Abstract
ObjectiveTo explore the possibilities of radioligands against the mitochondrial outer membrane translocator protein (TSPO) as biomarkers for mitochondrial disease, we performed brain PET-MRI with [11C]PK11195 in 14 patients with genetically confirmed mitochondrial disease and 33 matched controls.MethodsCase–control study of brain PET-MRI with the TSPO radioligand [11C]PK11195.ResultsForty-six percent of symptomatic patients had volumes of abnormal radiotracer binding greater than the 95th percentile in controls. [11C]PK11195 binding was generally greater in gray matter and significantly decreased in white matter. This was most striking in patients with nuclear TYMP or mitochondrial m.3243A>G MT-TL1 mutations, in keeping with differences in mitochondrial density seen postmortem. Some regional binding patterns corresponded to clinical presentation and underlying mutation, even in the absence of structural changes on MRI. This was most obvious for the cerebellum, where patients with ataxia had decreased binding in the cerebellar cortex, but not necessarily volume loss. Overall, there was a positive correlation between aberrant [11C]PK11195 binding and clinical severity.ConclusionThese findings endorse the use of PET imaging with TSPO radioligands as a noninvasive in vivo biomarker of mitochondrial pathology.Classification of EvidenceThis study provides Class III evidence that brain PET-MRI with TSPO radioligands identifies mitochondrial pathology.
Highlights
Mitochondrial diseases have emerged as one of the most common inherited neurological disorders and together affect about 1 in 5,000 of the UK population 1
We found that regional binding abnormalities may correspond to clinical presentation, are mutation specific, and mostly occur in the absence of obvious structural changes on brain MRI. [11C]PK11195 positron emission tomography (PET) imaging of translocator protein (TSPO) is widely used as a marker of neuro-inflammation, due to its accumulation in activated microglia in the brain [16,17,18]
On average, in patients with mitochondrial disease, white matter was more likely to show reduced rather than increased TSPO abundance compared to controls
Summary
Mitochondrial diseases have emerged as one of the most common inherited neurological disorders and together affect about 1 in 5,000 of the UK population 1. Mitochondrial diseases are progressive multi-system disorders that can present at any stage in life and often affect the central nervous system 2. There are a growing number of agents being tested in pre-clinical animal models, few studies have demonstrated efficacy in humans [6,7,8]. This reflects in part the lack of objective clinical biomarkers that show change over a practical timescale or allow subgroup characterization, essential pre-requisites to provide evidence of efficacy in a heterogeneous rare disease cohort [9,10]. Given its localization to mitochondria [13,14,15], we sought to explore the utility of [11C]PK11195 PET imaging of TSPO as an in vivo biomarker of mitochondrial pathology in the brain, with a view to monitoring progression of mitochondrial disease
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