A Systematic Review of Positron Emission Tomography (PET) in X-Linked Adrenoleukodystrophy: Beyond Structural MRI

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by pathogenic variants in ABCD1, resulting in the accumulation of very long-chain fatty acids and risk of progressive neuroinflammatory demyelination in the cerebral form of ALD. Brain MRI is the current standard neuroimaging modality for diagnosis and monitoring of central nervous system involvement. However, MRI primarily detects structural abnormalities and may not fully reflect functional impairment, neuroinflammatory activity, or early cerebral involvement. Positron emission tomography (PET) may provide complementary information beyond conventional MRI. Therefore, we aimed to review the current literature on PET imaging in X-ALD. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 26, 2026. Studies evaluating brain PET imaging in individuals with X-ALD were included. Data on study design, phenotype, ABCD1 genotype, brain MRI findings, PET tracers, analytic methods, and key findings were extracted. A total of 48 records were screened, resulting in the inclusion of 10 case reports and one case series comprising 12 patients. PET tracers included ¹⁸F-fluorodeoxyglucose (FDG) (N = 19 patients), ¹¹C-(R)-PK11195 (N = 1), and L-[methyl-¹¹C]methionine (N = 1). One additional patient underwent PET assessment of cerebral blood flow and oxygen metabolism using unspecified tracers. In FDG-PET studies, cortical hypermetabolism was reported in 12/19 individuals, whereas cortical hypometabolism was observed in 18/19 individuals, with findings in one case being either not specified or inconclusive. FDG-PET demonstrated cortical glucose hypometabolism overlying the affected white matter (WM) in 6/18 individuals with T2 and/or FLAIR-hyperintense WM lesions on MRI. FDG-PET demonstrated cortical glucose hypometabolism in 12/18 individuals without WM lesions on MRI. The FDG-PET findings were reported to correlate with clinical symptoms. Neuroinflammation-targeted ¹¹C-(R)-PK11195 PET demonstrated increased tracer binding in active WM lesions. Similarly, protein synthesis-targeted L-[methyl-¹¹C]methionine PET demonstrated increased tracer uptake in active WM lesions. PET may detect functional and neuroinflammatory abnormalities beyond those identified by structural MRI in individuals with X-ALD, suggesting a potential role in evaluating the extent and severity of brain involvement. However, the available evidence is limited by small sample sizes, underrepresentation of pediatric and presymptomatic cases, heterogeneous PET tracers and analytic methodologies, and a lack of longitudinal data. Further multimodal and longitudinal studies are needed to establish the clinical utility of PET as a surveillance tool in X-ALD.