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 A.J. Larner
Editor

Cognitive
Screening Instruments

A Practical Approach
Second Edition

123
Cognitive Screening Instruments
A.J. Larner
Editor

Cognitive Screening
Instruments
A Practical Approach

Second Edition
Editor
A.J. Larner
Cognitive Function Clinic
Walton Centre for Neurology and Neurosurgery
Liverpool
United Kingdom

ISBN 978-3-319-44774-2 ISBN 978-3-319-44775-9 (eBook)

DOI 10.1007/978-3-319-44775-9

Library of Congress Control Number: 2016960297

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Preface to the Second Edition

It is extraordinary to think that it is only a little over 5 years ago that I first had the
idea for this book (my Munich “epiphany” of 9 April 2011 at the Ludwig-
Maximilians University, described in the preface to the first edition), and now a
second edition is going to press. The fact that the first edition, published in 2013,
achieved nearly 18,000 chapter downloads to the end of 2015 suggests that it is
meeting a need, hence justifying a new edition.
All the major sections of this book, which are now made explicit, have new chap-
ter additions from the first edition. In the introductory section, Terry Quinn and
Yemisi Takwoingi have written on the critical topic of the assessment of the utility
of cognitive screening instruments. In the section on patient performance-related
tests, Rónán O’Caoimh and William Molloy have written on the Quick Mild
Cognitive Impairment (Qmci) screen, and in the informant-related scales section
James E Galvin and Mary Goodyear have written on brief informant interviews
such as the AD8. These new authors extend the reach of the book both intellectually
and geographically (spanning eight countries in four continents).
I am delighted that all the corresponding authors in the first edition have
responded positively to the invitation to revise and update their chapters. Hence
there continue to be accounts of the Mini-Mental State Examination (Alex Mitchell)
and its variants; the Clock Drawing Test (Brian Mainland and Ken Shulman); the
Montreal Cognitive Assessment (Parunyou Julayanont and Ziad Nasreddine);
DemTect (Elke Kalbe and Josef Kessler); Test Your Memory (TYM) test (Jerry
Brown); the General Practitioner Assessment of Cognition (GPCOG; Katrin Seeher
and Henry Brodaty); the Six-Item Cognitive Impairment Test (6CIT; Tim Gale); and
the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE; Nicolas
Cherbuin and Tony Jorm). I am delighted that John Hodges has joined with me to
write the revised chapter on the Addenbrooke’s Cognitive Examinations which he
and his colleagues have developed, most recently the ACE-III and the Mini-
Addenbrooke’s Cognitive Examination (MACE).
Of course, a number of criticisms might be leveled at the project. First, the selec-
tion of screening instruments described in depth might potentially be seen as arbi-
trary, in light of the very large number of such instruments described in the literature,

v
vi Preface to the Second Edition

but all are in sufficiently frequent use to be familiar to the editor, from either per-
sonal use (see authored or co-authored chapters, and references 1–5) or encountered
in patient referrals (reference 6). Second, with the advent of disease biomarkers,
based on a more sophisticated understanding of the heterogeneous clinical pheno-
types of cognitive impairment, pen and paper tests may seem old-fashioned, possi-
bly even obsolete, even when replaced by apps or computerized tests. However,
facilities for biomarker investigation are not currently widespread, and this lack of
availability will ensure that cognitive screening instruments retain a place in clinical
practice for the foreseeable future.
Thanks are due to all the contributors for their timely production of chapters, and
all at Springer, past and present, who have supported the production of this volume,
particularly Joanna Renwick (née Bolesworth) and Andre Tournois.

Liverpool, UK A.J. Larner

References

1. Larner AJ. Screening utility of the Montreal Cognitive Assessment (MoCA): in place of – or as
well as – the MMSE? Int Psychogeriatr. 2012;24:391–6.
2. Larner AJ. DemTect: 1-year experience of a neuropsychological screening test for dementia.
Age Ageing. 2007; 36:326–7.
3. Hancock P, Larner AJ. Test Your Memory: diagnostic utility in a memory clinic population. Int
J Geriatr Psychiatry. 2011;26:976–80.
4. Hancock P, Larner AJ. Diagnostic utility of the Informant Questionnaire on Cognitive Decline
in the Elderly (IQCODE) and its combination with the Addenbrooke’s Cognitive Examination-
Revised (ACE-R) in a memory clinic-based population. Int Psychogeriatr. 2009;21:526–30.
5. Larner AJ. AD8 informant questionnaire for cognitive impairment: pragmatic diagnostic test
accuracy study. J Geriatr Psychiatry Neurol. 2015;28:198–202.
6. Wojtowicz A, Larner AJ. General Practitioner Assessment of Cognition: use in primary care
prior to memory clinic referral. Neurodegener Dis Manag. 2015; 5:505–10.
Contents

Part I Introduction to Cognitive Screening Instruments

1 Introduction to Cognitive Screening Instruments:

Rationale and Desiderata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Andrew J. Larner
2 Assessment of the Utility of Cognitive Screening Instruments . . . . . . . 15
Terence J. Quinn and Yemisi Takwoingi

Part II Patient Performance-Related Tests

3 The Mini-Mental State Examination (MMSE):

Update on Its Diagnostic Accuracy and Clinical
Utility for Cognitive Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Alex J. Mitchell
4 MMSE Variants and Subscores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Andrew J. Larner
5 Clock Drawing Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Brian J. Mainland and Kenneth I. Shulman
6 Addenbrooke’s Cognitive Examinations: ACE, ACE-R, ACE-III,
ACEapp, and M-ACE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
John R. Hodges and Andrew J. Larner
7 Montreal Cognitive Assessment (MoCA): Concept
and Clinical Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Parunyou Julayanont and Ziad S. Nasreddine
8 DemTect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Elke Kalbe and Josef Kessler

vii
viii Contents

9 TYM (Test Your Memory) Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Jeremy M. Brown
10 The General Practitioner Assessment of Cognition (GPCOG). . . . . . 231
Katrin M. Seeher and Henry Brodaty
11 Six-Item Cognitive Impairment Test (6CIT) . . . . . . . . . . . . . . . . . . . . 241
Tim M. Gale and Andrew J. Larner
12 The Quick Mild Cognitive Impairment Screen (Qmci) . . . . . . . . . . . . 255
Rónán O’Caoimh and D. William Molloy

Part III Informant-Related Scales

13 The IQCODE: Using Informant Reports to Assess

Cognitive Change in the Clinic and in Older
Individuals Living in the Community . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Nicolas Cherbuin and Anthony F. Jorm
14 Brief Informant Interviews to Screen for Dementia:
The AD8 and Quick Dementia Rating System . . . . . . . . . . . . . . . . . . . 297
James E. Galvin and Mary Goodyear

Part IV Conclusion

15 The Usage of Cognitive Screening Instruments:

Test Characteristics and Suspected Diagnosis . . . . . . . . . . . . . . . . . . . 315
Andrew J. Larner

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Contributors

Henry Brodaty, AO, MBBS, MD, DSc, FRACP Dementia Collaborative

Research Centre – Assessment and Better Care, University of New South Wales,
Sydney, NSW, Australia
Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Australia, Sydney,
NSW, Australia
Jeremy M. Brown, MD, MBBS, MA, FRCP Addenbrooke’s Hospital, Cambridge
and Queen Elizabeth Hospital NHS Trust, Kings Lynn, UK
Nicolas Cherbuin, PhD Centre for Research on Ageing, Health and Wellbeing,
Australian National University, Canberra, ACT, Australia
Tim M. Gale, PhD Research & Development Department, Hertfordshire
Partnership NHS Foundation Trust, Abbots Langley, UK
School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK
Research & Development Department, HPFT Learning & Development Centre,
Hatfield, Herts, UK
James E. Galvin, MD, MPH Charles E. Schmidt College of Medicine, Florida
Atlantic University, Boca Raton, FL, USA
Mary Goodyear Charles E. Schmidt College of Medicine, Florida Atlantic
University, Boca Raton, FL, USA
John R. Hodges Department of Cognitive Neurology, NeuRA and UNSW,
Randwick, NSW, Australia
Anthony F. Jorm, PhD, DSc Melbourne School of Population Health, University
of Melbourne, Parkville, VIC, Australia
Parunyou Julayanont, MD MoCA Clinic and Institute, Greenfield Park, QC,
Canada
Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

ix
x Contributors

Department of Neurology, Texas Tech University Health Science Center, Lubbock,

TX, USA
Elke Kalbe, PhD Medical Psychology/Neuropsychology and Gender Studies and
Center for Neuropsychological Diagnostics and Intervention (CeNDI), University
Hospital Cologne, Cologne, Germany
Department of Neurology, University Hospital Cologne, Cologne, Germany
Josef Kessler, PhD Department of Neurology, University Hospital Cologne,
Cologne, Germany
Andrew J. Larner, MD, PhD Cognitive Function Clinic, Walton Centre for
Neurology and Neurosurgery, Liverpool, UK
Brian J. Mainland, PhD Private Practice, Burlington, ON, Canada
Alex J. Mitchell Department of Psycho-oncology, Leicestershire Partnership Trust
and Department of Cancer Studies and Molecular Medicine, University of Leicester,
Leicester, UK
D. William Molloy Centre for Gerontology and Rehabilitation, University College
Cork, St Finbarr’s Hospital, Cork City, Ireland
Ziad S. Nasreddine, MD, FRCP(C) MoCA Clinic and Institute, Greenfield Park,
QC, Canada
McGill University, Montreal, QC, Canada
Sherbrooke University, Sherbrooke, QC, Canada
Rónán O’Caoimh, MB, MSc, PhD Health Research Board Clinical Research
Facility Galway, National University of Ireland, Galway, Ireland
Centre for Gerontology and Rehabilitation, University College Cork, St Finbarr’s
Hospital, Cork City, Ireland
Terence J. Quinn, MD Institute of Cardiovascular and Medical Sciences,
University of Glasgow, Glasgow, UK
Katrin M. Seeher, Dipl Psych, PhD Dementia Collaborative Research Centre –
Assessment and Better Care, University of New South Wales, Sydney, NSW,
Australia
Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Australia, Sydney,
NSW, Australia
Kenneth I. Shulman, MD, SM, FRCPsych, FRCPC Brain Sciences Program,
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
Yemisi Takwoingi Institute of Applied Health Research, University of Birmingham,
Birmingham, UK
 Part I
Introduction to Cognitive Screening
Instruments
Chapter 1
Introduction to Cognitive Screening
Instruments: Rationale and Desiderata

Andrew J. Larner

Contents
1.1 Introduction ................................................................................................................... 4
1.2 Rationale of Cognitive Screening .................................................................................. 5
1.3 Desiderata for Cognitive Screening Instruments ........................................................... 7
1.4 Conclusion ..................................................................................................................... 9
References ............................................................................................................................... 9

Abstract Cognitive disorders are common and likely to become more so as the
world population ages. Pending the definition of reliable disease biomarkers, the
identification of such disorders is likely to involve the use of cognitive screening
instruments, as a prelude to effective management. The rationale and desiderata
for effective cognitive screening instruments are considered in this chapter, prior
to the description of methods for their assessment and in-depth analysis of spe-
cific instruments in subsequent chapters. The potential role of factors such as
age, education, and culture on test performance and interpretation are also
considered.

Keywords Cognitive screening instruments • Desiderata • Rationale

A.J. Larner
Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK
e-mail: [email protected]

© Springer International Publishing Switzerland 2017 3

A.J. Larner (ed.), Cognitive Screening Instruments,
DOI 10.1007/978-3-319-44775-9_1
4 A.J. Larner

1.1 Introduction

Cognitive screening instruments may be encountered by practitioners in many

branches of clinical medicine, in both primary and secondary care. However, not all
clinicians may feel themselves either familiar with or competent in the use of such
instruments. This may stem in part from lack of appropriate training, or even frank
neurophobia, perhaps exacerbated by the profusion of potential tests available.
Although there have been a number of publications in recent years reviewing the
use of cognitive screening instruments in different clinical settings (e.g. [1–8]), and
books which are partially devoted to their examination (e.g. [9, 10]), texts entirely
devoted to this subject are few (e.g. [11]). This book aims to give practical advice
on some of the most commonly used cognitive screening instruments which are
suitable for day-to-day use in assessing patients with possible cognitive
impairments.
The rationale for this use of cognitive screening instruments relates, at least in
part, to the increasing numbers of individuals with cognitive impairment, related to
the aging of the population, numbers which have been predicted to increase dra-
matically worldwide in the coming decades with significant societal and financial
cost implications (e.g. [12–17]). Although some studies have suggested falling
overall prevalence and incidence of dementia in the UK [18, 19], nevertheless the
condition will continue to be a major public health issue.
Population screening for dementia has not been advocated hitherto, there being
insufficient evidence of benefit to justify such an undertaking. However, this remains
an issue in flux (e.g. [20–23]), not least because of a developing consensus regard-
ing the preventability of many cases of dementia through modification of risk fac-
tors (e.g. [24–26]). This may justify not only existing policies encouraging early
diagnosis of dementia as a stated health goal (e.g. in the United Kingdom (UK)
[27–29]), but also screening of at-risk groups, such as older people and individuals
with subjective memory complaints, possibly as a prelude to global population
screening.
Underdiagnosis of dementia and cognitive impairment certainly remains a sig-
nificant issue. In the UK, a comparison of estimated numbers of people with demen-
tia (based on applying prevalence rates to corresponding age groups) with the actual
number of people with dementia recorded on the National Health Service (NHS)
Quality Outcome Framework dementia register based in primary care have sug-
gested that only around 40–50 % of people with dementia have a diagnosis [30, 31].
Closing this “diagnostic gap” or “dementia gap” may be facilitated by appropriate
use of cognitive screening instruments.
Conversely, current clinical practice indicates that many individuals who attend
cognitive/memory clinics are found not to have dementia, but purely subjective
memory complaint. Physiological cognitive decline may be evident in early middle
age (45–49 years [32]). Although the UK National Institute for Health and Clinical
Excellence (NICE) [33] suggested a memory clinic base rate for dementia of 54 %,
this may greatly overestimate current clinical experience, where rates around
20–25 % may be seen [34]. A report from 30 Alzheimer’s Centers in the USA
1 Introduction to Cognitive Screening Instruments: Rationale and Desiderata 5

reported 50 % of patients seen were diagnosed as having normal cognition [35].

Identification and reassurance of those individuals with purely subjective memory
complaint is an important function of such clinics, a task which may also be facili-
tated by use of cognitive screening instruments.

1.2 Rationale of Cognitive Screening

What is the purpose of cognitive screening? This issue may be addressed by consid-
ering the classic criteria for disease screening published under the auspices of the
World Health Organization (WHO; see Box 1.1) [36, 37], and also published guide-
lines and criteria for developing screening programs [38] such as those from the UK
National Screening Committee (www.nsc.nhs.uk).

Box. 1.1 WHO Screening Criteria (After [36, 37])

• The disease/condition sought should be an important public health
problem.
• There should be a recognizable latent or presymptomatic stage of the
disease.
• The natural history of the disease should be adequately understood.
• There should be a treatment for the condition, which should be more ben-
eficial when applied at the presymptomatic stage compared to the later
symptomatic stage.
• There should be a suitable test or examination to detect the disease with
reasonable sensitivity and specificity.
• The test should be acceptable to the population.
• The healthcare system should have the capacity and policies in place to test
for the condition and deal with the consequences.
• The cost of case finding, including diagnosis and treatment of patients
diagnosed, should be economically balanced in relation to possible expen-
diture on medical care as a whole.
• Case finding should be a continuing process and not a “once and for all”
project.

Many of these conditions are fulfilled for dementia as a syndrome, and for
specific subtypes of dementia, most importantly Alzheimer’s disease (AD). For
example, the public health implications of dementia and its huge economic costs are
unequivocally established [12–17]. It is also evident that the natural history of most
forms of dementia encompasses a presymptomatic phase, with disease evolution
occurring over many years before clinical presentation. Longitudinal epidemiologi-
cal studies suggest almost 10 years of cognitive decline in AD preceding dementia
[39]. Biomarker studies indicate that the neurobiological changes which underpin
6 A.J. Larner

Alzheimer’s disease commence many years, indeed decades, before the emergence
of clinical symptomatology [40–42]. This long presymptomatic phase presents a
potential window of opportunity for disease identification, and intervention should
disease modifying drugs become available.
Equally, many of these screening criteria are yet to be fulfilled for dementia. For
example, it has yet to be established that any of the available pharmacotherapies for
AD are more beneficial when applied at the presymptomatic stage compared to the
later symptomatic stage. Application of pharmacotherapies in presymptomatic AD
has, to my knowledge, yet to be reported but there is no evidence that cholinesterase
inhibitors, a symptomatic treatment for AD, prevent conversion of prodromal AD
(mild cognitive impairment) to AD in the long term [43–45]. It is not clear that
healthcare systems have the capacity and policies to test for dementia and deal with
the consequences, nor that the cost of case finding, including diagnosis and treat-
ment, would be economically balanced in relation to possible expenditure on medi-
cal care as a whole.
Putting aside these issues, which may possibly be resolved by ongoing research,
the key screening criterion considered in this book is whether there are suitable tests
or examinations available to detect dementia and its subtypes with reasonable sen-
sitivity and specificity, and which are acceptable to the population. The population
in question needs careful definition in this context, since prevalence rates of demen-
tia may differ greatly in different populations. Hence, a cognitive screening instru-
ment to be applied at the whole population level might be very different to one
applied to at-risk groups (e.g. older persons) or to the highly selected population
attending cognitive/memory clinics. The latter, pretty much without exception, have
at minimum subjective memory complaints. It is to the constituency of those pre-
senting to clinical attention with memory complaints that the current volume is
addressed.
As with all medical activities, such as investigation and treatment, a screening
process may be associated with both clinical benefits and risks, which should be
recognized at the outset. Screening for dementia is not equivalent to diagnosis,
which remains at least in part a clinical judgment made by those experienced in the
diagnosis of these conditions, a process which needs to take into account the marked
clinical and etiological heterogeneity of the dementia syndrome [34, 46–51] and the
inadvisability of accepting “one size fits all” approaches [52, 53]. Screening can
therefore never replace the clinical interview.
Because screening tests for dementia can never have perfect sensitivity and spec-
ificity (i.e. = 1), there will always be a risk of false positive and false negative
diagnoses (see Chap. 2). Highly sensitive tests, which are generally thought desir-
able for screening purposes, will ensure that early cases are not missed but at the
risk of making false positive diagnoses (with all the attendant, and ultimately unnec-
essary, anxiety, treatment risks, etc., that false positive diagnosis may entail). Highly
specific tests minimize incorrect diagnoses but may miss early cases (false nega-
tives). Screening tests that disclose abnormalities only when a disease is clinically
obvious are of limited applicability, indeed measures of test performance may be
inflated by using patients with established diagnoses.
1 Introduction to Cognitive Screening Instruments: Rationale and Desiderata 7

1.3 Desiderata for Cognitive Screening Instruments

What features would be desirable for the optimal cognitive screening instrument?
A number of criteria for such an instrument were enunciated nearly 20 years ago
by the Research Committee of the American Neuropsychiatric Association [54]:
1. Ideally it should take <15 min to administer by a clinician at any level of
training.
2. Ideally it should sample all major cognitive domains, including memory, atten-
tion/concentration, executive function, visual-spatial skills, language, and
orientation.
3. It should be reliable, with adequate test-retest and inter-rater validity.
4. It should be able to detect cognitive disorders commonly encountered by
neuropsychiatrists.
To these criteria one may add:

• Ease of test administration, i.e. not much equipment required beyond pencil and
paper, or laptop computer.
• Ease of interpretation, i.e. clear test cut-offs, perhaps operationalized, e.g. a par-
ticular score on the test should lead to particular actions, such as patient reassur-
ance, continued monitoring of cognitive function over specified time periods, or
immediate initiation of further investigations and/or treatment. This recommen-
dation stems in part from the fact that scores on cognitive screening instruments
are non-linear (they have no specific units), some test items are more informa-
tive/better predictors than others (see Chap. 4, at Sect. 4.2.3), and tests are sub-
ject to ceiling and floor effects.
• Possibility for repeated, longitudinal use. Although classifications and older
diagnostic criteria reify dementia as a binary condition (dementia/not dementia),
it is in fact a dimensional construct which is unstable across time, a fact recog-
nized by delayed verification studies of test accuracy (see Chap. 2, at Sect. 2.3.2).
Availability of variant forms of cognitive screening instruments may permit
repeated testing over time whilst avoiding practice effects [55], and interpreta-
tion may be facilitated by provision of reliable change indices (RCI) from nor-
mative population studies [56], as for the Mini-Mental State Examination
(MMSE; see Chap. 3) [57–60], Modified Mini-Mental State Examination (3MS;
see Chap. 4, at Sect. 4.2.2) [58], and the Montreal Cognitive Assessment (MoCA;
see Chap. 7) [60].

Other issues may also require consideration when selecting a cognitive screening
instrument, for example the location in which testing is undertaken (primary or
secondary care) and the suspected dementia diagnosis being screened for (see Chap.
15, at Sects. 15.2.1 and 15.3 respectively). In primary care settings, briefer tests may
be optimal [8, 61, 62]. If the suspected diagnosis being screened for is AD then tests
which focus on the examination of episodic memory, to the relative exclusion of
other cognitive domains, may be preferred.
8 A.J. Larner

Cognitive screening instruments are “noisy”, which is to say that a variety of

factors may influence patient performance to obscure any signal of cognitive impair-
ment due to brain disease (i.e. factors unrelated to the construct the tests have been
designed to assess). These include patient age, educational status, culture, language,
the presence of primary psychiatric disorder (anxiety, depression), and presence of
primary sensory deficits (visual or hearing impairment). For example, one study
found that poor performance on the MMSE [63] due to causes other than dementia
was recorded in around 10 % of an elderly population, increasing with age (>40 %
in those ≥85 years), most commonly due to poor vision and hearing, deficient
schooling, and the consequences of stroke [64].
It is well-recognized that test performance may vary with factors such as the
environment in which testing is undertaken (e.g. the alien surroundings of an
impersonal clinic room vs. the familiar location of the patient’s home) and tester
(e.g. perceived to be sympathetic and encouraging vs. brusque and impatient).
All these factors may need to be taken into account when using cognitive screening
instruments, rather than relying solely on raw test scores. Corrections to test scores
or revision of cut-offs may be applicable to allow for patient age and education
[65–67].
Educational and cultural biases are evident in many typical screening test items
[68]. For example, tests which rely heavily on literacy will be challenging for indi-
viduals with limited education or from cultures using a different language. Screening
tests may thus need adaptation for these factors. Tests which may be characterized
as tests of performance have a long history [69] and continue to be developed [70].
Similar considerations apply to patient ethnicity. Cultural modifications have been
reported for a variety of cognitive screening instruments, including the MMSE, the
Short Portable Mental Status Questionnaire, and the Short Orientation-Memory-
Concentration Test [68]. Cultural factors may also affect willingness to be screened
for cognitive impairment [71]. Ideally culture-free cognitive screening tests should
be developed: claims for such status have been made for the Mini-Cog [72] and the
Time and Change Test [73]. Patient assessment by means of informant reports (see
Part III of this book) may be relatively culture-free, as may also be the case for
functional assessments.
Cognitive screening instruments are not equivalent to a neuropsychological
assessment administered by a clinical neuropsychologist, which remains the “gold”
or reference standard for cognitive assessment. The tests used in neuropsychologi-
cal assessment are potentially many [10, 74–76] and tend to focus on function
within individual cognitive domains or give a global measure of intelligence (ver-
bal, performance, and full-scale IQ). Requirement for a trained neuropsychologist
to administer such tests means that access is not universal. The test battery adminis-
tered is often time-consuming (much greater than the 15 min suggested by the
Research Committee of the American Neuropsychiatric Association [54]), fatiguing
for patients, and may sometimes require multiple outpatient visits. Hence neuropsy-
chological assessment is not a plausible means for screening cognitive function,
although it may be necessary to clarify diagnosis in those identified as cognitively
impaired by screening instruments.
1 Introduction to Cognitive Screening Instruments: Rationale and Desiderata 9

1.4 Conclusion

In an age in which dementia biomarkers, based on the findings of sophisticated

neuroimaging and biochemical testing, are beginning to be used to define disease
entities even before the onset of dementia per se [77–79], it may be questioned what
role there may be for cognitive screening instruments in dementia diagnosis. The
interrelationships of cognitive screening instruments and biomarkers are only begin-
ning to be investigated [80].
Other investigations certainly play a role in the definition of the etiology of cog-
nitive impairment and dementia [34]. Since the dementia construct
encompasses non-cognitive as well as cognitive impairments [81], assessment of
other domains (functional, behavioral, neurovegetative, global) may also be required
[34]. However, it has been reported that cognitive testing may be as good as, if not
better than, neuroimaging and CSF tests in predicting conversion and decline in
patients with mild cognitive impairment at risk of progressing to dementia [82].
Moreover, the newer diagnostic criteria incorporating biomarkers are more appli-
cable to research environments than to daily clinical practice, since many of the
investigations recommended are not widely available. Hence, cognitive screening
instruments are likely to remain an integral part of clinical assessment of cognitive
complaints for the foreseeable future. Their appropriate application and interpreta-
tion are therefore of paramount importance to ensure early and correct diagnosis.
Having now established the rationale and desiderata of cognitive screening
instruments, the methods available for the assessment of their utility, in other words
their diagnostic accuracy, are next considered ([83–85]; see Chap. 2).

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Chapter 2
Assessment of the Utility of Cognitive
Screening Instruments

Terence J. Quinn and Yemisi Takwoingi

Contents
2.1 Importance of Measuring the Diagnostic Accuracy of Dementia Assessments ............ 16
2.2 Statistical Methods for Comparing Tests....................................................................... 17
2.3 Nomenclature of Test Accuracy..................................................................................... 17
2.3.1 Index Test .......................................................................................................... 18
2.3.2 Target Condition ................................................................................................ 18
2.3.3 Reference Standard ............................................................................................ 19
2.3.4 Target Population ............................................................................................... 20
2.4 Test Accuracy Metrics ................................................................................................... 20
2.4.1 Sensitivity and Specificity ................................................................................. 21
2.4.2 Predictive Values ............................................................................................... 22
2.4.3 Receiver Operating Characteristic (ROC) Plots ................................................ 23
2.5 Interpreting Test Accuracy Results ................................................................................ 24
2.6 Issues in Cognitive Test Accuracy ................................................................................. 25
2.6.1 Reference Standards for Dementia .................................................................... 26
2.6.2 Partial Completion of Assessment ..................................................................... 26
2.6.3 Incorporation Bias ............................................................................................. 27
2.7 Assessing Study Design and Study Reporting .............................................................. 27
2.7.1 Quality Assessment of Diagnostic Accuracy Studies (QUADAS).................... 28
2.7.2 Standards for Reporting Diagnostic Accuracy Statement (STARD) ................. 28
2.8 Meta-analysis of Test Accuracy in Dementia ................................................................ 29
2.9 Conclusions ................................................................................................................... 30
References ............................................................................................................................... 31

T.J. Quinn (*)

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
e-mail: [email protected]
Y. Takwoingi
Institute of Applied Health Research, University of Birmingham, Birmingham, UK
e-mail: [email protected]

© Springer International Publishing Switzerland 2017 15

A.J. Larner (ed.), Cognitive Screening Instruments,
DOI 10.1007/978-3-319-44775-9_2
16 T.J. Quinn and Y. Takwoingi

Abstract There are a substantial and increasing variety of test instruments

available to guide the clinician in making a diagnosis of dementia. An apprecia-
tion of the methods and outputs associated with test accuracy research is useful
for all clinicians, not just academics. Test accuracy is best considered using a
framework that clearly defines the index test, the gold standard (reference stan-
dard) used to define the condition of interest and the population in which testing
will take place. By creation of a two by two table, cross classifying the results of
the index test and the reference standard, we can derive various metrics describ-
ing the properties of the test. Test accuracy studies where the condition of inter-
est is dementia present particular challenges. Using best practice statements in
the conduct, reporting and assessment of study validity can assist the interpreta-
tion of test accuracy research papers and also for planning future studies.
Techniques for systematic review and meta-analysis of test accuracy studies
have been developed and are being applied to certain commonly used cognitive
screening tests.

Keywords Accuracy • Diagnosis • Sensitivity • Specificity • QUADAS • STARD

2.1 Importance of Measuring the Diagnostic Accuracy

of Dementia Assessments

Studies of diagnostic test accuracy, sometimes abbreviated to DTA, describe how

well a test(s) can correctly identify or exclude a condition of interest. In this chapter
we consider DTA studies where the condition of interest is dementia or a related
cognitive syndrome.
An understanding of the language, methodology and interpretation of DTA is
important for any clinician working with people affected by dementia. There is
increasing pressure to make an accurate diagnosis of dementia early in the clinical
process [1]. Indeed in certain countries, routine screening of older adults for poten-
tial dementia has been proposed [2, 3]. Against this context, the variety and sophis-
tication of assessments for dementia is increasing [4]. Recent revisions of clinical
diagnostic criteria for dementia make specific reference to novel technologies such
as tissue biomarkers and quantitative neuroimaging [5]. Increasing the diagnostic
toolkit available to clinicians is exciting but we should not make assumptions about
the accuracy of these novel biomarkers.
The guidance presented in this chapter is based, in part, on an active program
of work coordinated through the Cochrane Screening and Diagnostic Test
Methods Group and the Cochrane Dementia and Cognitive Improvement Group
(CDCIG). Together these groups have produced systematic review and
meta-analyses of cognitive assessment instruments and have taken a role in
developing guidance and best practice statements for DTA work with a dementia
focus [6, 7]. The DTA field is constantly evolving and this chapter aims to pro-
vide an overview of current guidance. We have included key papers in the refer-
ences, for the reader wishing a more detailed discussion of the science and
methodology of DTA.
2 Assessment of the Utility of Cognitive Screening Instruments 17

2.2 Statistical Methods for Comparing Tests

This chapter will focus on test accuracy metrics. Other statistics for comparing tests
have been used in the literature. For example agreement between screening tests such
as the Mini-Mental State Examination (MMSE; see Chap. 3) and the Montreal
Cognitive Assessment (MoCA; see Chap. 7) could be assessed using kappa statistics; or
could be described as correlation. Such analyses have value but they are not test accu-
racy and if the question of interest is around test accuracy then these analyses are not
appropriate. It is difficult to make any clinical interpretation of agreement or correlation
based analyses. Two poor screening tests that are unsuitable for clinical usage may still
have excellent agreement and correlation. We will not describe association, correlation,
agreement based medical statistics or other associated measures in this chapter.

2.3 Nomenclature of Test Accuracy

When designing or interpreting a primary test accuracy study, it is essential to under-

stand the research question. A DTA question can be described in four components:
index test, target condition, reference standard, and population [7]. The research
question informs study design, conduct and interpretation. The terminology for the
four main components of the question are illustrated in Fig. 2.1 and explained below.

For diagnosis of As defined by In

Index
Target Reference Target
test
condition standard population

As defined by clinical In older adults

Mini Mental State For diagnosis of
diagnosis presenting to primary
Examination dementia
(ICD-10 or DSM-5) care

For diagnosis of As defined by

Mini Mental State In patients enrolled in
Alzheimer’s disease neuropathological
Examination a brain banking study
dementia diagnosis

As defined by clinical
For diagnosis of In older adults with
diagnosis
Mini Mental State Alzheimer’s disease mild cognitive
(ICD-10 or DSM-5) at
Examination dementia or other impairment assessed
more than one year
dementias at a memory clinic
following index test

Fig. 2.1 Components of a basic test accuracy question with examples. The top row gives the ter-
minology used. Other rows give examples of varying complexity; these include both the traditional
“cross-sectional” assessment and a delayed verification based study (bottom row)
18 T.J. Quinn and Y. Takwoingi

2.3.1 Index Test

The index test is the assessment or tool of interest. Index tests in dementia take
many forms—examples include cognitive screening tests (e.g., MMSE [8]); tissue/
imaging based biomarkers (e.g., cerebrospinal fluid proteins) or clinical examina-
tion features (e.g., presence of anosmia for diagnosis of certain dementias).
The classical test accuracy paradigm requires binary classification of the index
test. However, many tests used in clinical practice, particularly those used in demen-
tia, are not binary in nature. Taking MMSE as an example, the test can give a range
of scores suggestive of cognitive decline. In this situation, criteria for determining
test positivity are required to create a dichotomy (test positive and test negative).
The score at which the test is considered positive or negative is often referred to as
a cut-point or threshold. Thresholds may vary depending on the purpose and setting
of the assessment. For example in many acute stroke units, the suggested threshold
MMSE score is lower than that often used in memory clinic settings [9]. Sometimes,
within a particular setting, a range of thresholds may be used in practice and test
accuracy can be described for each threshold [6, 9].
In many fields there is more than one potential index test and the clinician will
want to know which test has the best properties for a certain population. Ideally, the
diagnostic accuracy of competing alternative index tests should be compared in the
same study population. Such head-to-head evaluations may compare tests to identify
the best performing test(s) or assess the incremental gain in accuracy of a combina-
tion of tests relative to the performance of one of the component tests [10]. Well-
designed comparative studies are invaluable for clinical decision making because
they can facilitate evaluation of new tests against existing testing pathways and guide
test selection [11]. However, many test evaluations have focused on the accuracy of
a single test without addressing clinically important comparative questions [12, 13].
A DTA study can compare tests by either giving all patients all the tests (within-
subject or paired design) or by randomly assigning a test to each subject (random-
ized design). In both designs, all patients are verified using the same gold or
reference standard. As an example, Martinelli et al. [14] used the within-subject
design to compare the accuracy of neuropsychological tests for differentiating
Alzheimer’s disease from the syndrome of mild cognitive impairment (MCI).
Although comparative accuracy studies are generally scarce, the within-subject
design is more common than the randomized design [12]. Nevertheless, both designs
are valid and relevant comparative studies should be more routinely conducted.

2.3.2 Target Condition

The target condition is the disease or syndrome or state that you wish to diagnose or
differentiate. When considering a test accuracy study of cognitive assessment, the
target condition would seem intuitive—diagnosis of dementia. However, dementia
2 Assessment of the Utility of Cognitive Screening Instruments 19

is a syndrome and within the dementia rubric there are degrees of severity, patho-
logical diagnoses and clinical presentations [4]. The complexity is even greater if
we consider the broader syndrome of cognitive impairment.
As a central characteristic of dementia is the progressive nature of the disorder,
some have chosen to define an alternative target condition as development of
dementia in a population free of dementia at point of assessment [15]. This para-
digm is based on the argument that evidence of cognitive and functional decline
over time is a more clinically valid marker than a cross-sectional “snap shot”. For
example, we may wish to evaluate the ability of detailed structural brain imaging to
distinguish which patients from a population with MCI will develop frank demen-
tia. This study design is often used when assessing biomarkers that purport to define
a pre-clinical stage of dementia progression [16]. The approach can be described as
longitudinal, predictive or ‘delayed verification’ because it includes a necessary
period of follow up.
In formulating a question or in reading a DTA paper it is important to be clear
about the nature of the target condition. We should be cautious of extrapolating DTA
results from a narrow to a broader target condition; interpretation of results is par-
ticularly difficult if the disease definition is ambiguous or simply not described. For
example, the original derivation and validation work around the MoCA focused on
community dwelling older adults with MCI [17]. Some have taken the favorable test
accuracy reported in these studies and used this to endorse the use of MoCA for
assessment of all cause dementia [18]. The ideal would be that MoCA is subject to
further assessments of test accuracy for this new target condition.

2.3.3 Reference Standard

The gold or reference standard is the means of verifying the presence or absence of
the target condition. There is no gold standard for many conditions, hence the use of
the term reference standard. The reference standard is the best available test for
determining the correct final diagnosis and may be a single test or a combination of
multiple pieces of information (composite reference standard) [19]. The term gold
standard is particularly misleading in studies with a dementia focus. There is no in-
vivo, consensus standard for diagnosis of the dementias [20]. Historically, neuro-
pathological examination was considered the gold standard, however availability of
subjects is limited and the validity of neuropathological labels for older adults with
dementia has been questioned [21]. Thus we have no single or combination assess-
ment strategy that will perfectly classify “positive” and “negative” dementia status.
This lack of a gold standard is not unique to cognitive test accuracy studies, but it is
particularly relevant to dementia where there is ongoing debate regarding the opti-
mal diagnostic approach [22].
Rather than use a gold standard, many studies employ a reference standard that
approximates to the (theoretical) gold standard as closely as possible. A common
reference standard is clinical diagnosis of dementia using a recognized classification
20 T.J. Quinn and Y. Takwoingi

system such as International Classification of Disease (ICD) or Diagnostic and

Statistical Manual of Mental Disorders (DSM). Validated and consensus diagnostic
classifications are also available for dementia subtypes such as Alzheimer’s disease
dementia and vascular dementia and these may be preferable where the focus is on
a particular pathological type.

2.3.4 Target Population

The final, often forgotten, but crucial part of the test accuracy question is the popu-
lation that will be tested with the index test. It is known that test accuracy varies
with the characteristics of the population (i.e., spectrum) being tested [23, 24].
Therefore, it is important to describe the clinical context in which testing takes
place, presenting features and any tests received by participants prior to being
referred for the index test (i.e., the referral filter). Cognitive assessment may be
performed for different purposes in different settings. The prevalence, severity and
case-mix of cognitive syndromes will differ accordingly and this will impact on test
properties and interpretation of results. For example a multi-domain cognitive
screening tool will perform differently when used by a General Practitioner assess-
ing someone with subjective memory problems compared to a tertiary specialist
memory clinic assessing an inpatient referred from secondary care [25, 26]. In
describing the context of testing it is useful to give some detail on the clinical path-
way in routine care; whether there will have been any prior cognitive testing; the
background and experience of the assessor and the supplementary tools available.

2.4 Test Accuracy Metrics

The perfect index test will correctly classify all subjects assessed, i.e., no false nega-
tives and no false positives. However, in clinical practice such a test is unlikely to
exist and so the ability of an index test to discriminate between those with and with-
out the target condition needs to be quantified. Different metrics are available for
expressing test accuracy, and these may be paired or single descriptors of test per-
formance. Where a test is measured on a continuum, such as the MMSE, paired
measures relate to test performance at a particular threshold. Some single measures
are also threshold specific while others are global, assessing performance across all
possible thresholds.
The foundation for all test accuracy measures is the two by two table, describing
the results of the index test cross classified against those of the reference standard
[27]. The four cells of the table give the number of true positives, false positives,
true negatives and false negatives (Table 2.1). We have summarized some of the
measures that can be derived from the table (Table 2.2). Paired measures such as
sensitivity and specificity, positive and negative predictive values, and positive and
negative likelihood ratios (LR+ and LR–), are typically used to quantify test perfor-
mance because of the need to distinguish between the presence and absence of the
2 Assessment of the Utility of Cognitive Screening Instruments 21

Table 2.1 Cross classification of index test and reference standard results in a two by two table
Dementia present (or Dementia absent (or
other target condition) other target condition)
Index test True positives (a) False positives (b) Positive predictive value =
positive number of true positives ÷
number of test positives
Index test False negatives (c) True negatives (d) Negative predictive
negative value = number of true
negatives ÷ number of test
negatives
Sensitivity = number of Specificity = number of
true positives ÷ number true negatives ÷ number
with dementia without dementia

Table 2.2 Some of the potential measures of test accuracy that can be derived from a two by two
table
Test accuracy metric Formula
Paired measures of test performance
Sensitivity a/(a + c)
Specificity d/(b + d)
Positive predictive value (PPV) a/(a + b)
Negative predictive value (NPV) d/(c + d)
False positive rate 1 – specificity
False negative rate 1 – sensitivity
False alarm rate 1 – PPV
False reassurance rate 1 – NPV
Positive likelihood ratio (LR+) Sensitivity/(1 – specificity)
Negative likelihood ratio (LR−) (1 – sensitivity)/specificity
Clinical utility index (positive) Sensitivity × PPV (rule in)
Clinical utility index (negative) Specificity × NPV (rule out)
Single measures of test performance
Diagnostic odds ratio (DOR) ad/bc
Overall test accuracy (a + d)/(a + b + c + d)
Youden index Sensitivity + specificity – 1

target condition. We will focus our discussion below on two of these commonly
used paired measures and one global measure derived from receiver operating char-
acteristic (ROC) curves.

2.4.1 Sensitivity and Specificity

Sensitivity and specificity are the most commonly reported measures [28]. Sensitivity
is the probability that those with the target condition are correctly identified as hav-
ing the condition while specificity is the probability that those without the target
condition are correctly identified as not having the condition. Sensitivity and
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