Cerebral atrophy as outcome measure in short-term phase 2 clinical trials in multiple sclerosis

Elskamp, I.J. van den; Boden, B.H.; Dattola, Vincenzo; Knol, Dirk L.; Filippi, Massimo; Kappos, Ludwig; Fazekas, Franz; Wagner, K.; Pohl, Christoph; Sandbrink, Rupert; Polman, Chris H.; Uitdehaag, Bernard M. J.; Barkhof, Frederik

doi:10.1007/s00234-009-0645-1

Cited by 33 publications

(21 citation statements)

References 21 publications

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“…This appears to be true in both relapsing–remitting multiple sclerosis (RRMS) and benign MS, suggesting a silent progression of cognitive impairment independent of MS clinical course (Gonzalez‐Rosa et al., 2006). Indeed, while MS is characterized by WM lesions, GM atrophy is considered to be a relevant biomarker of permanent disability in MS (Bermel & Bakshi, 2006; van den Elskamp et al., 2010; Fisher et al., 2002). In fact, GM atrophy has been found to be associated with changes in all cognitive domains in MS (Morgen et al., 2006).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Quantitative magnetic resonance imaging (MRI) studies indicate that gray matter atrophy occurs even in the earliest stages of disease (Calabrese et al, 2007; Dalton et al, 2004; De Stefano et al, 2003) and is more closely related to physical disability and cognitive impairment than either T2 or T1 white matter lesion volumes (Amato et al, 2004; Chard et al, 2002; Sailer et al, 2003; Sanfilipo et al, 2006). Indeed, it is now considered to be one of the most relevant markers of permanent disability in MS (Bermel and Bakshi, 2006; Fisher et al, 2002; van den Elskamp et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

Bringing CLARITY to gray matter atrophy

et al. 2014

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Gray matter atrophy has been shown to be a strong correlate to clinical disability in multiple sclerosis (MS) and its most commonly used animal model, experimental autoimmune encephalomyelitis (EAE). However, the relationship between gray mater atrophy and the spinal cord pathology often observed in EAE has never been established. Here EAE was induced in Thy1.1-YFP mice and their brains imaged using in vivo magnetic resonance imaging (MRI). The brains and spinal cords were subsequently optically cleared using Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY). Axons were followed 5 mm longitudinally in three dimensions in intact spinal cords revealing that 61% of the axons exhibited a mean of 22 axonal ovoids and 8% of the axons terminating in axonal end bulbs. In the cerebral cortex, we observed a decrease in the mean number of layer V pyramidal neurons and a decrease in the mean length of the apical dendrites of the remaining neurons, compared to healthy controls. MRI analysis demonstrated decreased cortical volumes in EAE. Cross-modality correlations revealed a direct relationship between cortical volume loss and axonal end bulb number in the spinal cord, but not ovoid number. This is the first report of the use of CLARITY in an animal model of disease and the first report of the use of both CLARITY and MRI.

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“…The recent research shows that the axonal loss is one of the main reasons for the atrophy, which is associated with the number of T2 lesions. Also, the rate of cerebral atrophy is a detectable outcome measure in short term clinical trials in RRMS and applicable in terms of study power while a potent drug is applied [6]. Quarantelli et al [7], Pagani et al [8], Horakova et al [9], Fisher et al [10], and Fisniku et al [11] have confirmed that tissue loss in GM compartment is greater than the WM.…”

Section: Introductionmentioning

confidence: 88%