The Medical Research Council Prion Disease Rating Scale: a new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies

Abstract

Progress in therapeutics for rare disorders like prion disease is impeded by the lack of validated outcome measures and a paucity of natural history data derived from prospective observational studies. The first analysis of the U.K. National Prion Monitoring Cohort involved 1337 scheduled clinical assessments and 479 telephone assessments in 437 participants over 373 patient-years of follow-up. Scale development has included semi-quantitative and qualitative carer interviews, item response modelling (Rasch analysis), inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point Medical Research Council prion disease rating scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence, according to their relative importance documented by carer interviews. It is quick and simple to administer, and has been validated for use by doctors and nurses and for use over the telephone, allowing for frequent assessments that capture the rapid change typical of these diseases. The Medical Research Council Scale correlates highly with widely used cognitive and single item scales, but has substantial advantages over these including minimal floor effects. Three clear patterns of decline were observed using the scale: fast linear decline, slow linear decline (usually inherited prion disease) and in some patients, decline followed by a prolonged preterminal plateau at very low functional levels. Rates of decline and progress through milestones measured using the scale vary between sporadic, acquired and inherited prion diseases following clinical expectations. We have developed and validated a new functionally-oriented outcome measure and propose that future clinical trials in prion disease should collect data compatible with this scale, to allow for combined and comparative analyses. Such approaches may be advantageous in orphan conditions, where single studies of feasible duration will often struggle to achieve statistical power.

Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel-based morphometry study

“…All participants underwent detailed systematic neurological and neuropsychological examination and scoring on the MRC Scale (Thompson et al, 2013). The MRC Scale examination assesses domains of cognitive function, speech, mobility, personal care/feeding and continence, weighted according to their relative importance in the disease, and gives a global indication of disease severity.…”

“…As part of the UK National Prion Monitoring Cohort study (Thompson et al, 2013), in this work we examined serially with 3T high-resolution brain structural MRI a cohort of patients with various forms of prion disease, the majority being diagnosed with inherited prion disease. We aimed to use longitudinal VBM to objectively characterise progressive structural brain changes without a priori assumptions.…”

“…We hypothesized that measurable macroscopic changes in brain tissue volumes reflect the development of microscopic brain pathology. Measuring local brain-tissue volume changes between first and last scan in patients, we identified regions in which longitudinal tissue volume loss correlated with the concomitant change in the recently proposed MRC Prion Disease Rating Scale (MRC Scale), a functionally-orientated outcome measure for prion disease patients (Thompson et al, 2013). We also computed the yearly rate of tissue volume change in order to map the regional distribution of longitudinal brain atrophy for prion patients in comparison with age-matched healthy individuals.…”

Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation

“…The most recently described mutation in this subgroup was an insertion of 12 OPRI causing a FTD-like disorder. 3 To further clarify genotype-phenotype associations for IPD with extra OPRI as well as rate of disease progression additional thorough phenotype characterizations using validated tools such as the recently published scale for prion diseases, 38 functional imaging studies, EEG and biochemical analysis of neurodegenerative markers in the CSF and plasma would be needed. We therefore encourage other researchers and clinicians to report cases of IPDs with extra OPRI.…”

Feasibility of Remote Assessment of Human Prion Diseases for Research and Surveillance

“…Cognition was evaluated using the Telephone Interview for Cognitive Status (TICS) [11]. The Medical Research Council (MRC) Prion Disease Rating Scale was used to assess functional status, and neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) [12, 13]. The MRC Prion Disease Rating Scale and NPI-Q were performed when the study partner was separated from the study subject.…”