DTI-ALPS: An MR biomarker for motor dysfunction in patients with subacute ischemic stroke

You described a possible problem but DID NOTHING TO SOLVE IT. Useless. I'd fire everyone involved for totally missing the only goal in stroke. 100% recovery for all!.  Biomarker in the title is the first clue this will be useless.

DTI-ALPS: An MR biomarker for motor dysfunction in patients with subacute ischemic stroke

Yue Qin^1,2†, Xin Li^2†, Yanqiang Qiao^1,2†, Huili Zou³, Yifan Qian², Xiaoshi Li², Yinhu Zhu², Wenli Huo¹, Lei Wang^1,2* and Ming Zhang^1*

• ¹Department of Medical Imaging, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
• ²Department of Radiology, Xi'an Daxing Hospital, Xi'an, China
• ³Department of Rehabilitation Medicine, Xi'an Daxing Hospital, Xi'an, China

Purpose: Brain glymphatic dysfunction is involved in the pathologic process of acute ischemic stroke (IS). The relationship between brain glymphatic activity and dysfunction in subacute IS has not been fully elucidated. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was used in this study to explore whether glymphatic activity was related to motor dysfunction in subacute IS patients.

Methods: Twenty-six subacute IS patients with a single lesion in the left subcortical region and 32 healthy controls (HCs) were recruited in this study. The DTI-ALPS index and DTI metrics (fractional anisotropy, FA, and mean diffusivity, MD) were compared within and between groups. Spearman's and Pearson's partial correlation analyses were performed to analyze the relationships of the DTI-ALPS index with Fugl-Meyer assessment (FMA) scores and with corticospinal tract (CST) integrity in the IS group, respectively.

Results: Six IS patients and two HCs were excluded. The left DTI-ALPS index of the IS group was significantly lower than that of the HC group (t = −3.02, p = 0.004). In the IS group, a positive correlation between the left DTI-ALPS index and the simple Fugl-Meyer motor function score (ρ = 0.52, p = 0.019) and a significant negative correlation between the left DTI-ALPS index and the FA (R = −0.55, p = 0.023) and MD (R = −0.48, p = 0.032) values of the right CST were found.

Conclusions: Glymphatic dysfunction is involved in subacute IS. DTI-ALPS could be a potential magnetic resonance (MR) biomarker of motor dysfunction in subacute IS patients. These findings contribute to a better understanding of the pathophysiological mechanisms of IS and provide a new target for alternative treatments for IS.

1. Introduction

Ischemic stroke (IS) remains one of the leading causes of disability and death worldwide (Campbell et al., 2019; Campbell and Khatri, 2020; Fukuta et al., 2022). Approximately 69.6% of stroke incidents in China are IS, similar to the global average (Wang W. et al., 2017; Feigin et al., 2018). The most common symptom associated with IS sensorimotor dysfunction (Langhorne et al., 2009; Alawieh et al., 2018), which can recover spontaneously within 3 months (Kwakkel et al., 2006; van der Vliet et al., 2020). A previous study has pointed out that, throughout the recovery process, early subacute IS is a critical period for neuroplasticity and recovery (Bernhardt et al., 2017).

Previous research demonstrated that brain lymphatic activity not only contributed to the pathologic process of IS but also influenced its recovery. The glymphatic system is the perivascular network used for the exchange between cerebrospinal fluid (CSF) and interstitial fluid (ISF) in the brain (Iliff et al., 2012; Klostranec et al., 2021). It consists of three main structures (Iliff et al., 2012; Benveniste et al., 2019): para-arterial CSF influx channels, para-venous ISF efflux channels, and astrocyte exchange channels connecting the two channels (aquaporin-4, AQP4). Brain glymphatic dysfunction is involved in the pathologic process of acute IS (Iliff et al., 2014; Chen S. et al., 2021). We proposed that pathological changes in subacute IS were associated with brain glymphatic dysfunction in subacute IS. The brain glymphatic system is involved in the clearance of brain metabolic waste (Choi et al., 2021). However, the brain glymphatic pathway attenuates brain edema by clearing cellular debris from ISF and promotes central nervous system (CNS) recovery after IS (Benveniste et al., 2019; Li et al., 2019; Zhou et al., 2021). Studies used variant animal models of cerebral ischemia to examine ischemia-induced functional changes at different time points and the role of AQP4 in brain edema after IS and found that the inhibition of AQP4 reduced cerebral edema and improved motor recovery and long-term prognosis (Hirt et al., 2017; Liu et al., 2017). Further research is needed to confirm whether glymphatic dysfunction in humans is related to motor dysfunction and altered white matter microstructure in subacute IS in order to understand the role of the glymphatic system in the pathophysiology of IS.

The corticospinal tract (CST) is the primary descending motor pathway carrying movement-related information and has been widely studied after stroke (Liu et al., 2020), with the main research directions being the correlation between CST injury and motor dysfunction and the prediction of motor function recovery using CST integrity after stroke (Lim et al., 2020; Hayward et al., 2022). Diffusion tensor image (DTI) metrics are currently the most common indices depicting the microstructural integrity of white matter. Among them, fractional anisotropy (FA) represents axonal alterations (Tavazzi et al., 2022), and mean diffusivity (MD) is associated with cerebral edema (Chormai et al., 2022). Previous studies showed that DTI metrics are the reliable quantitative metrics of CST that correlate with motor function outcomes and Fugl-Meyer assessment (FMA) scores in stroke rehabilitation (Haque et al., 2021; Lee et al., 2021). Although DTI metrics play an important role in describing the anatomical and pathological changes caused by IS, the lack of biological specificity and interpretation of pathophysiological disease information (for example, the mechanism of cerebral edema after IS) limit its clinical applications (Ji et al., 2021; Kamagata et al., 2021; Andica et al., 2022). Recently, a study on an epileptic seizure exploring differences in white matter integrity and glymphatic function indicated that the impairment of the glymphatic system may precede white matter microstructure in the early stage of epilepsy and implicated the potential role of measuring brain lymphatic activity in the expression and comprehensive understanding of early pathological changes of brain disorders (Salimeen et al., 2021). Therefore, quantitative measurement of changes in stroke-related lymphatic activity in CST may help explain the mechanism underlying motor disruption in IS patients and provide possible medical interference of stroke for IS patients with motor dysfunction.

Diffusion tensor image analysis along the perivascular space (DTI-ALPS) is a non-invasive method for evaluating glymphatic system function in individual subjects based on diffusion tension imaging (Taoka et al., 2017). DTI-ALPS has been demonstrated to produce results within minutes with good stability and intra-observer consistency (Si et al., 2022) and can be used as an alternative to DTI for wider use in clinical practice (Taoka et al., 2022a). Using both glymphatic magnetic resonance imaging (MRI) and DTI-ALPS methods, Zhang et al. (2021) measured and compared glymphatic clearance function and found a significant correlation between the DTI-ALPS index and the brain glymphatic clearance rate calculated by classical glymphatic MRI, indicating that DTI-ALPS might represent the precise function of brain glymphatic clearance (Siow et al., 2022). The DTI-ALPS index has been used to assess variations in the glymphatic system in several diseases, such as Alzheimer's disease, type 2 diabetes mellitus, idiopathic normal pressure hydrocephalus, Parkinson's disease, cancer pain, and other diseases (Taoka et al., 2017; Yang et al., 2020; Bae et al., 2021; Heo et al., 2021; Ma et al., 2021; Okada et al., 2021; Toh and Siow, 2021a; Wang et al., 2022). Zhang et al. (2022) used the DTI-ALPS method in patients with hemorrhagic stroke and found the impairment of the ipsilateral glymphatic system function on the lesion side. Another study used the same method to investigate glymphatic system function in patients with ischemic stroke (Toh and Siow, 2021b) and found similar results of glymphatic system dysfunction. However, these two studies did not address the relationship between glymphatic system dysfunction and stroke-related clinical symptoms, which requires further research.

In this study, we used the DTI-ALPS method to investigate glymphatic activity and white matter integrity of CST in subacute IS patients with motor dysfunction. We assumed that glymphatic activity was impaired after subacute IS, which might be related to motor dysfunction and changes in white matter microstructure.

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