Comment on: Changes of cerebral structure and perfusion in subtypes of systemic sclerosis: a brain magnetic resonance imaging study

Dear Editor, We would like to express our concerns and provide constructive critique regarding the recently published study on cerebral structure and perfusion changes in SSc subtypes, particularly focusing on the methodological approaches and the interpretation of results—‘Changes of cerebral structure and perfusion in subtypes of systemic sclerosis: a brain magnetic resonance imaging study’ by Tong et al. [1]. While the study offers valuable insights into the neuroimaging characteristics of SSc, certain aspects of the methodology and analysis may limit the robustness of the findings. First, the study utilizes a cross-sectional design to compare grey matter volume and cerebral blood flow (CBF) among patients with diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and healthy controls. A critical limitation of this approach is the inherent variability in disease duration and severity among the SSc subtypes, which could significantly impact brain structure and perfusion. The authors mention that most patients had received treatment prior to imaging, which might have alleviated some of the symptoms and potentially affected the CBF measurements. However, they do not account for the variability in treatment duration or intensity, which could confound the results. Longitudinal studies would be more appropriate to assess the progression of cerebral involvement in SSc and to account for the effects of ongoing treatment. A longitudinal design could also help to elucidate whether the observed changes in brain structure and perfusion are progressive or static, providing a clearer understanding of the disease trajectory. Second, the statistical methods used to analyze the imaging data, specifically the voxel-based morphometry and arterial spin labelling techniques, raise some concerns. The authors report significant reductions in grey matter volume in the para-hippocampal region of dcSSc patients and increased CBF in lcSSc patients. However, the use of cluster-level statistics with family-wise error correction at P < 0.01 might have masked smaller, yet clinically relevant, effects. The reliance on a stringent correction method could lead to type II errors, where true differences are not detected. A more nuanced approach, such as applying both cluster-level and voxel-wise corrections, could provide a more comprehensive understanding of the neuroanatomical changes associated with SSc. Additionally, the authors do not discuss potential biases introduced by the spatial normalization and smoothing processes inherent in voxel-based morphometry, which could distort the localization of grey matter changes. Moreover, the interpretation of increased CBF in lcSSc patients as a compensatory mechanism for microvascular dysfunction is intriguing but lacks direct evidence. The authors speculate that this increase is an adaptive response to maintain adequate perfusion despite underlying vascular pathology. However, without direct measures of vascular function or corroborative data from other imaging modalities, such as perfusion-weighted imaging or dynamic contrast-enhanced MRI, this interpretation remains speculative. For instance, a study demonstrated distinct patterns of cerebral perfusion in patients with systemic lupus erythematosus using a combination of arterial spin labelling and perfusion-weighted imaging, highlighting the need for multimodal approaches to fully understand the vascular contributions to brain changes in autoimmune diseases [2]. Incorporating such techniques could strengthen the conclusions and provide a more robust framework for understanding the cerebrovascular changes in SSc. Lastly, the discussion section includes a statement suggesting that the increased CBF observed in lcSSc patients might be protective against cognitive decline. However, this interpretation is not supported by direct cognitive assessments or longitudinal data demonstrating a correlation between CBF and cognitive outcomes over time. While the Montreal Cognitive Assessment (MoCA) scores were collected, they were not compared between SSc patients and healthy controls, nor were they correlated with specific brain regions showing CBF changes. Without these data, it is difficult to assert a protective role of increased CBF in preserving cognitive function. A more cautious interpretation would be to acknowledge the potential for increased CBF to be a compensatory mechanism, while also recognizing the need for further research to determine its impact on cognition. No new data were generated or analysed in support of this article. NATCM’s Project of High-level Construction of Key TCM Disciplines (NO: zyyzdxk-2023070). Disclosure statement: The authors have declared no conflicts of interest.

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