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Longitudinal visual evoked potentials in alzheimer's disease: A preliminary report
Longitudinal Visual Evoked Potentials in Alzheimer' s Disease: A Preliminary Report Gregory R.J. Swanwick, Michael Rowan, Robert F. Coen, Denis O'Mahony, Brian A. Lawlor, J. Bernard Walsh, and Davis Coakley Key Words:
Longitudinal, visual e v o k e d potentials, A l z h e i m e r ' s disease
BIOL PSYCmATRY 1996;39:455--457
Introduction
Methods
Alzheimer's disease (AD) is a disorder characterized by a progressive decline in cognitive and functional ability. Because of the marked variability in the clinical course of AD, accurate and acceptable methods of monitoring progression are essential. In established AD the rate of progression, as measured by psychometric tests, has been shown to be non-linear (Stem et al 1994) and may not be a true reflection of the pathological process (Thai et al 1988). Therefore, biological markers which more directly reflect neuronal damage might provide more useful prognostic information. In 1976 Visser et al reported that components of the flash visual evoked potential (FVEP) were delayed in senile and presenile dementia. A number of research groups have since documented FVEP latency delays in AD (Harding et al 1981; Cosi et al 1982; Wright et al 1984; Philpot et al 1990). Although Orwin et al (1986) reported increasing FVEP P2 component latency delay with progression in a single case of AD followed for 40 months, no longitudinal studies of VEPs in AD have yet been published. The aim of this paper is to evaluate FVEP P2 and N2 latency change over a one-year interval as a marker of progression in AD.
FVEP recordings were obtained from 22 patients meeting NINCDS-ADRDA criteria for probable AD (McKhann et al 1984) recruited from the memory clinic at St James' Hospital, Dublin. The assessment procedures have been described elsewhere (Swanwick et al in press). These were 18 females and four males with a mean age of 70.8 years (SD = 5.6 years; Range 58-79 years). At the initial assessment they encompassed a wide spread of cognitive scores within the very mild to moderate range of dementia severity: mean Mini-Mental state examination (MMSE) (Folstein et al 1975) score = 19.9 (SD = 3.9; range 13-27); mean CAMCOG (Roth et al 1986) score = 64.0 (SD = 14.1; range 40-93). In addition to a composite score (maximum = 107), the CAMCOG provides separate scores for attention, orientation, language, memory, praxis, perception, abstract thinking, and calculation. A cut-off point of 79/80 has a sensitivity and specificity of 92% and 96%, respectively for normal function vs. dementia (Roth et al 1986). The primary out-come measures for assessment of progression were the MMSE, CAMCOG, and an abbreviated form of the Blessed-Roth Dementia Scale (BRDS) (Blessed et al 1968). The FVEPs were recorded using left (O t) and right (02) occipital electrode sites referenced to Fz (midline frontal site). Binocular flash stimuli were presented at a rate of 2 Hz using a stroboscope placed 30 cm from the eye. The stroboscope was triggered by the Medelec ® "Mistral II" system. A filter band width of 0.1-30 Hz was applied and the response signals were amplified by a factor of 5 X 104. Taking a mean from the two channels, the N2 and P2 components were derived from 128 averaged evoked response sweeps. These measures were then repeated after a 12-month interval. The component latency
From the Mercer's Institute for Research on Ageing (GRJS, RFC, DO, JBW, DC), Department of Psychiatry (BAL), St. James's Hospital; Department of Pharmacology, Trinity College (MJR), Dublin, Ireland Address reprint requests to Dr Gregory R.J. Swanwick, Psychiatric Unit, University College Hospital Galway, Galway, Ireland. Received May 11, 1995; revised September 18, 1995.
© 1996 Society of Biological Psychiatry
0006-3223/96/$15.00 0006-3223(95)00523-4
456
BIOL PSYCHIATRY
Brief Reports
1996;39:455-457
Table 1. Annual Rates of Change for Cognitive/Functional Scales and for Flash Visual Evoked Potential Component Latencies Annual rate of change (SD)
df
Paired t
2.6 (3.9) 6.5 (9.7) -1.8 (1.6) 2.5 rnsec (11.7) 2.5 msec (17.6)
20 19 17 17 17
3.02 2.98 -4.81 -0.9 -0.6
MMSE CAMCOG BRDS FVEP N2 FVEP P2
November I991
L0,V
1 = 92
msec
2 = 124 m s e c M M S E = 18
Significance p p p p p
< < < = =
0.007 0.008 0.0002 0.19 0.28
CAMCOG = 72
May 1992
lO~,V
1 = 97 rnsee 2 = 132 m s e c MMSE=t7 C A M C O G = 63
values were all estimated by one rater (GS). These values were estimated blind with regard to the dates of the recordings. The cognitive, functional, and FVEP measures at the baseline and 12-month follow-up assessments were compared using paired t tests. As the FVEP latencies were expected to change only in the direction of increased duration, one-tailed significance levels were used. Ranking on the basis of annual rate of change (ARC) on cognitive and functional scales versus FVEP measures was compared using the Kendall rank correlation coefficient (x). The study was approved by the Federated Dublin Voluntary Hospitals ethics committee and informed consent was obtained from each subject or next of kin.
May 1993 I = 96
I0,~V
msec
2 = 144 m s e e MMSE=15 CAMCOG
= 52
1 =FVEPN2 3 0 m s e c / division
2 = FVEP P2
Figure 1. Serial flash visual evoked potential recordings from a 68-year-old woman with probable Alzheimer's disease.
Results The MMSE, CAMCOG, and BRDS all demonstrated a significant deterioration over the 12-month study period (Table 1). Follow-up FVEP recordings were not available for four subjects who were unwilling to have repeat testing. The FVEP P2 component latency had increased by greater than 5 milliseconds in only five subjects and neither the N2 nor the P2 component latency differences at follow-up reached statistical significance (Table 1). To date, two subjects have had further repeat testing after 18 months and another after 24 months. The P2 component latency increased by at least 10 milliseconds over the longer study period in all three of these subjects (Fig 1). There was a weak association between the FVEP N2 and MMSE ARCs ('r = 0.32,p = 0.025). Otherwise the FVEP ARCs were not related to change on the cognitive/functional scales. Neither was there any association between the baseline FVEP latencies and the subsequent rate of progression on cognitive or functional scales.
Discussion Orwin et al (1986) reported a progressive increase in FVEP P2 latency in a single 'presenile' case of AD with a relatively rapid clinical deterioration over 40 months. Only three of our subjects demonstrated an increase in P2 latency of the similar magnitude as that reported by Orwin et al. Overall, there was no significant change on either of the FVEP measures over the 12-month follow-up period. Although all three patients who were followed for over one year showed a progressive increase in P2 latency, the change was less than that reported by Orwin et al.
A more rapid rate of clinical progression was not noted in patients who had an obvious increase in P2 latency. Neither was the baseline P2 latency predictive of the subsequent clinical course. Thus, in the majority of our patients FVEP latency abnormalities were not directly related to dementia severity. There remains the possibility, as previously suggested by Pollock et al (1989), that VEP abnormalities may characterize a specific subgroup of AD patients with predominant visuospatial impairments. As none of the subjects in the present study had predominant deterioration in visuo-spatial function we cannot comment on this further. In conclusion, our findings do not support the clinical utility of FVEP latencies as markers for progression in AD over an interval of one year.
The authors thank Irene Bruce and Fiona Buggy, Mercer's Institute for Research on Ageing, for their invaluable assistance with the running of this study. Dr. Swanwick is a Health Research Board Research Fellow.
References Blessed G, Tomlinson BE, Roth M (1968): The association between quantitative measures of dementia and of senile change in the cerebral gray matter of elderly subjects. Br J Psychiatry 114:797-811. Cosi V, Vitelli E, Gozzoli L, Corona A, Ceroni M, Callieco R (1982): Visual evoked potentials in aging of the brain. In Courjon J, Manguiere F, Revol M (eds), Clinical applications
Brief Reports
of evoked potentials in neurology. New York: Raven Press, pp 109-115. Folstein MF, Folstein SE, McHugh PR (1975): 'Mini-Mental State': A practical method for grading the cognitive state of patients for the clinician. J Psychiatric Res 12:189-198. Harding GFA, Dogget CE, Orwin A, Smith EJ (1981): Visual evoked potentials in pre-senile dementia. In Spekreijse H, Apkarian PA (eds), Documenta Ophthalmologica Series No. 27. The Hague: Junk Publishers, pp 193-202. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task force on Alzheimer's Disease. Neurology 34:939-944. Orwin A, Wright CE, Harding GFA, Rowan DC, Rolfe EB (1986): Serial visual evoked potential recordings in Alzheimer's disease. Br Med J 293:9-10. Philpot M, Amin D, Levy R (1990): Visual evoked potentials in Alzheimer's disease: correlations with age and severity. EEG Clin Neurophysiol 77:323-329. Pollock VE, Schneider LS, Chui HC, Henderson V, Zemansky M, Sloane RB (1989): Visual evoked potentials in dementia: A meta-analysis and empirical study of Alzheimer's disease
BIOL PSYCHIATRY 1996;39:455-457
457
patients. Biol Psychiatry 25:1003-1013. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, Goddard R (1986): CAMDEX A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br J Psychiatry 149:698-709. Stern RG, Mohs RC, Davidson M, Schmeidler J, Silverman J, Kramer-Ginsberg E, Searcey T, Bierer L, Davis KL (1994): A longitudinal study of Alzheimer's disease: Measurement, rate, and predictors of cognitive deterioration. Am J Psychiatry 151:390-396. Swanwick GRJ, Coen RF, O'Mahony D, Tully M, Bruce I, Buggy F, Lawlor BA, Walsh JB, Coakley D: A memory clinic for the assessment of mild dementia. Ir Med J, in press. Thal LJ, Grundman M, Klauber MR (1988): Dementia: Characteristics of a referral population and factors associated with progression. Neurology 38:1083-1090. Visser SL, Stam FC, Van Tilburg W, Op Den Velde W, Blom JL, De Rijke W (1976): Visual evoked response in senile and presenile dementia. EEG Clin Neurophysiol 40:385-392. Wright CE, Harding GFA, Orwin A (1984): Pre-senile dement i a - t h e use of the flash and pattern VEP in diagnosis. EEG Clin Neurophysiol 57:405-415.
Longitudinal, visual e v o k e d potentials, A l z h e i m e r ' s disease
BIOL PSYCmATRY 1996;39:455--457
Introduction
Methods
Alzheimer's disease (AD) is a disorder characterized by a progressive decline in cognitive and functional ability. Because of the marked variability in the clinical course of AD, accurate and acceptable methods of monitoring progression are essential. In established AD the rate of progression, as measured by psychometric tests, has been shown to be non-linear (Stem et al 1994) and may not be a true reflection of the pathological process (Thai et al 1988). Therefore, biological markers which more directly reflect neuronal damage might provide more useful prognostic information. In 1976 Visser et al reported that components of the flash visual evoked potential (FVEP) were delayed in senile and presenile dementia. A number of research groups have since documented FVEP latency delays in AD (Harding et al 1981; Cosi et al 1982; Wright et al 1984; Philpot et al 1990). Although Orwin et al (1986) reported increasing FVEP P2 component latency delay with progression in a single case of AD followed for 40 months, no longitudinal studies of VEPs in AD have yet been published. The aim of this paper is to evaluate FVEP P2 and N2 latency change over a one-year interval as a marker of progression in AD.
FVEP recordings were obtained from 22 patients meeting NINCDS-ADRDA criteria for probable AD (McKhann et al 1984) recruited from the memory clinic at St James' Hospital, Dublin. The assessment procedures have been described elsewhere (Swanwick et al in press). These were 18 females and four males with a mean age of 70.8 years (SD = 5.6 years; Range 58-79 years). At the initial assessment they encompassed a wide spread of cognitive scores within the very mild to moderate range of dementia severity: mean Mini-Mental state examination (MMSE) (Folstein et al 1975) score = 19.9 (SD = 3.9; range 13-27); mean CAMCOG (Roth et al 1986) score = 64.0 (SD = 14.1; range 40-93). In addition to a composite score (maximum = 107), the CAMCOG provides separate scores for attention, orientation, language, memory, praxis, perception, abstract thinking, and calculation. A cut-off point of 79/80 has a sensitivity and specificity of 92% and 96%, respectively for normal function vs. dementia (Roth et al 1986). The primary out-come measures for assessment of progression were the MMSE, CAMCOG, and an abbreviated form of the Blessed-Roth Dementia Scale (BRDS) (Blessed et al 1968). The FVEPs were recorded using left (O t) and right (02) occipital electrode sites referenced to Fz (midline frontal site). Binocular flash stimuli were presented at a rate of 2 Hz using a stroboscope placed 30 cm from the eye. The stroboscope was triggered by the Medelec ® "Mistral II" system. A filter band width of 0.1-30 Hz was applied and the response signals were amplified by a factor of 5 X 104. Taking a mean from the two channels, the N2 and P2 components were derived from 128 averaged evoked response sweeps. These measures were then repeated after a 12-month interval. The component latency
From the Mercer's Institute for Research on Ageing (GRJS, RFC, DO, JBW, DC), Department of Psychiatry (BAL), St. James's Hospital; Department of Pharmacology, Trinity College (MJR), Dublin, Ireland Address reprint requests to Dr Gregory R.J. Swanwick, Psychiatric Unit, University College Hospital Galway, Galway, Ireland. Received May 11, 1995; revised September 18, 1995.
© 1996 Society of Biological Psychiatry
0006-3223/96/$15.00 0006-3223(95)00523-4
456
BIOL PSYCHIATRY
Brief Reports
1996;39:455-457
Table 1. Annual Rates of Change for Cognitive/Functional Scales and for Flash Visual Evoked Potential Component Latencies Annual rate of change (SD)
df
Paired t
2.6 (3.9) 6.5 (9.7) -1.8 (1.6) 2.5 rnsec (11.7) 2.5 msec (17.6)
20 19 17 17 17
3.02 2.98 -4.81 -0.9 -0.6
MMSE CAMCOG BRDS FVEP N2 FVEP P2
November I991
L0,V
1 = 92
msec
2 = 124 m s e c M M S E = 18
Significance p p p p p
< < < = =
0.007 0.008 0.0002 0.19 0.28
CAMCOG = 72
May 1992
lO~,V
1 = 97 rnsee 2 = 132 m s e c MMSE=t7 C A M C O G = 63
values were all estimated by one rater (GS). These values were estimated blind with regard to the dates of the recordings. The cognitive, functional, and FVEP measures at the baseline and 12-month follow-up assessments were compared using paired t tests. As the FVEP latencies were expected to change only in the direction of increased duration, one-tailed significance levels were used. Ranking on the basis of annual rate of change (ARC) on cognitive and functional scales versus FVEP measures was compared using the Kendall rank correlation coefficient (x). The study was approved by the Federated Dublin Voluntary Hospitals ethics committee and informed consent was obtained from each subject or next of kin.
May 1993 I = 96
I0,~V
msec
2 = 144 m s e e MMSE=15 CAMCOG
= 52
1 =FVEPN2 3 0 m s e c / division
2 = FVEP P2
Figure 1. Serial flash visual evoked potential recordings from a 68-year-old woman with probable Alzheimer's disease.
Results The MMSE, CAMCOG, and BRDS all demonstrated a significant deterioration over the 12-month study period (Table 1). Follow-up FVEP recordings were not available for four subjects who were unwilling to have repeat testing. The FVEP P2 component latency had increased by greater than 5 milliseconds in only five subjects and neither the N2 nor the P2 component latency differences at follow-up reached statistical significance (Table 1). To date, two subjects have had further repeat testing after 18 months and another after 24 months. The P2 component latency increased by at least 10 milliseconds over the longer study period in all three of these subjects (Fig 1). There was a weak association between the FVEP N2 and MMSE ARCs ('r = 0.32,p = 0.025). Otherwise the FVEP ARCs were not related to change on the cognitive/functional scales. Neither was there any association between the baseline FVEP latencies and the subsequent rate of progression on cognitive or functional scales.
Discussion Orwin et al (1986) reported a progressive increase in FVEP P2 latency in a single 'presenile' case of AD with a relatively rapid clinical deterioration over 40 months. Only three of our subjects demonstrated an increase in P2 latency of the similar magnitude as that reported by Orwin et al. Overall, there was no significant change on either of the FVEP measures over the 12-month follow-up period. Although all three patients who were followed for over one year showed a progressive increase in P2 latency, the change was less than that reported by Orwin et al.
A more rapid rate of clinical progression was not noted in patients who had an obvious increase in P2 latency. Neither was the baseline P2 latency predictive of the subsequent clinical course. Thus, in the majority of our patients FVEP latency abnormalities were not directly related to dementia severity. There remains the possibility, as previously suggested by Pollock et al (1989), that VEP abnormalities may characterize a specific subgroup of AD patients with predominant visuospatial impairments. As none of the subjects in the present study had predominant deterioration in visuo-spatial function we cannot comment on this further. In conclusion, our findings do not support the clinical utility of FVEP latencies as markers for progression in AD over an interval of one year.
The authors thank Irene Bruce and Fiona Buggy, Mercer's Institute for Research on Ageing, for their invaluable assistance with the running of this study. Dr. Swanwick is a Health Research Board Research Fellow.
References Blessed G, Tomlinson BE, Roth M (1968): The association between quantitative measures of dementia and of senile change in the cerebral gray matter of elderly subjects. Br J Psychiatry 114:797-811. Cosi V, Vitelli E, Gozzoli L, Corona A, Ceroni M, Callieco R (1982): Visual evoked potentials in aging of the brain. In Courjon J, Manguiere F, Revol M (eds), Clinical applications
Brief Reports
of evoked potentials in neurology. New York: Raven Press, pp 109-115. Folstein MF, Folstein SE, McHugh PR (1975): 'Mini-Mental State': A practical method for grading the cognitive state of patients for the clinician. J Psychiatric Res 12:189-198. Harding GFA, Dogget CE, Orwin A, Smith EJ (1981): Visual evoked potentials in pre-senile dementia. In Spekreijse H, Apkarian PA (eds), Documenta Ophthalmologica Series No. 27. The Hague: Junk Publishers, pp 193-202. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task force on Alzheimer's Disease. Neurology 34:939-944. Orwin A, Wright CE, Harding GFA, Rowan DC, Rolfe EB (1986): Serial visual evoked potential recordings in Alzheimer's disease. Br Med J 293:9-10. Philpot M, Amin D, Levy R (1990): Visual evoked potentials in Alzheimer's disease: correlations with age and severity. EEG Clin Neurophysiol 77:323-329. Pollock VE, Schneider LS, Chui HC, Henderson V, Zemansky M, Sloane RB (1989): Visual evoked potentials in dementia: A meta-analysis and empirical study of Alzheimer's disease
BIOL PSYCHIATRY 1996;39:455-457
457
patients. Biol Psychiatry 25:1003-1013. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, Goddard R (1986): CAMDEX A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br J Psychiatry 149:698-709. Stern RG, Mohs RC, Davidson M, Schmeidler J, Silverman J, Kramer-Ginsberg E, Searcey T, Bierer L, Davis KL (1994): A longitudinal study of Alzheimer's disease: Measurement, rate, and predictors of cognitive deterioration. Am J Psychiatry 151:390-396. Swanwick GRJ, Coen RF, O'Mahony D, Tully M, Bruce I, Buggy F, Lawlor BA, Walsh JB, Coakley D: A memory clinic for the assessment of mild dementia. Ir Med J, in press. Thal LJ, Grundman M, Klauber MR (1988): Dementia: Characteristics of a referral population and factors associated with progression. Neurology 38:1083-1090. Visser SL, Stam FC, Van Tilburg W, Op Den Velde W, Blom JL, De Rijke W (1976): Visual evoked response in senile and presenile dementia. EEG Clin Neurophysiol 40:385-392. Wright CE, Harding GFA, Orwin A (1984): Pre-senile dement i a - t h e use of the flash and pattern VEP in diagnosis. EEG Clin Neurophysiol 57:405-415.