Paths to hippocampal damage in neuromyelitis optica spectrum disorders.

AIMS: Many patients with neuromyelitis optica spectrum disorders (NMOSD) suffer from cognitive impairment affecting memory, processing speed and attention and suffer from depressive symptoms. Because some of these manifestations could trace back to the hippocampus, several magnetic resonance imaging (MRI) studies have been performed in the past, with a number of groups describing volume loss of the hippocampus in NMOSD patients, whereas others did not observe such changes. Here, we addressed these discrepancies. METHODS: We performed pathological and MRI studies on the hippocampi of NMOSD patients, combined with detailed immunohistochemical analysis of hippocampi from experimental models of NMOSD. RESULTS: We identified different pathological scenarios for hippocampal damage in NMOSD and its experimental models. In the first case, the hippocampus was compromised by the initiation of astrocyte injury in this brain region and subsequent local effects of microglial activation and neuronal damage. In the second case, loss of hippocampal volume was seen by MRI in patients with large tissue-destructive lesions in the optic nerves or the spinal cord, and the pathological work-up of tissue derived from a patient with such lesions revealed subsequent retrograde neuronal degeneration affecting different axonal tracts and neuronal networks. It remains to be seen whether remote lesions and associated retrograde neuronal degeneration on their own are sufficient to cause extensive volume loss of the hippocampus, or whether they act in concert with small astrocyte-destructive, microglia-activating lesions in the hippocampus that escape detection by MRI, either due to their small size or due to the chosen time window for examination. CONCLUSIONS: Different pathological scenarios can culminate in hippocampal volume loss in NMOSD patients.

Iron accumulation in the choroid plexus, ependymal cells and CNS parenchyma in a rat strain with low-grade haemolysis of fragile macrocytic red blood cells.

Iron accumulation in the CNS is associated with many neurological diseases via amplification of inflammation and neurodegeneration. However, experimental studies on iron overload are challenging, since rodents hardly accumulate brain iron in contrast to humans. Here, we studied LEWzizi rats, which present with elevated CNS iron loads, aiming to characterise choroid plexus, ependymal, CSF and CNS parenchymal iron loads in conjunction with altered blood iron parameters and, thus, signifying non-classical entry sites for iron into the CNS. Non-haem iron in formalin-fixed paraffin-embedded tissue was detected via DAB-enhanced Turnbull Blue stainings. CSF iron levels were determined via atomic absorption spectroscopy. Ferroportin and aquaporin-1 expression was visualised using immunohistochemistry. The analysis of red blood cell indices and serum/plasma parameters was based on automated measurements; the fragility of red blood cells was manually determined by the osmotic challenge. Compared with wild-type animals, LEWzizi rats showed strongly increased iron accumulation in choroid plexus epithelial cells as well as in ependymal cells of the ventricle lining. Concurrently, red blood cell macrocytosis, low-grade haemolysis and significant haemoglobin liberation from red blood cells were apparent in the peripheral blood of LEWzizi rats. Interestingly, elevated iron accumulation was also evident in kidney proximal tubules, which share similarities with the blood-CSF barrier. Our data underscore the importance of iron gateways into the CNS other than the classical route across microvessels in the CNS parenchyma. Our findings of pronounced choroid plexus iron overload in conjunction with peripheral iron overload and increased RBC fragility in LEWzizi rats may be seminal for future studies of human diseases, in which similar constellations are found.

Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat.

It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses. We further demonstrate that the established tissue-destructive lesions trigger the formation of additional lesions by short and far reaching effects on blood vessels and their branches, and that AQP4-abs have profound effects on the AQP4 expression in peripheral tissues which counter-act possible titer loss by antibody absorption outside the CNS. Cumulatively, these data indicate that directly induced pathological changes caused by AQP4-abs inside and outside the CNS are efficient drivers of disease evolution in seropositive organisms.