Correlation of Clinical Factors and Audiometric Characteristics with MRI Findings in Patients with Asymmetric Sensorineural Hearing Loss.

CONTEXT: To identify the presence of any correlative factors between presenting symptoms and characteristics of asymmetrical sensorineural hearing loss on audiogram, and if retrocochlear pathology was identified on MRI in patients presenting in a private practice setting. METHODS: A retrospective study of patients meeting inclusion criteria who underwent MRI for asymmetric hearing loss between March 2014 to March 2017 was reviewed using Allscripts electronic health records. This data was then compiled in an excel spreadsheet and submitted for statistical analysis. RESULTS: Of the initial 687 study patients, N = 303 patients met the inclusion criteria for review. Of these 303, 48 patients (15.8%) had abnormal MRI findings. Chi-square analysis performed showed no significant association of varied clinical variables (e.g. uni and bi-lateral tinnitus, vertigo, etc.) with abnormal MRI. Point Biserial Correlation analysis revealed no statistically significant correlations, with the exception of that between AS (Left Ear) 6 kHz and MRI lesions (r = -0.115, p = 0.045). Logistic and multinomial logistic regression analysis used to calculate odds ratios showed that for patients with hearing loss at the 6 kHz (dB) level, there is a very slightly lower, statistically significant likelihood of lesions showing up on MRI (OR, 0.984 (95% CI, 0.970-0.998), p = 0.0251). CONCLUSIONS: The results lead to the conclusion that there may be an association between experiencing hearing loss at the level of 6 kHz and a slightly lower chance of the presence of retrocochlear lesion noted on MRI.

Targeting Metal-Aß Aggregates with Bifunctional Radioligand [11C]L2-b and a Fluorine-18 Analogue [18F]FL2-b.

Interest in quantifying metal-Aß species in vivo led to the synthesis and evaluation of [11C]L2-b and [18F]FL2-b as radiopharmaceuticals for studying the metallobiology of Alzheimer's disease (AD) using positron emission tomography (PET) imaging. [11C]L2-b was synthesized in 3.6% radiochemical yield (nondecay corrected, n = 3), >95% radiochemical purity, from the corresponding desmethyl precursor. [18F]FL2-b was synthesized in 1.0% radiochemical yield (nondecay corrected, n = 3), >99% radiochemical purity, from a 6-chloro pyridine precursor. Autoradiography experiments with AD positive and healthy control brain samples were used to determine the specificity of binding for the radioligands compared to [11C]PiB, a known imaging agent for ß-amyloid (Aß) aggregates. The Kd for [11C]L2-b and [18F]FL2-b were found to be 3.5 and 9.4 nM, respectively, from those tissue studies. Displacement studies of [11C]L2-b and [18F]FL2-b with PiB and AV-45 determined that L2-b binds to Aß aggregates differently from known radiopharmaceuticals. Finally, brain uptake of [11C]L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress (n = 2).

High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

Evaluation of [(11)C]N-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary Tangles.

[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [(11)C]MeI), 99% radiochemical purity, and 16095 Ci/mmol specific activity (n = 5). Log P was determined to be 2.18. A lack of brain uptake in rodent microPET imaging revealed [(11)C]NML to be a substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by pretreating with cyclosporin A to block the PGP. Contrastingly, [(11)C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [(11)C]NML uptake in the healthy primate brain of ∼1600 nCi/cc maximum at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiography between wild-type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [(11)C]NML in the cortex of brains expressing human tau. Further autoradiography with tau positive brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [(11)C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K d and Bmax values of [(11)C]NML as 700 pM and 0.214 fmol/µg, respectively.