Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects.

PURPOSE: [18F]MK6240 was developed for PET imaging of tau aggregates, which are implicated in Alzheimer's disease. The goal of this work was to evaluate the kinetics of [18F]MK6240 and to investigate different strategies for in-vivo quantification of tau aggregates in humans. METHODS: Thirty-five subjects, consisting of 18 healthy controls (CTRL), 11 subjects with mild cognitive impairment (MCI) and six with Alzheimer's Disease (AD), underwent dynamic [18F]MK6240 PET scans. Arterial blood measurements were collected in 16 subjects (eight CTRLs, six MCIs and two AD) to measure whole blood and plasma concentration time courses. Radiometabolite analysis was performed on a subset of plasma samples. Various compartmental model configurations as well as the Logan and multilinear analysis (MA1) graphical methods with arterial plasma input function were tested. Simplified reference tissue methods were investigated, including Logan distribution volume ratio (DVR), multilinear reference tissue method (MRTM2), and static SUV ratio using the cerebellum as a reference region. RESULTS: Whole blood:plasma ratio stabilized to 0.66 ± 0.01 after 15 min. Percent parent in plasma (%PP) followed a single exponential and ranged from 0 to 10% at 90 min. [18F]MK6240 in gray matter peaked quickly (SUV > 2 at ~3 min). The preferred compartmental model was a reversible two-tissue compartment model, with the blood contribution included as a model parameter (2T4k1v). Compartmental and graphical analysis methods with arterial input functions yielded concordant results, but rapid metabolism raised challenges for blood-based quantification. MCI and AD subjects demonstrated a broad range of VT as compared to CTRL subjects. DVR from MRTM2 and Logan reference tissue methods correlated with DVR calculated indirectly from compartmental modeling, but underestimation was observed in data sets with very high binding (DVR > 3). SUVR also underestimated indirect DVR from blood-based analyses in high binding regions, although a non-linear relationship was exhibited. CONCLUSIONS: [18F]MK6240 exhibited a wide dynamic range of uptake, with binding patterns in MCI/AD subjects consistent with neurofibrillary tau deposition patterns. Linearized reference tissue methods using an estimated average tissue-to-plasma efflux constant [Formula: see text] and static SUVR agreed well with blood-based methods for most data sets; however, discrepancies were noted in the highest binding cases. Caution should therefore be exercised in application of simplified methods to such data sets, and in quantitative interpretation of corresponding outcomes.

Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

OBJECTIVE: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC. METHODS: Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD. RESULTS: The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%). SIGNIFICANCE: Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.

Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease.

OBJECTIVE: To compare how structural MRI, Fluorodeoxyglucose (FDG), and Flortaucipir (FTP) PET signal predict cognitive decline in high-amyloid versus low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. METHODS: In this prospective cohort study, we analyzed data from clinically-normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and PiB-PET acquired within a year, and prospective cognitive evaluations over a mean three-year follow-up. We focused analyses on pre-defined regions-of-interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed using the Preclinical Alzheimer's Cognitive Composite (PACC5). We evaluated the association between biomarkers and cognitive decline using linear-mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. RESULTS: Data from 131 participants [52 females, 73.98±8.29 years old] were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high-PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high-PiB. DISCUSSION: In preclinical Alzheimer's disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with preclinical Alzheimer's disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.