Video Rating in Neurodegenerative Disease Clinical Trials: The Experience of PRION-1.

BACKGROUND/AIMS: Large clinical trials including patients with uncommon diseases involve assessors in different geographical locations, resulting in considerable inter-rater variability in assessment scores. As video recordings of examinations, which can be individually rated, may eliminate such variability, we measured the agreement between a single video rater and multiple examining physicians in the context of PRION-1, a clinical trial of the antimalarial drug quinacrine in human prion diseases. METHODS: We analysed a 43-component neurocognitive assessment battery, on 101 patients with Creutzfeldt-Jakob disease, focusing on the correlation and agreement between examining physicians and a single video rater. RESULTS: In total, 335 videos of examinations of 101 patients who were video-recorded over the 4-year trial period were assessed. For neurocognitive examination, inter-observer concordance was generally excellent. Highly visual neurological examination domains (e.g. finger-nose-finger assessment of ataxia) had good inter-rater correlation, whereas those dependent on non-visual clues (e.g. power or reflexes) correlated poorly. Some non-visual neurological domains were surprisingly concordant, such as limb muscle tone. CONCLUSION: Cognitive assessments and selected neurological domains can be practically and accurately recorded in a clinical trial using video rating. Video recording of examinations is a valuable addition to any trial provided appropriate selection of assessment instruments is used and rigorous training of assessors is undertaken.

Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial.

BACKGROUND: The propagation of prions, the causative agents of Creutzfeldt-Jakob disease and other human prion diseases, requires post-translational conversion of normal cellular prion protein to disease-associated forms. The antimalarial drug quinacrine (mepacrine) prevents this conversion in vitro, and was given to patients with various prion diseases to assess its safety and efficacy in changing the course of these invariably fatal and untreatable diseases. METHODS: Patients with prion disease were recruited via the UK national referral system and were offered a choice between quinacrine (300 mg daily), no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine in an open-label, patient-preference trial. The primary endpoints were death and serious adverse events possibly or probably related to the study drug. This study is registered, ISRCTN 06722585. FINDINGS: 107 patients with prion disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) were enrolled, 23 in a pilot study and 84 in the main study. Only two patients chose randomisation; 40 took quinacrine during follow-up (37 who chose it at enrollment). Choice of treatment was associated with disease severity, with those least and most severely affected more likely to choose not to receive quinacrine. 78 (73%) patients died: one randomly assigned to deferred treatment, 26 of 38 who chose immediate quinacrine, and 51 of 68 who chose no quinacrine. Although adjusted mortality was lower in those who chose to take quinacrine than in those who did not, this was due to confounding with disease severity, and there was no difference in mortality between groups after adjustment. Four of 40 patients who took quinacrine had a transient response on neurological rating scales. Only two of 14 reported serious adverse events were judged quinacrine-related. INTERPRETATION: Quinacrine at a dose of 300 mg per day was reasonably tolerated but did not significantly affect the clinical course of prion diseases in this observational study.

Imaging cadavers: cold FLAIR and noninvasive brain thermometry using CSF diffusion.

There is increasing interest in imaging cadavers for noninvasive autopsies for research purposes. However, the temperature is well below that of in vivo imaging, and a variety of interesting 'cold brain' effects are observed. At lower temperatures conventional FLAIR sequences no longer produce dark cerebrospinal fluid (CSF); T(1) is reduced from about 4.0 sec in vivo to 1.7 sec at 1 degrees C. The diffusion coefficient (DC) of CSF is much reduced (from 3.1 10(-9) m(2)s(-1) in vivo to 1.1 at 1 degrees C). DC values therefore provide a noninvasive thermometer to measure brain core temperature to within 1.0 degrees C. In three cadavers DC values were 1.1-1.5 10(-9) m(2)s(-1), indicating brain core temperatures of 1-10 degrees C, consistent with external thermocouple measurements. An improved inversion time (TI(0)) can then be found for FLAIR. At 10 degrees C this Cold FLAIR sequence (TI(0) = 1.5 sec) gave black CSF. Expressions for CSF DC and T(1) as a function of temperature were produced. A measurement of CSF DC could be converted directly to temperature and the required TI(0) found. In vitro values of CSF DC were about 1% lower than that of water. Thus, FLAIR imaging can be optimized for cadaveric brains at low and unknown temperatures, thereby improving value for autopsy purposes and facilitating comparisons with in vivo imaging.