Hypoperfusion predicts lesion progression in cerebral X-linked adrenoleukodystrophy.

Magnetic resonance imaging sequences such as diffusion and spectroscopy have been well studied in X-linked adrenoleukodystrophy, but no data exist on magnetic resonance perfusion imaging. Since inflammation is known to modulate the microcirculation, we investigated the hypothesis that changes in the local perfusion might be one of the earliest signs of lesion development. Twenty patients with different phenotypes of adrenoleukodystrophy and seven age-matched controls were evaluated between 2006 and 2011. Fluid attenuated inversion recovery, post-contrast T(1)-weighted and normalized dynamic susceptibility contrast magnetic resonance perfusion cerebral blood volume maps were co-registered, segmented when cerebral lesion was present, and normalized cerebral blood volume values were analysed using a Food and Drug Association approved magnetic resonance perfusion software (NordicICE). Clinical and imaging data were reviewed to determine phenotype and status of progression. All eight patients with cerebral adrenoleukodystrophy had an average 80% decrease in normalized cerebral blood volume at the core of the lesion (P < 0.0001). Beyond the leading edge of contrast enhancement cerebral perfusion varied, patients with progressive lesions showed an average 60% decrease in normalized cerebral blood volume (adults P < 0.05; children P < 0.001), while one child with arrested progression normalized cerebral blood volume in this region. In six of seven patients with cerebral adrenoleukodystrophy lesions and follow-up imaging (2-24 month interval period), we found progression of contrast enhancement into the formerly hypoperfused perilesional zone. Asymptomatic, adrenomyeloneuropathy and female heterozygote patients had no significant changes in cerebral perfusion. Our data indicate that decreased brain magnetic resonance perfusion precedes leakage of the blood-brain barrier as demonstrated by contrast enhancement in cerebral adrenoleukodystrophy and is an early sign of lesion progression.

Bone marrow stromal cells induce changes in pain behavior after sciatic nerve constriction.

Peripheral nerve injury, i.e. a single ligature nerve constriction (SLNC), triggers neuropathic pain. Bone marrow stromal cells (MSCs) have been observed to migrate to the injured tissues and mediate functional recovery following brain, spinal cord and peripheral nerve lesions. We have recently shown MSC selective migration to the ipsilateral lumbar (L3-6) dorsal root ganglia (DRGs) after a sciatic nerve SLNC. In this study, we have analyzed the thermal and mechanical sensitivities of animals subjected to a SLNC of the sciatic nerve and an ipsilateral intraganglionic MSC injection, using the von Frey and Choi tests. Control animals were subjected to the nerve lesion either alone or followed by the administration of phosphate-buffered saline (PBS) or bone marrow non-adherent mononuclear cells (BNMCs). All the animals were tested both before surgery and after 1, 3, 7, 14, 21, 28 and 56 days. Animals subjected to the sciatic nerve constriction developed ipsilateral mechanical and thermal allodynia already 3 days after the lesion. The allodynic responses were maintained even after 56 days. MSC administration prevented the generation of mechanical allodynia and reduced the number of allodynic responses to cold stimuli. On the contrary, the injection of either PBS or BNMCs could not counteract allodynia. These results suggest that MSCs may modulate pain generation after sciatic nerve constriction. The underlying mechanisms by which MSCs exert their actions on pain behavior need to be clarified.

Selective migration and engraftment of bone marrow mesenchymal stem cells in rat lumbar dorsal root ganglia after sciatic nerve constriction.

Bone marrow mesenchymal stem cells (MSCs) preferentially migrate to the injured hemisphere when administered intravenously to rats with traumatic or ischemic brain injuries. In this study, we have investigated the localization of MSCs injected into the lumbar-4 dorsal root ganglion (L4-DRG) of rats with a sciatic nerve single ligature nerve constriction (SLNC). MSCs were isolated by their adherence to plastic, cultured until confluence and labelled with Hoechst. Animals with a unilateral injection of MSCs were subjected to an ipsilateral, bilateral or contralateral SLNC. After 9 days, they were perfused and the lumbar DRGs were dissected out, cut in a cryostat and observed with a fluorescence microscope. Large numbers of Hoechst-positive cells were observed in the injected L4-DRG, distributed around primary afferent neurons, resembling the anatomical localization of glial cells. In animals with an ipsilateral SLNC, some cells were detected in the ipsilateral L3, L5 or L6-DRGs but not in the contralateral ganglia. In animals with a bilateral lesion, MSCs migrated to both the ipsilateral and contralateral DRGs whereas in animals with a contralateral ligature, MSCs migrated to the contralateral DRGs. These results suggest that MSCs preferentially engraft in DRGs hosting primary sensory neurons affected by a lesion of their peripheral branches. Further studies should be carried out in order to elucidate the molecular mechanisms involved in this migration and homing, in order to evaluate the possible use of MSCs as a new therapeutic strategy for the treatment of peripheral nerve neuropathies.