The few established causal genes in Alzheimer's disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. SORL1, a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mutations lead to partial loss of protein function. Here, in an effort to test whether SORL1 can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of SORL1 haploinsufficiency in Goettingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young minipigs was found to phenocopy the preclinical in vivo profile of AD observed with other causal genes, resulting in spinal fluid abnormalities in Aβ and tau, with no evident neurodegeneration or amyloid plaque formation. These studies provide functional support that SORL1 is a bona fide causal gene in AD, and when taken together with recent insight on other AD-causal genes, support the idea that dysfunctional endosomal recycling is a dominant pathogenic pathway in the disease.
Hyperpolarized carbon-13 MRI is a promising technique for in vivo metabolic interrogation of alterations between health and disease. This study introduces a model-free formalism for quantifying the metabolic information in hyperpolarized imaging. This study investigated a novel model-free perfusion and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain. Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and kPL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 +- 2 vs 89 +- 6 mL/100g/min, p < 0.01, respectively) and pigs (139 +- 12 vs 95 +- 5 mL/100g/min, p = 0.04, respectively), along with an increase in fractional metabolism (26 +- 5 vs 4 +- 2 %, p < 0.01, respectively) in the rodent brain. In addition, a significant increase in ipsilateral vs contralateral MCR (0.034 +- 0.007 vs 0.017 +- 0.02 s-1, p = 0.03, respectively) and a decrease in mean transit time (MTT) (31 +- 8 vs 60 +- 2, p = 0.04, respectively) was observed in the porcine brain. In conclusion, MCR mapping is a simple and robust approach to the post-processing of hyperpolarized magnetic resonance imaging.
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