Info
Background:
Alzheimer’s disease (AD) is the most common form of dementia, with over 90% of cases classified as sporadic or late-onset AD (LOAD). Although multiple risk factors contribute to disease onset, AD pathology converges on progressive amyloid-β (Aβ) accumulation, tau pathology, and neurodegeneration. Recent studies implicate dysfunction of the autophago-lysosomal system and altered lipid metabolism as early drivers of LOAD. We recently found that the loss of lysosomal acid lipase (LAL) leads to lipid accumulation within neuronal lysosomes, impairing lysosomal function and promoting AD pathology. LAL expression declines with aging and is further reduced in AD, suggesting potential as a biomarker for disease risk and progression. Further, LAL gene therapy replacement, to overexpress LAL in neurons, reduces AD pathology and slows disease progression.
Hypothesis/Objective:
Herein, we aim to develop the LAL-PET tracer as superior to Aβ-PET and blood biomarkers for the early diagnosis of AD and monitoring of LAL gene therapy efficacy.
Methods:
We developed a first-in-class LAL-targeted PET tracer, [¹⁸F]LAL (US patent approved), capable of crossing the blood–brain barrier. [¹⁸F]LAL was synthesized via nucleophilic substitution, achieving 15–16% radiochemical yield and >98% radiochemical purity, confirmed by HPLC co-injection with the ¹⁹F standard. LAL-PET was performed in 3xTg-AD and wild-type mice across multiple ages using static and dynamic acquisitions. It was also used to assess the LAL expression level following LAL gene therapy replacement. Binding specificity was evaluated using competitive autoradiography in mouse brain. Human AD brain slices were analyzed by autoradiography and compared with [¹¹C]PiB. We also compared [¹⁸F]LAL autoradiography in human male and female AD brain slices to [¹¹C]PiB, a highly developed Aβ-targeting AD tracer.
Results:
[¹⁸F]LAL brain uptake was significantly reduced in 10-month-old and 18-month-old 3xTg-AD mice compared with age-matched controls. Dynamic imaging demonstrated sustained reductions in tracer uptake in 18-mon (late-stage) AD mice. LAL-PET detected restoration of LAL signal following viral replacement therapy in AD mice. Autoradiography showed marked signal reduction following Lalistat (specific LAL inhibitor) competition, confirming high binding specificity. In human brain tissue, loss of [¹⁸F]LAL signal predicted AD disease duration, whereas [¹¹C]PiB did not.
Conclusion:
[¹⁸F]LAL is a novel, mechanism-based PET tracer that sensitively detects age- and disease-related LAL loss and enables monitoring of LAL gene therapy for AD. LAL-PET has the potential to serve as a superior biomarker for early AD risk assessment, disease staging, and treatment monitoring, offering advantages over Aβ-based imaging and blood biomarkers.
Image/Figure:
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Image/Figure Caption:
Figure. a. PET/CT image and quantification of the brain uptake of [18F]LAL in WT, 6-mon AD, and 10-mon AD mice at 0.5h and 1.5h post injection of [18F]LAL . b. 1h dynamic PET/CT image and quantification of the brain uptake of [18F]LAL in 13-mon WT, 13-mon AD, and 13-mon AD mice after LAL replacement therapy. c. 1h dynamic quantification of the brain uptake of [18F]LAL in 18-mon WT and 18-mon AD. d. [18F]LAL competitive autoradiography with Lalistat in mouse brain slices. e. [18F]LAL autoradiography in female and male human AD brain slices
Author
Xinrui Ma
University of North Carolina at Chapel Hill