Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

Abstract

IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%–70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing–remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol‐treated compared to placebo‐treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty‐two estriol‐ and forty‐nine placebo‐treated RRMS patients underwent clinical evaluations and brain MRI. Voxel‐based morphometry (VBM) was used to evaluate voxelwise GM sparing from high‐resolution T1‐weighted scans.ResultsA region of treatment‐induced sparing (TIS) was defined as the areas where GM was spared in estriol‐ as compared to placebo‐treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability‐specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol‐treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability‐specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

Drug repurposing for Alzheimer’s disease based on transcriptional profiling of human iPSC-derived cortical neurons

“…Nonetheless, the enrichment of immune-associated pathways points to a possible anti-inflammatory activity of the candidate drugs. Interestingly, the following drugs have been reported to have neuroprotective activity: fluocinonide 59 , kawain 60–63 , allantoin 64 , dipyridamole 65–67 , estriol 68 , levamisole 69 , mycophenolic acid 70 , neostigmine 71 , probenecid 72,73 , chlorpromazine 74 , and phenoxybenzamine 75 , and xamoterol has been reported to ameliorate neuroinflammation and pathology in 5xFAD mice 76 and shown to enhance cognition in a Down syndrome mouse model 77 . The atypical antipsychotic risperidone prescribed to manage psychosis in AD has demonstrated neuroprotection in animal models of ischemia 78 .…”

Reproductive history and progressive multiple sclerosis risk in women

“…While the type of oestrogen preparation does matter in terms of potential impact in multiple sclerosis, oestriol was shown to be immunomodulatory ( Soldan et al , 2003 ; Gold et al , 2009 ) and to reduce number of enhancing lesions ( Sicotte et al , 2002 ). In a multicentre phase 2 trial, higher oestriol levels were associated with a reduction in relapses, cognitive improvement and dampening of cortical grey matter atrophy ( Voskuhl et al , 2016 ; MacKenzie-Graham et al , 2018 ). Of course, such a neuroprotective effect cannot be suggested as being multiple sclerosis specific.…”

Sex differences in brain atrophy in multiple sclerosis

“…Previous studies have suggested that cognitive disability in particular may be worse in males as compared to females with MS [25], and differences in atrophy of major GM structures have been correlated with cognitive disability [28,54,[59][60][61][62][63]. Further studies are needed comparing MS women and MS men using biology-driven functional connectivity analysis [26, and voxel-wise mapping of localized GM atrophy aligned with cognitive disability [30,31]. Sex differences in other disabilities such as in walking or vision, for example, should also be mapped to contrast with cognitive disability maps.…”

“…Brain atrophy, specifically gray matter (GM) atrophy, serves as a putative surrogate for neurodegeneration in MS. Regional differences in GM atrophy have been shown in MS, and clinical disabilities have been shown to correlate with GM atrophy in clinically eloquent neuroanatomic regions [27][28][29][30][31]. Regional differences in gene expression in astrocytes, microglia, and oligodendrocytes have also been shown in both health and disease [32][33][34][35], including a sex-specific astrocytic response to injury in an MS model [36].…”