Creutzfeldt-Jakob disease associated with a T188K homozygous mutation in the prion protein gene: a case report and review of the literature.

Genetic Creutzfeldt-Jakob disease (gCJD) is a prion disease caused by mutations in the prion protein gene (PRNP). It has an autosomal dominant inheritance, so gCJD with homozygous mutations is extremely rare, and the influence of homozygous mutations on the gCJD phenotype is unknown. We describe the clinical and laboratory features of a patient with a PRNP T188K homozygous mutation and perform a literature review of gCJD cases with PRNP homozygous mutations. The patient was presented with cerebellum symptoms, cognitive decline and visual disturbances. Auxiliary examinations revealed restricted diffusion in magnetic resonance imaging and glucose hypometabolism on 18Fluorodeoxyglucose-positron emission tomography. No periodic sharp wave complexes were detected in electroencephalography, and the cerebrospinal fluid 14-3-3 protein was negative. PRNP sequencing revealed the presence of a homozygous T188K variant. The patient died 15 months after disease onset. A literature review revealed PRNP V203I, E200K and E200D as the only three mutations reported as homozygous in gCJD. To the best of our knowledge, this is the first report of a gCJD patient with a PRNP T188K homozygous mutation. Although the clinical manifestations of our patient were similar to those with PRNP T188K heterozygous mutations, she presented with a slightly earlier onset and had a longer survival time. This is consistent with previous observations from patients with PRNP V203I and E200K homozygous mutations. Further studies are essential to clarify the influence of homozygous mutations on the gCJD phenotype.

Acyclovir Brain Disposition: Interactions with P-gp, Bcrp, Mrp2, and Oat3 at the Blood-Brain Barrier.

BACKGROUND AND OBJECTIVE: Acyclovir is effective in treating herpes simplex virus infections of the central nervous system. The purpose of this study was to investigate the interactions between acyclovir and the efflux pumps P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), multidrug resistance protein 2 (Mrp2), and organic anion transporter 3 (Oat3) at the blood-brain barrier (BBB). METHODS: Acyclovir concentrations in the blood and brain were evaluated by microdialysis and high-performance liquid chromatography. Acyclovir pharmacokinetic parameters, including the area under the unbound blood concentration-time curve (AUCu,blood), the area under the unbound brain concentration-time curve (AUCu,brain), and the ratio of AUCu,brain to AUCu,blood (Kp.uu.brain), were evaluated in the presence and absence of elacridar (P-gp/Bcrp inhibitor, 7.5 mg/kg), tariquidar (P-gp/Bcrp inhibitor, 7.5 mg/kg), MK571 (Mrp2 inhibitor, 7.5 mg/kg), cyclosporine (P-gp/Bcrp/Mrp2 inhibitor, 25 mg/kg), and probenecid (Oat3 inhibitor, 50 mg/kg). RESULTS: The average AUCu,blood, AUCu,brain, and Kp.uu.brain in rats who received acyclovir (25 mg/kg, intravenous) alone were 1377.7 min · µg/ml, 435.4 min · µg/ml, and 31.6%, respectively. Probenecid drastically increased the AUCu,blood of acyclovir 1.73-fold, whereas coadministration with elacridar, tariquidar, MK571, and cyclosporine did not alter the blood pharmacokinetic parameters of acyclovir. Elacridar, tariquidar, MK571, cyclosporine, and probenecid significantly increased the AUCu,brain of acyclovir 1.51-, 1.54-, 1.47-, 1.95-, and 2.34-fold, respectively. Additionally, the Kp.uu.brain of acyclovir markedly increased 1.48-, 1.63-, 1.39-, 1.90-, and 1.35-fold following elacridar, tariquidar, MK571, cyclosporine, and probenecid administration, respectively. CONCLUSION: The present study demonstrated that P-gp, Bcrp, Mrp2, and Oat3 inhibition increased the penetration of acyclovir across the BBB, supporting the hypothesis that these efflux pumps restrict the distribution of acyclovir in the brain.

Effect of P-glycoprotein Inhibition on the Penetration of Ceftriaxone Across the Blood-Brain Barrier.

Recent studies indicate that inhibition of the efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may represent a putative strategy to increase the BBB penetration of several antibiotics. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of ceftriaxone (CFX) across the BBB. Blood and brain microdialysis in rats was used to monitor blood and brain unbound CFX concentrations following intravenous administration (50 mg/kg), with or without pretreatment with one of the P-gp inhibitors, cyclosporin A (6.25, 12.5, 25 mg/kg) or verapamil (5, 10, 20 mg/kg). An inhibitory effect was demonstrated by an increase in the ratio of unbound brain to unbound blood concentration (Kp.uu.brain) of CFX. The concentrations of CFX in blood and brain from 0 to 180 min after intravenous administration (CFX, 50 mg/kg) ranged from 3 to 40 µg/ml and 1 to 10 µg/ml, respectively. The Kp.uu.brain of CFX was 24.74 ± 1.34%. Pretreatment with cyclosporin A increased the brain concentration and the Kp.uu.brain of CFX in a dose-dependent manner. However, pretreatment with verapamil increased the brain concentration of CFX but not the Kp.uu.brain. The present data shows that CFX might be a substrate of P-gp efflux transporter at the BBB and P-gp inhibition might enhance the brain concentration of CFX. Future studies involving more selective P-gp inhibitors or knockout mouse models should be conducted to specifically elucidate the impact of P-gp inhibition on penetration of CFX across the BBB.

Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid for the Diagnosis of Cerebral Aspergillosis.

Purpose: Cerebral aspergillosis (CA) is a rare but often fatal, difficult-to-diagnose, opportunistic infection. The utility of metagenomic next-generation sequencing (mNGS) for diagnosis of CA is unclear. We evaluated the usefulness of mNGS of the cerebrospinal fluid (CSF) for the diagnosis of CA. Methods: This prospective study involved seven consecutive patients with confirmed CA in whom CSF mNGS was performed. Serum (1→3)-ß-D-glucan and galactomannan levels were determined, and histopathological examination and mNGS of the CSF were conducted. CSF specimens from three non-infected patients were used as positive controls. Results: mNGS of the CSF was positive in six of the seven confirmed CA cases (85.71% sensitivity). In the cryptococcal meningitis group (control), mNGS of the CSF was positive for Aspergillus in two patients (84.62% specificity). The positive likelihood ratio, negative likelihood ratio, and Youden's index of mNGS for CA in the CSF were 5.565, 0.169, and 0.7, respectively. Among the six mNGS-positive cases, more than two Aspergillus species were found in four (4/6, 66.67%). In the positive controls, the addition of one A. fumigatus spore yielded a standardised species-specific read number (SDSSRN) of 25.45 by mNGS; the detection rate would be 0.98 if SDSSRN was 2. Conclusion: mNGS facilitates the diagnosis of CA and may reduce the need for cerebral biopsy in patients with suspected CA. Trial Registration Number: Chinese Clinical Trial Registry, ChiCTR1800020442.