This is the first study to investigate the relation between MTI parameters of the brain and aCLs in NPSLE patients. MTI parameters demonstrated brain damage in aCL-positive SLE patients in the absence of explanatory abnormalities on conventional MRI. Therefore, our results suggest that, apart from giving rise to macroscopic cerebral infarctions, aCLs may play a role in the pathogenesis of diffuse microscopic brain damage in NPSLE.
MTI has proved to be a sensitive tool for detecting diffuse brain involvement in NPSLE patients [4
]. In previous work, based on whole-brain MTR histograms, it was found that SLE patients with active neuropsychiatric symptoms, past neuropsychiatric symptoms, and SLE patients without neuropsychiatric symptoms could be distinguished, suggesting diagnostic potential for these parameters [6
]. The previously observed correlations between whole-brain MTR histogram parameters and measures of neurological, psychiatric and cognitive function [9
] emphasized the functional relevance of MTI parameters in such patients. In the present study SLE patients with a history of neuropsychiatric symptoms were included. Apart from overt diffuse neuropsychiatric manifestations, some patients suffered from chronic multifocal neuropsychiatric symptoms and were classified as having cerebrovascular disease, subclassification chronic multifocal disease [2
]. Although two of the four patients classified as such exhibited nonspecific MRI abnormalities, in none of the patients was there evidence of cerebral infarcts or any other abnormality on conventional MRI to explain their neuropsychiatric symptoms. Therefore, in all patients diffuse involvement of the CNS was thought to underlie the neuropsychiatric manifestations. We observed lower values for mean MTR and peak location in grey and white matter in patients positive for aCLs and Lac.
The pathological conditions underlying the MTR histogram abnormalities and neuropsychiatric manifestations in SLE patients remain unclear. Although neuropathological studies in NPSLE patients are limited, vasculopathy and microinfarcts have been noted in several studies [3
]. A recent MTI study examining cerebral grey and white matter separately in SLE patients with a history of diffuse neuropsychiatric manifestations [23
] identified MTR histogram abnormalities specifically in the grey matter, suggesting that neuronal injury is among the key factors in diffuse NPSLE. This hypothesis is supported by increased levels of neuronal and astrocytic degradation products observed in the cerebrospinal fluid of NPSLE patients [25
]. Microscopic brain damage was also suggested given the data from other quantitative neuroimaging techniques, such as magnetic resonance spectroscopy [26
], spin-spin relaxation time measurements [32
] and diffusion-weighted imaging [33
]. A recent study combining these MRI techniques [10
] indicated that the presence of neuronal and axonal injury, atrophy, demyelination and gliosis are aspects of the processes involved in neuropsychiatric involvement in SLE.
Although several studies have reported abnormalities on conventional MRI in patients with antiphospholipid antibodies [34
], to our knowledge the only previous MTI study in patients with a known antiphospholipid antibody status is that by Rovaris and coworkers [8
]. That study included healthy control individuals, patients suffering from SLE with and without neuropsychiatric symptoms, and patients suffering from the antiphospholipid antibody syndrome. No significant differences were observed between the patients with antiphospholipid antibody syndrome patients and healthy control individuals, whereas lower mean MTR values were observed in NPSLE patients than in non-NPSLE patients. These observations and the findings of our study suggest that the mere presence of antiphospholipid antibodies, including aCLs, does not lead to diffuse microscopic brain damage as detected by MTI, but they implicate that aCLs are involved in the pathogenetic events that lead to neuropsychiatric manifestations in SLE. A role for antiphospholipid antibodies in the pathogenesis of NPSLE has also been suggested by studies using magnetic resonance spectroscopy. In a study conducted by Sabet and coworkers [28
], a reduced N
-acetyl-aspartate to creatine ratio suggesting neuronal loss or injury was observed in SLE patients with the antiphospholipid antibody syndrome, as compared with SLE patients without – an effect that was mainly attributed to the presence of IgG aCLs.
Much in the order of the pathogenetic events that occur in SLE patients with diffuse neuropsychiatric manifestations remains unknown, although evidence for involvement of antineuronal antibodies, complement activation and proinflammatory cytokines has been found [3
]. There are at least three possible explanations for how aCLs could be involved. First, the thrombotic tendency of antiphospholipid antibodies, including aCLs, may cause aggregation of thrombocytes and an increase in blood viscosity [3
]. This may affect blood flow in small cerebral blood vessels in particular and cause widespread hypoperfusion, which subsequently causes ischaemic damage to brain tissue [38
]. The trend observed with Lac in the present study supports this hypothesis. Second, aCLs may activate endothelial cells and cause a diffuse small-vessel vasculopathy – a neuropathological finding that was reported as long ago as 1968 [3
]. The resulting increase in blood–brain barrier permeability permits entrance to the brain parenchyma of substances such as circulating antibodies [3
]. Third, it has been shown in vitro
that IgG aCLs themselves may interfere with glutamatergic pathways by a mechanism involving over-activation of the N
-methyl-d-aspartate receptor [41
The present study has several limitiations, and the results are preliminary. First, patient numbers were small, and control individuals were not available. Second, aCL status at the time of active neuropsychiatric manifestations was not available in this SLE patient cohort with past neuropsychiatric symptoms, which precludes evaluation of our results in the light of fluctuation in aCL levels [19
]. Possibly, an even stronger association could be found between MTI measures of brain damage and aCL status at the time of active neuropsychiatric symptomatology. A prospective study should therefore include a larger NPSLE patient group with inactive and active neuropsychiatric symptoms, as well as control groups consisting of non-NPSLE patients and patients suffering from similar neuropsychiatric conditions, preferably with measurements of aCLs in serum and cerebrospinal fluid. Also, the specific role of IgM and IgG aCLs remains to be identified.