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12 Interventions in Alzheimer’s Disease KCE Reports 111 • focal neurologic findings such as hemiparesis, sensory loss, visual field deficits, and • incoordination early in the course of the illness • seizures or gait disturbances at the onset or very early in the course of the illness. The sensitivity and specificity of a probable AD diagnosis made according to the NINCDS-ADRDA criteria with postmortem pathology as reference standard are 0.65 and 0.75. 19 Sensitivity and specificity are generally above 80% when the diagnosis is made in expert centres and when healthy subjects are used as controls, but are much lower when patients with other forms of dementia are used as controls. Recently a revision of these criteria for clinical diagnosis has been proposed, 20 reflecting the increasing importance of new markers. The criteria were based on a literature review, followed by an expert meeting in June 2005. The new proposed criteria for the diagnosis of probable AD consist of the core diagnostic criterion of early episodic memory impairment (episodic memory is memory for events that the patient experienced and should be able to recall, more specifically for recent events) plus one or more of the following supportive features: • presence of medial temporal lobe (MTL) atrophy on MRI • abnormal cerebrospinal fluid biomarkers (amyloid beta1-42, total tau, and phospho-tau) • a specific pattern on functional neuroimaging with 18F-FDG PET (SPECT technique did not meet criteria for diagnostic accuracy) • a proven AD autosomal dominant mutation within the immediate family The Dubois criteria are very specific and they are currently mainly used in clinical research studies in order to get validated. Further standardization of these new tests is needed before their routine use can be considered. 1 In Belgium, reimbursement of medication for AD requires confirmation of the diagnosis (based on DSM-IV criteria) by a psychiatrist, a neurologist, or a geriatrician specialist in internal medicine. The care and support team should include the specialist and the patient general practitioner. Exclusion of other pathology (infarction) is required using a brain CT or MRI scan. The MMSE score should be in agreement with the indication approved for the medication class. The functional evaluation should include the 6 points ADL Katz scale, the instrumental ADL Lawton scale (9 points), as well as the NPI (Neuro-Psychiatric Inventory) for behaviour. A re-evaluation of the patient after 6 months is required before reimbursement can be prolonged. Conclusions There are no diagnostic instruments sufficiently developed to be used for dementia screening. Many methods (scales and indices) are used to measure the severity of various symptoms of dementia, such as cognitive deterioration, functional decline and behavioural changes. The insufficient evaluation to which most methods have been subjected makes it more difficult to assess the efficacy of specific care and treatment approaches. An initial selection or screening of patients for possible further diagnosis can be made by general practitioners and be based on standardised interviews with collateral sources, such as informal or family caregivers, as well as simple tests such as the MMSE, the clock drawing test and other simple exercises. Such initial selection by GPs is to be distinguished from diagnosis and is considered more difficult in mild AD and in MCI compared with more advanced disease. Neuropsychological testing is recommended after a baseline assessment in all patients and is particularly useful in patients with MCI and mild AD. The reference standards for the diagnosis of AD are given in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV-TR) and the National Institute of Neurological Disorders and Stroke – Alzheimer Disease and Related Disorders (NINCDS-ADRDA) working group.
KCE Reports 111 Interventions in Alzheimer’s Disease 13 Recently a revision of these latter criteria for clinical diagnosis has been proposed by Dubois et al, reflecting the increasing importance of new markers, in addition to the core diagnostic criterion of early episodic memory impairment (episodic memory is memory for events that the patient experienced and should be able to recall, more specifically for recent events). These new supportive features are the presence of medial temporal lobe (MTL) atrophy on MRI, abnormal cerebrospinal fluid biomarkers (amyloid beta1-42, total tau, and phospho-tau),a specific pattern on functional neuroimaging with 18F-FDG PET, or a proven AD autosomal dominant mutation within the immediate family. 2.3 HEALTH-ECONOMICS Studies are lacking that have combined different types of testing. As a result, it is not known with certainty which approaches are most cost-effective. 14 2.4 ASSESSING THE IMPACT OF INTERVENTIONS IN AD The most relevant endpoints may be quality of life of the patient and the caregiver and delay in institutionalization. However, assessment of interventions is often focused on other endpoints, such as scales for cognitive functioning. In this section we briefly list the most commonly used scales. For details, we refer the interested reader to full HTA reports. 14 The MMSE, Katz-scale (ADL), Lawton-scale (IADL), and NPI are used in Belgium in the context of reimbursement of drugs for AD. According to the SBU, there is strong evidence that neuropsychological testing including at least 4 of 6 cognitive domains (spatial, verbal, executive, attention, memory, general) contributes substantially to the diagnosis of dementia. 21 From a scientific point-of-view, outcome scales have to be thoroughly evaluated on their psychometric properties, including reliability as well as validity and ability to measure change. This subject was beyond the scope of the current study, but the HTA report by the SBU deals with it. 21 These authors conclude from an evidence-based literature review (up to July 2004), that only for the Clock test and the CAMCOG (the cognitive and self-contained part of the Cambridge Examination for Mental Disorders of the Elderly) moderate evidence exists in their ability to discriminate dementia patients from normal controls, if the administration of the tests is standardized. For the MMSE or other tests, not enough evidence is available to discriminate AD from age-matched controls without dementia. In the Belgian context, the Qualidem-study 3 also comments on the value of several outcome scales, but unfortunately without providing documentation on quality appraisal of the included publications. Despite their frequent use in daily practice and in scientific publications, the psychometric quality of many dementia scales remains questionable and a thorough evaluation of their diagnostic value is still to be performed. 2.4.1 Frequently used global function rating scales The CIBIC+ (Clinician’s Interview-Based Impression of Change scale) provides a global rating of function in four areas: general, cognitive, behaviour and ADL. All participants are scored on a scale of 1 to 7 relative to baseline, with 1 showing marked improvement and 7 marked worsening. Information is ideally obtained from the caregiver and the patient by a blinded independent clinician. Any change in score is considered clinically relevant. Older studies used the less detailed CGI-C (The Clinical Global Impression of Change), also a seven point global rating of change. The GDS (Global Deterioration Scale) reflects the assessment of the severity of the dementia by the physician, from 1 (normal) to 7 (very severe dementia). 2.4.2 Frequently used cognitive assessments The most widely used test, certainly in clinical research studies, is the ADAS-cog, the cognitive part of the Alzheimer’s Disease Assessment Scale. It comprises 11 individual tests, spoken language ability (0 to 5), comprehension of spoken language (0 to 5), recall of test instructions (0 to 5), word finding difficulty (0 to 5), following commands (0 to 5), naming object (0 to 5), construction drawing (0 to 5), ideational praxis (0 to 5), orientation (0 to 8), word recall (0 to 10) and word recognition (0 to 12). The total score ranges from 0 to 70, the high score indicating greater impairment.
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