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Visual evoked potentials in mild senile dementia of alzheimer type
Electroencephalography and clinical Neurophysiology, 1983, 55: 121 - 130
121
Elsevier Scientific Publishers Ireland, Ltd.
Clinical Section VISUAL EVOKED POTENTIALS IN MILD SENILE DEMENTIA OF ALZHEIMER TYPE LAWRENCE A. COBEN I WARREN L. DANZIGER and CHARLES P. HUGHES
Washington University Memory" and Aging Project, Department of Neurology and Neurological Surgery (Neurology), Washington University School of Medicine, 660 South Euclid, Box 8111, St. Louis, Mo. 63110 (U.S.A.) (Accepted for publication: September 15, 1982)
Senile dementia of the Alzheimer type (SDAT) is a fatal, incurable disease of unknown etiology. Although the natural history of SDAT is incompletely known, some patients have a rapidly progressive course, whereas others show less rapid deterioration and survive for up to ten or more years (Katzman 1976; Katzman et al. 1978). In a longitudinal study of SDAT we are gathering data on spontaneous EEG (Coben et al. 1982), visual evoked potentials, psychometric tests, computed tomography (CT) of the brain and clinical assessments. We report here the results for visual evoked potentials at initial evaluation of 40 subjects with mild SDAT and 40 matched healthy control subjects.
Methods
(1) Subjects and stimulation Eighty subjects enrolled in the Washington University Memory and Aging Project received an initial clinical dementia rating (CDR) from a 1.5 h interview and examination. Sufficient data are collected to allow the interviewer to rate the subject in each of 6 cognitive and behavioral categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The rater considers the subject's function only in relation to cognitive ability and to the subject's past performance. Possible ratings in each category are 0, 0.5, 1, 2 and 3, which range Address reprint requests to: Dr. Lawrence A. Coben, Department of Neurology and Neurosurgery (Neurology), 660 South Euclid Avenue, Box 8111, St. Louis, Mo. 63110, U.S.A.
from healthy (rating 0) to severe impairment (rating 3). The method of deriving the CDR from the ratings in each of the 6 categories and a discussion of the reliability and validity of CDR are given elsewhere (Hughes et al. 1982). This global rating of cognitive ability scores subjects as healthy (CDR 0), questionably (CDR 0.5), mildly (CDR 1), moderately (CDR 2), or severely demented (CDR 3). A typical CDR 1 subject has (1) moderate memory loss, more marked for recent events, sufficient to interfere with everyday activities; (2) difficulty with orientation for time but not for place and person; (3) moderate difficulty in solving complex problems, but usually with maintained social judgment; (4) inability to function independently in community affairs, although the subject may still engage in some and may still appear normal to casual inspection; (5) mild but definite impairment of function at home, with abandonment of more difficult chores and more complicated interests; and (6) a need for occasional prompting in personal care. A subject with CDR 0 has healthy ratings in all 6 categories. Forty subjects were classified as CDR 1, indicating definite mild dementia, but all were still living in the community. The other 40 subjects were healthy controls (CDR 0) individually matched for age, sex, socioeconomic status and race. Age range was 64.2-82.5 years. Twenty-one of the 40 pairs were female. The procedures used to exclude persons with depression, physical disorder, systemic illness, medication intake and other neurological disease, to establish the diagnosis of SDAT and to rate its severity are detailed elsewhere (Berg et al. 1982; Hughes et al. 1982). For the chessboard shift VEP, a modified func-
0013-4649/83/0000-0000/$03.00 © 1983 Elsevier Scientific Publishers Ireland, Ltd.
122 tion generator driven by a programmable acquisition system moved the rotating mirror of a Devices Ltd. pattern stimulator. The black and white chessboard pattern, 15 cm square, was placed 50 cm from the subject's eyelids. Each 8 m m x 8 m m square subtended 57 min of arc. The entire pattern was displaced to right or left alternately at an interval that was randomized within a + 110 msec range about an average value of 660 msec. The room was dimly lit overhead. Pattern luminance was 627 c d / m 2 for white squares, 63 c d / m 2 for black squares. One run comprised 128 pattern shifts. The stimulated eye was open and fixating on a black dot at the center of the pattern. The unstimulated eye was patched. The left eye was stimulated for two runs and then the right eye for two. For the flash VEP, a Grass PS2 photic stimulator set at intensity 2 was placed 38.5 cm from the eyelid. It delivered white flashes every 2000 _+ 110 msec. One run comprised 64 flashes. In masked runs, the subject wore Telex 1470 head phones which delivered binaural white noise at 40 dB HL, to mask photic stimulator noise. Monocular stimulation was delivered to the left eye for two runs, then the right eye for two runs, with both eyes closed and the unstimulated eye patched. Runs 1-4 were for chessboard shift. In half the subjects, runs 5 - 8 were masked flash, runs 9-12 unmasked. Alternate subjects within SDAT and control groups received unmasked before masked flash runs. Four runs of spontaneous resting E E G with the eyes closed, each lasting 16 sec, were recorded before the VEP runs (Coben et al. 1982).
(2) VEP signal acquisition and processing Silver-silver chloride discs were applied to the scalp with collodion and Grass electrode paste. Interelectrode impedances were 3 - 5 kI2. Discs were located at left and right occipital sites (2.5 cm above and 3.5 cm lateral to the midline of the inion); at the vertex (estimated Cz), and at estimated Fz (ground). A two-channel montage, left occipital (LO) to vertex (V) and right occipital (RO) to vertex was amplified (Grass P511J) at bandpass 1-3000 Hz, and put through a programmable Bessel linear phase analogue filter, 24 dB/octave, set at 200 Hz
L.A. COBEN ET AL. low pass. Each of the two channels of E E G was sampled at 500/sec, digitized, and averaged by an M-6800 microprocessor-based p r o g r a m m a b l e acquisition system (Montrose 1979 2; Montrose et al. 1980). The analysis epoch was 500 msec for chessboard shift and 1000 msec for flash. A calibrator inserted a pulse of 10 ~V into the first 60 msec of each analysis epoch (Emde 1964). All analogue E E G and E O G data were recorded on a Hewlett-Packard FM tape recorder. Flexible diskettes were used to store the on-line-averaged VEPs from chessboard and flash runs. Diskette data were transferred to a minicomputer (Artronix PC1200). One of us used predetermined scoring rules to manually edit the results obtained by an automatic feature-extraction program ('peak-picker') (Browder et al. 1980). Peak latencies and peak-topeak amplitudes were transferred to 9-track magnetic tape for archival storage and also for transport to a SAS data base on an IBM computer, where statistical calculations were done. Before peak-picking, the VEPs were digitally filtered at low pass 30 Hz, 24 dB/octave, with zero phase delay.
(3) Monitoring The subject sat in a recliner chair tilted back 45 ° . Pupils were dilated to 5 m m or more by applying 1% tropicamide (Mydriacyl) about 1 h before the start of the recording session. Each subject had an ophthalmological examination to rule out glaucoma and other intraocular disorders. An observer with a stopwatch sat next to the subject and recorded not only the percentage of each run during which the subject maintained target fixation during pattern shift stimulation, as judged by the chessboard's reflection in the pupil, but also the percentage of time that the subject maintained eye closure for flash stimulation. A second observer ran a 3-channel Grass E E G polygraph (Model 78 with 7P5 AC preamplifiers and 7DA driver amplifiers) to monitor drowsiness by recording the E E G from the right occipital-vertex
2 Montrose, J.K. Acquisition and Processing of the Visual Evoked Response. Thesis presented to Sever Institute of Washington University for Master of Science, Dec. 1979.
VEP IN SENILE DEMENTIA E E G derivation, and slow eye movements (SEMs) from both the left outer canthus to left ear, and the right outer canthus to left ear derivations (Rechtschaffen and Kales 1968). Time constant for eye movement channels was 0.45 sec. The subject was observed for behavioral signs of drowsiness. He was asked to keep his eyes open between runs. After each run he was asked whether he had been sleepy during that run. If clear signs of drowsiness were present behaviorally or in the polygraphic recording, the subject was alerted while the run continued, or in rare instances, the run was repeated after alerting the subject• To assess drowsiness, 3 measures were scored for each run. Behavior was scored as drowsy if any of the following was observed: eyelid ptosis or closure; yawning; and in a single subject, head lolling• The E E G was scored as stage I sleep (stage I drowsiness) if at least 50% of a 60 sec scoring period was free of alpha rhythm, or contained mixed slow (theta or delta) and fast waves (Rechtschaffen and Kales 1968)• The scoring period comprised 3 consecutive 20 sec scoring segments. Any unequivocal EEG pattern intervening between the fully awake state and stage I sleep was scored as drowsiness (pre-stage I drowsiness) (Davis et al. 1938)• Unequivocal slow eye movements lasting from one to several seconds, which begin in prestage I drowsiness (Liberson and Liberson 1967; Rechtschaffen and Kales 1968; Gabersek and Ghiloni 1973), were counted in each run. Fourteen subjects in each group were taking medications known to affect the E E G (benzodiazepines, tricyclic antidepressants, thyroid, chloral hydrate, haloperidol). A significant effect on the VEP is not considered likely• However, there are no studies of the effect on the chessboard shift VEP of these commonly used medications.
(4) Data analysis For each kind of VEP (chessboard shift and flash), a repeated measures analysis of variance was done. The between variable was group (SDAT vs. control). The three within variables were eye (left vs. right), run (first vs. second), and hemisphere (left vs. right)• A P value < 0.01 was taken to be significant•
123
Results
(a) Preliminary studies A bipolar derivation was chosen for the full study protocol because it gave higher amplitude peaks than did derivations using either ear as reference• This choice is supported by the field studies of Fender and Santoro (1977). We chose occipital and vertex electrode sites because they provided significantly higher amplitudes when compared to simultaneous recordings from International 10+20 system sites O1 and Cz for both chessboard shift and flash VEP. Test-retest reliability of peak latency for two recordings made in the same subject 1 week apart, using right eye stimulation, was as good (Pearson Product Moment r = 0.83) as the correlation between latency for left and right eye stimulation at the first recording session ( r = 0 . 8 2 ) . We concluded that test-retest reliability was satisfactory for our longitudinal study•
(b) Results at entry into the study Wave forms and peak nomenclature are shown in sample plots from the 'peak-picker' after interP2 ,
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Fig. I. Sample wave form plot from 'peak-picker' for chessboard shift VEP, after editing. Left eye stimulation (run 1), left occipital to vertex (LO-V) recording. Stimulus onset occurs at 0 msec. The first 60 msec are occupied by a 10 #V calibration signal, whose decay continues briefly after stimulus onset. Positivity at LO causes an upward deflection. Digitally filtered off-line at 30 Hz.
124
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larger in the SDAT group (Table I). These differences in latency and amplitude are shown in the composite wave form diagrams of Fig. 3, and in the individual wave forms of one SDAT subject and matched control subject in Fig. 4. There were no significant differences between the means of the VEPs evoked by left eye versus right eye stimulation, nor between the VEPs in the first and second run for a given eye. Amplitude was larger in the right hemisphere for NI-P2, P2-N2 and N2-P3. For controls, the N1-P2 amplitudes (mean ± S.D.) were, for the left hemisphere, 4.30 /W + 2.76, and for the right hemisphere 5.14/~V + 3.26. For P2-N2 the respective values were 10.03 _+ 3.82 and 11.64 + 3.87. For N2-P3 they were 2.50 _+ 1.50 and 3.13 + 1.86. For demented subjects the respective values for N1-P2 were 4.23 + 3.29 and 4.57 + 3.62. For P2-N2 they were 10.42 _+ 5.03 and 11.77 + 5.98. For N2-P3 they were 5.20 + 3.79 and 5.65 __+4.10. There was also an eye-hemisphere interaction for P2-N2, such that in the right hemisphere the amplitude for right eye stimulation was smaller than for left eye stimulation. The mean of the 8 values available in a given subject for a given latency or amplitude (two eyes, two runs, two hemispheres) was designated the 'subject mean.' The mean and standard deviation of these subject means were calculated for each latency and each amplitude in the control group, and also in the SDAT group. Thirteen of the 40
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0 120 240 msec Fig. 2. Sample wave form plot from 'peak-picker' for flash VEP, after editing. Left eye stimulation, left occipital to vertex (LO-V) recording. Stimulus onset occurs at 0 msec. The first 60 msec are occupied by a 10 #V calibration signal whose decay continues briefly after stimulus onset. Positivity at LO causes an upward deflection. Digitally filtered off-line at 30 Hz.
active editing for chessboard shift VEPs in Fig. 1, and for flash VEPs in Fig. 2. Table I shows the mean latencies and amplitudes for chessboard shift VEPs. Among latencies, only P3 and N3 showed a significant difference between the means of SDAT (CDR 1) and control subjects (CDR 0). The mean latency was longer in the SDAT group. Among amplitudes, only N2-P3 showed a significant difference, the mean being TABLE I
Latencies and amplitudes of chessboard shift VEPs a for 40 mildly b demented S D A T and 40 matched control ~ subjects• Latency (msec)
Amplitude (#V)
NI
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N2
P3
N3
NI-P2
P2-N2
N2-P3
P3-N3
CDR0
Mean (S.D.) Min Max
82.0 (10.0) 64 105
104.9 (8.0) 83 122
148.1 (12.6) 130 175
178.6 (14.6) 148 203
205.4 (16.9) 175 253
4.7 (2.9) 1.5 12.4
10.8 (3.7) 5.3 19.8
2.8 (1.6) 0.5 6.6
2.5 (1.5) 0.6 6.5
CDR1
Mean (S.D.) Min Max
83.5 (8.3) 67 102
106.3 (7.9) 87 123
151.6 (11.7) 126 178
193.9 (21.0) 157 235
218.2 (21.2) 184 276
4.4 (3.4) 0.6 16.2
11.1 (5.3) 3.3 24.5
5.4 (3.7) 0.6 14.0
2.8 (2.6) 0.4 13.0
"Leftandrighthemispherescombined. bCDR1. CCDR0.
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Fig, 3. Composite diagram of the wave form of the VEP to chessboard shift in mildly demented (solid line) and matched control subjects (dashed line). Plotted from the mean latency and amplitude values for each peak. Peak NI is taken as zero amplitude. Occipital positivity causes un upward deflection.
Fig. 4. Individual wave forms of chessboard shift VEP in a demented subject (bottom) and the matched control subject (top). Right eye stimulation (run 3), left occipital to vertex recording. Stimulus onset occurs at 0 msec. The first 60 msec are occupied by a 10 p,V calibration signal whose decay continues briefly after stimulus onset. Positivity at LO causes an upward deflection. Digitally filtered off-line at 30 Hz.
T A B L E II Latencies and amplitudes of flash VEPs a for 40 mildly b demented SDAT and 40 matched control c subjects. Latency (msec)
Amplitude (~V)
NI
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N2
P3
N3
N1-P2
P2-N2
N2-P3
P3-N3
CDR0
Mean (S.D.) Min Max
98.0 (11.3) 77 120
139.4 (14,9) 109 185
193.0 (21.7) 154 239
219.5 (25.0) 176 275
265.1 (31.7) 220 348
13.4 (6.2) 5.4 30.1
12.1 (5.7) 5.5 32.5
4.3 (3.1) 0.2 14.1
7.8 (3.7) 2.4 19.1
CDR1
Mean (S.D.) Min Max
99.7 (11.4) 78 120
143.4 (18.8) 103 186
190.5 (26.8) 125 252
219.7 (26.4) 181 294
267.2 (29.8) 212 346
14.7 (8.3) 1.7 35.4
10.9 (6.7) 0.8 28.0
4.9 (3.5) 0.2 16.4
9.6 (5,0) 2.3 22,5
~Unmaskedflashes, leftandrighthemispherescombined. hCDRI. CCDR0.
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L.A. COBEN ET AL.
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Fig. 5. Composite diagram of the wave form of the VEP to flash in mildly demented (solid line) and matched control subjects (dashed line). Plotted from the mean latency and amplitude values for each peak. Peak N I is taken as zero amplitude. Occipital positivity causes an upward deflection.
SDAT subjects had a subject mean P3 l a t e n c y larger than the highest value in the control group, and in 8 SDAT subjects the value was more than 2.5 S.D.s above the control group mean. Twelve SDAT subjects had a subject mean N2-P3 amplitude higher than that of any control subject, and all 12 values were more than 2.5 S.D.s above the control group mean. Table 1I shows the mean latencies and amplitudes for flash VEPs. Composite wave form diagrams for the SDAT and control groups are shown in Fig. 5. There were no significant differences
between the means of clinical groups, eyes, or runs. However, the mean amplitude of N1-P2, P2-N2 and P3-N3 was significantly larger in the right hemisphere. For controls, the N1-P2 amplitudes (mean + S.D.) were, for the left hemisphere 12.97 # V + 6.24, and for the right hemisphere 13.91 + 6.31. For P2-N2 the respective values were 11.40 + 5.75 and 12.87 + 5.80. For P3-N3 the values were 7.62 + 3.50, and 8.05 + 4.22. For demented subjects the respective values for N1-P2 were 13.89 #V ___7.95 and 15.43 + 9.30. For P2-N2 they were 11.40 + 5.75 and 12.87 + 5.80. For P3N3 they were 9.42 + 4.95 and 9.74 _ 5.40. There were significant eye-by-hemisphere interactions amplitudes N1-P2 and P2-N2, such that lower amplitude occurred with stimulation of the ipsilateral eye. Finally, an eye-by-hemisphere interaction for peak latency of N1 showed that latency was longer when the ipsilateral eye was stimulated. Masked and unmasked flash data showed no significant differences, except that the mean amplitude of P3-N3 was larger for the unmasked flashes than for the masked flashes. In Table III is shown the evidence of drowsiness that was obtained by observing the subject's behavior, and by recording the EEG and EOG. During the chessboard shift VEP runs sleepy behavior was seen in 4 runs in SDAT subjects (3% of runs) and in two runs in controls (1%). The EEG never showed any evidence of drowsiness. Slow eye movements (SEMs) were present in two runs in SDAT subjects (1% of runs) and in no runs (0%) in controls. In both runs in which SEMs appeared, there was only a single SEM, and it was at the lowermost limit of amplitude to be scored. During the flash VEP runs the earliest indicators of drowsiness, SEMs, were much more common than was a change in either the EEG or the behavior. SEMs occurred in 84% of runs in controls and less often but still in a substantial number (70%) in SDAT subjects. A change in the EEG, which occurs shortly after the SEMs appear, was also more common in control runs (11% vs. 4%), and was more than twice as common as were behavioral indications of sleepiness. No subject reached stage I; only pre-stage I drowsiness was seen. In only one instance were SEMs absent when EEG changes were present.
VEP IN SENILE DEMENTIA
127
TABLE II1 Evidence of drowsiness: Behavior, EEG and EOG a.
Slow eye movements (SEMs) in EOG a EEG change (pre-stage I) Looks or acts sleepy
Check VEP runs (84 sec recording period)
Flash VEP runs (128 sec recording period)
Control e
Demented e
Control e
Demented e
0% (0)
1% (2)b 0% (0) 3% (4)
84% (128)*** 11% (17) c** 0,7% (1)
70% (103) 4% (6) d 5% (8) *
0% (0) 1% (2)
a Electro-oculogram, b These rare SEMs are unexpected in the eyes-open condition. They are regarded as false positives in the polygraph recording. In all 17 runs there were also SEMs. d In 5 of the 6 runs there were also SEMs. e Percentages are based upon 152 runs (recording periods) in controls and 148 runs in demented subjects. Number in parentheses is the number of runs in which this feature of drowsiness appeared. *** X2, control vs. demented, = 9.0 P < 0.005. ** X2, control vs. demented, = 5.4 P < 0.02. * X2, control vs. demented, = 5.8 P < 0.05.
Discussion Both the P3 a n d N 3 p e a k s in the V E P for c h e s s b o a r d shift have significantly longer m e a n latencies in the S D A T subjects ( C D R l) t h a n in their m a t c h e d c o n t r o l s ( C D R 0). This is the earliest c h a n g e r e p o r t e d thus far in the l a t e n c y of the V E P w i t h a d v a n c i n g A l z h e i m e r disease, since our dem e n t e d subjects are only m i l d l y i m p a i r e d mentally, a n d no significant differences have yet app e a r e d in the latencies of their flash VEPs. A l t h o u g h drowsiness is 'a p o s s i b l e e x p l a n a t i o n for our finding of increased p e a k latency, the evidence does n o t s u p p o r t this possibility. T h e significant differences b e t w e e n g r o u p s in the VEP involve only P3 a n d N 3 latency, whereas drowsiness might be e x p e c t e d to affect P2 as well (Shagass a n d T r u s t y 1966). Also, the significant differences b e t w e e n g r o u p s involve o n l y the c h e s s b o a r d VEP, even though the flash V E P is k n o w n to be affected b y drowsiness (Shagass a n d T r u s t y 1966). M o r e direct evidence c o n c e r n i n g the presence of drowsiness is p r o v i d e d b y our behavioral, E E G a n d E O G data. T h e r e was so little evidence of drowsiness d u r i n g the check V E P runs in b o t h groups that the significant differences in latency a n d a m p l i t u d e b e t w e e n S D A T a n d c o n t r o l subjects c a n n o t be
e x p l a i n e d b y drowsiness. Also, drowsiness w o u l d be expected to cause a decrease in a m p l i t u d e , b u t we o b s e r v e d an increase in a m p l i t u d e in the S D A T group. T h e situation with respect to drowsiness d u r i n g the flash V E P runs is m o r e complex. If drowsiness h a d been m o r e p r e v a l e n t in the d e m e n t e d t h a n in controls, it could have falsely increased the l a t e n c y a n d decreased the a m p l i t u d e of the p e a k s (Shagass a n d T r u s t y 1966). However, we f o u n d no such changes in latency. (A decrease in a m p l i t u d e due to drowsiness c o u l d have been negated b y an increase d u e to dementia.) The alternative supposition, that drowsiness was m o r e p r e v a l e n t in controls, is s u p p o r t e d b y the fact that the two m o s t sensitive i n d i c a t o r s of drowsiness, S E M s a n d a c h a n g e in the E E G , were b o t h m o r e prevalent in the c o n t r o l subjects. A greater prevalence of drowsiness in the controls could have m a s k e d a difference of l a t e n c y between the two groups of subjects b y falsely increasing control latencies. However, it w o u l d also have falsely increased a difference of a m p l i t u d e b y decreasing c o n t r o l amplitudes. W e f o u n d no such difference in a m p l i tude. W e therefore c o n c l u d e that drowsiness did n o t m a s k a difference between the two groups. Also, slow eye m o v e m e n t s p r o v e d to be a useful
128
warning signal that the early EEG change of prestage I drowsiness was imminent. Our finding of increased latency in the VEP raises the question whether the delay arises in the cortex itself, in some portion of the visual pathway afferent to the cortex, or both. An increased central conduction time has been reported in a group of patients with pre-senile and senile Alzheimer disease, as shown by an increased interpeak latency V - I of the auditory brain stem evoked potential (Harkins and Lenhardt 1980). Thus, by analogy, there is the possibility that in the visual system, a delayed cortical evoked potential may be due in part to increased central conduction time rather than to a cortical impairment. Structural changes in the occipital cortex, including the visual cortex, are found in both normal aging and senile dementia (McMenemy 1940, p. 224; Blessed et al. 1968; Tomlinson et al. 1968; Devaney and Johnson 1980). Our finding that only the late peaks of the chessboard shift VEP are delayed in mild SDAT does not distinguish between a causative lesion in the visual path afferent to the cortex and one in the cortex. However, the increased amplitude of N2-P3 is consistent with an intracortical loss of inhibitory potentials. Scheibel and Scheibel (1975) and Scheibel et al. (1976) suggested that a loss of inhibition might occur with synaptic uncoupling of cortico-cortical connections as a consequence of the loss of horizontal dendritic components of cortical neurons that was found in prefrontal and superior temporal cortex as well as in the limbic lobe in senile dementia. In parahippocampal gyrus sections Buell and Coleman (1979) noted the atrophic dendritic trees described by Scheibel et al., but were unable, on that basis, to distinguish between the adult, aged and senile dementia groups. Dustman et al. (1981) suggested that inhibitory functioning is reduced in the visual systems of the elderly as well as in those of children, because the similarity between patterned and unpatterned flash visual evoked potentials was greater at these extremes of the life span than in the middle range. Still another possibility, as yet unexplored, is that extracortical structures outside the visual pathway might be altered in SDAT, as for example the reticular system, which was shown to influence the VEP by Fuster and by
L.A. COBEN ET AL.
Lindsley and Griffiths (see Lindsley 1961). There are no prior studies concerning the chessboard shift VEP in dementia. Using flash stimulation, however, Straumanis et al. (1965) found that demented elderly subjects had longer latencies than did elderly control subjects for their 3 latest peaks (peaks 6, 7, 8). Their peaks 6 and 7 probably correspond to our peaks P3 and N3, although the recording sites and stimulation method were different in the two studies. Our subjects are only mildly demented and still live in the community, in contrast to the subjects of Straumanis et al. who were institutionalized, and who had more severe dementia. This difference in severity of dementia probably explains the absence of latency differences in the flash VEPs of our subjects. We expect to see differences develop in our longitudinal study as dementia progresses. Visser et al. (1976) reported increased latency for all but the first of 6 peaks in the flash VEPs of elderly demented subjects, but did not have an elderly control group. Increasing latency of late components (100-400 msec) of flash VEP with age in normals has been found in studies by Kooi and Bagchi (1964), Straumanis et al. (1965) and Dustman et al. (1981) (see also Beck et al. (1979) p. 210); and of chessboard shift VEP by Celesia and Daly (1977), Coben (1977), Allison et al. (1978, pp. 11-12) and Shaw and Cant (1980). The details of this aging curve are not settled. Latency changes may relate in part to luminance (Shaw and Cant 1980). It has been suggested that there may be an increase in the variance rather than an increase in the mean of the latency (Stockard et al. 1979). In the present study, the use of matched healthy controls assures that the observed changes are not due to normal aging. The higher amplitudes in the right hemisphere for both chessboard shift and flash VEPs in the present study are not likely to be due to a consistent asymmetry of electrode placement, since not all peak-to-peak amplitudes are asymmetrical. Also, the right hemisphere showed larger occipital VEPs at all ages in the study of Beck et al. (1975, p. 187). Among college students, larger VEPs were found on the right in the central area, but not in the occipital area (Beck and Dustman 1979, p.
454).
VEP IN SENILE DEMENTIA T h e absence of significant a m p l i t u d e differences b e t w e e n o u r S D A T a n d c o n t r o l g r o u p s for the flash V E P is consistent with the findings of S t r a u m a n i s et al. (1965). T h e y f o u n d n o a m p l i t u d e differences a m o n g the late c o m p o n e n t s (latency > 100 msec).
Summary Visual e v o k e d p o t e n t i a l s (VEPs) to c h e s s b o a r d shift a n d to flash s t i m u l a t i o n were r e c o r d e d from 40 subjects with senile d e m e n t i a of A l z h e i m e r t y p e ( S D A T ) a n d 40 i n d i v i d u a l l y m a t c h e d c o n t r o l subjects. All of the S D A T subjects h a d only a mild degree of d e m e n t i a a n d were still living in the community. A n a l y s i s of v a r i a n c e showed significant differences b e t w e e n d e m e n t e d a n d c o n t r o l g r o u p m e a n s for 3 c h e s s b o a r d shift V E P measures, the d e m e n t e d g r o u p having longer l a t e n c y o f p e a k s P3 a n d N3, a n d larger a m p l i t u d e of segment N2-P3. T h e s e three are the earliest r e p o r t e d changes in the V E P in A l z h e i m e r disease, since the flash VEPs s h o w e d no m e a s u r e in which the d e m e n t e d a n d c o n t r o l group m e a n s differed significantly.
R~sum~
Potentiels ~voqu& v&uels clans la d~mence s~nile l~gkre de type Alzheimer O n a enregistr~ les p o t e n t i e l s visuels 6voqu~s (PEV) p a r d r p l a c e m e n t s de d a m i e r s et s t i m u l a t i o n s t r o b o s c o p i q u e d a n s 40 cas de d r m e n c e s~nile de t y p e A l z h e i m e r ( D S T A ) et 40 t~moins srlectionn~s de faqon adequate. Les D S T A sblectionn~s ne p r r s e n t a i e n t q u ' u n degr~ 16ger de d r m e n c e et ~taient encore c a p a b l e d e vivre en famille. L ' a n a l y s e de v a r i a n c e des P E aux d r p l a c e m e n t d e d a m i e r a rbvrl6 des diffrrences significatives de la m o y e n n e p o u r 3 mesures prises sur c h a c u n des d e u x g r o u p e s ( D S T A et contrSles), le g r o u p e d & m e n t pr~sentant une latence allong~e des pics P3 et N 3 et une a m p l i t u d e plus i m p o r t a n t e du segm e n t N2-P3. Ces 3 mesures sont les c h a n g e m e n t s les plus pr~coces du PEV au tout d r b u t de la
129 m a l a d i e d ' A l z h e i m e r , alors que les PEV o b t e n u s d a n s les deux g r o u p e s p a r s t i m u l a t i o n stroboscop i q u e n ' o n t pr~sent~ a u c u n e d i f f & e n c e significative. So many people helped in this study that space permits only a list rather than a full description of their contributions: Drs. James Blaine, Lewis Thomas; Ronald Burde and William Landau; Professor Harold Shipton; Michael Browder, James Montrose, Stanley Phillips, Bonnie Schumann, Toby Schumann, Emogene Jackson, David Chi, Helen Gavigan. This work was supported in part by Grant No. RO 1 MH31054 from the National Institutes of Mental Health and by Grant RR 00396 from the Division of Research Resources, N.I.H.
References Allison, T., Goff, W.R. and Wood, C.C. Auditory, somatosensory and visual evoked potentials in the diagnosis of neuropathology: recording considerations and normative data. In: F. Lehmann and E. Callaway (Eds.), Human Evoked Potentials: Applications and Problems. Plenum, New York, 1978: 1-16. Beck, E.C. and Dustman, R.E. Changes in evoked responses during maturation and aging in man and macaque. In: N. Burch and H.L. Altshuler (Eds.), Behavior and Brain Electrical Activity. Plenum, New York, 1975: 431-472. Beck, E.C., Dustman, R.E. and Schenkenberg, T. Life span changes in the electrical activity of the human brain as reflected in the cerebral evoked response. In: J,M. Ordy and K.R. Brizzee (Eds.), Neurobiology of Aging. Adv. in Behav. Biol., Vol. 16. Plenum, New York, 1975: 175-192. Beck, E.C., Dustman, R.E., Blusewica, M.Ju. and Cannon, W.G. Cerebral evoked potentials and correlated neuropsychological changes in the human brain during aging: a comparison of alcoholism and aging. In: J.M. Ordy and K. Brizzee (Eds.), Sensory Systems and Communication in the Elderly. Aging, Vol. 10. Raven Press, New York, 1979: 203-226. Berg, L., Hughes, C.P., Coben, L.A., Danziger, W.L., Martin, R. and Knesevitch, J. Mild senile dementia of Alzheimer type (SDAT): research diagnostic criteria, recruitment and description of a study population. J. Neurol. Neurosurg. Psychiat., 1982, in press. Blessed, G., Tomlinson, B.E. and Roth, M. The association between quantitative measures of dementia and a senile change in the cerebral grey matter of elderly subjects. Brit. J. Psychiat., 1968, 114: 797-811. Blumenhardt, L.D. and Halliday, A.M. Hemisphere contributions to the composition of the pattern-evoked potential waveform. Exp. Brain Res., 1979, 36: 53-69. Browder, M.W., Blaine, G.J., Montrose, J.K., Coben, L.A. and Thomas, L.J. Visual evoked potential: computer assisted acquisition and processing. In: Proc. 4th Ann. Symp. on Computer Applications in Medical Care, 1980:1240-1249.
130 Buell, S.J. and Coleman, P.D. Dendritic growth in the aged human brain and failure of growth in senile dementia. Science, 1979, 206: 854-856. Celesia, G.G. and Daly, R.F. Effects of aging on visual evoked response. Arch. Neurol. (Chic.), 1977, 34: 403-407. Coben, L.A. The effect of aging and of dimming the stimulus upon the visual evoked response to reversing checks in man. Electroenceph. clin. Neurophysiol., 1977, 43: 559. Coben, L.A., Danziger, W.L. and Berg, L. Frequency analysis of the resting awake EEG in mild senile dementia of Alzheimer type. Submitted to Electroenceph, clin. Neurophysiol., 1982. Davis, H., Davis, P.A., Loomis, A.L., Harvey, E.N. and Hobart, G. Human brain potentials during the onset of sleep. J. Neurophysiol., 1938, 1: 24-38. Devaney, K.O. and Johnson, H.A. Neuron loss in the aging visual cortex of man. J. Gerontol., 1980, 35: 836-841. Dustman, R.E., Snyder, E.W. and Schlehuber, C.J. Life-span alterations in visually evoked potentials and inhibitory function. Neurobiol. Aging, 1981, 2: 187-192. Emde, J.W. A time-locked, low level calibrator. Electroenceph. clin. Neurophysiol., 1964, 16: 616. Fender, D.H. and Santoro, T.P. Spatiotemporal mapping of scalp potentials. J. opt. Soc. Amer., 1977, 67: 1489-1494. Gabersek, V. and Ghiloni, H. Analysis of the ocular movements during the onset of sleep. In: W. Koella (Ed.), Sleep: Physiology, Biochemistry, Psychology, Pharmacology, Clinical Implications. 1st Europ. Congr. Sleep Res., Basel, 1972. Karger, Basel, 1973: 376-379. Harkins, W. and Lenhardt, M. Brainstem auditory evoked potentials in the elderly. In: L.W. Poon (Ed.), Aging in the 1980's, Psychological Issues. Amer. Psychol. Ass., 1980: Ch. 7. Hughes, C.P., Berg, L., Danziger, W.L., Coben, L.A. and Martin, R. A new clinical scale for the staging of dementia. Brit. J. Psychiat., 1982, 140: 566-572. Katzman, R. The prevalence and malignancy of Alzheimer's disease: a major killer. Arch. Neurol. (Chic.), 1976, 33: 218-219. Katzman, R., Terry, R.D. and Bick, K.L. Recommendations of the nosology, epidemiology, and etiology and pathophysiology commissions of the workshop-conference on Alzheimer's disease-senile dementia and related disorders. In: R. Katzman, R.D. Terry and K.L. Bick (Eds.), Aging, Vol. 7. Raven Press, New York, 1978: 579-585. Kooi, K.A. and Bagchi, B.K. Visual evoked responses in man: normative data. Ann. N.Y. Acad. Sci., 1964, 112: 254-269. Liberson, C.W. and Liberson, W.T. Eye movements during the alert state (pscyhophysiological correlations under resting
L.A. COBEN ET AL. conditions). Electroenceph. clin. Neurophysiol., 1967, 23: 594. Lindsley, D.B. Electrophysiology of the visual system and its relation to perceptual phenomena. In: M.A. Brazier (Ed.), Brain and Behavior, Vol. 1. American Institute of Biological Sciences, Washington, D.C., 1961: 359-392. McMenemy, W.H. Alzheimer's disease: a report of six cases. J. Neurol. Psychiat.. 1940, 3:211-240. Montrose, J. VER System Users Manual. Biomedical Computer Lab., Washington University School of Medicine, Monogr. 368, 1979. Montrose, J.K., Browder, M.W. and Blaine, G.J. VER System-Technical Reference Manual. Biomedical Computer Lab., Washington University School of Medicine, Monogr. 371, 1980. Rechtschaffen, A. and Kales, A. (Eds.) A Manual of Standardized Terminology, Techniques and Scoring System for Sleep States of Human Subjects. U.S. Dept. of Health, Education and Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological Diseases and Blindness, Neurological Information Network, Bethesda, Md., 1968. Scheibel, M.E. and Scheibel, A.B. Structural changes in the aging brain. In: H. Brady, D. Harman and J.M. Ordy (Eds.), Aging, Vol. 1. Raven Press, New York, 1975:11-37. Scheibel, M.E., Lindsay, R.D., Tomiyasu, U. and Scheibel, A.G. Progressive dendritic changes in the aging human limbic system. Exp. Neurol., 1976, 53: 420-430. Shagass, C. and Trusty, D. Somatosensory and visual cerebral evoked response changes during sleep. In: J. Wortis (Ed.), Recent Advances in Biological Psychiatry, Vol. VIII. Plenum Press, New York, 1966: 321-334. Shaw, N.A. and Cant, B.R. Age-dependent changes in the latency of the pattern visual evoked potential. Electroenceph. clin. Neurophysiol., 1980, 48: 237-241. Stockard, J.J., Hughes, J.F. and Sharbrough, F.W. Visually evoked potentials to electronic pattern reversal: latency variations with gender, age, and technical factors. Amer. J. EEG Technol., 1979, 19: 171-204. Straumanis, J.J., Shagass, C. and Schwartz, M. Visually evoked cerebral response changes associated with chronic brain syndromes and aging. J. Gerontol., 1965, 20: 498-506. Tomlinson, B.E., Blessed, G. and Roth, M. Observations on the brains of non-demented old people. J. neurol. Sci., 1968, 7: 331-356. Visser, S.L., Stam, F.C., Van Tilburg, W. et al. Visual evoked response in senile and presenile dementia. Electroenceph. clin. Neurophysiol., 1976, 40: 385-392.
121
Elsevier Scientific Publishers Ireland, Ltd.
Clinical Section VISUAL EVOKED POTENTIALS IN MILD SENILE DEMENTIA OF ALZHEIMER TYPE LAWRENCE A. COBEN I WARREN L. DANZIGER and CHARLES P. HUGHES
Washington University Memory" and Aging Project, Department of Neurology and Neurological Surgery (Neurology), Washington University School of Medicine, 660 South Euclid, Box 8111, St. Louis, Mo. 63110 (U.S.A.) (Accepted for publication: September 15, 1982)
Senile dementia of the Alzheimer type (SDAT) is a fatal, incurable disease of unknown etiology. Although the natural history of SDAT is incompletely known, some patients have a rapidly progressive course, whereas others show less rapid deterioration and survive for up to ten or more years (Katzman 1976; Katzman et al. 1978). In a longitudinal study of SDAT we are gathering data on spontaneous EEG (Coben et al. 1982), visual evoked potentials, psychometric tests, computed tomography (CT) of the brain and clinical assessments. We report here the results for visual evoked potentials at initial evaluation of 40 subjects with mild SDAT and 40 matched healthy control subjects.
Methods
(1) Subjects and stimulation Eighty subjects enrolled in the Washington University Memory and Aging Project received an initial clinical dementia rating (CDR) from a 1.5 h interview and examination. Sufficient data are collected to allow the interviewer to rate the subject in each of 6 cognitive and behavioral categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The rater considers the subject's function only in relation to cognitive ability and to the subject's past performance. Possible ratings in each category are 0, 0.5, 1, 2 and 3, which range Address reprint requests to: Dr. Lawrence A. Coben, Department of Neurology and Neurosurgery (Neurology), 660 South Euclid Avenue, Box 8111, St. Louis, Mo. 63110, U.S.A.
from healthy (rating 0) to severe impairment (rating 3). The method of deriving the CDR from the ratings in each of the 6 categories and a discussion of the reliability and validity of CDR are given elsewhere (Hughes et al. 1982). This global rating of cognitive ability scores subjects as healthy (CDR 0), questionably (CDR 0.5), mildly (CDR 1), moderately (CDR 2), or severely demented (CDR 3). A typical CDR 1 subject has (1) moderate memory loss, more marked for recent events, sufficient to interfere with everyday activities; (2) difficulty with orientation for time but not for place and person; (3) moderate difficulty in solving complex problems, but usually with maintained social judgment; (4) inability to function independently in community affairs, although the subject may still engage in some and may still appear normal to casual inspection; (5) mild but definite impairment of function at home, with abandonment of more difficult chores and more complicated interests; and (6) a need for occasional prompting in personal care. A subject with CDR 0 has healthy ratings in all 6 categories. Forty subjects were classified as CDR 1, indicating definite mild dementia, but all were still living in the community. The other 40 subjects were healthy controls (CDR 0) individually matched for age, sex, socioeconomic status and race. Age range was 64.2-82.5 years. Twenty-one of the 40 pairs were female. The procedures used to exclude persons with depression, physical disorder, systemic illness, medication intake and other neurological disease, to establish the diagnosis of SDAT and to rate its severity are detailed elsewhere (Berg et al. 1982; Hughes et al. 1982). For the chessboard shift VEP, a modified func-
0013-4649/83/0000-0000/$03.00 © 1983 Elsevier Scientific Publishers Ireland, Ltd.
122 tion generator driven by a programmable acquisition system moved the rotating mirror of a Devices Ltd. pattern stimulator. The black and white chessboard pattern, 15 cm square, was placed 50 cm from the subject's eyelids. Each 8 m m x 8 m m square subtended 57 min of arc. The entire pattern was displaced to right or left alternately at an interval that was randomized within a + 110 msec range about an average value of 660 msec. The room was dimly lit overhead. Pattern luminance was 627 c d / m 2 for white squares, 63 c d / m 2 for black squares. One run comprised 128 pattern shifts. The stimulated eye was open and fixating on a black dot at the center of the pattern. The unstimulated eye was patched. The left eye was stimulated for two runs and then the right eye for two. For the flash VEP, a Grass PS2 photic stimulator set at intensity 2 was placed 38.5 cm from the eyelid. It delivered white flashes every 2000 _+ 110 msec. One run comprised 64 flashes. In masked runs, the subject wore Telex 1470 head phones which delivered binaural white noise at 40 dB HL, to mask photic stimulator noise. Monocular stimulation was delivered to the left eye for two runs, then the right eye for two runs, with both eyes closed and the unstimulated eye patched. Runs 1-4 were for chessboard shift. In half the subjects, runs 5 - 8 were masked flash, runs 9-12 unmasked. Alternate subjects within SDAT and control groups received unmasked before masked flash runs. Four runs of spontaneous resting E E G with the eyes closed, each lasting 16 sec, were recorded before the VEP runs (Coben et al. 1982).
(2) VEP signal acquisition and processing Silver-silver chloride discs were applied to the scalp with collodion and Grass electrode paste. Interelectrode impedances were 3 - 5 kI2. Discs were located at left and right occipital sites (2.5 cm above and 3.5 cm lateral to the midline of the inion); at the vertex (estimated Cz), and at estimated Fz (ground). A two-channel montage, left occipital (LO) to vertex (V) and right occipital (RO) to vertex was amplified (Grass P511J) at bandpass 1-3000 Hz, and put through a programmable Bessel linear phase analogue filter, 24 dB/octave, set at 200 Hz
L.A. COBEN ET AL. low pass. Each of the two channels of E E G was sampled at 500/sec, digitized, and averaged by an M-6800 microprocessor-based p r o g r a m m a b l e acquisition system (Montrose 1979 2; Montrose et al. 1980). The analysis epoch was 500 msec for chessboard shift and 1000 msec for flash. A calibrator inserted a pulse of 10 ~V into the first 60 msec of each analysis epoch (Emde 1964). All analogue E E G and E O G data were recorded on a Hewlett-Packard FM tape recorder. Flexible diskettes were used to store the on-line-averaged VEPs from chessboard and flash runs. Diskette data were transferred to a minicomputer (Artronix PC1200). One of us used predetermined scoring rules to manually edit the results obtained by an automatic feature-extraction program ('peak-picker') (Browder et al. 1980). Peak latencies and peak-topeak amplitudes were transferred to 9-track magnetic tape for archival storage and also for transport to a SAS data base on an IBM computer, where statistical calculations were done. Before peak-picking, the VEPs were digitally filtered at low pass 30 Hz, 24 dB/octave, with zero phase delay.
(3) Monitoring The subject sat in a recliner chair tilted back 45 ° . Pupils were dilated to 5 m m or more by applying 1% tropicamide (Mydriacyl) about 1 h before the start of the recording session. Each subject had an ophthalmological examination to rule out glaucoma and other intraocular disorders. An observer with a stopwatch sat next to the subject and recorded not only the percentage of each run during which the subject maintained target fixation during pattern shift stimulation, as judged by the chessboard's reflection in the pupil, but also the percentage of time that the subject maintained eye closure for flash stimulation. A second observer ran a 3-channel Grass E E G polygraph (Model 78 with 7P5 AC preamplifiers and 7DA driver amplifiers) to monitor drowsiness by recording the E E G from the right occipital-vertex
2 Montrose, J.K. Acquisition and Processing of the Visual Evoked Response. Thesis presented to Sever Institute of Washington University for Master of Science, Dec. 1979.
VEP IN SENILE DEMENTIA E E G derivation, and slow eye movements (SEMs) from both the left outer canthus to left ear, and the right outer canthus to left ear derivations (Rechtschaffen and Kales 1968). Time constant for eye movement channels was 0.45 sec. The subject was observed for behavioral signs of drowsiness. He was asked to keep his eyes open between runs. After each run he was asked whether he had been sleepy during that run. If clear signs of drowsiness were present behaviorally or in the polygraphic recording, the subject was alerted while the run continued, or in rare instances, the run was repeated after alerting the subject• To assess drowsiness, 3 measures were scored for each run. Behavior was scored as drowsy if any of the following was observed: eyelid ptosis or closure; yawning; and in a single subject, head lolling• The E E G was scored as stage I sleep (stage I drowsiness) if at least 50% of a 60 sec scoring period was free of alpha rhythm, or contained mixed slow (theta or delta) and fast waves (Rechtschaffen and Kales 1968)• The scoring period comprised 3 consecutive 20 sec scoring segments. Any unequivocal EEG pattern intervening between the fully awake state and stage I sleep was scored as drowsiness (pre-stage I drowsiness) (Davis et al. 1938)• Unequivocal slow eye movements lasting from one to several seconds, which begin in prestage I drowsiness (Liberson and Liberson 1967; Rechtschaffen and Kales 1968; Gabersek and Ghiloni 1973), were counted in each run. Fourteen subjects in each group were taking medications known to affect the E E G (benzodiazepines, tricyclic antidepressants, thyroid, chloral hydrate, haloperidol). A significant effect on the VEP is not considered likely• However, there are no studies of the effect on the chessboard shift VEP of these commonly used medications.
(4) Data analysis For each kind of VEP (chessboard shift and flash), a repeated measures analysis of variance was done. The between variable was group (SDAT vs. control). The three within variables were eye (left vs. right), run (first vs. second), and hemisphere (left vs. right)• A P value < 0.01 was taken to be significant•
123
Results
(a) Preliminary studies A bipolar derivation was chosen for the full study protocol because it gave higher amplitude peaks than did derivations using either ear as reference• This choice is supported by the field studies of Fender and Santoro (1977). We chose occipital and vertex electrode sites because they provided significantly higher amplitudes when compared to simultaneous recordings from International 10+20 system sites O1 and Cz for both chessboard shift and flash VEP. Test-retest reliability of peak latency for two recordings made in the same subject 1 week apart, using right eye stimulation, was as good (Pearson Product Moment r = 0.83) as the correlation between latency for left and right eye stimulation at the first recording session ( r = 0 . 8 2 ) . We concluded that test-retest reliability was satisfactory for our longitudinal study•
(b) Results at entry into the study Wave forms and peak nomenclature are shown in sample plots from the 'peak-picker' after interP2 ,
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Fig. I. Sample wave form plot from 'peak-picker' for chessboard shift VEP, after editing. Left eye stimulation (run 1), left occipital to vertex (LO-V) recording. Stimulus onset occurs at 0 msec. The first 60 msec are occupied by a 10 #V calibration signal, whose decay continues briefly after stimulus onset. Positivity at LO causes an upward deflection. Digitally filtered off-line at 30 Hz.
124
L.A. C O B E N ET AL.
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larger in the SDAT group (Table I). These differences in latency and amplitude are shown in the composite wave form diagrams of Fig. 3, and in the individual wave forms of one SDAT subject and matched control subject in Fig. 4. There were no significant differences between the means of the VEPs evoked by left eye versus right eye stimulation, nor between the VEPs in the first and second run for a given eye. Amplitude was larger in the right hemisphere for NI-P2, P2-N2 and N2-P3. For controls, the N1-P2 amplitudes (mean ± S.D.) were, for the left hemisphere, 4.30 /W + 2.76, and for the right hemisphere 5.14/~V + 3.26. For P2-N2 the respective values were 10.03 _+ 3.82 and 11.64 + 3.87. For N2-P3 they were 2.50 _+ 1.50 and 3.13 + 1.86. For demented subjects the respective values for N1-P2 were 4.23 + 3.29 and 4.57 + 3.62. For P2-N2 they were 10.42 _+ 5.03 and 11.77 + 5.98. For N2-P3 they were 5.20 + 3.79 and 5.65 __+4.10. There was also an eye-hemisphere interaction for P2-N2, such that in the right hemisphere the amplitude for right eye stimulation was smaller than for left eye stimulation. The mean of the 8 values available in a given subject for a given latency or amplitude (two eyes, two runs, two hemispheres) was designated the 'subject mean.' The mean and standard deviation of these subject means were calculated for each latency and each amplitude in the control group, and also in the SDAT group. Thirteen of the 40
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0 120 240 msec Fig. 2. Sample wave form plot from 'peak-picker' for flash VEP, after editing. Left eye stimulation, left occipital to vertex (LO-V) recording. Stimulus onset occurs at 0 msec. The first 60 msec are occupied by a 10 #V calibration signal whose decay continues briefly after stimulus onset. Positivity at LO causes an upward deflection. Digitally filtered off-line at 30 Hz.
active editing for chessboard shift VEPs in Fig. 1, and for flash VEPs in Fig. 2. Table I shows the mean latencies and amplitudes for chessboard shift VEPs. Among latencies, only P3 and N3 showed a significant difference between the means of SDAT (CDR 1) and control subjects (CDR 0). The mean latency was longer in the SDAT group. Among amplitudes, only N2-P3 showed a significant difference, the mean being TABLE I
Latencies and amplitudes of chessboard shift VEPs a for 40 mildly b demented S D A T and 40 matched control ~ subjects• Latency (msec)
Amplitude (#V)
NI
P2
N2
P3
N3
NI-P2
P2-N2
N2-P3
P3-N3
CDR0
Mean (S.D.) Min Max
82.0 (10.0) 64 105
104.9 (8.0) 83 122
148.1 (12.6) 130 175
178.6 (14.6) 148 203
205.4 (16.9) 175 253
4.7 (2.9) 1.5 12.4
10.8 (3.7) 5.3 19.8
2.8 (1.6) 0.5 6.6
2.5 (1.5) 0.6 6.5
CDR1
Mean (S.D.) Min Max
83.5 (8.3) 67 102
106.3 (7.9) 87 123
151.6 (11.7) 126 178
193.9 (21.0) 157 235
218.2 (21.2) 184 276
4.4 (3.4) 0.6 16.2
11.1 (5.3) 3.3 24.5
5.4 (3.7) 0.6 14.0
2.8 (2.6) 0.4 13.0
"Leftandrighthemispherescombined. bCDR1. CCDR0.
125
VEP IN SENILE D E M E N T I A P2
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Fig, 3. Composite diagram of the wave form of the VEP to chessboard shift in mildly demented (solid line) and matched control subjects (dashed line). Plotted from the mean latency and amplitude values for each peak. Peak NI is taken as zero amplitude. Occipital positivity causes un upward deflection.
Fig. 4. Individual wave forms of chessboard shift VEP in a demented subject (bottom) and the matched control subject (top). Right eye stimulation (run 3), left occipital to vertex recording. Stimulus onset occurs at 0 msec. The first 60 msec are occupied by a 10 p,V calibration signal whose decay continues briefly after stimulus onset. Positivity at LO causes an upward deflection. Digitally filtered off-line at 30 Hz.
T A B L E II Latencies and amplitudes of flash VEPs a for 40 mildly b demented SDAT and 40 matched control c subjects. Latency (msec)
Amplitude (~V)
NI
P2
N2
P3
N3
N1-P2
P2-N2
N2-P3
P3-N3
CDR0
Mean (S.D.) Min Max
98.0 (11.3) 77 120
139.4 (14,9) 109 185
193.0 (21.7) 154 239
219.5 (25.0) 176 275
265.1 (31.7) 220 348
13.4 (6.2) 5.4 30.1
12.1 (5.7) 5.5 32.5
4.3 (3.1) 0.2 14.1
7.8 (3.7) 2.4 19.1
CDR1
Mean (S.D.) Min Max
99.7 (11.4) 78 120
143.4 (18.8) 103 186
190.5 (26.8) 125 252
219.7 (26.4) 181 294
267.2 (29.8) 212 346
14.7 (8.3) 1.7 35.4
10.9 (6.7) 0.8 28.0
4.9 (3.5) 0.2 16.4
9.6 (5,0) 2.3 22,5
~Unmaskedflashes, leftandrighthemispherescombined. hCDRI. CCDR0.
126
L.A. COBEN ET AL.
P2
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60
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20
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1 180 LATENCY (msec)
I
240
CDR 0 N3 I
I
300
Fig. 5. Composite diagram of the wave form of the VEP to flash in mildly demented (solid line) and matched control subjects (dashed line). Plotted from the mean latency and amplitude values for each peak. Peak N I is taken as zero amplitude. Occipital positivity causes an upward deflection.
SDAT subjects had a subject mean P3 l a t e n c y larger than the highest value in the control group, and in 8 SDAT subjects the value was more than 2.5 S.D.s above the control group mean. Twelve SDAT subjects had a subject mean N2-P3 amplitude higher than that of any control subject, and all 12 values were more than 2.5 S.D.s above the control group mean. Table 1I shows the mean latencies and amplitudes for flash VEPs. Composite wave form diagrams for the SDAT and control groups are shown in Fig. 5. There were no significant differences
between the means of clinical groups, eyes, or runs. However, the mean amplitude of N1-P2, P2-N2 and P3-N3 was significantly larger in the right hemisphere. For controls, the N1-P2 amplitudes (mean + S.D.) were, for the left hemisphere 12.97 # V + 6.24, and for the right hemisphere 13.91 + 6.31. For P2-N2 the respective values were 11.40 + 5.75 and 12.87 + 5.80. For P3-N3 the values were 7.62 + 3.50, and 8.05 + 4.22. For demented subjects the respective values for N1-P2 were 13.89 #V ___7.95 and 15.43 + 9.30. For P2-N2 they were 11.40 + 5.75 and 12.87 + 5.80. For P3N3 they were 9.42 + 4.95 and 9.74 _ 5.40. There were significant eye-by-hemisphere interactions amplitudes N1-P2 and P2-N2, such that lower amplitude occurred with stimulation of the ipsilateral eye. Finally, an eye-by-hemisphere interaction for peak latency of N1 showed that latency was longer when the ipsilateral eye was stimulated. Masked and unmasked flash data showed no significant differences, except that the mean amplitude of P3-N3 was larger for the unmasked flashes than for the masked flashes. In Table III is shown the evidence of drowsiness that was obtained by observing the subject's behavior, and by recording the EEG and EOG. During the chessboard shift VEP runs sleepy behavior was seen in 4 runs in SDAT subjects (3% of runs) and in two runs in controls (1%). The EEG never showed any evidence of drowsiness. Slow eye movements (SEMs) were present in two runs in SDAT subjects (1% of runs) and in no runs (0%) in controls. In both runs in which SEMs appeared, there was only a single SEM, and it was at the lowermost limit of amplitude to be scored. During the flash VEP runs the earliest indicators of drowsiness, SEMs, were much more common than was a change in either the EEG or the behavior. SEMs occurred in 84% of runs in controls and less often but still in a substantial number (70%) in SDAT subjects. A change in the EEG, which occurs shortly after the SEMs appear, was also more common in control runs (11% vs. 4%), and was more than twice as common as were behavioral indications of sleepiness. No subject reached stage I; only pre-stage I drowsiness was seen. In only one instance were SEMs absent when EEG changes were present.
VEP IN SENILE DEMENTIA
127
TABLE II1 Evidence of drowsiness: Behavior, EEG and EOG a.
Slow eye movements (SEMs) in EOG a EEG change (pre-stage I) Looks or acts sleepy
Check VEP runs (84 sec recording period)
Flash VEP runs (128 sec recording period)
Control e
Demented e
Control e
Demented e
0% (0)
1% (2)b 0% (0) 3% (4)
84% (128)*** 11% (17) c** 0,7% (1)
70% (103) 4% (6) d 5% (8) *
0% (0) 1% (2)
a Electro-oculogram, b These rare SEMs are unexpected in the eyes-open condition. They are regarded as false positives in the polygraph recording. In all 17 runs there were also SEMs. d In 5 of the 6 runs there were also SEMs. e Percentages are based upon 152 runs (recording periods) in controls and 148 runs in demented subjects. Number in parentheses is the number of runs in which this feature of drowsiness appeared. *** X2, control vs. demented, = 9.0 P < 0.005. ** X2, control vs. demented, = 5.4 P < 0.02. * X2, control vs. demented, = 5.8 P < 0.05.
Discussion Both the P3 a n d N 3 p e a k s in the V E P for c h e s s b o a r d shift have significantly longer m e a n latencies in the S D A T subjects ( C D R l) t h a n in their m a t c h e d c o n t r o l s ( C D R 0). This is the earliest c h a n g e r e p o r t e d thus far in the l a t e n c y of the V E P w i t h a d v a n c i n g A l z h e i m e r disease, since our dem e n t e d subjects are only m i l d l y i m p a i r e d mentally, a n d no significant differences have yet app e a r e d in the latencies of their flash VEPs. A l t h o u g h drowsiness is 'a p o s s i b l e e x p l a n a t i o n for our finding of increased p e a k latency, the evidence does n o t s u p p o r t this possibility. T h e significant differences b e t w e e n g r o u p s in the VEP involve only P3 a n d N 3 latency, whereas drowsiness might be e x p e c t e d to affect P2 as well (Shagass a n d T r u s t y 1966). Also, the significant differences b e t w e e n g r o u p s involve o n l y the c h e s s b o a r d VEP, even though the flash V E P is k n o w n to be affected b y drowsiness (Shagass a n d T r u s t y 1966). M o r e direct evidence c o n c e r n i n g the presence of drowsiness is p r o v i d e d b y our behavioral, E E G a n d E O G data. T h e r e was so little evidence of drowsiness d u r i n g the check V E P runs in b o t h groups that the significant differences in latency a n d a m p l i t u d e b e t w e e n S D A T a n d c o n t r o l subjects c a n n o t be
e x p l a i n e d b y drowsiness. Also, drowsiness w o u l d be expected to cause a decrease in a m p l i t u d e , b u t we o b s e r v e d an increase in a m p l i t u d e in the S D A T group. T h e situation with respect to drowsiness d u r i n g the flash V E P runs is m o r e complex. If drowsiness h a d been m o r e p r e v a l e n t in the d e m e n t e d t h a n in controls, it could have falsely increased the l a t e n c y a n d decreased the a m p l i t u d e of the p e a k s (Shagass a n d T r u s t y 1966). However, we f o u n d no such changes in latency. (A decrease in a m p l i t u d e due to drowsiness c o u l d have been negated b y an increase d u e to dementia.) The alternative supposition, that drowsiness was m o r e p r e v a l e n t in controls, is s u p p o r t e d b y the fact that the two m o s t sensitive i n d i c a t o r s of drowsiness, S E M s a n d a c h a n g e in the E E G , were b o t h m o r e prevalent in the c o n t r o l subjects. A greater prevalence of drowsiness in the controls could have m a s k e d a difference of l a t e n c y between the two groups of subjects b y falsely increasing control latencies. However, it w o u l d also have falsely increased a difference of a m p l i t u d e b y decreasing c o n t r o l amplitudes. W e f o u n d no such difference in a m p l i tude. W e therefore c o n c l u d e that drowsiness did n o t m a s k a difference between the two groups. Also, slow eye m o v e m e n t s p r o v e d to be a useful
128
warning signal that the early EEG change of prestage I drowsiness was imminent. Our finding of increased latency in the VEP raises the question whether the delay arises in the cortex itself, in some portion of the visual pathway afferent to the cortex, or both. An increased central conduction time has been reported in a group of patients with pre-senile and senile Alzheimer disease, as shown by an increased interpeak latency V - I of the auditory brain stem evoked potential (Harkins and Lenhardt 1980). Thus, by analogy, there is the possibility that in the visual system, a delayed cortical evoked potential may be due in part to increased central conduction time rather than to a cortical impairment. Structural changes in the occipital cortex, including the visual cortex, are found in both normal aging and senile dementia (McMenemy 1940, p. 224; Blessed et al. 1968; Tomlinson et al. 1968; Devaney and Johnson 1980). Our finding that only the late peaks of the chessboard shift VEP are delayed in mild SDAT does not distinguish between a causative lesion in the visual path afferent to the cortex and one in the cortex. However, the increased amplitude of N2-P3 is consistent with an intracortical loss of inhibitory potentials. Scheibel and Scheibel (1975) and Scheibel et al. (1976) suggested that a loss of inhibition might occur with synaptic uncoupling of cortico-cortical connections as a consequence of the loss of horizontal dendritic components of cortical neurons that was found in prefrontal and superior temporal cortex as well as in the limbic lobe in senile dementia. In parahippocampal gyrus sections Buell and Coleman (1979) noted the atrophic dendritic trees described by Scheibel et al., but were unable, on that basis, to distinguish between the adult, aged and senile dementia groups. Dustman et al. (1981) suggested that inhibitory functioning is reduced in the visual systems of the elderly as well as in those of children, because the similarity between patterned and unpatterned flash visual evoked potentials was greater at these extremes of the life span than in the middle range. Still another possibility, as yet unexplored, is that extracortical structures outside the visual pathway might be altered in SDAT, as for example the reticular system, which was shown to influence the VEP by Fuster and by
L.A. COBEN ET AL.
Lindsley and Griffiths (see Lindsley 1961). There are no prior studies concerning the chessboard shift VEP in dementia. Using flash stimulation, however, Straumanis et al. (1965) found that demented elderly subjects had longer latencies than did elderly control subjects for their 3 latest peaks (peaks 6, 7, 8). Their peaks 6 and 7 probably correspond to our peaks P3 and N3, although the recording sites and stimulation method were different in the two studies. Our subjects are only mildly demented and still live in the community, in contrast to the subjects of Straumanis et al. who were institutionalized, and who had more severe dementia. This difference in severity of dementia probably explains the absence of latency differences in the flash VEPs of our subjects. We expect to see differences develop in our longitudinal study as dementia progresses. Visser et al. (1976) reported increased latency for all but the first of 6 peaks in the flash VEPs of elderly demented subjects, but did not have an elderly control group. Increasing latency of late components (100-400 msec) of flash VEP with age in normals has been found in studies by Kooi and Bagchi (1964), Straumanis et al. (1965) and Dustman et al. (1981) (see also Beck et al. (1979) p. 210); and of chessboard shift VEP by Celesia and Daly (1977), Coben (1977), Allison et al. (1978, pp. 11-12) and Shaw and Cant (1980). The details of this aging curve are not settled. Latency changes may relate in part to luminance (Shaw and Cant 1980). It has been suggested that there may be an increase in the variance rather than an increase in the mean of the latency (Stockard et al. 1979). In the present study, the use of matched healthy controls assures that the observed changes are not due to normal aging. The higher amplitudes in the right hemisphere for both chessboard shift and flash VEPs in the present study are not likely to be due to a consistent asymmetry of electrode placement, since not all peak-to-peak amplitudes are asymmetrical. Also, the right hemisphere showed larger occipital VEPs at all ages in the study of Beck et al. (1975, p. 187). Among college students, larger VEPs were found on the right in the central area, but not in the occipital area (Beck and Dustman 1979, p.
454).
VEP IN SENILE DEMENTIA T h e absence of significant a m p l i t u d e differences b e t w e e n o u r S D A T a n d c o n t r o l g r o u p s for the flash V E P is consistent with the findings of S t r a u m a n i s et al. (1965). T h e y f o u n d n o a m p l i t u d e differences a m o n g the late c o m p o n e n t s (latency > 100 msec).
Summary Visual e v o k e d p o t e n t i a l s (VEPs) to c h e s s b o a r d shift a n d to flash s t i m u l a t i o n were r e c o r d e d from 40 subjects with senile d e m e n t i a of A l z h e i m e r t y p e ( S D A T ) a n d 40 i n d i v i d u a l l y m a t c h e d c o n t r o l subjects. All of the S D A T subjects h a d only a mild degree of d e m e n t i a a n d were still living in the community. A n a l y s i s of v a r i a n c e showed significant differences b e t w e e n d e m e n t e d a n d c o n t r o l g r o u p m e a n s for 3 c h e s s b o a r d shift V E P measures, the d e m e n t e d g r o u p having longer l a t e n c y o f p e a k s P3 a n d N3, a n d larger a m p l i t u d e of segment N2-P3. T h e s e three are the earliest r e p o r t e d changes in the V E P in A l z h e i m e r disease, since the flash VEPs s h o w e d no m e a s u r e in which the d e m e n t e d a n d c o n t r o l group m e a n s differed significantly.
R~sum~
Potentiels ~voqu& v&uels clans la d~mence s~nile l~gkre de type Alzheimer O n a enregistr~ les p o t e n t i e l s visuels 6voqu~s (PEV) p a r d r p l a c e m e n t s de d a m i e r s et s t i m u l a t i o n s t r o b o s c o p i q u e d a n s 40 cas de d r m e n c e s~nile de t y p e A l z h e i m e r ( D S T A ) et 40 t~moins srlectionn~s de faqon adequate. Les D S T A sblectionn~s ne p r r s e n t a i e n t q u ' u n degr~ 16ger de d r m e n c e et ~taient encore c a p a b l e d e vivre en famille. L ' a n a l y s e de v a r i a n c e des P E aux d r p l a c e m e n t d e d a m i e r a rbvrl6 des diffrrences significatives de la m o y e n n e p o u r 3 mesures prises sur c h a c u n des d e u x g r o u p e s ( D S T A et contrSles), le g r o u p e d & m e n t pr~sentant une latence allong~e des pics P3 et N 3 et une a m p l i t u d e plus i m p o r t a n t e du segm e n t N2-P3. Ces 3 mesures sont les c h a n g e m e n t s les plus pr~coces du PEV au tout d r b u t de la
129 m a l a d i e d ' A l z h e i m e r , alors que les PEV o b t e n u s d a n s les deux g r o u p e s p a r s t i m u l a t i o n stroboscop i q u e n ' o n t pr~sent~ a u c u n e d i f f & e n c e significative. So many people helped in this study that space permits only a list rather than a full description of their contributions: Drs. James Blaine, Lewis Thomas; Ronald Burde and William Landau; Professor Harold Shipton; Michael Browder, James Montrose, Stanley Phillips, Bonnie Schumann, Toby Schumann, Emogene Jackson, David Chi, Helen Gavigan. This work was supported in part by Grant No. RO 1 MH31054 from the National Institutes of Mental Health and by Grant RR 00396 from the Division of Research Resources, N.I.H.
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