness and spasticity predominantly affecting the lower limbs. Limited pathological accounts have described a 'dying back' axonal degeneration in this disease. However, the distribution and extent of axonal loss has not been elucidated in a quantitative way. We have studied post-mortem material from six HSP patients and 32 controls in detail. The population of axons was examined quantitatively in the corticospinal tracts from the medulla to the lumbar spinal cord and the sensory tracts from the lumbar to upper cervical spinal cord. Myelin and axon-stained sections were employed to estimate the notional area and axonal density, respectively, of both tracts. Our results indicate that in the corticospinal tracts there is a significant reduction in area and axonal density at all levels investigated in HSP compared to controls. In the corticospinal tracts, the ratio of medulla and lumbar total axonal number was significantly greater in HSP cases compared to controls suggesting more pronounced axonal loss in the distal neuraxis in HSP than in controls. The sensory tracts in HSP, in contrast, showed a significant reduction in area and axonal density only in the upper regions of the spinal cord. Similar to the corticospinal tracts, the ratio of lumbar and upper cervical cord total axonal number in the sensory tracts was increased in HSP cases compared to controls. These findings are consistent with a length-dependent 'dying back' axonopathy. Nerve fibre loss was not size-selective with both small and large diameter fibres affected. In HSP, axonal loss is widespread and symmetrical and its extent tract-specific. The characterization of the nature of axonal loss in HSP, where this is a primary phenomenon, may help the interpretation of axonal loss in conditions such as multiple sclerosis where the sequence of events is less clear.

Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance

“…With sustained NTE-deficiency over many months, massively swollen axons are present in motor and sensory spinal tracts. The relative distribution of axonal lesions in the motor corticospinal and sensory dorsal tracts in upper and lower spinal cord of NTE-cKO mice closely mirrors that reported in human HSP (Deluca et al, 2004). Despite the numerous forms of human HSP, relatively few animal models of these syndromes have been reported, and so NTE-deficient mice comprise a useful new model of an HSP.…”

“…Hereditary spastic paraplegias (HSP) comprise a genetically heterogenous group of neurological disorders characterized by degeneration of distal parts of long spinal axons (Deluca et al, 2004). Increasing evidence suggests that defects in membrane trafficking and/or axonal transport are important factors in the pathogenesis of these syndromes (Reid, 2003;Soderblom and Blackstone, 2006;Salinas et al, 2008).…”

Brain White Matter Involvement in Hereditary Spastic Paraplegias: Analysis with Multiple Diffusion Tensor Indices

“…11,18 The major neuropathologic feature in HSPs is axonal degeneration, which is maximal in the terminal portions of the longest descending and ascending tracts due to the disruption of the axonal transport. 19 The most severely affected pathways are the corticospinal tracts and the fasciculus gracilis. Spinocerebellar tracts may also be involved in approximately 50% of cases.…”

The Hsp60-(p.V98I) Mutation Associated with Hereditary Spastic Paraplegia SPG13 Compromises Chaperonin Function Both in Vitro and in Vivo

“…The disease is traditionally classified into "pure" and "complicated" forms depending on the presence of additional neurological or systemic abnormalities. The major pathological feature is a progressive degeneration of the longest axons of the descending (corticospinal) and the ascending (sensory) tracts in the spinal cord (2). Presently Ͼ30 gene loci have been mapped, and disease-associated mutations have been identified in 15 genes (3).…”