Dementia trials and dementia tribulations: methodological and analytical challenges in dementia research

Abstract

Dementia is a substantial and increasing public health concern. Despite decades of research, a cure or effective preventative treatment for dementia remains elusive. We offer critical review of contemporary dementia research and discuss potential reasons why progress in the field has not been as rapid as in other disciplines. We adopt a broad approach in keeping with the broad nature of the topic. We cover the difficulties inherent in studying dementia from 'bench' to 'bedside' to 'population'. We make particular reference to issues of operationalisation of the dementia syndrome and our evolving understanding of dementia as a research 'outcome'. We discuss contemporary 'hot topics' in dementia research methodology focussing on dementia models, pre-dementia states and biomarkers. Recognising the importance of prospective epidemiological cohorts and large-scale clinical trials we pay particular attention to these approaches and the challenges of generating results that have 'real world' external validity. Based on our thoughts we end with suggestions for future dementia research. Our review is designed to be critical but not unnecessarily negative. There is reason for cautious optimism in dementia research. The recent G8 summit on dementia and subsequent establishment of the World Dementia Council are examples of initiatives that reflect societal and political will to increase research efforts in dementia.

Figure 1

The theory and reality of contemporary dementia research paradigms. (a) An 'ideal' model, wherein older adults with early biomarker-detected changes of dementia can be selected and this cohort then progresses through a stage of 'cognitive impairment non-dementia' (CIND) with eventual overt dementia of a particular pathological subtype. (b) A more complex situation that is closer to the 'real world' of dementia research, wherein predictive accuracy of biomarkers is not 100% sensitive or specific, CIND to dementia conversion is neither predictable nor inevitable and the final syndrome of dementia is often a mix of underlying pathologies. CSF, cerebrospinal fluid; MCI, mild cognitive impairment.

Figure 2

Methods of assigning dementia diagnosis for clinical research. Differing methods of assigning the dementia outcome are described in terms of the time and effort required to make the diagnosis (x-axis) and the external validity of that diagnosis (y-axis). The positions are illustrative only and designed to show the 'trade off' between effort and validity. In assigning validity we assume that expert clinical assessment is the reference standard; hence, neuropathological assessment requires substantial time/effort but validity is relatively low.

Figure 3

Properties of cognitive assessment tools. The first column describes the properties of an 'ideal' cognitive assessment tool (Ferris) and the second column describes a popular assessment tool (Folstein’s Mini-Mental State Examination; MMSE) against these desired properties. RCT, randomised controlled trial.

Figure 4

Modelling cognitive trajectory. (a) Comparing time to dementia and age to describe cognitive trajectories. Mini-Mental State Examination (MMSE) trajectories of a random sample of Origins of Variance in the Oldest-Old Twin Study participants plotted as a function of age and dementia diagnosis. As an illustration of how heterogeneity of trajectories is reduced when scores are modelled using a process-based approach, MMSE scores of a random sample of participants plotted as a function of age and time to dementia diagnosis are depicted [57]. (b) Graphical illustration of a change point model. A schematic representation of the typical change point model trajectory as assumed in the broken stick model [58].