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Published 9 June 2009, doi:10.1136/bmj.b2030
Cite this as: BMJ 2009;338:b2030
Jeremy Brown, consultant neurologist, George Pengas, clinical research fellow, Kate Dawson, research nurse, Lucy A Brown, honorary research assistant, Philip Clatworthy, clinical research fellow
1 Department of Neurology, Addenbrookes Hospital, Cambridge CB2 2QQ
Correspondence to: J Brown jmb75{at}medschl.cam.ac.uk
Design Cross sectional study.
Setting Outpatient departments in three hospitals, including a memory clinic.
Participants 540 control participants aged 18-95 and 139 patients attending a memory clinic with dementia/amnestic mild cognitive impairment.
Intervention Cognitive test designed to use minimal operator time and to be suitable for non-specialist use.
Main outcome measures Performance of normal controls on the TYM. Performance of patients with Alzheimers disease on the TYM compared with age matched controls. Validation of the TYM with two standard tests (the mini-mental state examination (MMSE) and the Addenbrookes cognitive examination-revised (ACE-R)). Sensitivity and specificity of the TYM in the detection of Alzheimers disease.
Results Control participants completed the TYM with an average score of 47/50. Patients with Alzheimers disease scored an average of 33/50. The TYM score shows excellent correlation with the two standard tests. A score of
42/50 had a sensitivity of 93% and specificity of 86% in the diagnosis of Alzheimers disease. The TYM was more sensitive in detection of Alzheimers disease than the mini-mental examination, detecting 93% of patients compared with 52% for the mini-mental state exxamination. The negative and positive predictive values of the TYM with the cut off of
42 were 99% and 42% with a prevalence of Alzheimers disease of 10%. Thirty one patients with non-Alzheimer dementias scored an average of 39/50.
Conclusions The TYM can be completed quickly and accurately by normal controls. It is a powerful and valid screening test for the detection of Alzheimers disease.
Assessment of a patients cognition is a crucial part of many medical consultations. Cognitive tests aid the diagnosis of dementia and are important in the medical and social management of patients and in the assessment of capacity. Once there are effective treatments for Alzheimers disease there will be an even greater need for a quick sensitive test that is suitable for use in primary care and by non-specialists.
Many cognitive tests are available but none meets the three critical requirements for widespread use by a non-specialist—that is, take minimal operator time to administer, test a reasonable range of cognitive functions, and are sensitive to mild Alzheimers disease. We designed the TYM ("test your memory") to fulfil these requirements. The paradox of thorough testing in minimal time was achieved by allowing patients to fill in the test themselves.
The TYM was administered to 540 normal controls aged 18-95, 108 patients with Alzheimers disease/amnestic mild cognitive impairment, and 31 patients with non-Alzheimers degenerative dementias. The test was validated by comparing scores with those obtained with the mini-mental state examination3 and Addenbrookes cognitive examination-revised.4 The Addenbrookes revised test was developed from the original examination5 and is similar in both content and scoring.4 We determined the specificity and sensitivity of the TYM in the detection of Alzheimers disease by comparing the scores of 94 patients with Alzheimers disease with the scores of 282 age matched controls. Three scorers of differing backgrounds marked 100 tests to assess inter-rater reliability.
Participants
Selection of patients with Alzheimers disease
Patients were seen and diagnosed by a consultant neurologist with an interest in dementia in a dedicated memory clinic at Addenbrookes Hospital. Patients attended the memory clinic between March and December 2007 and underwent neurological assessment, the Addenbrookes cognitive examination-revised (which includes the mini-mental state examination), structural imaging, and blood tests. Many also had a psychiatric and neuropsychological assessment. The diagnosis of Alzheimers disease was made with the NINCDS-ARDRA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimers Disease and Related Disorders Association) criteria for probable Alzheimers6 without reference to the TYM result. The diagnosis of amnestic mild cognitive impairment was made according to published criteria.7 We excluded patients whose cognitive problems were thought to be substantially caused by depression.
A total of 108 patients (59 men, 49 women) received a clinical diagnosis of Alzheimers disease or amnestic mild cognitive impairment. Alzheimers disease was diagnosed in 85 and amnestic mild cognitive impairment in 23. Amnestic mild cognitive impairment has clinical and pathological similarities to Alzheimers disease8 9 and patients with amnestic mild cognitive impairment who score poorly on the Addenbrookes cognitive examination are likely to progress to Alzheimers disease.10 These patients were regarded as having early Alzheimers disease. Nine patients with a diagnosis of amnestic mild cognitive impairment who scored below the cut off for dementia on the Addenbrookes cognitive examination-revised (
834) were included in the Alzheimers cohort. Patients with a diagnosis of amnestic mild cognitive impairment who score well on the Addenbrookes cognitive examination are unlikely to progress to Alzheimers disease over the next two years10; such patients might never progress to Alzheimers disease and might return to normal.11 The 14 patients with a diagnosis of amnestic mild cognitive impairment who scored >83 on the ACE-R were analysed separately.
Selection of controls
Controls were recruited from relatives accompanying patients to the memory clinic. Additional controls were recruited from relatives of patients attending neurology and medical outpatients departments at two other hospitals. We also included some dermatology outpatients. We excluded people with a history of neurological disease, memory problems, or brain injury. All participants gave informed consent.
We tested 540 controls aged 18-95. Over half (54%) were women. We calculated normal values for each decade from the age of 30 with standard errors. Three age matched controls were selected for each patient with Alzheimers disease. To assess any differences in controls between different hospitals, we compared 100 controls from Addenbrookes with 100 age matched controls from the other hospitals. To assess any sex differences, we compared 100 male controls with 100 age matched female controls.
Testing and validation
The 94 patients in the Alzheimers cohort were given the TYM as well as the Addenbrookes cognitive examination-revised (that includes the mini-mental state examination). The TYM was administered when the patient first arrived in the clinic.
We compared the scores of patients and age matched controls on subsets and total scores using t tests with Bonferroni correction for multiple comparisons (equal variances not assumed). We compared the TYM scores of patients with the Addenbrookes and mini-mental scores using Pearsons correlation coefficients. The internal consistency of the TYM was assessed with Cronbachs
.
Sensitivity and specificity of TYM in mild Alzheimers disease
We used data from the 94 patients with Alzheimers disease to plot a receiver operating characteristic curve. We randomly selected three age matched controls (n=282) from the 540 controls for each patient with mild Alzheimers disease. We calculated positive and negative predictive values for different TYM scores for different prevalences of Alzheimers disease.
Sensitivity of TYM v mini-mental state examination
A direct comparison between the TYM and the mini-mental state examination in identifying the 94 patients with Alzheimers disease was performed by calculating the percentage of patients with Alzheimers disease who were detected using the cut off of
42 for the TYM and
23 for the mini-mental state examination (the accepted cut off for dementia12).
Performance of TYM v other tests in other forms of dementia and mild cognitive impairment
In the same period, 31 patients (17 men, 14 women; average age 63.3) with other degenerative dementias seen in the Addenbrookes memory clinic as new patients were given the TYM and Addenbrookes cognitive examination-revised. Of these patients, 16 had dementia with Lewy bodies, 13 had frontotemporal dementia, and two had progressive supranuclear palsy. The diagnoses were made according to accepted criteria.13 14 15 Pearson coefficients were used to calculate the correlation between the TYM scores and the other examinations.
TYM in mild cognitive impairment
Fourteen patients in the mild cognitive impairment cohort (average age 67.9) were given the TYM as well as the Addenbrookes examination. We compared these scores with the TYM scores attained by the controls used for the Alzheimers cohort.
Inter-rater variability
Three individuals scored the same 100 TYM sheets (38 patients, 62 controls) using the scoring sheet. One was a consultant experienced in the diagnosis of degenerative dementia (JB), one was a neurology specialist registrar working in the memory clinic (GP), and one a registered general nurse (LAB) with no specialised experience of patients with dementia who received 10 minutes of tuition. The tests were scored independently.
The value of Cronbachs
for all participants and subsets was 0.80. Figure 1 shows the results for control participants grouped by age
. The average TYM score was about 47 for ages 18-70. Above the age of 70, there was a small decline in performance, which became significant above the age of 80. One way analysis of variance confirmed a significant effect of age group on total TYM score (F5,534=6.4, P<0.001) and showed a significant effect of age on the subscores: for copy (F5,534=5.4, P<0.001), semantic knowledge (F5,534=3.7, P=0.003), calculation (F5,534=3.1, P=0.008), fluency (F5,534=5.2, P<0.001), similarities (F5,534=3.7, P=0.002), anterograde memory (F5,534=3.5, P<0.004), and help required (F5,534=8.0, P<0.001). All subscores except semantic knowledge showed a mild decrease with increasing age; semantic knowledge showed a small improvement.
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We examined the effect of sex on TYM scores by comparing the average scores for 100 men and 100 women in a cohort of age matched controls. Mean age for both groups was 61 years (t200=0.1, P=0.92). The mean score for both groups was 47.4 (t200=0.05, P=0.96).
Alzheimers disease and test validation
Ninety four patients with Alzheimers with an average age of 69.0 (SD 8.5) were tested with the TYM, the Addenbrookes cognitive examination-revised, and the mini-mental state examination. Table 1 shows the average scores
.
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Older patients with Alzheimers (aged over 70) scored slightly better on the TYM than the younger patients with Alzheimers, though the differences did not approach significance (average score 33.8 v 32.8, t78=0.57, P=0.57).
Comparison of TYM scores
Table 2
shows comparisons between the total TYM score and subscores for patients and controls. The mean age was the same in both groups (69.0). As expected, patients with Alzheimers were particularly impaired on anterograde memory scores relative to controls. Patients also scored poorly on semantic knowledge, fluency, visuospatial tasks, and executive function. After Bonferroni correction for multiple comparisons all subtests except sentence copying showed a significant decrease in patients with Alzheimers compared with controls.
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42 predicts mild Alzheimers in this population, with a sensitivity of 93% and specificity of 86%. Reducing the cut off to
39 increases the specificity to 95%, while raising the cut off to
44 increases the sensitivity to 96%.
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42 with a prevalence of Alzheimers up to 5%. Positive predictive values are lower: a score of
42 has a predictive value of 26% with a prevalence of Alzheimers of 5%.
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42 the TYM detected 93%. With the established cut off of
23 the mini-mental state examination detected 52%.12
TYM in non-Alzheimers dementias
For the 31 patients with non-Alzheimers dementia the mean TYM score was 38.9/50 (SD 8.6), the mean Addenbrookes score was 77/100 (SD 16.0), and the mean mini-mental score was 25.3/30 (SD 4.1). The average mini-mental score is above the cut off for dementia, while the TYM and Addenbrookes average scores are well below it, suggesting superior sensitivity of the TYM and the Addenbrookes test in the diagnosis of non-Alzheimers dementias.
The numbers with these individual diseases are too small to be meaningful, but there is a good correlation between the TYM scores of these 31 patients and the other scores (TYM v Addenbrookes, Pearsons R2=0.77; TYM v mini-mental, Pearsons R2=0.74; both P<0.001).
TYM in patients with mild cognitive impairment
The patients with mild cognitive impairment scored highly on all cognitive tests, averaging 27.8/30 on the mini-mental state examination, 86.9 on the Addenbrookes examination, and 45/50 on the TYM. Their scores on 10 of the subtests of TYM were similar to controls, but they tended to score worse than controls on anterograde memory (3.4/6 v 5.2/6, t13.5=2.7, P=0.02 uncorrected).
Inter-rater variability
The TYM scores calculated by the three raters were highly correlated (table 4)
.
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Many of the controls were relatives of patients attending the memory clinic and came from the same population base. There was a slight male bias in the patients and slight female bias in the controls, but there was no significant difference in TYM scores between male and female controls. We recruited more controls from two other hospitals in East Anglia because the age range and number of the memory clinic controls was limited. The controls from the Cambridge memory clinic might have been expected to score slightly higher, but actually scored slightly lower. This effect was not large enough to be significant or to affect the results. Control participants were screened for a history of memory problems and neurological disease but not for other problems such as depression or vascular disease; such influences would be expected to reduce the TYM scores of controls and reduce differences in cognitive function between patients and control participants.
The TYM score of controls remained remarkably constant in widely different age ranges in both sexes and all geographical backgrounds. This is likely to be a ceiling effect. The TYM test was designed to be easy for normal controls to allow quick and accurate completion. Most controls of all ages scored almost full marks (for example, 68% of controls aged 60-69 scored 48-50). This ceiling effect suggests that education and social class would have only mild effects on the TYM score, but we did not formally assess this. The reason for the low scoring controls was often apparent from the score sheet—lack of interest, reading problems, or a sense of humour. Some low scoring controls aged over 70 show a typical pattern for mild Alzheimers and might be in the early stages (they were still included in the control group).
Use in patients with Alzheimers disease
Patients with Alzheimers disease performed much poorer than controls on the TYM. They scored an average of 33/50; 13.4 points below the control group. Subtest analysis of scores in patients with Alzheimers showed that all parts of the test, except copying a sentence, are performed less well by patients than controls. There is the expected pattern in patients with Alzheimers performing poorly on tests of anterograde memory, semantic knowledge, fluency, and visuospatial tasks. They perform better (although still significantly worse than controls) on naming, orientation, similarities, and calculation subtests. Patients performed worse than controls in the copying subtest, but the difference was not significant; this test was probably too easy to identity patients with mild Alzheimers.
We separately analysed patients with mild memory problems. These patients had a clinical diagnosis of amnestic mild cognitive impairment and scored well on the Addenbrookes examination (>83). Amnestic mild cognitive impairment can be a prodrome of Alzheimers, but some affected patients have mild problems that do not progress.11 The Addenbrookes test is a good indicator of which patients with amnestic mild cognitive impairment (or questionable dementia) will develop progressive dementia in the two years after testing: patients who score
80 are likely to progress, patients who score >80 are unlikely to progress.10 In this study as we used the higher cut off of
83, the accepted cut off for dementia for the Addenbrookes test,5 some non-progressive patients might have been included in the Alzheimers cohort. The patients with mild cognitive impairment scored an average of 45/50 on the TYM, with a trend towards problems in anterograde memory; they scored well in other subtests of the test.
Patients seen in the memory clinic in Cambridge could be different from those seen in other clinics. Cambridge attracts some younger patients with Alzheimers from a wide area. The memory clinic serves a dual purpose in Cambridge, and many of the older patients in the study were local and referred directly from primary care. We separately examined the performance of the 42 patients with Alzheimers aged 70 or over (average age 76.8). There was little difference in these patients compared with the younger patients either in overall TYM score (33.9 v 32.6) or in the subtest pattern. This suggests that it is a useful test to detect older patients with Alzheimers.
The sensitivity and specificity of the TYM for detecting Alzheimers in this cohort is high. A score of
42 detects 93% of cases of mild Alzheimers with a specificity of 86%; a score of
44 detects 96% of patients with mild Alzheimers. The prevalence of dementia and mild cognitive problems (often with reduced insight) in the population sets a limit on the specificity of a test.
The testers and raters were usually aware of whether individuals were patients or controls at the time of testing or rating. As individuals fill in the test sheet themselves, the tester has minimal influence on the score. All scores were checked by a single rater (JB) using the scoring sheet. The use of a strict scoring scheme minimises the influence of the rater. Scores calculated by the single rater correlated closely with the scores of the other two raters in the inter-rater analysis.
TYM v mini-mental state examination
The mini-mental state examination has been the standard short cognitive test for 30 years. It has proved valuable in the assessment of patients with established dementia. It has many strengths but fails three of the requirements for a brief screening test for the non-specialist: minimal operator time, testing a wide range of cognitive domains, and sensitivity to mild Alzheimers.
The mini-mental state examination takes an average of eight minutes to administer. Many clinicians find time to complete this but with an average consultation time in general practice in Europe of 10.7 minutes16 this is too long. Around 58% of physicians in hospital practice thought the length of time taken to administer the mini-mental examination was too long.17
The mini-mental state examination tests several different cognitive domains but has a bias towards dominant parietal and temporal lobe function. It is a useful test of orientation, but the language and memory tests are too easy18 19 and there is only a single point for visuospatial tasks. These drawbacks lead to the major problem with the test—that it is insensitive in the diagnosis of mild Alzheimers.5 18 19 20 In community and hospital studies the sensitivity of the mini-mental state examination in detecting Alzheimers using the established cut off of
23 is low, varying from 49% to 69%.5 19 20 21 In our study it detected 52% of patients with Alzheimers. This low detection rate probably reflects the high number of patients with mild Alzheimers.
The TYM fulfils the three requirements. If a patient completes the test while in the waiting area supervised by the receptionist, it can be scored and analysed by the doctor in two minutes. If there is time during the consultation to observe the patients filling in the test, this can also be a useful aid to diagnosis.
The 11 TYM tasks examine more cognitive domains than the mini-mental state examination, with less bias towards dominant hemisphere language functions. The language and memory tests are more difficult. The inclusion of two visuospatial tasks, contributing 7/50 points, is important in distinguishing Alzheimers disease from pure amnestic syndromes. The test has a high sensitivity for detecting Alzheimers. In our study it detected 93% of cases of Alzheimers compared with 52% detected by the mini-mental state examination.
There are some additional problems with the mini-mental state examination. The score is influenced by how the tester asks the questions and also location—spatially disorientated patients might score 4 more points at home than in the clinic on the question of current location. The TYM is less influenced by the tester as it is filled in by the patient and will not vary with location.
The small range of scores in the mini-mental state examination limit its suitability for monitoring, but it is widely used for this purpose. It is the main test chosen by the National Institute for Health and Clinical Excellence (NICE) for deciding which patients in the United Kingdom should have cholinesterase inhibitors and for monitoring their response to treatment.22 The TYM has a much wider scoring range than the mini-mental state examination, with over 13 points between the average control and the average patient with mild Alzheimers. In the group of 94 patients with Alzheimers in this study the range of mini-mental scores was 14-30 while the range of TYM scores was 9-50 (2.5 times greater).
TYM v Addenbrookes cognitive examination
The original and revised Addenbrookes examinations are sensitive and specific in the diagnosis of degenerative dementia.4 5 The major drawback of the revised examination is that it fails to fulfil the time requirement for a test for non-specialists, taking 20 minutes to administer and score. It tests a similar number of cognitive domains to the TYM and is sensitive to mild Alzheimers.
There was a strong correlation between the memory score and the Addenbrookes score in both Alzheimers and non-Alzheimers dementias. The TYM score averages 50% of Addenbrookes score, enabling the two tests to be easily compared. Both tests provide a permanent record of the patients performance, which can be assessed later.
TYM v abbreviated mental test and other brief tests
Several brief cognitive tests have been published for screening for memory problems.23 24 Many of these are simple—such as clock drawing tests. These can be useful in distinguishing patients with established Alzheimers from normal controls but are too limited for routine screening for mild Alzheimers.25
The abbreviated mental test26 27 is the established brief test. It fulfils the time requirement, taking only two minutes to administer. It does not test many cognitive domains and has a strong bias (40% of the score) towards orientation, which is useful to detect delirium.28 It is less sensitive and specific than the mini-mental state examination in detecting mild Alzheimers.29 There are additional problems with the abbreviated mental test, which is not given and scored consistently by regular users.30
Other strengths and weaknesses of TYM
The TYM has several other advantages over current bedside cognitive tests. There is a brief but rigorous scoring system. Inter-rater agreement for scoring is excellent. Ten minutes training and the scoring sheet allowed a nurse, without experience of memory clinics, to score the TYM sheets as accurately as a specialist. The standardisation of the scoring should avoid the confusion that arises with scoring and interpreting the mini-mental state examination and the abbreviated mental test.
Cognitive testing usually depends on the tester and patient speaking the same language. The simplicity of the TYM should allow it to be administered and scored in a different language with help from a relative. It is currently being translated into four different languages. A minor adjustment to the semantic knowledge question (president for prime minister) is needed for American, Irish, and Australian use. Versions are being developed for UK patients who do not speak English as their first language; in these versions there are variations in the semantic knowledge and drawings to suit the background of the individual.
Normal values, sensitivity, and specificity are on the scoring sheet. As the test is filled in by the patient with little help and marked with the help of a scoring sheet, the tester and rater have little influence on the score.
The high negative predictive value of scores
42 shows that in unselected groups a good score makes Alzheimers disease unlikely and the TYM is a good screening test for memory problems. A score above 42 (that is,
43) correctly excludes the diagnosis of Alzheimers disease on 97% of occasions, even when the prevalence is as high as 30%. In unselected groups the positive predictive value of a score of
42 is relatively low, showing that the test alone cannot be used to diagnose Alzheimers disease. In selected groups where the prevalence of Alzheimers will be higher—for example, older patients with memory complaints—the positive predictive value of a score
42 is much higher.
The TYM was used successfully in patients outside this study with more severe dementia, visual problems, or other physical disability. The tester needs to fill in the form with these patients and some tasks might be too difficult, so the scores of these patients are not comparable with scores of the patients or controls in this study. The test is also useful for patients with hearing impairment who have difficulty with verbal cognitive tests.
The TYM seems more sensitive than the mini-mental state examination in screening for non-Alzheimers dementias. In the small group of such patients in our study the average mini-mental score was 25, close to the average for the population. The TYM score in the same group was 39, eight points below the average control score.
A disadvantage of the memory test is the need for the specially printed sheets, though the Addenbrookes cognitive examination-revised has a similar requirement. A website is being developed to help to solve this problem.
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Cite this as: BMJ 2009;338:b2030
Contributors: JB devised and helped to design the TYM, he helped to perform and coordinated the clinical research, and wrote the first draft of the paper. GP helped in the clinical testing and in the writing of the paper and was an inter-rater tester. KD performed much of the clinical testing and scoring. PC performed the statistical analysis and prepared the figures and tables. LAB helped design the test and was an inter-rater tester. JB is guarantor.
Funding: GP was supported by Alzheimers Research Trust (UK) and the Cambridge Commonwealth Trust. PC was supported by the Stroke Association. The authors are independent of any funders for this work. All authors had access to all data in this study.
Competing interests: None declared.
Ethical approval: This study was performed under ethical approval from Cambridgeshire 2 research ethics committee. All participants gave informed consent.
© Brown et al 2009
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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