title: Cerebral hyperperfusion and decreased cerebrovascular reactivity correlate with neurologic disease severity in MELAS.
abstract: OBJECTIVE
  To study the mechanisms underlying stroke-like episodes (SLEs) in MELAS syndrome.
  
  
  METHODS
  We performed a case control study in 3 siblings with MELAS syndrome (m.3243A>G tRNA(Leu(UUR))) with variable % mutant mtDNA in blood (35 to 59%) to evaluate regional cerebral blood flow (CBF) and arterial cerebrovascular reactivity (CVR) compared to age- and sex-matched healthy study controls and a healthy control population. Subjects were studied at 3T MRI using arterial spin labeling (ASL) to measure CBF; CVR was measured as a change in % Blood Oxygen Level Dependent signal (as a surrogate of CBF) to repeated 10 mmHg step increase in arterial partial pressure of CO2 (PaCO2).
  
  
  RESULTS
  MELAS siblings had decreased CVR (p ≤ 0.002) and increased CBF (p < 0.0026) compared to controls; changes correlated with disease severity and % mutant mtDNA (inversely for CVR: r = -0.82 frontal, r = -0.91 occipital cortex; directly for CBF: r = +0.85 frontal, not for occipital infarct penumbra). Mean CVR was reduced more in frontal (p < 0.001) versus occipital cortex (p = 0.002); mean CBF was increased more in occipital (p = 0.001) than frontal (p = 0.0026) cortices compared to controls. CBF correlated inversely with CVR (r = -0.99 in frontal; not in occipital infarct penumbra) suggesting that increased frontal resting flows are at the expense of flow reserve.
  
  
  CONCLUSIONS
  MELAS disease severity and mutation load were inversely correlated with Interictal CVR and directly correlated with frontal CBF. These metrics offer further insight into the cerebrovascular hemodynamics in MELAS syndrome and may serve as noninvasive prognostic markers to stratify risk for SLEs.
  
  
  METHODS
  Class III.
authors: Division of Neurology, Dept. of Pediatrics, Hospital for Sick Children, The University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: L H
authors: LH
authors: Rodan
authors: Dept. of Medical Imaging, The Toronto Western Hospital, The University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: J
authors: J
authors: Poublanc
authors: Dept. of Anesthesiology, University Health Network, The University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: J A
authors: JA
authors: Fisher
authors: Dept. of Medical Imaging, The Toronto Western Hospital, The University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: O
authors: O
authors: Sobczyk
authors: Dept. of Medical Imaging, The Toronto Western Hospital, The University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: T
authors: T
authors: Wong
authors: Dept. of Medical Imaging, The Toronto Western Hospital, The University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: E
authors: E
authors: Hlasny
authors: Dept. of Medical Imaging, The Toronto Western Hospital, The University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: D
authors: D
authors: Mikulis
authors: Division of Neurology, Dept. of Pediatrics, Hospital for Sick Children, The University of Toronto, Toronto, ON M5G 1X8, Canada; Dept. of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: Ingrid.tein@sickkids.ca.
authors: I
authors: I
authors: Tein
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D016022:Case-Control Studies; D002560:Cerebrovascular Circulation; D005260:Female; D006801:Humans; D017241:MELAS Syndrome / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D012720:Severity of Illness Index; D020301:Vasospasm, Intracranial; D055815:Young Adult
keywords: BOLD-fMRI; Cerebral blood flow; Cerebrovascular reactivity; MELAS syndrome; Mitochondrial disorders