The use of CANTAB PAL in Alzheimer’s disease

Author: Dr Andrew Blackwell, PhD, Chief Scientific Officer, Cambridge Cognition
Document ID: NMI-008
Date: 12 July 2011

Background and Significance
It is estimated that dementia currently affects approximately 37 million people worldwide and, as the population ages, these prevalence rates can be expected to increase substantially. In addition to the devastating personal impact that a diagnosis of dementia may have upon the lives of patients and their carers, there is also a financial burden. The total cost of Alzheimer’s disease (AD) alone in the US for the year 2000 has been estimated to be US$1.75 billion (WHO, 2001).

Current criteria for the diagnosis of probable AD stipulates deterioration in two or more areas of cognition, including memory, of sufficient magnitude to interfere with work or social function. Critically however, substantial neuropathological change may have occurred before clinically significant symptoms appear.

Thus, commencing treatment of AD at the time of clinical diagnosis (whether with cholinergic / glutamatergic drugs, anti-amyloid deposit agents or other putative disease-modifying agents) may be sub-optimal or even ineffective because of the advanced stage of neurodegeneration at that time. The identification of cognitive tests that are sensitive to early pathological changes would facilitate the diagnosis of patients in a ‘prodromal’ state (i.e. those in whom the pathological process is present but whose symptoms are currently sub-clinical).

Such early detection would serve to maximise the potential therapeutic benefit of treatment, enhance patient quality of life  and, in so doing, reduce the burden on residential and nursing care services. Consequently, a very high therapeutic and economic premium is placed on the early detection and diagnosis of AD.

A series of independent studies have demonstrated that CANTAB measures of visuospatial associative learning and semantic memory are sensitive in detecting the earliest signs of prodromal Alzheimer’s disease (up to 32 months prior to clinical diagnosis) both in memory clinic attendees (Fowler et al., 1995, Fowler et al., 1997; Fowler et al., 2002; Swainson et al., 2001; Blackwell et al., 2004) and in community dwelling cohorts of individuals classified as asymptomatic using current clinical measures (De Jager et al., 2002); De Jager et al., 2005). (WHAT is their definition of prodromal Alzheimer’s? This is crucial. These studies were done between 10 and 18 years ago)

Preliminary Data
Until relatively recently, the early detection of dementia has been neglected, partly due to the absence of effective treatments and also because sufficiently sensitive neuropsychological tests were not available.

The emergence of drugs to treat the symptoms of Alzheimer.s Disease (e.g. rivastigmine, donepezil, galantamine) brings an end the therapeutic nihilism previously seen in the dementias, and excitingly, several drugs are currently in development that are hoped will modify disease progression (Cambridge Cognition is involved in many of these trials). However, it is widely believed that if neuroprotective agents that modify the disease process are to be effective (or indeed for their efficacy to be evaluated) then it is vital that clinicians are able to detect a dementia early and accurately, before the emergence of global cognitive impairment and substantial and irreversible atrophic damage (Fox et al., 1999; Blackwell et al., 2004).

Early detection of dementias can also offer patients and their families more time to come to terms with the diagnosis of dementia, to make the necessary personal and financial arrangements, and to reduce the anxiety patients may feel when they are unsure of their diagnosis (Morgan and Baade, 1997; see also Holroyd et al., 1996, 2002; Geldmacher et al., 2003).  .

Over the past few years, attempts to identify individuals in the prodrome of AD (and other dementias) have largely focused upon patients who report memory problems but who do not fulfil criteria for clinically probable AD owing to their activities of daily living and non-memory cognitive faculties remaining intact. This condition has been given several labels, including „Questionable Dementia. (see e.g. Swainson et al., 2001; Blackwell  et al., 2004) and Mild Cognitive Impairment (MCI). (Petersen et al., 1999).

According to Petersen (2003), “the concept of MCI represents the earliest point in the cognitive decline of an individual who is destined to develop AD” and approximately 7-15% per annum of a sample meeting criteria for MCI will convert to meet criteria for probable AD, several fold the conversion rate expected in a general population (Celsis, 2000; Petersen 2003). Identifying appropriate tests with which to objectively quantify memory impairment characteristic of MCI, that can be used in multiple ethnicities by non-specialist clinicians, represents a crucial step in identifying patients who may benefit from disease-modifying treatments whilst avoiding exposure of those who do not have prodromal AD to potential side-effects of these drugs (and unnecessary costs).

In attempting to identify neuropsychological tests that are sensitive to the cognitive markers of prodromal AD (and thus appropriate indices of memory function in MCI), it is critical to ensure that performance on such tests is not deleteriously affected by other neuropsychiatric complaints that may confuse diagnosis. Furthermore, in order for maximum diagnostic sensitivity to be achieved, it is important to test those cognitive functions that are subserved by brain areas directly implicated in AD neuropathogenesis. The earliest pathological markers of AD, neurofibrillary tangles and neuropil threads, are first seen in the transentorhinal cortex, before neuropathology later spreads to the entorhinal cortex and hippocampus proper (Braak et al., 1991). Converging evidence from lesion studies in humans (Smith et al., 1981) and experimental animals (Macdonald et al., 1993; Miyashita et al., 1998) and functional neuroimaging studies in healthy volunteers (Owen et al., 1996, Maguire et al., 1998) suggests that these brain areas are necessarily involved in visuospatial associative learning. Accordingly, it is likely that a decline in visuospatial associative learning ability may be a good candidate marker of early neuropathological abnormality.

A number of longitudinal studies have investigated the relative merits of various neuropsychological tests of memory for announcing AD in its prodromal phase. Fox et al. (1998) followed 63 asymptomatic individuals at risk of autosomal dominant AD over a six year period. The ten subjects who developed dementia during this time could be identified at first assessment (when they were ostensibly unaffected) by significantly lower verbal memory and performance IQ on cognitive testing. These subjects were initially no different in terms of age, family history and initial Mini-Mental State Examination scores. First assessment was typically 2-3 years before symptoms were manifest and 4- 5 years before a diagnosis of probable AD was made, a result which clearly illustrates the potential sensitivity of cognitive testing. Blinded assessment of serial structural magnetic resonance imaging (MRI) showed that diffuse cerebral and medial temporal lobe atrophy was found in subjects only after they were clinically affected, suggesting that a patient.s neuropsychological profile may be a more sensitive early indicator than structural brain imaging data (see also Laakso et al., 2000). These results support the notion that neuropsychological tests can detect the earliest signs of cognitive deficits seen in AD.

Other longitudinal studies in elderly subjects generally concur with these results. In the Framingham study pre-clinical. deficits in verbal recall (as indexed by the percentage retained in the Logical Memory Test and Paired Associate Learning Test) preceded clinical diagnosis of AD in some cases by more than six years (Linn et al, 1995; Elias et al., 2000). Similarly, in the Bronx ageing study, two tests of verbal memory, the Fuld Object Memory Evaluation and the Bushke Selective Reminding Test, predicted many subjects who would go on to develop AD (Masur et al, 1995) (see also Albert et al., 2001, Artero et al., 2003).

Fowler et al., (1995, 1997, 2002) used the Cambridge Neuropsychological Test Automated Battery (CANTAB) to ascertain whether early AD could be detected in a group of individuals with questionable dementia. (QD). QD is a nosological entity similar in definition to MCI but is more representative of patients presenting for the first time in non-specialist care. These are people who present with subjective memory complaints, may or may not show some degree of impairment on standard neuropsychological tests (this differentiates QD from MCI criteria), but do not fulfil NINCDS-ADRDA criteria for dementia (McKhann et al.,1984). Fowler et al. (1997) demonstrated that the CANTAB PAL scores of the QD group fell into two clusters; follow-up longitudinal data revealed that individuals in one cluster (characterised by declining PAL performance) had a poor prognosis and an increased likelihood of a diagnosis of Alzheimer.s Disease whereas those in the other cluster (characterised by stable PAL performance) had a good prognosis and remained unimpaired. A later study (Swainson et al., 2001; Blackwell et al., 2004) found that PAL performance could be used to accurately predict incident probable AD diagnosis in a QD group based on assessment at one time point alone (see below).

The CANTAB PAL requires participants to learn and remember abstract visual patterns associated with various locations on a touch-sensitive computer screen. Patterns are presented in one of six or eight boxes around the edge of the screen (Figure 1). After a brief delay, the same patterns are presented in the middle of the screen and the subject is required to touch the box in which they saw that pattern appear. If this is not completed correctly the subject is reminded where each pattern belonged and tested again. This process continues until the task is satisfactorily completed or ten trials have been attempted.

Further studies using CANTAB PAL have confirmed it to be of utility in early and differential diagnosis in AD on a case-by-case basis. The CANTAB PAL performance of patients with mild AD was impaired relative to both demographically-matched healthy controls (Sahakian et al., 1988) and to individuals with frontal variant fronto-temporal dementia (Lee et al, 2003). Of critical importance, CANTAB PAL was also found to be relatively insensitive to major unipolar depression (only 7 percent of scores of patients with depression and AD fell within an overlapping range) (Swainson et al., 2001) (see Figure 2). This result suggests that PAL is of utility in the differential diagnosis of early AD and depression (unlike word recall tests – see O.Carroll et al., 1997). Unlike ADAS-COG, performance on PAL was also found to correlate significantly with subsequent deterioration in global cognitive function. Furthermore, in a group of individuals with QD, baseline PAL results revealed an apparent sub-group of patients who performed like AD patients. In a follow up study,

Blackwell et al. (2004) showed that by taking into account age and performance on one other neuropsychological test (The Graded Naming Test, McKenna & Warrington, 1980), CANTAB PAL gave a 100% distinction between subjects with QD who either did or did not convert to probable AD (NINCDS-ADRDA criteria) 32 months after baseline testing (see also De Jager et al., 2002). These studies also revealed that the sensitivity (in detecting prodromal AD in a QD group) and specificity (in differentiating AD from depression) of CANTAB PAL was considerably better than that of all other frequently-used tests included in the study (including ADAS-cog and Wechsler Logical Memory Delayed Passage Recall).

The accumulating evidence demonstrating the sensitivity and specificity of CANTAB PAL for the early and differential diagnosis of AD suggest that this test is an excellent tool for operationalising the criteria for objective memory impairment in MCI and related syndromes (e.g. MCI due to AD). t is noteworthy that  CANTAB PAL has the additional advantage of existing in a form that can be used in experimental animals (Taffe et al., 2002), facilitating translational medicine phases of treatment development. As such, behavioural effects on these CANTAB tests are more likely to predict efficacy in the clinic. CANTAB tests also benefit from the major advantage of being non-language based enabling global deployment.

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CANTAB Bibliography and Dementia
There are currently 79 papers published on dementia and CANTAB. The references for these papers are included below. Some of the references below are also included in the references above.

[1] Morris R.G., Evenden J.L., Sahakian B.J., Robbins T.W., (1987) Computer-aided assessment of dementia: comparative studies of neuropsychological deficits in Alzheimer-type dementia and Parkinson’s disease, Cognitive Neurochemistry, 21-36

[2] Sahakian B.J., Morris R.G., Evenden J.L., Heald A., Levy R., Philpot M.P., Robbins T.W., (1988) A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson’s disease, Brain, 111, 695-718

[4] Rusted J.M., Warburton D.M., (1988) The effects of scopolamine on working memory in healthy young volunteers, Psychopharmacology, 96, 145-152

[8] Sahakian B.J., Downes J.J., Eagger S.A., Evenden J.L., Levy R., Philpot M.P., Roberts B.J., Robbins T.W., (1990) Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type, Neuropsychologia, 28(11), 1197-1213

[9] Abas M.A., Sahakian B.J., Achard S., (1990) Neuropsychological deficits and CT scan changes in elderly depressives, Psychological Medicine, 20, 507-520

[11] Sahakian B.J., (1990) Computerized assessment of neuropsychological function in Alzheimer’s disease and Parkinson’s disease, International Journal of Geriatric Psychiatry, 5, 211-213

[13] Sahgal A., Sahakian B.J., Robbins T.W., Wray C.J., Lloyd S., Cook J.H., McKeith I.G., Disley J.C.A., Eagger S.A., Boddington S., Edwardson J.A., (1991) Detection of visual memory and learning deficits in Alzheimer’s disease using the Cambridge Neuropsychological Test Automated Battery, Dementia, 2, 150-158

[15] Eagger S.A., Levy R., Sahakian B.J., (1991) Tacrine in Alzheimer’s disease, The Lancet, 989-992

[18] Sahgal A., Lloyd S., Wray C.J., Galloway P.H., Robbins T.W., Sahakian B.J., McKeith I.G., Cook J.H., Disley J.C.A., Edwardson J.A., (1992) Does visuospatial memory in senile dementia of the Alzheimer type depend on the severity of the disorder?, International Journal of Geriatric Psychiatry, 7, 427-436

[20] Eagger S.A., MorantN.J., Levy R., Sahakian B.J., (1992) Tacrine in Alzheimer.s disease: Time course of changes in cognitive function and practice effects, British Journal of Psychiatry, 160, 36-40

[21] Sahakian B.J., Owen A.M., (1992) Computerized assessment in neuropsychiatry using CANTAB: discussion paper, Journal of the Royal Society of Medicine, 85, 399-402

[22] Sahgal A., Galloway P.H., McKeith I.G., Lloyd S., Cook J.H., Ferrier I.N., Edwardson J.A., (1992) Matching-to-sample deficits in patients with senile dementias of the Alzheimer and Lewy body types, Archives of Neurology, 49, 1043-1046

[23] Galloway P.H., Sahgal A., McKeith I.G., Lloyd S., Cook J.H., Ferrier I.N., Edwardson J.A., (1992) Visual pattern recognition memory and learning deficits in senile dementias of the Alzheimer and Lewy body types, Dementia, 3, 101-107

[24] Sahgal A., Galloway P.H., McKeith I.G., Edwardson J.A., Lloyd S., (1992) A comparative study of attentional deficits in senile dementias of Alzheimer and Lewy body types, Dementia, 3, 350-354

[25] Sahakian B.J., Owen A.M., Morant N.J., Eagger S.A., Boddington S., Crayton L., Crockford H.A., Crooks M., Hill K., Levy R., (1993) Further analysis of the cognitive effects of tetrahydroaminoacridine (THA) in Alzheimer’s disease: assessment of attentional and mnemonic function using CANTAB, Psychopharmacology, 110, 395-401

[27] Charlesworth G.M., Hymas N., Wischik C.M., Hodges J.R., Sahakian B.J., (1993) Case conference report: Late paraphrenia, advanced schizophrenic deterioration and dementia, International Journal of Geriatric Psychiatry, 8, 765-773

[28] Forstl H., Sahakian B.J., (1993) Thalamic radiodensity and cognitive performance in mild and moderate dementia of the Alzheimer type, Journal of Psychiatry and Neuroscience, 18(1), 33-37

[39] Sahakian B.J., Coull J.T., (1994) Nicotine and Tetrahydroaminoacridine: evidence for improved attention in patients with dementia of the Alzheimer type, Drug Development Research, 31, 80-88

[42] Sahgal A., McKeith I.G., Galloway P.H., Tasker N., Steckler T., (1995) Do differences in visuospatial ability between senile dementias of the Alzheimer and Lewy body types reflect differences solely in mnemonic function, Journal of Clinical and Experimental Neuropsychology, 17, 35-43

[44] Lange K.W., Sahakian B.J., Quinn N.P., Marsden C.D., Robbins T.W., (1995) Comparison of executive and visuospatial memory function in Huntington’s disease and dementia of Alzheimer type matched for degree of dementia, Journal of Neurology, Neurosurgery & Psychiatry, 58, 598-606

[51] Coull J.T., Sahakian B.J., Hodges J.R., (1996) The alpha 2 antagonist idazoxan remediates certain attentional and executive dysfunction in patients with dementia of frontal type, Psychopharmacology, 123, 239-249

[63] Fowler K.S., Saling M.M., Conway E.L., Semple J., Louis W.J., (1995) Computerized delayed matching to sample and paired associate performance in the early detection of dementia, Applied Neuropsychology, 2, 72-78

[74] Sahakian B.J., Jones G., Levy R., Gray J., Warburton D.M., (1989) The effects of nicotine on attention, information processing and short-term memory in patients with dementia of the Alzheimer type, British Journal of Psychiatry, 154, 797-800

[75] Jones G., Sahakian B.J., Levy R., Warburton D.M., Gray J., (1992) Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer’s disease, Psychopharmacology, 108, 485-494

[77] Lawrence A.D., Sahakian B.J., (1996) The neuropsychology of fronto-striatal dementias, Handbook of the Clinical Psychology of Ageing, 243-265

[79] Robbins T.W., Elliott R., Sahakian B.J., (1996) Neuropsychology – dementia and affective disorders, British Medical Bulletin, 52 (no.3), 627-643

[93] Lawrence A.D., Sahakian B.J., (1995) Alzheimer disease, attention and the cholinergic system, Alzheimer Disease and Associated Disorders, 9, 43-49

[97] Fowler K.S., Saling M.M., Conway E.L., Semple J., Louis W.J., (1997) Computerized neuropsychological tests in the early detection of dementia: prospective findings, Journal of the International Neuropsychological Society, 3, 139-146

[101] Robbins T.W., Semple J., Kumar R., Truman M.I., Shorter J., Ferraro A., Fox B., McKay G., Matthews K., (1997) Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia, Psychopharmacology, 134, 95-106

[105] Sahakian B.J., Coull J.T., (1993) Tetrahydroaminoacridine (THA) in Alzheimer’s disease: an assessment of attentional and mmnemonic function using CANTAB, Acta Neurologica Scandinavica, 149 Suppl, 29-35

[110] Lawrence A.D., Sahakian B.J., (1998) The cognitive psychopharmacology of Alzheimer’s disease: focus on cholinergic systems, Neurochemical Research, 23, 787-794

[111] Rahman S., Sahakian B.J., (1998) Dementia, European Textbook of Clinical Pharmacology, 127-141

[112] Lawrence A.D., Sahakian B.J., (1998) Outcome variables in dementia trials: conceptual and practical issues, Clinical Trials in Neurology, 171-182

[121] Oliver C., Crayton L., Holland A., Hall S., Bradbury J., (1998) A four year prospective study of age-related cognitive decline in adults with Down’s syndrome, Psychological Medicine, 28, 1365-1377

[127] Curtis-Prior P., Vere D., Fray P., (1999) Therapeutic value of Ginkgo biloba in reducing symptoms of decline in mental function, Journal of Pharmacy and Pharmacology, 51, 535-541

[128] Iddon J.L., Pickard J.D., Cross J.J.L., Griffiths P.D., Czosnyka M., Sahakian B.J., (1999) Specific patterns of cognitive impairment in patients with idiopathic normal pressure hydrocephalus and Alzheimer’s disease: a pilot study, Journal of Neurology, Neurosurgery & Psychiatry, 67, 723-732

[130] Riekkinen M., Soininen H., Riekkinen P. SR, Kuikka J., Laakso M., Helkala E.-L., Partanen J., Riekkinen P. JR, (1998) Tetrahydroaminoacridine improves the recency effect in Alzheimer’s disease, Neuroscience, 83(2), 471-479

[131] Riekkinen P. JR, Riekkinen M., (1999) THA improves word priming and clonidine enhances fluency and working memory in Alzheimer’s disease, Neuropsychopharmacology, 20, 357-364

[132] Riekkinen M., Laakso M., Jakala P., Riekkinen P. JR, (1999) Clonidine impairs sustained attention in Alzheimer’s disease, Alzheimer’s Disease and Related Disorders, 641-647

[142] Rahman S., Robbins T.W., Sahakian B.J., (1999) Comparative cognitive neuropsychological studies of frontal lobe function: implications for therapeutic strategies in frontal variant frontotemporal dementia, Dementia and Geriatric Cognitive Disorders, 10, 15-28

[143] Rahman S., Sahakian B.J., Hodges J.R., Rogers A.C., Robbins T.W., (1999) Specific cognitive deficits in mild frontal variant frontotemporal dementia, Brain, 122, 1469-1493

[144] Perry E., Walker M., Grace J., Perry R., (1999) Acetylcholine in mind: a neurotransmitter correlate of consciousness?, Trends in Neurosciences, 22(6), 273-280

[159] Dunn B.D., Owen A.M., Sahakian B.J., (2000) Neuropsychological assessment of dementia, Dementia, 49-59

[160] Swainson R., Hodges J.R., Galton C.J., Paykel E.S., Semple J., Michael A., Dunn B.D., Iddon J.L., Robbins T.W., Sahakian B.J., (2001) Early detection and differential diagnosis of Alzheimer’s disease and depression with neuropsychological tasks, Dementia and Geriatric Cognitive Disorders, 12, 265-280

[168] Dorion A.A., Duyme M., Zanca M., Dubois B., Beau J., (2001) Relationship between discrimination tasks of the CANTAB and the corpus callosum morphology in Alzheimer’s disease, Perceptual and Motor Skills, 92, 1205-1210

[169] Fowler K.S., Saling M.M., Conway E.L., Semple J., Louis W.J., (2002) Paired associate performance in the early detection of DAT, Journal of the International Neuropsychological Society, 8, 58-71

[175] De Jager C.A., Milwain E., Budge M.M., (2002) Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests, Psychological Medicine, 32, 483-491

[199] Rahman S., Swainson R., Sahakian B.J., (2002) Dementia of the Alzheimer type, Cognitive Deficits in Brain Disorders, Chapter 8, 139-167

[209] Porter R.J., Lunn B.S., O’Brien J.T., (2003) Effects of acute tryptophan depletion on cognitive function in Alzheimer’s disease and in the healthy elderly, Psychological Medicine, 33, 41-49

[219] Dorion A.A., Sarazin M., Hasboun D., Hahn-Barma V., Dubois B., Zouaoui A., Marsault C., Duyme M.,

(2002) Relationship between attentional performance and corpus callosum morphometry in patients with Alzheimer’s disease, Neuropsychologia, 40, 946-956

[227] Blackwell A.D., Sahakian B.J., Vesey R., Semple J., Robbins T.W., Hodges J.R., (2004) Detecting dementia: novel neuropsychological markers of preclinical Alzheimer’s disease, Dementia and Geriatric Cognitive Disorders, 17, 42-48

[231] Lee A.C.H., Rahman S., Hodges J.R., Sahakian B.J., Graham K.S., (2003) Associative and recognition memory for novel objects in dementia: implications for diagnosis, European Journal of Neuroscience, 18, 1660-1670

[250] Deakin J.B., Rahman S., Nestor P.J., Hodges J.R., Sahakian B.J., (2003) Paroxetine does not improve symptoms and impairs cognition in frontotemporal dementia: a double-blind randomised controlled study, Psychopharmacology, 172(4), 400-408

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