Detection of preclinically latent hyperperfusion due to stroke-like episodes by arterial spin-labeling perfusion MRI in MELAS patients
Introduction
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common type of mitochondrial disease and is mainly caused by an A-to-G transition at the nucleotide position 3243 (A3243G) in mitochondrial DNA (mtDNA) (Goto et al., 1990). Of the MELAS syndrome symptoms, which include myopathy, lactic acidosis, diabetes mellitus and cardiomyopathy, stroke-like episodes (SEs) are not only a characteristic feature but also a crucial factor determining the prognosis of patients with this syndrome (Pavlakis et al., 1984). SEs occur abruptly and repeatedly, and they provoke various neurological symptoms including headaches, epilepsy, hemiparesis and dementia due to “stroke-like” brain lesions in affected patients (Pavlakis et al., 1984). Several causal hypotheses of SEs such as mitochondrial angiopathy (Matsuzaki et al., 2010, Ohama et al., 1987), cytopathy and neuronal hyperexcitability (Iizuka et al., 2002) have been proposed. Mitochondrial angiopathy, which is caused by endothelial dysfunction in cerebral blood vessels with impaired mitochondria, is assumed to play a particularly crucial role in the pathogenesis of SEs through changes in cerebral perfusion, vasodilatation and vasogenic edema in acute lesions of SEs (Ikawa et al., 2009, Matsuzaki et al., 2010, Nishioka et al., 2008, Ohama et al., 1987, Yoneda et al., 1999). However, the pathogenesis associated with mitochondrial angiopathy in the initial, “preclinical” phase of SEs remains to be elucidated, and the prediction and prevention of upcoming SEs are great challenges.
The arterial spin labeling (ASL) method of brain magnetic resonance imaging (MRI) is a promising technique for the non-invasive evaluation of brain perfusion using magnetically labeled blood as an endogenous tracer instead of contrast media. Moreover, ASL imaging is readily acquired as an adjunctive sequence to conventional MRI and is capable of providing absolute cerebral blood flow (CBF) mapping within minutes (Detre et al., 2012, Kimura et al., 2005, Tsujikawa et al., 2010, Uchihashi et al., 2011). Thus, ASL imaging has been widely and extensively used in basic research and clinical settings.
To clarify changes in regional CBF (rCBF) in preclinically latent lesions of SEs that would subsequently develop into obvious lesions on conventional images at the clinical onset of SEs, we sequentially performed brain MRI including ASL perfusion imaging at the time of clinical onset and in the previous preclinical phase of the SEs in 3 Japanese MELAS patients carrying A3243G. Then, we retrospectively evaluated serial changes of CBF in the lesions before and after the clinical onset of SEs. The clinical onset of SEs was defined by the occurrence of new neurological symptoms associated with SEs and the emergence of fresh brain lesions on conventional MRI sequences such as diffusion-weighted images (DWIs) and fluid-attenuated inversion recovery (FLAIR) images corresponding to the symptoms. Thus, patients in the preclinical phase of SEs were free of symptoms indicating SEs and did not have any acute lesions on conventional MR images (DWIs and FLAIR images).
Section snippets
MR imaging protocol
All of the patients sequentially underwent brain MRI with routine protocols and ASL perfusion imaging using a 3T-MR unit (Signa Excite HD, GE Healthcare, Milwaukee, WI, USA). Routine protocols included axial diffusion-weighted echo planar sequences (b value = 1000 s/mm2, TR/TE = 6000/66.9) and FLAIR sequences (TR/TE/TI = 10,000/120/2450).
ASL perfusion imaging was prepared using a three-dimensional (3D) spiral FSE sequence with background suppression covering the entire brain. A 1.5-s
Serial changes of rCBF in ASL images in Case 1
At the clinical onset of the first SE (5.5 months before the onset of the second SE) in Case 1, the ASL images showed focal hyperperfusion in the right temporo-occipital lobe, corresponding with hyperintensities in the DWIs (fresh lesion of the first SE) and normoperfusion in the left temporo-occipital lobe (Fig. 1A). Three months before the onset of the second SE (preclinical phase), the ASL images demonstrated regional hyperintensities, indicating hyperperfusion in the left temporo-occipital
Discussion
ASL perfusion images demonstrated preclinically latent hyperperfusion 3 to 5 months before the clinical onset of SEs in the 3 MELAS patients presented in this report. These areas were distinguished from acute lesions of SEs because these were apparently normal on conventional MR images (DWIs and FLAIR images) without a high lactate peak on MRS or symptoms indicating SEs in the preclinical phase, and acute lesions emerged within these hyperperfused areas at the clinical onset and spread
Conflict of interest
Dr. Kimura has an agreement with GE Healthcare Ltd. (Waukesha, WI, USA) on a collaborative research project for arterial spin labeling imaging. The remaining authors have no conflicts of interest to declare.
Acknowledgments
This work was supported in part by Grants-in-Aid for the Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Young Scientists (B) from the Japan Society for the Promotion of Science (23790985, 25461311), and the Research on Intractable Diseases (Mitochondrial Disorder) from the Ministry of Health, Labour and Welfare of Japan.
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2021, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Our studies with ASL imaging showed serial changes in the regional CBF related to the clinical phase (i.e., disease activity) of SEs with increase in the acute phase and gradual decrease with the clinical improvement [48]. Interestingly, ASL imaging revealed latent regional hyperperfusion even in the preclinical phase of SEs [50]. These hyperperfused areas were not detected by conventional MRI in the preclinical phase and developed into acute lesions during the clinical onset of SEs.