INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 7: 573-578 (1992)

CONCURRENT VALIDITY OF CRITICAL FLICKER FUSION IN PATIENTS WITH

PRIMARY DEGENERATIVE DEMENTIA OF THE ALZHEIMER TYPE

STEPHEN CURRAN Registrar in Psychiatry, Academic Unit of Psychiatry, Roundhay Wing, St James S University Hospital,

Leeds, LS9 7TF, UK

JOHN P. WATTIS Senior Lecturer and Consultant in the Psychiatry of Old Age, Clinical Sciences Building,

St James’s University Hospital, Leeds, LS9 7TF, UK

Professor of Human Psychopharmacology, Human Psychopharmacology Research Unit, Milford Hospital, University of Surrey, Godalming, Surrey, GU7 1 UF, UK

IAN HINDMARCH

SUMMARY The concurrent validity of critical flicker fusion threshold (CFFT) and flicker threshold measurement was examined in 23 female and three male patients with primary degenerative dementia of the Alzheimer type (PDDAT). Patients had a mean age of 8 1.7 6.05 years (range 67-89). Diagnosis of PDDAT was based on the DSM-111-R classification. Both the CFFT and flicker thresholds were found to be highly and significantly correlated with standardized clinical assessment (Global Deterioration Scale), cognitive function (Abbreviated Mental Test) and psychomotor performance (Choice Reaction Time). The implications of these two measures for clinical trial research and the longitudinal assessment of patients with Alzheimer’s disease are discussed.

KEY woms-Critical flicker fusion threshold, primary degenerative dementia of the Alzheimer’s type, concurrent validity.

Alzheimer’s disease affects the individual, the family and society. Because of its prevalence in very old people and the age structure of the population, it represents an increasing economic burden. Clini- cal trials in dementia are expensive, time-consum- ing and, to date, not very successful. Despite the wide range of potential drugs available, Byrne and Arie (1990) noted ‘the time has not yet come to use these drugs other than as part of carefully designed research’. Although there are standar- dized diagnostic criteria (NINCDS-ADRA, DSM- 111-R, etc) there is little agreement on which psy- chometric measures are the most valid and reliable for clinical evaluation of change. These and other differences between clinical trials make it difficult to compare different studies. It is therefore import-

C:orrespondciice to first author.

ant to have standardized, reliable and valid mea- sures to assess new pharmaceutical compounds.

Critical flicker fusion threshold (CFFT) has been widely used in psychopharmacology for the past 30 years to evaluate psychotropic drugs including antidepressants, anxiolytics and nootropic drugs. However, most of these studies have been per- formed on young and elderly volunteers (Simonson and Brozek, 1952; Turner, 1968; Smith and Misiak, 1976; Hindmarch, 1982; Curran, 1990; Alford and Hindmarch, 1990; Curran and Hindmarch, 1992). The potential of CFFT for psychopharmacological research in Alzheimer’s disease has been largely overlooked. However, the test has been demon- strated to be age-sensitive (eg McFarland et nl., 1958). In addition, it is able to distinguish between patients with Alzheimer’s disease and age, sex and occupational matched controls (Curran et al., 1991 a) and has high split-half and test-retest relia-

0885-6230/92~080573-06$08.00 GI 1992 by John Wiley & Sons, Ltd

Received 12 November 1991 Accepted3 March 1992

574 S . CURRAN, J . P. WATTIS AND I . HINDMARCH

bility (Curran et ul., 1991b) in patients with Alz- heimer’s disease.

The present study examines for the first time the concurrent validity of CFFT in patients with Alz- heimer’s disease and discusses the face validity of this potentially important measure.

METHOD

Patients

Three male and 23 female community based patients were included in the study. Their ages ranged from 67 to 89 with a mean of 81.7 years -t 6.05. Twenty-five patients lived in residential homes and one patient lived at home cared for by her family.

Patients were identified initially by consultation with general practitioners and by examination of case records with the GPs’ consent. McLean’s (1987) definition of dementia was used at an initial assessment by a research nurse. A questionnaire about general health compiled by the authors, the Abbreviated Mental Test (AMT) (Hodkinson, 1972) and the Mini-Mental State Examination (MMSE) (Folstein et al., 1975) were completed. Patients scoring 7 or less on the AMT and/or 23 or less on the MMSE received a diagnostic visit from the study physician.

Patients satisfying DSM-111-R criteria (APA, 1987) for dementia underwent further evaluations including: medical and psychiatric history (from patient and next of kin); mental state examination; physical examination including neurology; routine haematology and biochemistry; thyroid function tests; plasma B 12/folate; syphilis screen; serum car- otene, urinalysis; chest X-ray; ECG; and CT scan. The chest X-ray, ECG and CT scan were all inde- pendently reported. In addition, only patients scor- ing 3 or less on the Hachinski Ischaemic Scale (Hachinski, 1978) were included in the study.

Patients with evidence of significant physical ill- ness, other psychiatric diagnoses including depression, the secondary causes of dementia or taking concomitant medications known to have CNS activity were excluded. In addition, it is well known that the CFFT can be decreased in patients with visual deficits, especially cataracts. For this reason patients received an ophthalmological examination to exclude the presence of gross patho- logy. In addition, patients were expected to be able to pass a standard reading test before being con- sidered for entry into the study.

All patients were rated as mild-moderate (APA, 1987) by the study physician. The majority were moderately impaired. All assessments were carried out in patients’ normal surroundings (ie home/resi- dential home).

Materials The following measures were chosen because of

their established use in dementia research or because they have been demonstrated to be impaired in patients with Alzheimer’s disease.

Global Deterioration Scale (GDS) (Reisberg et al., 1988). This is a seven-point rating instrument for the staging of the degree of functional and cog- nitive impairmentkapacity in patients with primary degenerative dementia of the Alzheimer type (PDDAT) in addition to normal ageing and age- associated memory impairment. This scale is widely used and helps to standardize the clinical assess- ment of severity. Details of its validity and reliabi- lity are described in Reisberg et al. (1988) (no cognitive decline = 1; very severe cognitive decline = 7).

The Abbreviated Mentul Test (Hodkinson, 1972) and the Mini-Mental State Examination (Folstein et al., 1975). These were used to assess global cogni- tive function.

SCAG (Shader et al., 1974). The Sandoz Clinical Assessment Geriatric Scale was designed specifi- cally for geriatric patients. The five main areas assessed are cognitive function, interpersonal rela- tionships, affective disorder, apathy and somatic symptoms. Eighteen questions in total are asked and each is rated on a scale of 1-7 (1 =not present; 7 =severe).

Critical Picker fusion threshold (CFFT). A detailed account of the measurement of critical flicker fusion threshold and its subcomponents fusion threshold (ascending method) and flicker threshold (descending method) has been published (Curran et al., 1991a,b). Theoretical aspects of flicker phenomena are reviewed in Ott and Kranda (1982). Since the test apparatus generates flicker with fixed starting points (12 Hz in the ascending mode and 50Hz in the descending mode), there is a risk of patients habituating and only respond- ing after a certain period of time. During the prac- tice phase, patients received instructions to begin the experiment at a variable number of seconds after flicker had started (0-10 s). Patients were not

CRITICAL FLICKER FUSION IN PATIENTS WITH PDDAT 575

aware that this latter variable was being manipu- lated. Provided that there was no evidence of habi- tuation, patients entered the test phase with the fixed starting points as previously described. After several years of experience using this technique by the authors, habituation has not been found to be a problem in patients with Alzheimer’s disease and is essentially a ‘theoretical’ risk. Subjects were fully familiarized during the practice phase with the test procedure, with four fusionifour flicker thresholds being determined prior to testing. There are no absolute guidelines with regard to how many indivi- dual scores should be measured. Most authors take the average of between 4 and 20. A balance has to be maintained between reliability, which is likely to reduce as the number of scores decreases, and keeping the test procedure to a reasonable length of time. This is particularly important in the elderly and where the patient has to complete a battery of tests (Curran, 1991). The authors have pre- viously shown that measuring four scores is reliable in patients with Alzheimer’s disease (Curran et al., 1991 b). A one minute interval between each ascend- ing and descending series decreased the possibility of visual fatigue. In the test phase, four fusion and four flicker thresholds were measured alternately, and the means were calculated. Only the results obtained during the test phase are reported in this study. The possible effects of adaptation were mini- mized in this study by employing foveal fixation and short exposure to both flicker and supra- threshold flicker. The measurement of CFFTs and flicker thresholds is quick and easy, typically taking 5--10 minutes for completion.

Choice Reuction Time (CRT).The Leeds psycho- motor tester was used to measure CRT. The stimu- lus consisted of six light sources arranged in an arc of 120 degrees and equally spaced. The light sources were turned on in random succession and were under microchip control. The required response was a movement of the index finger from the resting pad to the response pad adjacent to the stimulus light. The test apparatus was placed on a flat surface 50 cm from the subject’s eyes. The dominant hand was used. The hand was clenched with only the index finger extended. The start and response pads were all touch-sensitive and reaction times were recorded automatically. Mean total reaction times were obtained after 20 presentations of stimulus lights. Preexperimental training con- sisted of 100 stimulus presentations. This is suffi- cient to establish pretrial plateau reaction times.

Normal reaction times in individuals aged 25-55 years are 350-700 ms (Frewer and Hindmarch, 1988). The CRT has been shown to be significantly increased in patients with Alzheimer’s disease com- pared with normal controls (Pirozzolo et al., 1982; Simpson et al., 1991).

For each test a testing manual was consulted to improve consistency of testing across subjects. The same investigator undertook all the training and testing.

RESULTS The patients included in the study had a mean MMSE score of 17.7 (range 10-23). Two patients fulfilling the study criteria (both of whom were moderately severe) were unable to complete the CFFT test procedure. Individual patients were assessed using the GDS, AMT, MMSE, SCAG, CFFT and CRT. Summary statistics of the data are detailed in Table 1. Spearman rank correlation

Table 1. Summary data in patients with primary degener- ative dementia of the Alzheimer type: GDS, Global Deterioration Scale; AMT, Abbreviated Mental Test; MMSE, Mini-Mental State Examination; SCAG, Sandoz Clinical Assessment-Geriatric; CFFT, critical flicker fusion threshold; DES, flicker thresholds; CRT, choice reaction time

Test Mean SD Range

GDS 4.3 1.05 2-6 AMT 4.4 0.85 3-6 MMSE 17.7 3.5 10-23 SCAG 43.9 10.2 25-69 CFFT 23.5 Hz 2.34 19.0-28.2 Hz DES 22.3 Hz 2.21 18.5--27.6 Hz CRT 1834.5 ms 188.7 15 18-2200 ms

coefficients were calculated between CFFT, flicker thresholds, GDS, AMT, MMSE, SCAG and CRT. The results with significance levels are summarized in Table 2.

Flicker thresholds and CFFTs were both signifi- cantly correlated with AMT, GDS and CRT scores but not with MMSE and SCAG scores. In addition, the correlations between flicker thresholds and AMT were greater than between CFFT and AMT. Conversely, CFFT had a greater correlation than flicker thresholds with CRT and GDS. The correla- tion between MMSE and GDS was relatively low and not significant (0.342, p < 0.08) and between GDS and AMT -0 .495 ,~ < 0.001. The correlation between AMT and MMSE was intermediate (0.433, p < 0.026).

576 S. CURRAN, J. P. WATTIS AND I. HINDMARCH

Table 2. Spearman rank correlation coefficients in patients with primary degenerative dementia of the Alzheimer type

CRT AMT MMSE SCAG GDS

DESt -0.582 0.709 0.167 0.093 -0.597 p < 0.002* p < O.OOl* p < 0.581 p < 0.655 p < O.OOl*

p < 0.001 * p<O.OOl* p < 0.532 p < 0.730 p < 0.001* CFFT -0.764 0.644 0.151 0.071 -0.677

CRT - -0.575 -0.216 -0.033 0.552 p < 0.002* p < 0.29 p < 0.87 p < 0.003*

AMT -0.575 - 0.433 -0.114 -0.495 p < 0.002* p < 0.026* p < 0.59 p < 0.01*

MMSE -0.216 - - -0.354 0.342 p < 0.29 p < 0.074 p < 0.083

- 0.270 - - - SCAG p < 0.18

*Significant result. t Flicker thresholds.

DISCUSSION

A discussion of the relationship between CFFT and measures of CNS function including the EEG has been previously described (Curran et al., 1991b). The theoretical model currently adopted to explain flicker phenomena is the low pass jilter model; the temporal resolution of each of the components of the visual system becomes lower from retina to cor- tex (Kranda, 1982). It is not entirely clear from the literature what CFFT measures. However, there is some agreement that it measures the inte- grative capacity of the CNS/information processing capacity (Hindmarch and Wattis, 1988).

Measurement of CFFT/flicker thresholds in patients with Alzheimer’s disease has previously been demonstrated to be a reliable technique (Cur- ran et al., 1991b). The study reported here has demonstrated that both CFFTs and flicker thresh- olds are significantly correlated with measures of clinical global impression (GDS), cognitive impair- ment as measured using the AMT and psychomotor performance (CRT). CFFT and flicker thresholds are also quick and easy to measure, do not suffer from ceiling or floor effects, are non-invasive and can be readily used in the community. More cum- bersome techniques such as PET scans are largely confined to a few large teaching centres and are not available to the vast majority of patients, especially those in the community.

In choosing measures with which to compare CFFT and flicker thresholds, it is important to be aware that there are no agreed reference measures,

ie ‘gold’ standards, or any biological markers to fully confirm the clinical diagnosis. Neuropatho- logy has traditionally been the ‘gold’ standard but this has been recently challenged (Byrne et al., 199 1) and disagreements among neuropathologists seem as great as those among clinicians. Poor corre- lations between rating instruments may therefore be due to incorrect diagnosis (with consequent cli- nical heterogeneity), inappropriate choice of criter- ion measures and/or genuine lack of correlation.

The poor correlations between CFFT/flicker thresholds and the MMSE and SCAG scores might possibly be explained by the diverse range of func- tions/symptoms measured in the MMSE and the SCAG. There is some support for this in the data as the correlations are higher with the MMSE com- pared with the SCAG, whose content is even broader than the MMSE. It is interesting that the correlation between AMT and MMSE was less than might have been predicted (0.433, p < 0.026). Such findings again emphasize the point that it can be very difficult choosing criterion measures. The MMSE contains a broader range of items than the AMT, which is heavily weighted for memory and orientation. Loebel et al. (1990) have suggested that different symptoms/signs in Alzheimer’s disease progress independently and at varying rates during the natural history of the syndrome. On this basis, one would expect that the more heterogeneous the contents of a rating instrument, the smaller the cor- relation between the global measure (eg MMSE) and measures of discrete function (eg CFFT). In the case of CFFT and flicker thresholds it is un-

CRITICAL FLICKER FUSION IN PATIENTS WITH PDDAT 577

likely to be due to lack of correlation with the sever- ity of dementia as they are both highly and signifi- cantly correlated with the AMT and GDS.

The correlation between flicker thresholds and CFFT was very high (Y =0.93, p < 0.001). The majority of studies in normal subjects have indi- cated that the flicker thresholds are significantly higher than fusion thresholds and may reflect the effects of temporal adaptation to flicker. This mechanism, which seems to reduce the sensitivity to flicker, is absent in the measurement of flicker thresholds (Aufdembrinke, 1982). If the flicker and fusion thresholds are measures of the same pheno- menon, the slight differences might be explained by the erects of temporal adaptation thus resulting in less than ‘perfect’ correlations.

An alternative explanation is that CFFT and flicker thresholds measure slightly different CNS functions. As the age of the individual increases there is a significant reduction in the CFFT, eg McFarland et al. (1958), and most of this reduction appears to be due to changes in the flicker thresh- olds (Curran et al., 1990). In addition, in patients with Alzheimer’s disease, there is a marked reduc- tion in flicker thresholds with no concomitant change in fusion thresholds when compared to age, sex and occupational matched controls (Curran et al., 1991a). Interestingly, if normal young volun- teers are exposed to 40% nitrous oxide, flicker thresholds are significantly decreased whereas fusion thresholds remain unchanged (Fagan and Deary, 1989). There may therefore be potential to develop a ‘nitrous oxide’ test as a volunteer model of Alzheimer’s disease to facilitate development of pharmaceutical products. This procedure may have a role similar to scopolamine and benzodiazepines which have been used to induce memory deficits in volunteer subjects.

Both the CFFT and flicker thresholds were highly and significantly correlated with CRT, AMT and GDS but not with MMSE and SCAG. There is therefore good evidence that both the CFFT and flicker thresholds provide an objective and quanti- tative measure of the degree of severity of dementia. Flicker thresholds may be preferable because these appear to be more sensitive to cognitive change in patients with Alzheimer’s disease and are not affected by temporal adaptation. However, flicker thresholds run the risk of being contaminated by reaction time delays. CFFTs are slightly less dis- ease-sensitive but eliminate any influence of reac- tion time since the CFFT is an average of the flicker and fusion scores. On balance, CFFT measurement

is probably the preferred choice in studies using patients with Alzheimer’s disease.

CFFT measurement may also have an important role in monitoring change in cognitive function in patients with Alzheimer’s disease exposed to new pharmaceutical compounds. In addition, the pro- cedure could also assist as part of a battery of tests in monitoring cognitive decline in borderline cases of Alzheimer’s disease in the community. This approach would contribute to our understanding of the natural history of this syndrome by identify- ing patients with rapid decline in performance com- pared with normal controls. The latter application is important as it would influence the decision to start a pharmacological intervention and so reverse, arrest or slow down the disease process at an early stage, before deterioration was too advanced for therapeutic intervention to be suc- cessful.

Attention to improved volunteer models of Alz- heimer’s disease, diagnostic accuracy, neuropatho- logy and psychometric measures are all needed if developments in therapeutic interventions are to make any clinically meaningful progress. CFFT/ flicker thresholds should be considered for inclu- sion as part of a battery of tests for the assessment of patients with Alzheimer’s disease. This could be useful both to monitor change in the community and to demonstrate change in a clinical trial con- text.

ACKNOWLEDGEMENTS

The authors would like to thank the many general practitioners in the Leeds area for allowing access to their patients, the Violet M. Richards charity for its generous equipment grant, Dr John Rodgers, Reader in Psychology, Department of Psychology, Leeds University, for his helpful comments and the anonymous referees for their constructive criti- cisms

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