Application Of Magnetic Resonance Imaging To Understanding The Pathogenesis Of The X-Linked Leukodystrophy Pelizaeus-Merzbacher Disease

摘要

Myelin is a multilamellar membrane structure surrounding axons in both the CNS and PNS that facilitates nerve conduction. In the CNS, myelin is synthesized by oligodendrocytes, while in the PNS, myelin is synthesized by Schwann cells. In the CNS, Proteolipid protein 1 (PLP1), an integral membrane protein, is the major protein component of myelin, constituting ~50% of myelin protein. Mutations of the PLP1 gene in man cause a spectrum of neurological disease, ranging from the severe Pelizaeus-Merzbacher disease (PMD), that typically begins during infancy with nystagmus, seizures and hypotonia and evolves into spastic quadriparesis, cognitive impairment and ataxia, to ¡¥pure¡¦ spastic paraparesis, that is characterized exclusively by leg spasticity and weakness. The predominant pathological abnormality in PMD consists of thinning to almost complete absence of myelin in the CNS. Gow and colleagues have proposed that the severity of mutations that alter the structure of PLP1 (typically missense mutations) correlates with the degree to which they cause protein misfolding, activate the unfolded protein response, and cause oligodendrocyte apoptosis (Gow and Sharma, Neuromolecular Med 4:73, 2003). Implicit in this mechanism is that the degree of myelination should inversely correlate with the degree to which oligodendrocyte apoptosis is activated. We speculated that the early PMD phenotype predominantly is dictated by the effect on oligodendrocyte viability. In contrast, we have found that complete absence of PLP1 in both mice and humans is characterized by well-formed myelin, but late length-dependent pattern of axonal degeneration (Garbern et al. Brain 125:551, 2002). We speculate that progression of disease correlates with the rate of axonal damage. The goal of this study was to investigate whether non-invasive MR techniques to assess extent of myelination and degree of axonal disruption correlated with measures of clinical capacity. Furthermore we wanted to differentiate between axonal and myelin pathology using diffusion tensor imaging as a reliable imaging modality to assess the effects of PLP1 mutations on water diffusion in central nervous system (CNS) white matter. The most dramatic difference between PMD patients and age-matched controls was increased £ffÎ, most marked in the corpus callosum. Moreover, this was most prominent in patients with PLP1 null mutations. Increased radial diffusion has been reported in dysmyelinating rodents, including the myelin synthesis deficient rat (md) that has a severe Plp1 missense mutation. Interestingly, £f// was also increased in the severely affected PMD patients, whereas in severely dysmyelinated rodents, the £ffÎ is reported to be normal to decreased. £f// in patients with PLP1 null mutations was relatively unaffected relative to controls. Since the degree of myelination is relatively preserved in PLP1 null myelin, the increased radial diffusion is not the result of thinner myelin sheaths. Therefore the increased radial diffusion is more likely due to increased myelin water, due to decreased compaction, and which may be in part due to the existence of a ¡§radial component¡¨ to myelin, described in Plp1 null mice, created by aqueous channels that span the myelin sheath. Additional factors, such as astrocytosis, may also contribute to the increased radial diffusion.Genetic abnormalities effecting the PLP1 gene has been shown to cause axonal injury and significant early-onset dysmyelination and late-onset demyelination. The exact mutational mechanism remains to be described, although substantial progress had been made to make reasonable assessments that may provide a better understanding towards the disease pathogenesis. In the study involving autopsy tissue from genetically characterized patients has provided valuable information that describes the changes in the structural architecture of the tissue over time. These pathologic changes corroborate with the findings from the diffusion imaging making these two methods extremely reliable for describing the pathologic state as each patient experience a slightly different pathogenic course that is dependent on the exact PLP1 mutation.