Differences between Alzheimer's Disease and Vascular Dementia on Information Processing Measures

34, 301–310 (1997) BR970923

BRAIN AND COGNITION ARTICLE NO.

Differences between Alzheimer’s Disease and Vascular Dementia on Information Processing Measures Mario F. Mendez, Monique M. Cherrier, and Kent M. Perryman Departments of Neurology and Biobehavioral Sciences, The University of California at Los Angeles, and The West Los Angeles Veterans Affairs Medical Center This study evaluated information processing differences between 30 vascular dementia (VaD) patients, 30 Alzheimer’s disease (AD) patients, and 30 normal elderly (NE) controls. They were administered a complex reaction time test, a continuous performance test (CPT), and a neuropsychological battery. Compared to NE, both dementia groups had significantly slower motor reaction times and made more errors on the CPT. Compared to AD patients, the VaD patients were slower in stimulus categorization time and had increasing omission errors and persistent commission errors throughout the CPT trial. VaD, which usually includes frontal–subcortical circuit injury, can impair mental speed and stimulus response initiation.  1997 Academic Press

INTRODUCTION

After Alzheimer’s disease (AD), cerebrovascular disease is the second most frequent cause of dementia. Autopsy studies indicate that vascular dementia (VaD) accounts for 17–29% of all dementias, and a mixed group with the neuropathology of both AD and VaD accounts for another 10–23% (Erkinjuntti, Haltia, Palo, Sulkava, & Paetau, 1988; O’Brien, 1988; Tomlinson, Blessed, & Roth, 1970). Recent advances in neuroimaging support an even greater spectrum and prevalence of VaD with the frequent disclosure of periventricular white matter degeneration attributed to cerebrovascular disease (Hachinski, 1990). Patients with VaD may be difficult to distinguish from those with AD. VaD can have a static or slowly progressive course, and AD patients can have vascular risk factors and periventricular changes on magnetic resonance imaging (MRI). Neuropsychological attempts to differentiate VaD and AD Address correspondence and reprint requests to M. F. Mendez, Neurobehavior Unit (691/ 116AF), West Los Angeles V.A. Medical Center, 13001 Wilshire Boulevard, Los Angeles, CA 90073. Fax: (310) 268-4929; e-mail: [email protected]. 301 0278-2626/97 $25.00 Copyright  1997 by Academic Press All rights of reproduction in any form reserved.

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have also yielded contradictory results (Villardita, 1993). Although many studies have contrasted memory and other cognitive functions between different dementias, few have compared them on information processing measures. Compared to AD patients, VaD patients may have greater mental slowing and poorer tonic arousal, possibly on the basis of greater frontal– subcortical circuit disease (Huber, Shuttleworth, Paulson, Bellchambers, & Clapp, 1986). This study investigated whether a computerized choice reaction time (CRT) test of mental speed and a continuous performance test (CPT) of tonic arousal could distinguish between patients VaD and AD irrespective of degree of motor slowing (Rosvold, Mirsky, Sarason, Bransome, & Beck, 1956). The contrast between CRT and simple reaction time provides a means to determine cognitive decision time based on stimulus classification and response selection. Vigilance tasks such as the CPT, which require participants to respond to the same target over time reflect tonic arousal, or baseline receptivity to slow and repetitive environmental stimuli (Nebes & Brady, 1993). Because of general motor slowing, ease of fatigueability, and task impersistence in dementia (Nebes & Brady, 1992), this study evaluated error rates on a low-event rate CPT. We further compared changes in these error rates over the three time periods of the CPT (Parasuraman, 1984). METHODS Participants. Participants included 30 patients with AD, 30 patients with VaD, and 30 normal elderly (NE) controls tested between 1990 and 1995. The VaD and AD patients were recruited from neurological or memory disorder clinics after presenting for a dementia evaluation. The NE controls were the spouses and other caregivers of our patients and recruits from a hospital registry of volunteers (St. Paul–Ramsey Medical Center). All patients and controls underwent a screening neuropsychiatric evaluation, the Mini-Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, 1975), and the Clinical Dementia Rating Scale (CDR) (Hughes, Berg, Danziger, Coben, & Martin, 1982). The NE controls did not have a history of cognitive decline or signs and symptoms of cerebrovascular disease and had MMSE scores of .23 and CDR scores of $.5. The AD patients met established criteria for clinically probable AD (McKhann, Drachman, Folstein, Katzman, Price, & Stadlan, 1984) and did not have clinical or neuroimaging evidence of strokes. The other exclusion criteria for this study were the following: visual acuity scores of less than 20/40 (OU near; OU, OS, OD far), the presence of visual field defects by confrontation testing, glaucoma, a history of drug abuse or alcoholism, serious psychiatric illness, psychoactive medication use, or any premorbid neurological impairment. Moreover, participants were excluded from participation if, on mental status testing, they lacked sufficient language comprehension and motor praxis to perform the current protocol. The criteria for VaD followed NINDS-AIREN guidelines (Roma´n et al., 1993). They included the following: (1) dementia as evidenced by an acquired decline in two or more domains of cognition; (2) signs or symptoms referable to cerebrovascular events and supported by cerebrovascular changes on MRI of the brain; and (3) a presumed or temporally related association between the dementia and the cerebrovascular disease. Although this study began before the NINDS-AIREN criteria were introduced, our earlier VaD patients retrospectively met these criteria. In addition, the original Hachinski Ischemia Scale (HIS) was used, with a score of

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TABLE 1 Summary of Participant Characteristics and ANOVA Significance VaD

Age (years) Education (years) MMSE CDR HIS

Sex

AD

NE

df (2, 87) f p

M

SD

M

SD

M

SD

69.6 10.9 21.1 1.2 8.5

6.5 4.3 4.6 0.5 1.4

72.2 11.1 19.2 1.2 2.7

6.7 4.5 4.2 0.5 2.0

72.9 12.1 29.2 0.0 1.7

7.0 2.7 1.0 0.0 1.9

0.94 0.81 77.71 a 86.41 a 126.77 b

Female

Male

Female

Male

Female

Male

χ 2 Value

13

17

18

12

19

11

0.248

ns ns ,.001 ,.001 ,.001

ns

Note. MMSE, Mini-Mental State Examination scores; CDR, Clinical Dementia Rating scores; HIS, Hachinski Ischemic Scale scores; ns, nonsignificant. a Scheffe´ VaD and AD vs. NE groups, p , .05. b Scheffe´ VaD vs. AD and NE groups, p , .05. $7 supportive of the diagnosis of VaD (see Table 1). The 30 VaD patients had primarily small vessel disease or large areas of white matter involvement on both T1 and T2 weighted MRIs felt vascular in etiology (14), nonaphasic major vessel disease with associated subcortical changes (8), multiple lacunar strokes with or without other cerebrovascular disease (7), and one strategic stroke in the medial left thalamus. None of the patients had aphasia, hemiparesis, or other visuospatial deficits that would interfere with performance on the CRT or CPT. The three groups did not differ significantly in mean age, education, or sex ratio (see Table 1). The two dementia groups were similarly impaired community-based patients with comparable scores on the MMSE and on the CDR. As expected, the VaD group had larger HIS scores compared to the AD group. Apparatus and procedure. The CRT and CPT visual stimuli were presented on a microcomputer. Participants set 46 cm from a NEC Multisync color monitor on which clear, focused, single letters subtending a vertical angle of one degree were presented for up to 1 sec. The environment and luminance were held constant. The participants lightly rested their dominant hand index finger on a ‘‘1’’ numeric pad key. Participants indicated the presence of an ‘‘A’’ during a sequence of letters by depressing this response key (Rosvold et al., 1956). Simple reaction time (Simple RT) involved the presentation of A’s which required a 1 key response (in a 2: 1 ratio of A to non-A). The stimulus categorization condition added non-A letters which required no response. Stimulus categorization time (Stimulus RT) was derived from this stimulus categorization condition minus Simple RT. The response selection condition additionally added a ‘‘B’’ response choice which required a ‘‘2’’ key response. Response selection time (Response RT) was derived from the response selection condition minus Stimulus RT. Stimulus RT plus Response RT together are often termed Decision RT. The interstimulus delay was 1500 msec, and the order of presentation of the three conditions was counterbalanced. After 3 practice trials for each condition, the mean of the correct responses among the next 10 trials was used for analysis. The CPT was identical to the stimulus categorization part of the CRT except that it continued over 5 min, and errors were recorded. Each trial consisted of approximately one letter/second for a total of 300 stimuli. Of these, 100 were target stimuli. Participants in the CPT had a 1min practice period consisted of 60 trials prior to the actual test. Scoring included the number of errors of omission (CPTo), the inverse of hit rate, and the number of errors of commission (CPTc), the false alarm rate. Furthermore, the CPT was divided into three equal time periods for evaluation of changes in error rates over time.

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TABLE 2 ANOVA Results of CRT VaD

Simple RT Decision RT Stimulus RT Response RT a b

AD

NE

M

SD

M

SD

M

SD

427.53 270.40 109.57 160.83

127.99 89.92 81.37 103.10

398.57 226.24 64.47 161.77

97.80 64.49 65.82 77.03

290.00 225.00 74.00 151.00

71.92 18.57 18.57 22.74

df (2, 87) f p 15.2 a 4.78 b 4.5 b 0.19

,.001 .011 .014 ns

Scheffe´ VaD and AD vs. NE groups, p , .001. Scheffe´ VaD vs. AD and NE groups, p , .05.

In addition to the CRT and the CPT, the dementia patients, but not the NE controls, were administered a battery of 10 neuropsychological tests aimed at assessing background intellectual functions. They were given the Wechsler Adult Intelligence Scale—Revised Information Subtest (WAISin) and the Digit Symbol Subtest (WAISds) (Wechsler, 1981), the Controlled Word Fluency Test (FAS fluency) and a categories fluency measure (Cat fluency) (Spreen & Benton, 1989), the Boston Naming Test (BNT) (Kaplan, Goodglass, & Weintraub, 1983), the Trailmaking Test—Parts A&B (TMK-A and TMK-B) (Reitan, 1958), and the California Verbal-Learning Test with measures of registration on the fifth trial (Register), 30-min delayed recall (D. Recall), and recognition (Recognize) (Delis, Kramer, Kaplan, & Ober, 1983). Statistical analysis. Multivariate analysis of variance (MANOVA) tests were used to compare the three groups on the CRT measures followed by post hoc ANOVAs. Scheffe´ adjustments were performed for differences between the three groups. The CPT errors, which was categorical data, were analyzed with the Kruskall–Wallis test, Mann–Whitney post hoc evaluations, and the Friedman test for decrements over the three periods of the CPT. Partial correlational values were obtained between CRT and CPT performance and the neuropsychological tests.

RESULTS

CRT results. The MANOVA statistic with group as the independent variable and Simple RT, Stimulus RT, and Response RT as the dependent variables revealed significant group differences (Pillais F(6, 172) 5 7.80, p , .001). Post hoc ANOVAs showed overall group differences in Simple RT and Stimulus RT (as well as the total Decision RT) (see Table 2). Both dementia groups were slower than controls on Simple RT but only the VaD patients were slower than controls on Decision RT due to their slower time for stimulus categorization (Stimulus RT). CPT results. CPTo and CPTc were significantly different between all three groups (see Table 3). The VaD patients had more errors of both omission and commission than both the AD patients and the NE controls. Over the three periods of the CPT, only the VaD patients had significantly increasing omission errors by the third period (Friedman χ 2 8.01, , .05) (see Fig. 1), and only the VaD patients failed to show a decline in initial commission errors after the first period (χ 2 8.52, p , .05 for NE; χ 2 6.05, p , .05 for the AD patients (see Fig. 2).

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TABLE 3 Summary of CPT Errors and Significance VaD

CPTo CPTc

AD

NE

Median

Range

Median

Range

Median

Range

9.0 15.0

1–36 2–46

5.0 4.0

1–15 1–21

.01 1.0

0–4 0–8

Significance p χ2 49.87 A 48.12 B

,.001 ,.001

Mann–Whitney post-hoc analysis A 5 CPTo

VaD vs. AD VaD vs. NE AD vs. NE

B 5 CPTc

Value

Significance

Value

Significance

196.0 26.0 158.0

p , .001 p , .001 p , .001

284.0 20.0 102.0

p , .014 p , .001 p , .001

Neuropsychological tests. There were no differences between dementia groups except for more impaired FAS fluency and TMK-A performance among the VaD patients (see Table 4). The partial correlations did not reveal close relationships between the CRT and CPT measures (see Table 5) or between these measures and the neuropsychological tests with two exceptions: the CPTo correlated significantly with increased recognition performance and the CPTc with increased registration performance (see Table 6).

FIG. 1. Continuous performance test errors of omission (CPTo) are shown. Mean number of errors per period, i.e., first, second, and third periods of the CPT is charted. The asterisk indicates significant differences on the Friedman test, i.e., only the VaD patients had significantly increasing omission errors by third period.

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FIG. 2. Continuous performance test errors of commission (CPTc) are shown. Mean number of errors per period, i.e., first, second, and third periods of the CPT is charted. The asterisks indicate significant differences on the Friedman test, i.e., the NE and AD groups, but not the VaD patients, had a significant decline in first period commission errors. NE, normal elderly; AD, Alzheimer’s disease; VaD, vascular dementia.

TABLE 4 Results of Neuropsychological Tests VaD

WAISin WAISds BNT FAS fluency Cat fluency Register D. Recall Recognize TMK-A TMK-B

AD

df (1, 58)

M

SD

M

SD

t

p

33.73 14.62 38.00 15.53 27.13 5.92 3.00 9.75 123.00 272.57

26.09 14.30 19.12 8.60 7.45 3.64 3.71 4.72 64.01 73.53

22.54 18.31 35.86 25.47 24.93 5.10 1.33 10.13 90.00 242.50

19.57 16.43 13.47 9.00 9.27 1.74 1.82 3.12 30.63 96.00

21.79 .86 2.47 4.37 21.01 2.94 21.77 .28 22.53 2.90

ns ns ns ,.001 ns ns ns ns .014 ns

TABLE 5 Partial Correlations between Experiments

Stimulus RT Response RT CPTo CPTc

Simple RT

Stimulus RT

Response RT

CPTo

2.30 .16 .15 2.18

.27 .23 2.13

.19 .01

.29

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TABLE 6 Partial Correlations between Experiments and Neuropsychological Tests

WAISin WAISds BNT FAS fluency Cat fluency Register D. Recall Recognize TMK-A TMK-B a

Simple RT

Stimulus RT

Response RT

CPTo

CPTc

2.26 2.05 .02 2.05 2.38 2.13 2.06 .01 .34 .36

2.03 .14 .19 .31 2.02 2.40 2.33 2.07 .01 2.03

.10 .26 .43 2.15 .23 .05 2.16 2.02 2.17 .06

2.25 .03 .07 .09 2.27 2.18 2.36 .49 a .05 2.06

.44 2.28 2.30 2.25 2.03 .50 a .02 .13 2.43 2.42

p , .05.

DISCUSSION

These results demonstrate differences between VaD and AD patients on information processing measures. In addition to slower Simple RTs from dementia, the VaD patients had slower CRT decision times than the AD patients primarily due to the increased time needed for stimulus categorization. On the CPT, as the trial progressed, the VaD patients had increasing errors of omission and persistent errors of commission. These CRT and CPT differences were unlikely to result from differences in dementia severity since the dementia groups did not differ on the MMSE, the CDR, and most neuropsychological tests. Furthermore, CPT findings did not correlate strongly with CRT findings, and, hence, the CPT errors were unlikely to result from mental slowing. It can be difficult to differentiate patients with VaD from those with AD. VaD may develop as an insidiously progressive cognitive decline similar to AD, and neuroimaging scans may fail to show vascular lesions in a quarter or more of VaD patients (Ladurner, Iliff, & Lechner, 1982). Neuropsychological tests can also fail to distinguish patients with these two dementias (Erkinjuntti, Laaksonen, Sulkava, Syrjalainen, & Palo, 1988; Perez, Rivera, Meyer, Gay, Taylor, & Mathew, 1975; Tierney, Snow, Reid, Zorzitto, & Fischer, 1987; Villardita, 1993). This study, however, found greater impairments in FAS fluency and in Trailmaking A time among VaD patients compared to AD patients. Although a letter processing deficit among VaD patients could explain both decreased stimulus categorization and FAS fluency, there were no significant correlations between stimulus categorization and FAS fluency or any other language measure. In comparing patients with VaD or AD, there may be detectable differences in information processing between these two dementias. In contrast to AD, which preferentially affects temporal limbic and temporoparietal as-

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sociation cortex (Tomlinson et al., 1970), VaD preferentially results from multiple deep strokes or vascular-induced periventricular white matter changes which congregate in the subfrontal regions (Aharon-Peretz, Cummings, & Hill, 1988; Hachinski, 1990; Ishii, Nishihara, & Imamura, 1986). Although there is some mental slowing in AD (Gordon & Carson, 1990; Vrtunski, Patterson, Mack, & Hill, 1983), a greater decline in mental speed correlates with white matter involvement in VaD and cerebrovascular disease (Boone et al., 1992; Matsubayashi, Shimada, Kawamoto, & Ozawa, 1992). The findings in the present study show that VaD patients are specifically slower in categorizing or processing stimuli. Consistent with these findings, patients with multiple infarctions are slow on N2 event-related potentials but not on P2 and P3 potentials, suggesting an uncertainty in classifying perceived events rather than a slowed motor organization time (Tachibana, Toda, Aragane, & Sugita, 1993). This is the first study showing an abnormal tonic arousal on a low-event CPT in VaD as compared to AD. In contrast, several studies fail to show a clear vigilance decrement in AD versus NE controls (Alexander, 1973; Mayeux, Stern, Sano, Cote, & Williams, 1987; Nebes & Brady, 1993). The use of a slower, low-event CPT task allows dementia patients to improve over time as they reset their response criterion to a more accurate and automatic level. The VaD patients, however, did not improve in rates of omission or commission errors over the three time periods of the CPT. The disturbed tonic arousal in VaD patients may represent subcortically mediated interference in the timing and activation of cortical functions. Alternatively, the persistent errors reflect an inability to reset their response criterion. This lack of criterion shift may be due to frontal inability to regulate response initiation or response inhibition and may occur in patients with frontal lesions (Wilkins, Shallice, & McCarthy, 1987). The deep frontal pathology in most VaD patients affects frontal–subcortical circuits, and investigators note frequent frontal–executive deficits in VaD with decreased response inhibition and response initiation (Fukada, Kobayashi, Okada, & Tsunematsu, 1990; Matsubayashi et al., 1992; Mendez & Ashla-Mendez, 1991; Wolfe, Linn, Babikian, Knoefel, & Albert, 1990). In addition, an altered response criterion in VaD could explain the correlation between CPTc and registration and between CPTo and recognition. Compared to AD and normal controls, this study suggests that VaD patients are slower in decision times due to decreased stimulus categorization and are less able to sustain tonic alertness. Although the magnitude of these differences was small, they are consistent with the presence of slow mental speeds and CPT errors from vascular injury to white matter and frontal– subcortical circuits. Future work can test whether information processing measures with linguistic and nonlinguistic stimuli, in conjunction with neuropsychological tests, can be clinically helpful in distinguishing AD,

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