As pointed out some years ago (Larner 2001:xii), the diagnostic accuracy of most clinical signs, neurological or otherwise, remains to be defined, despite that fact that many are routinely taught to medical students and postgraduate trainees. Although an initiative to rectify this was commenced (CARE: Clinical Assessment of the Reliability of the Examination; McAlister et al. 1999), relatively little seems to have emerged from this programme, at least in the field of neurological signs.

Some attempt has been made to assess the accuracy of a few signs relevant to dementia, including the “attended alone” sign, the head turning sign, and the applause sign, all of which may be defined as non-canonical neurological signs (Larner 2014b; Table 6.1). However, this remains a neglected field which invites further studies, ideally suited to the day-to-day workings of an outpatient clinic.

It is clear from many disparate studies that the neurobiological changes which underpin Alzheimer’s disease commence many years, indeed decades, before the emergence of clinical symptomatology (Amieva et al. 2005; Bateman et al. 2012; Jack et al. 2013). The need for tools to detect the preclinical and presymptomatic stages of AD, as well as mild cognitive impairment due to AD, is well recognised (Snyder et al. 2014). Diagnostic accuracy studies for any tests developed to identify these very earliest disease stages will be of paramount importance if meaningful trials of disease-modifying agents are to be undertaken in AD. Delayed verification studies of tests measuring disease biomarkers, such as amyloid PET imaging and CSF biomarkers (Sect. 3.​3), represent a start in this process. A small study has suggested that CSF Abeta42 and hippocampal volume measurement may be used in combination to best identify prodromal AD (Prestia et al. 2013) and certain neuropsychological test batteries might also predict incident AD (Wolfsgruber et al. 2014).

Diagnostic test accuracy studies assessing different sequences or batteries of tests, rather than a single test in isolation, might be a fruitful undertaking. The dementia syndrome encompasses not only cognitive but behavioural, functional, and neurovegetative changes (American Psychiatric Association 2000) and hence diagnostic tests addressing more than one of these domains or constructs might be appropriate (Larner 2014c:184–9). Some attempts to combine results of tests from different diagnostic domains has been essayed (Sect. 4.​3.​3.​3), and this might be extended.

In the nomenclature describing the architecture of clinical research devised by Sackett and Haynes (Sackett and Haynes 2002), phase III questions ask whether diagnostic test results distinguish those with and without the target disorder amongst those in whom the test would be used (my italics), i.e. those in whom it is clinically sensible to suspect the target disorder (Sect. 1.​3.​1.​2). Phase III studies therefore address the clinical problem for which the test should be evaluated. It might be possible to extend this (perhaps to be denoted “Phase IIIb”?) to ask whether diagnostic test results distinguish those with and without the target disorder among those in whom the test could be used, or to address the clinical problem for which the test could be evaluated. For example, since the dementia syndrome encompasses many domains, could cognitive scales be used to identify patients with cognitive complaints who in fact have depression rather than dementia, even though this was not what the scale was originally designed for? This is simply to recognise the clinical truism that cognitive complaints and impairments have a differential diagnosis which encompasses both cognitive and affective disorders.

Although at first glance this might seem somewhat counterintuitive or even inappropriate, there are some examples available of such a “phase IIIb” approach, where the utility of a cognitive scale in differentiating cognitive and psychiatric causes of memory disturbance has been shown, for example using a computerized battery (CANTAB-PAL; Swainson et al. 2001), the Addenbrooke’s Cognitive Examination (ACE; Dudas et al. 2005) and its revision, ACE-R (P Hancock, cited in Larner 2014c:168–9; Rotomskis et al. 2015). Conversely, depression screening instruments have been examined in pragmatic test accuracy studies for the diagnosis of dementia, such as the Patient Health Questionnaire-9 (PHQ-9; Hancock and Larner 2009) and the Cornell Scale for Depression in Dementia (CSDD; Hancock and Larner 2015). Although both the latter proved inadequate for dementia diagnosis in terms of sensitivity and specificity, nevertheless they were of pragmatic value in identifying patients who might benefit from trials of antidepressant medication (Hancock and Larner 2009, 2015).

Such diagnostic test accuracy studies have the potential to broaden or extend the scope of test use. For example, the Montreal Cognitive Assessment (MoCA), originally designed to diagnose Alzheimer’s disease and mild cognitive impairment (Nasreddine et al. 2005), has found application for the diagnosis of cognitive impairment in many other neurological disorders including cerebrovascular disease, Parkinson’s disease, Huntington’s disease, brain tumours, systemic lupus erythematosus, substance use disorders, obstructive sleep apnoea, and epilepsy (Julayanont et al. 2013). MoCA might also have a role as a cognitive screener in psychiatric disease (Musso et al. 2014) and has been recommended as one of the screening tools to detect fluctuations in cognition in the context of delirium (Inouye et al. 2014). All of these scenarios require “phase IIIb” diagnostic test accuracy studies. Mini-Mental Parkinson (MMP), originally designed to identify cognitive impairments in Parkinson’s disease (Mahieux et al. 1995), may also have utility as a general cognitive screening instrument (Larner 2012b).

Phase IV questions (Sackett and Haynes 2002) ask whether patients undergoing a diagnostic test fare better in their ultimate health outcomes than similar patients who do not (prognostic test impact), hence constitute an evaluation of the entire diagnostic test-treatment pathway for clinical effectiveness (Ferrante di Ruffano et al. 2012). Such phase IV studies remain unexplored in dementia, undoubtedly because of the currently very limited treatment options (symptomatic treatment with cholinesterase inhibitors and/or memantine). When more meaningful dementia treatments become available, this will be an important area for diagnostic test accuracy studies, although such studies will, due to the nature of the disease, be of long duration, especially if commenced at early, even presymptomatic, stages, with many years of follow-up required to test the efficacy of interventions. They might be easier to undertake in dementia disorders with currently poor survival rates, such as prion disease or frontotemporal dementia with motor neurone disease.

Phase IV questions add layers of complexity to diagnostic test accuracy studies. For example, a study of which diagnostic modalities should be used to identify the epileptogenic zone in patients with refractory epilepsy being considered for surgery found that extant diagnostic test accuracy studies could not provide information on diagnostic accuracy or clinical utility, with all likelihood ratios close to unity (Burch et al. 2012). Dichotomizing the data into a standard 2 × 2 table proved difficult, and indeed may be inappropriate when the object of tests is something other than identifying the presence or absence of disease (Burch et al. 2012).

It is inevitable, in the author’s opinion, that phase IV questions will also eventually attract health economic evaluations (“Phase IVb”?), as for randomised controlled trials of dementia treatments (Wimo et al. 2013). In times of economic recession or retrenchment, cost implications will factor highly with those charged with commissioning services, over and above issues of efficacy which are of most concern to clinicians and patients.

Because of the societal and economic impact of the increasing prevalence of dementia associated with the demographic ageing of populations, dementia has become a subject of interest to politicians as well as clinicians and neurobiologists (e.g. in the UK, the Prime Minister’s Challenge on Dementia; Department of Health 2012a). A consequence of this interest is the promulgation of policies, ostensibly aimed at improving the lot of dementia sufferers, which may have consequences rather different to those anticipated (if contemplated at all) by the policy formulators.