British Medical Journal – BMJ – Journal review

journal2Dr Beenadas

Published 9 June 2009, doi:10.1136/bmj.b2030

Research – Self administered cognitive screening test  (tym) for detection of alzheimer’s disease: cross sectional study

Jeremy Brownconsultant neurologistGeorge Pengasclinical research fellowKate Dawsonresearch nurseLucy A Brownhonorary research assistantPhilip Clatworthyclinical research fellow

Department of Neurology, Addenbrooke’s Hospital, Cambridge

Abstract :Objective To evaluate a cognitive test, the TYM (“test your memory”), in the detection of Alzheimer’s disease.

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 Alzheimer’s 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 Addenbrooke’s cognitive examination-revised (ACE-R)). Sensitivity and specificity of the TYM in the detection of Alzheimer’s disease.

Results Control participants completed the TYM with an average score of 47/50. Patients with Alzheimer’s 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 Alzheimer’s disease. The TYM was more sensitive in detection of Alzheimer’s disease than the mini-mental examination, detecting 93% of patients compared with 52% for the mini-mental state examination. The negative and positive predictive values of the TYM with the cut off of 42 were 99% and 42% with a prevalence of Alzheimer’s 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 Alzheimer’s disease.

Dementia and other cognitive problems are common. An estimated 24 million individuals in the world have dementia and the number affected will double every 20 years. Milder forms of cognitive dysfunction, including mild cognitive impairment, affect many more people. Alzheimer’s disease is the commonest form of dementia. Cognitive problems are a feature of many neurological and medical diseases including stroke, Parkinson’s disease, head injury, and epilepsy.

Assessment of a patient’s 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.

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 Alzheimer’s disease. We designed the TYM (“test your memory”) to fulfil these requirements.

The TYM was administered to 540 normal controls aged 18-95, 108 patients with Alzheimer’s disease/amnestic mild cognitive impairment, and 31 patients with non-Alzheimer’s degenerative dementias. The test was validated by comparing scores with those obtained with the mini-mental state examination and Addenbrooke’s cognitive examination-revised. The Addenbrooke’s revised test was developed from the original examination and is similar in both content and scoring. We determined the specificity and sensitivity of the TYM in the detection of Alzheimer’s disease by comparing the scores of 94 patients with Alzheimer’s disease with the scores of 282 age matched controls.

The TYM test
The TYM is a series of 10 tasks on a double sided sheet of card. The patient’s ability to complete the test is an 11th task. The tasks are orientation (10 points), ability to copy a sentence (2 points), semantic knowledge (3 points), calculation (4 points), verbal fluency (4 points), similarities (4 points), naming (5 points), visuospatial abilities ( 2 tasks, total 7 points), and recall of a copied sentence (6 points). The ability to do the test is also scored (5 points), giving a possible total of 50 points.

Selection of patients with Alzheimer’s disease
Patients were seen and diagnosed by a consultant neurologist with an interest in dementia in a dedicated memory clinic at Addenbrooke’s Hospital. Patients attended the memory clinic underwent neurological assessment, the Addenbrooke’s 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 Alzheimer’s disease was made with the NINCDS-ARDRA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association).

A total of 108 patients (59 men, 49 women) received a clinical diagnosis of Alzheimer’s disease or amnestic mild cognitive impairment. Alzheimer’s disease was diagnosed in 85 and amnestic mild cognitive impairment in 23. Amnestic mild cognitive impairment has clinical and pathological similarities to Alzheimer’s disease  and patients with amnestic mild cognitive impairment who score poorly on the Addenbrooke’s cognitive examination are likely to progress to Alzheimer’s disease.   These patients were regarded as having early Alzheimer’s disease. Nine patients with a diagnosis of amnestic mild cognitive impairment who scored below the cut off for dementia on the Addenbrooke’s cognitive examination-revised (83 ) were included in the Alzheimer’s cohort. Patients with a diagnosis of amnestic mild cognitive impairment who score well on the Addenbrooke’s cognitive examination are unlikely to progress to Alzheimer’s disease over the next two years ; such patients might never progress to Alzheimer’s disease and might return to normal.  The 14 patients with a diagnosis of amnestic mild cognitive impairment who scored >83 on the ACE-R were analysed separately.

Testing and validation
The 94 patients in the Alzheimer’s cohort were given the TYM as well as the Addenbrooke’s cognitive examination-revised (that includes the mini-mental state examination). The TYM was administered when the patient first arrived in the clinic.

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 Addenbrooke’s memory clinic as new patients were given the TYM and Addenbrooke’s cognitive examination-revised. Of these patients, 16 had dementia with Lewy bodies, 13 had frontotemporal dementia, and two had progressive supranuclear palsy.

Results : 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. The mean score for both groups was 47.4.

Alzheimer’s disease and test validation
Ninety four patients with Alzheimer’s with an average age of 69.0 were tested with the TYM, the Addenbrooke’s cognitive examination-revised, and the mini-mental state examination.

We found strong and significant correlations between all scores in patients with Alzheimer. Older patients with Alzheimer’s (aged over 70) scoredslightly better on the TYM than the younger patients with Alzheimer’s.

Comparison of TYM scores
As expected, patients with Alzheimer’s were particularly impaired on anterograde memory scores relative to controls. Patients also scored poorly on semantic knowledge, fluency, visuospatial tasks, and executive function.

TYM in non-Alzheimer’s dementias
The average mini-mental score is above the cut off for dementia, while the TYM and Addenbrooke’s average scores are well below it, suggesting superior sensitivity of the TYM and the Addenbrooke’s test in the diagnosis of non-Alzheimer’s dementias.

TYM in patients with mild cognitive impairment 
The patients with mild cognitive impairment scored highly on all cognitive tests. Their scores on 10 of the subtests of TYM were similar to controls, but they tended to score worse than controls on anterograde memory.

Discussion :In this cross sectional study, the new “test your memory” test (TYM) was quick to use and detected 93% of cases of Alzheimer’s disease. Control participants completed the TYM quickly and accurately. From the age of 18 to 70 the average score was stable at 47/50, with a small decline after this age. Scores on all subsets of the TYM deteriorated with age, with the exception of semantic knowledge (these questions were designed for older patients).

There was no significant difference in TYM scores between male and female controls.

Use in patients with Alzheimer’s disease
Patients with Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s.

We separately analysed patients with mild memory problems. These patients had a clinical diagnosis of amnestic mild cognitive impairment and scored well on the Addenbrooke’s examination (>83). Amnestic mild cognitive impairment can be a prodrome of Alzheimer’s, but some affected patients have mild problems that do not progress. The Addenbrooke’s 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. In this study as we used the higher cut off of 83, the accepted cut off for dementia for the Addenbrooke’s test, some non-progressive patients might have been included in the Alzheimer’s 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.

Other strengths and weaknesses of TYM
The TYM has several other advantages over current bedside cognitive tests. TYM is a good screening test for memory problems. A score above 42 (that is, 43) correctly excludes the diagnosis of Alzheimer’s 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 Alzheimer’s disease. In selected groups where the prevalence of Alzheimer’s will be higher—for example, older patients with memory complaints—the positive predictive value of a score 42 is much higher.

Dementia :It is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Memory is the most common cognitive ability lost with dementia. In addition to memory, other mental faculties are also affected in dementia; these include language, visuospatial ability, calculation, judgment, and problem solving. Neuropsychiatric and social deficits also develop in many dementia syndromes, resulting in depression, withdrawal, hallucinations, delusions, agitation, insomnia, and disinhibition.

Functional Anatomy of the Dementias : Dementia results from the disruption of cerebral neuronal circuits. Behavior and mood are modulated by noradrenergic, serotonergic, and dopaminergic pathways, while acetylcholine seems to be particularly important for memory. Therefore, the loss of cholinergic neurons in Alzheimer’s disease (AD) may underlie the memory impairment, while in patients with non-AD dementias, the loss of serotonergic and glutaminergic neurons causes primarily behavioral symptoms, leaving memory relatively spared.

AD begins in the entorhinal cortex, spreads to the hippocampus, and then moves to posterior temporal and parietal neocortex, eventually causing a relatively diffuse degeneration throughout the cerebral cortex

AD primarily presents as memory loss and is often associated with aphasia or other disturbances of language. In contrast, patients with frontal lobe or subcortical dementias such as frontotemporal dementia (FTD) or Huntington’s disease (HD) are less likely to begin with memory problems and more likely to have difficulties with attention, judgment, awareness, and behavior.

The dorsolateral prefrontal cortex has connections with dorsolateral caudate, globus pallidus, and thalamus. Lesions of these pathways result in poor organization and planning, decreased cognitive flexibility, and impaired judgment.

The lateral orbital frontal cortex connects with the ventromedial caudate, globus pallidus, and thalamus. Lesions of these connections cause irritability, impulsiveness, and distractibility.

The anterior cingulate cortex connects with the nucleus accumbens, globus pallidus, and thalamus. Interruption of these connections produces apathy and poverty of speech or even akinetic mutism.

The single strongest risk factor for dementia is increasing age

Most Common Causes of Dementia 

  1. Alzheimer’s disease
  2. Vascular dementia
  3. Multi-infarct
  4. Diffuse white matter disease (Binswanger’s)
  5. Alcoholisma
  6. Parkinson’s disease Drug/medication intoxicationa

Benign forgetfulness of the elderly- loss of memory is a natural part of aging.

Mild cognitive impairment (MCI)- A cognitive problem that has begun to subtly interfere with daily activities. MCI will progress to frank dementia, usually caused by AD.

Vascular Dementia :Dementia associated with cerebral vascular disease can be divided into two general categories: multi-infarct dementia and diffuse white matter disease (also called leukoaraiosis, subcortical arteriosclerotic encephalopathy or Binswanger’s disease). Cerebral vascular disease appears to be a more common cause of dementia in Asia

Individuals who have had several strokes may develop chronic cognitive deficits, commonly called multi-infarct dementia. Many multi-infarct dementia patients have a history of hypertension, diabetes, coronary artery disease, or other manifestations of widespread atherosclerosis. Physical examination usually shows focal neurologic deficits such as hemiparesis, a unilateral Babinski reflex, a visual field defect, or pseudobulbar palsy.

Some individuals with dementia are discovered on MRI to have bilateral abnormalities of subcortical white matter, termed diffuse white matter disease, often occurring in association with lacunar infarctions. Early symptoms are mild confusion, apathy, changes in personality, depression, psychosis, memory, and spatial or executive deficits.

Frontotemporal dementia (FTD) often begins when the patient is in the fifth to seventh decades, and in this age group it is nearly as common as AD. Most studies suggest that FTD is twice as common in men as it is in women. Unlike AD, behavioral symptoms predominate in the early stages of FTD. The distinguishing anatomic hallmark of FTD is a marked lobar atrophy of temporal and/or frontal lobes.

Pick’s disease was described as a progressive degenerative disorder characterized clinically by selective involvement of the anterior frontal and temporal neocortex and pathologically by intracellular inclusions (Pick bodies).

Parkinson’s disease (PD)- The occurrence of dementia in PD is more likely with increasing age, increasing severity of extrapyramidal signs, a long duration of disease, and the presence of depression. These patients also show cortical atrophy.There may be Alzheimer changes in the cortex , neuronal Lewy body inclusions in both the substantia nigra and the cortex, or no specific microscopic changes other than gliosis and neuronal loss.

Dementia with Lewy Bodies – The parkinsonian dementia syndromes  unified by the presence of Lewy bodies in both the substantia nigra and the cortex. The clinical syndrome is characterized by visual hallucinations, parkinsonism, fluctuating alertness, falls, and often REM sleep behavior disorder. Dementia can precede or follow the appearance of parkinsonism.

Approximately 10% of all persons over the age of 70 have significant memory loss, and in more than half the cause is AD.AD can occur in any decade of adulthood, but it is the most common cause of dementia in the elderly. AD most often presents with subtle onset of memory loss followed by a slowly progressive dementia that has a course of several years.

Pathologically, there is diffuse atrophy of the cerebral cortex with secondary enlargement of the ventricular system. Microscopically, there are neuritic plaques containing amyloid, silver-staining neurofibrillary tangles (NFTs) in neuronal cytoplasm, and accumulation of  amyloid in arterial walls of cerebral blood vessels.

Clinical Manifestations
The cognitive changes with AD tend to follow a characteristic pattern, beginning with memory impairment and spreading to language and visuospatial deficits. Once the memory loss begins to affect day-to-day activities or falls below 1.5 standard deviations from normal on standardized memory tasks, the disease is defined as MCI. Approximately 50% of MCI individuals will progress to AD within 5 years.

Slowly the cognitive problems begin to interfere with daily activities. Language becomes impaired—first naming, then comprehension, and finally fluency. In some patients, aphasia is an early and prominent feature. Apraxia emerges, and patients have trouble performing sequential motor tasks. Visuospatial deficits begin to interfere with dressing, eating, solving simple puzzles, and copying geometric figures. Patients may be unable to do simple calculations or tell time. In the late stages of the disease, some persons remain ambulatory but wander aimlessly. Loss of judgment, reason, and cognitive abilities is inevitable. Delusions are common.

Some patients develop a shuffling gait with generalized muscle rigidity associated with slowness and awkwardness of movement. Patients often look parkinsonian  but rarely have a rapid, rhythmic, resting tremor. In end-stage AD, patients become rigid, mute, incontinent, and bedridden.

Genetic Considerations
One genetic factor is the APP gene on chromosome 21. Adults with trisomy 21 (Down’s syndrome) consistently develop the typical neuropathologic hallmarks of AD if they survive beyond age 40.

Building rapport with the patient, family members, and other caregivers is essential. In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful. Communication and repeated calm reassurance are necessary.

Lecturer, Department of MM
Govt. Homeopathic Medical College. Calicut

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