AD-8 for diagnosis of dementia across a variety of healthcare settings

Target condition being diagnosed

The target condition for this diagnostic test accuracy review is all-cause dementia (clinical diagnosis) (Appendix 1).

Dementia is a syndrome characterised by cognitive or neuropsychological decline sufficient to interfere with usual functioning. The neurodegeneration and clinical manifestations of dementia are progressive and at present there is no 'cure', although numerous pharmacological (Birks 2006; McShane 2006) and non-pharmacological interventions (Bahar-Fuchs 2013) to slow or arrest cognitive decline have been described.

Dementia remains a clinical diagnosis, based on history from the person and suitable collateral sources and direct examination, including cognitive assessment. There is no universally-accepted, ante-mortem, gold-standard diagnostic strategy. We have chosen expert clinical diagnosis as our gold standard (reference standard) for describing AD-8 test properties, as we believe this is most in keeping with current diagnostic criteria and best practice.

Dementia diagnosis can be made according to various internationally-accepted diagnostic criteria, with exemplars being the World Health Organization, International Classification of Diseases (ICD) ICD-10 and the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM) DSM-IV for all-cause dementia and subtypes (Appendix 1). The label of dementia encompasses varying pathologies, of which Alzheimer’s disease is the most common. Diagnostic criteria are available for specific dementia subtypes, i.e. NINCDS-ADRDA criteria for Alzheimer’s dementia (McKhann 1984; McKhann 2011); McKeith criteria for Lewy Body dementia (McKeith 2005); Lund criteria for frontotemporal dementias (McKhann 2001); and the NINDS-AIREN criteria for vascular dementia (Román 1993).

Index test(s)

Our index test will be the Alzheimer Disease 8 (AD-8) (Galvin 2005) (Appendix 2; Appendix 3).

First published in 2005, the AD-8 is a screening tool which has been used to distinguish individuals with normal cognitive function from those with dementia or mild cognitive impairment. It is designed to be administered to a relevant proxy, usually a relative or carer, in questionnaire form. The AD-8 is a brief screening tool. With only eight questions it takes less than three minutes to complete and was developed to replace other lengthy informant questionnaires (Galvin 2006). The AD-8 was originally developed for administration in the English language but has been reproduced in other languages including Brazilian Portuguese (Correia 2011),Taiwanese (Yang 2011), and Korean (Ryu 2009).

The AD-8 items cover domains of judgement, hobby/activity level, repetitive conversations, learning ability, memory in relation to date/appointments, finances and daily thought processes. Informants indicate presence of change “over several years” using responses of ‘Yes, a change’, ‘No, no change’ or ‘NA, don’t know’. Each 'yes' answer is scored one point, giving scores ranging from zero, where no change has been noticed by the informant, to eight, where change has been noted across all domains. The commonly employed threshold score for AD-8 to differentiate cognitive from no cognitive impairment is greater than or equal to two out of eight (i.e. a 'yes' response for two or more items) (Galvin 2005).

AD-8 has a number of features that make it attractive for clinical and research use. The questions used have an immediacy and relevance that is likely to appeal to users. Assessment and (informant) scoring is brief, and as the scale is not typically interviewer-administered it requires minimal training in application and scoring. There are data to suggest that, compared to standard direct assessments, informant interviews may be less prone to bias from cultural norms and previous level of education (Jorm 2004). New diagnostic criteria for dementia make explicit reference to documenting decline and involving collateral informants, emphasising the potential utility of an informant interview tool such as AD-8.

Clinical pathway

Dementia develops over a trajectory of several years and screening tests may be performed at different stages in the dementia pathway. In this review we will consider any use of AD-8 as an initial assessment for cognitive decline and we will not limit to a particular healthcare setting. We have operationalised the various settings where AD-8 may be used as secondary care, primary care, and community.

In secondary-care settings, patients will have been referred for expert input but not exclusively due to memory complaints. Cognitive testing in secondary care involves two main groups: opportunistic screening of adults presenting as unscheduled admissions to hospitals, and those people referred to specific dementia, memory or psychiatry of older age services. Both populations will have a high prevalence of cognitive disorders and mimics. Secondary-care patients are more likely to have had a degree of prior cognitive assessment than those in other settings, although we recognise that cognitive screening prior to referral to specialist services is neither consistent nor guaranteed (Menon 2011).

In the general practice/primary care setting, the person will self present to a non-specialist service because of subjective memory complaints. There is unlikely to have been previous cognitive testing but prevalence of disease may be reasonably high. Using AD-8 in this setting could be described as 'triage' or 'case-finding'.

In the community setting, the cohort is largely unselected and the approach may be described as 'population screening'.

Most studies of test accuracy compare the test against contemporaneous reference standards (in this case, clinical dementia diagnosis). An alternative is to describe the test properties for detection of early, 'pre-clinical' problems that are formally diagnosed during prospective, longitudinal follow-up. This delayed verification approach is commonly employed in studies describing properties of dementia biomarkers, but may have utility for other test strategies such as informant interview.

Rationale

There is no consensus on the optimal initial assessment for dementia, and choice is currently dictated by experience with a particular instrument, time constraints and training. A better understanding of the diagnostic properties of various strategies would allow for an informed approach to testing. Critical evaluation of the evidence base for screening tests or other diagnostic markers is of major importance. Without a robust synthesis of the available information there is the risk that future research, clinical practice and policy will be built on erroneous assumptions about diagnostic validity.

AD-8 is commonly used in practice and research; it is used internationally and is one of only a few validated informant-based screening/diagnostic tools. A literature describing the test accuracy of AD-8 in different settings is available, although some of these studies have been modest in size. Thus systematic review and, if possible, meta-analysis of the diagnostic properties of AD-8 is warranted.

This review will form part of a body of work describing the diagnostic properties of commonly-used dementia tools (Appendix 4). At present we are conducting single-test reviews and meta-analyses. However the intention is then to collate these data, performing an overview allowing comparison of various test strategies.

Secondary objectives

Where data are available, we will describe the following:

1. Accuracy of AD-8 for early detection of cognitive problems, where a later diagnosis of dementia is made (delayed verification diagnosis).

2. Effects of heterogeneity on the reported diagnostic accuracy of AD-8. Potential sources of heterogeneity that we will explore include: case mix of cohort; method of dementia diagnosis; method AD-8 assessment.

Criteria for considering studies for this review

Search methods for identification of studies

We will use a variety of information sources to ensure all relevant studies are included. We will devise terms for electronic database searching in conjunction with the team at the Cochrane Dementia and Cognitive Improvement Group. As this AD-8 review forms part of a suite of reviews looking at informant scales we have created a comprehensive search strategy designed to pick up all cognitive assessment scales Quinn 2014; we will complement this generic search with searches specific to AD-8 terminology.

Data collection and analysis

Appendix 1. WHO International Classification of Disease - Dementia

World Health Organization International Classification of Diseases 10

F00 - F09 ORGANIC, INCLUDING SYMPTOMATIC, MENTAL DISORDERS

DEMENTIA

G1. Evidence of each of the following:

(1) A decline in memory, which is most evident in the learning of new information, although in more severe cases, the recall of previously learned information may be also affected. The impairment applies to both verbal and non-verbal material. The decline should be objectively verified by obtaining a reliable history from an informant, supplemented, if possible, by neuropsychological tests or quantified cognitive assessments. The severity of the decline, with mild impairment as the threshold for diagnosis, should be assessed as follows:

Mild: a degree of memory loss sufficient to interfere with everyday activities, though not so severe as to be incompatible with independent living. The main function affected is the learning of new material. For example, the individual has difficulty in registering, storing and recalling elements in daily living, such as where belongings have been put, social arrangements, or information recently imparted by family members.

Moderate: A degree of memory loss which represents a serious handicap to independent living. Only highly learned or very familiar material is retained. New information is retained only occasionally and very briefly. The individual is unable to recall basic information about where he lives, what he has recently been doing, or the names of familiar persons.

Severe: a degree of memory loss characterized by the complete inability to retain new information. Only fragments of previously learned information remain. The subject fails to recognize even close relatives.

(2) A decline in other cognitive abilities characterized by deterioration in judgement and thinking, such as planning and organizing, and in the general processing of information. Evidence for this should be obtained when possible from interviewing an informant, supplemented, if possible, by neuropsychological tests or quantified objective assessments. Deterioration from a previously higher level of performance should be established. The severity of the decline, with mild impairment as the threshold for diagnosis, should be assessed as follows:

Mild. The decline in cognitive abilities causes impaired performance in daily living, but not to a degree making the individual dependent on others. More complicated daily tasks or recreational activities cannot be undertaken.

Moderate. The decline in cognitive abilities makes the individual unable to function without the assistance of another in daily living, including shopping and handling money. Within the home, only simple chores are preserved. Activities are increasingly restricted and poorly sustained.

Severe. The decline is characterized by an absence, or virtual absence, of intelligible ideation. The overall severity of the dementia is best expressed as the level of decline in memory or other cognitive abilities, whichever is the more severe (e.g. mild decline in memory and moderate decline in cognitive abilities indicate a dementia of moderate severity).

G2. Preserved awareness of the environment during a period of time long enough to enable the unequivocal demonstration of G1. When there are superimposed episodes of delirium the diagnosis of dementia should be deferred.

G3. A decline in emotional control or motivation, or a change in social behaviour, manifest as at least one of the following:

(1) emotional lability;

(2) irritability;

(3) apathy;

(4) coarsening of social behaviour.

G4. For a confident clinical diagnosis, G1 should have been present for at least six months; if the period since the manifest onset is shorter, the diagnosis can only be tentative.

Comments: The diagnosis is further supported by evidence of damage to other higher cortical functions, such as aphasia, agnosia, apraxia.

Judgment about independent living or the development of dependence (upon others) need to take account of the cultural expectation and context.

Dementia is specified here as having a minimum duration of six months to avoid confusion with reversible states with identical behavioural syndromes, such as traumatic subdural haemorrhage (S06.5), normal pressure hydrocephalus (G91.2) and diffuse or focal brain injury (S06.2 and S06.3).

A fifth character may be used to indicate the presence of additional symptoms, in the categories F00-F03

(F00 Dementia in Alzheimer's disease; F01 Vascular dementia; F02 Dementia in diseases classified elsewhere; and

F03 Unspecified dementia), as follows:

.x0 without additional symptoms

.x1 with other symptoms, predominantly delusional

.x2 with other symptoms, predominantly hallucinatory

.x3 with other symptoms, predominantly depressive

.x4 with other mixed symptoms

A sixth character may be used to indicate the severity of the dementia:

.xx0 mild

.xx1 moderate

.xx2 severe

As mentioned above the overall severity of the dementia depends on the level of memory or intellectual impairment, whichever is the more severe.

F00 DEMENTIA IN ALZHEIMER'S DISEASE

A. The general criteria for dementia (G1 to G4) must be met.

B. There is no evidence from the history, physical examination or special investigations for any other possible cause of dementia (e.g. cerebrovascular disease, Parkinson's disease, Huntington's disease, normal pressure hydrocephalus), a systemic disorder (e.g. hypothyroidism, vit. B12 or folic acid deficiency, hypercalcaemia), or alcohol- or drug-abuse.

Comments: The diagnosis is confirmed by post mortem evidence of neurofibrillary tangles and neuritic plaques in excess of those found in normal ageing of the brain.

The following features support the diagnosis, but are not necessary elements: Involvement of cortical functions as evidenced by aphasia, agnosia or apraxia; decrease of motivation and drive, leading to apathy and lack of spontaneity; irritability and disinhibition of social behaviour; evidence from special investigations that there is cerebral atrophy, particularly if this can be shown to be increasing over time. In severe cases there may be Parkinson-like extrapyramidal changes, logoclonia, and epileptic fits.

Specification of features for possible subtypes. Because of the possibility that subtypes exist, it is recommended that the following characteristics be ascertained as a basis for a further classification: age at onset; rate of progression; the configuration of the clinical features, particularly the relative prominence (or lack) of temporal, parietal or frontal lobe signs; any neuropathological or neurochemical abnormalities, and their pattern.

The division of AD into subtypes can at present be accomplished in two ways: first by taking only the age of onset and labelling AD as either early or late, with an approximate cut-off point at 65 years; or secondly, by assessing how well the individual conforms to one of the two putative syndromes, early or late onset type. It should be noted that it is unlikely that a sharp distinction exists between early and late onset type. Early onset type may occur in late life, just as late onset type may occasionally have an onset under the age of 65. The following criteria may be used to differentiate F00.0 from F00.1, but it should be remembered that the status of this subdivision is still controversial.

F00.0 Dementia in Alzheimer's disease with early onset

1. The criteria for dementia in Alzheimer's disease (F00) must be met, and the age at onset being under 65 years.

2. In addition, at least one of the following requirements must be met:

(a) evidence of a relatively rapid onset and progression;

(b) in addition to memory impairment, there is aphasia (amnesic or sensory), agraphia, alexia, acalculia, or apraxia (indicating the presence of temporal, parietal and/or frontal lobe involvement).

F00.1 Dementia in Alzheimer's disease with late onset

1. The criteria for dementia in Alzheimer's disease (F00) must be met and the age at onset must be 65 or more.

2. In addition, at least one of the following requirements must be met:

(a) evidence of a very slow, gradual onset and progression (the rate of the latter may be known only retrospectively after a course of 3 years or more);

(b) predominance of memory impairment G1.1, over intellectual impairment G1.2 (see general criteria for dementia).

F00.2 Dementia in Alzheimer's disease, atypical or mixed type

Use this term and code for dementias that have important atypical features or that fulfil criteria for both early and late onset type of Alzheimer's disease. Mixed Alzheimer's and vascular dementia is also included here.

F00.9 Dementia in Alzheimer's disease, unspecified

F01 VASCULAR DEMENTIA

G1. The general criteria for dementia (G1 to G4) must be met.

G2. Unequal distribution of deficits in higher cognitive functions, with some affected and others relatively spared. Thus memory may be quite markedly affected while thinking, reasoning and information processing may show only mild decline.

G3. There is clinical evidence of focal brain damage, manifest as at least one of the following:

(1) unilateral spastic weakness of the limbs;

(2) unilaterally increased tendon reflexes;

(3) an extensor plantar response;

(4) pseudobulbar palsy.

G4. There is evidence from the history, examination, or tests, of a significant cerebrovascular disease, which may reasonably be judged to be etiologically related to the dementia (e.g. a history of stroke; evidence of cerebral infarction).

The following criteria may be used to differentiate subtypes of vascular dementia, but it should be remembered that the usefulness of this subdivision may not be generally accepted.

F01.0 Vascular dementia of acute onset

A. The general criteria for vascular dementia (F01) must be met.

B. The dementia develops rapidly (i.e. usually within one month, but within no longer than three months) after a succession of strokes, or (rarely) after a single large infarction.

F01.1 Multi-infarct dementia

A. The general criteria for vascular dementia (F01) must be met.

B. The onset of the dementia is gradual (i.e. within three to six months), following a number of minor ischaemic episodes.

Comments: It is presumed that there is an accumulation of infarcts in the cerebral parenchyma. Between the ischaemic episodes there may be periods of actual clinical improvement.

F01.2 Subcortical vascular dementia

A. The general criteria for vascular dementia (F01) must be met.

B. A history of hypertension.

C. Evidence from clinical examination and special investigations of vascular disease located in the deep white matter of the cerebral hemispheres, with preservation of the cerebral cortex.

F01.3 Mixed cortical and subcortical vascular dementia

Mixed cortical and subcortical components of the vascular dementia may be suspected from the clinical features, the results of investigations (including autopsy), or both.

F01.8 Other vascular dementia

F01.9 Vascular dementia, unspecified

F02 DEMENTIA IN OTHER DISEASES CLASSIFIED ELSEWHERE

F02.0 Dementia in Pick's disease

A. The general criteria for dementia (G1 to G4) must be met.

B. Slow onset with steady deterioration.

C. Predominance of frontal lobe involvement evidenced by two or more of the following:

(1) emotional blunting;

(2) coarsening of social behaviour;

(3) disinhibition;

(4) apathy or restlessness;

(5) aphasia.

D. Relative preservation, in the early stages, of memory and parietal lobe functions.

F02.1 Dementia in Creutzfeldt-Jakob disease

A. The general criteria for dementia (G1 to G4) must be met.

B. Very rapid progression of the dementia, with disintegration of virtually all higher cerebral functions.

C. The emergence, usually after or simultaneously with the dementia, of one or more of the following types of neurological symptoms and signs:

(1) pyramidal symptoms;

(2) extrapyramidal symptoms;

(3) cerebellar symptoms;

(4) aphasia;

(5) visual impairment.

Comments: An akinetic and mute state is the typical terminal stage. An amyotrophic variant may be seen, where the neurological signs precede the onset of the dementia. A characteristic electroencephalogram (periodic spikes against a slow and low voltage background), if present in association with the above clinical signs, will increase the probability of the diagnosis. However, the diagnosis can be confirmed only by neuropathological examination (neuronal loss, astrocytosis, and spongiform changes). Because of the risk of infection, this should be carried out only under special protective conditions.

F02.2 Dementia in Huntington's disease

A. The general criteria for dementia (G1 to G4) must be met.

B. Subcortical functions are affected first and dominate the picture of dementia throughout; manifest as slowness of thinking or movement and personality alteration with apathy or depression.

C. Presence of involuntary choreiform movements, typically of the face, hands or shoulders, or in the gait. The patient may attempt to conceal them by converting them into a voluntary action.

D. A history of Huntington's disease in one parent or a sibling; or a family history which suggests the disorder.

E. The absence of clinical features otherwise accounting for the abnormal movements.

Comments: In addition to involuntary choreiform movements there may be development of extrapyramidal rigidity or spasticity with pyramidal signs.

F02.3 Dementia in Parkinson's disease

A. The general criteria for dementia (G1 to G4) must be met.

B. Diagnosis of Parkinson's disease.

C. Absence of cognitive impairment attributable to anti-parkinsonian medication.

D. There is no evidence from the history, physical examination or special investigations for any other possible cause of dementia, including other forms of brain disease, damage or dysfunction (e.g. cerebrovascular disease, HIV disease, Huntington's disease, normal pressure hydrocephalus), a systemic disorder (e.g. hypothyroidism, vit. B12 or folic acid deficiency, hypercalcaemia), or alcohol or drug abuse.

If criteria are also fulfilled for dementia in Alzheimer's disease with late onset (F00.1), this category F00.1 should be used in combination with Parkinson's disease G20.

F02.4 Dementia in human immunodeficiency (HIV) disease

A. The general criteria for dementia (G1 to G4) must be met.

B. Diagnosis of HIV infection.

C. There is no evidence from the history, physical examination or special investigations for any other possible cause of dementia, including other forms of brain disease, damage or dysfunction (e.g. Alzheimer's disease, cerebrovascular disease, Parkinson's disease, Huntington's disease, normal pressure hydrocephalus), a systemic disorder (e.g. hypothyroidism, vit. B12 or folic acid deficiency, hypercalcaemia), or alcohol or drug abuse.

F02.8 Dementia in other specified diseases classified elsewhere

Dementia can occur as a manifestation or consequence of a variety of cerebral and somatic conditions. To specify the etiology, the ICD-10 code for the underlying condition should be added.

F03 UNSPECIFIED DEMENTIA

This category should be used when the general criteria for dementia are met, but when it is not possible to identify one of the specific types (F00.0-F02.9).

Appendix 2. AD8 Informant Questionnaire

Appendix 3. AD8 administration and scoring guidelines

A spontaneous self-correction is allowed for all responses without counting as an error.

The questions are given to the respondent on a clipboard for self–administration or can be read aloud to the respondent either in person or over the phone. It is preferable to administer the AD8 to an informant, if available. If an informant is not available, the AD8 may be administered to the patient.

When administered to an informant, specifically ask the respondent to rate change in the patient.

When administered to the patient, specifically ask the patient to rate changes in his/her ability for each of the items, without attributing causality.

If read aloud to the respondent, it is important for the clinician to carefully read the phrase as worded and give emphasis to note changes due to cognitive problems (not physical problems).

There should be a one second delay between individual items.

No timeframe for change is required.

The final score is a sum of the number items marked “Yes, A change”.

Appendix 4. Commonly used cognitive assessments/screening tools

For each test, the planned review will encompass diagnostic test accuracy in community; primary and secondary care settings.

Appendix 5. Search Strategy for use with MEDLINE electronic database

Appendix 6. Search strategy (MEDLINE Ovid SP) run for specialised register (ALOIS)

Search narrative: The searches detailed above are very simple, essentially single concept strategies based on the index test (AD8). This is a sensitive approach to take. More complex and developed searches are run each month for the dementia group.

Every month the following strategy is run in Medline (via Ovid SP). The results are screened based on a reading of title and abstract. The full texts (where there is one) are then obtained and a few key details about each study are extracted including Index test/s and details of population and setting. For this review it was expected that most studies would be identified through a search of multiple sources based on one concept (the index test in question). However, we felt it was worth also searching ALOIS for any studies which had evaluated the accuracy of AD8 but had not referred to it in the bibliographic details of the reference.

Appendix 7. Assessment of reporting quality - STARD checklist

Appendix 8. Assessment of methodological quality table QUADAS-2 tool

Appendix 9. Anchoring statements for quality assessment of AD-8 diagnostic studies

We provide some core anchoring statements for quality assessment of diagnostic test accuracy reviews of AD-8 in dementia. These statements are designed for use with the QUADAS-2 tool and were derived during a two-day, multidisciplinary focus group.Davis 2013

During the focus group and the piloting/validation of this guidance, it was clear that certain issues were key to assessing quality, while other issues were important to record but less important for assessing overall quality. To assist, we describe a system wherein certain items can dominate. For these dominant items, if scored “high risk” then that section of the QUADAS-2 results table is likely to be scored as high risk of bias regardless of other scores. For example, in dementia diagnostic test accuracy studies, ensuring that clinicians performing dementia assessment are blinded to results of index test is fundamental. If this blinding was not present then the item on reference standard should be scored “high risk of bias”, regardless of the other contributory elements.

We have detailed how QUADAS-2 has been operationalised for use with dementia reference standard studies below. In these descriptors dominant items are labelled as "high risk of bias for total section regardless of other items".

In assessing individual items, the score of unclear should only be given if there is genuine uncertainty. In these situations review authors will contact the relevant study teams for additional information.