Frontal Lobe Function in
Progressive Supranuclear Palsy Jordan Grafman, PhD; Irene Litvan, MD; Claudia Gomez, MA; Thomas N. Chase, MD
\s=b\ Performance on tasks evaluating "executive and attentional" processes presumably subserved by prefrontal cortex were compared in patients with progressive supranuclear palsy and with age- and education-matched control subjects. The results indicated that patients with pro-
gressive supranuclear palsy were particularly impaired when a task required sequential movements, conceptual shifting, monitoring the frequency with which stimuli are presented, or rapid retrieval of verbal knowledge. These deficits could not simply be accounted for by slowed information processing or by a deficit in representational knowledge. Conceivably, "weak activation" of frontal lobe representational knowledge characterized by an observed attentional deficit results in the neuropsychological impairments noted in patients with progressive supra\x=req-\ nuclear palsy. The oral administration of physostigmine, under double-blind placebo-controlled conditions, did not facilitate executive or attentional performance as evaluated by our tasks. (Arch Neurol. 1990;47:553-558)
Accepted for publication September 29, 1989. From the Cognitive Neuroscience Unit, Medical Neurology Branch (Dr Grafman) and Experimental Therapeutics Branch (Drs Litvan and Chase and Ms Gomez), National Institute of Neurological Disorders and Stroke, Bethesda, Md. The opinions and assertions contained herein are the private views of the authors, and are not to be construed as official or necessarily reflecting the views of the National Institutes of Health, the United States Public Health Service, the Department of Health and Human Services, or the Uniformed Services University of the Health Sciences.
Reprint requests to the Cognitive Neuroscience Unit, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg 10, Room 5C422, Bethesda, MD 20892 (Dr Grafman).
Qîubcortical
dementia is often ineluded in the clinical description of patients suffering from progressive su¬ pranuclear palsy (PSP).1 This demen¬ tia has been characterized by forgetfulness, slowing of information pro¬ cessing, mood changes, and difficulty in manipulating learned knowledge.23 The difficulty in manipulating learned knowledge may be attributable to frontal lobe dysfunction,4·5 while an associated deficit in orienting visual attention in the vertical plane appears independent of any impairment in ef¬ fortful manipulation of learned knowl¬ edge and may relate to the midbrain lesions found in this disorder.6 On the basis of poor performance by patients with PSP on tasks requiring effortful manipulation of learned knowledge, flexible thinking, and attention,7 spec¬ ulation has centered on the possible role that basal ganglia and basal fore¬ brain lesions have on frontal lobe func¬ tioning. Conceivably, degeneration of afferent fibers projecting from basal ganglia and basal forebrain structures to the frontal lobe may isolate prefron¬ tal cortex from subcortical structures (and/or cause some minor transneural degeneration in prefrontal cortex re¬ sulting in partially dysfunctional cor¬ tical tissue).8 Recent positron emission tomographic scan studies of patients with PSP910 have described decreased metabolism and regional blood flow in the area of the prefrontal cortex. The findings to date suggest that patients with PSP may be impaired on tasks used to assess "executive and at¬ tentional" processes presumably sub¬ served by prefrontal cortex. To test this hypothesis, we examined patients
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with PSP and matched control sub¬ on tests of executive and atten¬ tional processes. Next, we compared the performance of patients with PSP during baseline, placebo, and drug con¬ ditions on these same tests to deter¬ mine whether the administration of a cholinesterase inhibitor facilitated PSP cognitive performance.
jects
PATIENTS AND METHODS
Twelve patients with PSP were strati¬ fied, matched with 12 normal control sub¬ jects (Table 1). The diagnosis of PSP was based on the presence of all the following features: (1) age of onset, 50 years or older; (2) parkinsonian signs including bradykinesia, postural or gait disorder, axial rigidity, and no resting tremor; (3) pseudobulbar signs including dysarthria and dysphagia; (4) extraocular movement abnor¬ malities characterized by supranuclear ver¬ tical (with or without horizontal) palsy; (5) progressive course; and (6) no roentgenographic abnormalities other than subcortical and/or midbrain atrophy. All patients with PSP had magnetic resonance imaging scans except one who received a computed tomographic scan (the magnetic resonance imaging was contraindicated in his case because he had a pacemaker). Most, but not all, magnetic resonance imagings described mild subcortical and/or midbrain atrophy and third ventricle enlargement. All pa¬
tients with PSP also underwent electro-oculographic studies that demonstrated ver¬ tical gaze palsy with preservation of oculocephalic reflexes. Except for one patient who continued to receive a constant dose of levodopa-carbidopa (Sinemet, 600 mg/d), none of the patients took other centrally active drugs during the course of this clin¬ ical trial. There were no significant age or education differences between groups. To participate in this study, patients with PSP were required to show evidence that they
Subject Table*
Table 1. —
Control
PSP Characteristics Years of education
Age
(SD) (5.9) 15.1 (3.6)
63.4
Age at onset
60.3
(5.6)
35.0
(11.9)
Subjects (SD) 63.8 (5.5) 16.3 (2.9)
of disease
Duration of disease Hoehn-Yahr
Scale *
3.2
(.39)
score
progressive supranuclear palsy (PSP) (n 12) and control subjects (n 12) were as closely matched as possible for age and years of education. Patients with PSP were mild to moderately affected by their disease. The subjects' age is given Patients with =
=
in years and illness duration in months.
read, write, understand instructions, comprehend written and spoken language, and express themselves clearly. Cholinergic nuclei, including the pedunculopontine tegmental nucleus, are affected along with dopamine-producing neurons in PSP.1112 It has been suggested that some of the cognitive symptoms described in PSP may be due to cholinergic rather than dopaminergic deficiencies.1314 On this basis, an experimental trial of physostigmine (an acetylcholinesterase inhibitor) was offered to patients with PSP in the hopes of ame¬ liorating some of their cognitive deficits.15 Following their baseline evaluation, pa¬ tients first received 4 days of open-label dose finding. Physostigmine was adminis¬ tered orally every 2 hours, six times daily at doses that increased from 0.5 mg per dose (3 mg/d) on the first day to 2 mg per dose (12 mg/d) on the fourth day. Verbal memory was evaluated by alternate versions of the Selective Reminding Test5 administered twice daily, 30 minutes after taking the first and last daily doses of physostigmine. Mean performance on both tests at each dose was could
used to determine the best dose for each in¬ dividual. For the second part of this study, patients were randomized to a 10-day cross¬ over, placebo-controlled double-blind trial of physostigmine, at their previously deter¬ mined best dose (1.25 ± 0.2 mg per dose; range, 0.5 to 2.0 mg) orally administered every 2 hours, six times per day. There was a 3-day washout period between baseline and initiation of the crossover trial; while on the crossover trial, there was no washout period between phases. Patients received neuropsychological testing only after the third day of initiation of each phase (phy¬
sostigmine or placebo). The following neuropsychological tests were performed once during the third and fourth days of each study phase (baseline, placebo, and drug), starting 30 minutes af¬ ter the second daily dose of drug or placebo and lasting 1 to 2 hours. Tests
Wechsler Adult
Intelligence Scale-Revised
(WAIS-R).16-This test, WAIS-R, was ad¬ ministered to provide general indexes of intellectual performance. The full-scale,
verbal, and performance IQ scores are pre¬ sented. In addition, the age-corrected scale score for the similarities subtest is reported as a measure of verbal reasoning and the age-corrected scale score for the picture ar¬
rangement subtest is described sure
of
as a mea¬
pictorial reasoning.
Wechsler Memory Scale.17—Wechsler Memory Scale was used to obtain a general level of memory functioning. This test is composed of several subtests whose scores can be combined to produce a single mem¬ ory quotient that can be directly compared with the WAIS-R IQ scores. In this article, we present the memory quotient only. A companion article discusses the memory performance of patients with PSP in much more
detail.18
Mattis Dementia Rating Scale (MDRS).19— The MDRS was used to estimate the sever¬ ity of the PSP patient's cognitive decline. In addition, two subscales (conceptual think¬ ing and initiation and perseveration), which are often found diminished in pa¬ tients with frontal lobe dysfunction is de¬
mation-processing capacity.30 We also ad¬ ministered the Stroop color word test31 to obtain an estimate of automatic processing. Time Estimation.—Subjects were required to estimate the correct time during the testing session and the duration of the en¬ tire testing session. A tapping task was also used to assess the subject's estimation of time duration. The subjects heard 60,30,15, or 6 taps for 1 minute. They were then asked to estimate the number of taps they heard as well as the time that elapsed. Beck and Hamilton Depression Scales
used to estimate mood state. The tests were administered over several sessions in a set order for all subjects. No single testing session exceeded 2 hours. Pa¬ tients with PSP performance did not reveal specific effects of fatigue for the last few tests administered within a session. In¬ formed consent was obtained from all sub¬ jects after the procedures were explained. Other neurobehavioral data collected dur¬ ing the physostigmine trial will be pre¬ sented in separate articles. were
scribed.
Motor
hospital
Analysis Methods
Ability.—Manual dexterity was as¬
sessed by a set of 10 tests described by Luria20 as sensitive to frontal lobe lesions. Many of these tests require sequential mo¬ tor movements. A single score was used to estimate the number of tests "passed" by a subject. We also administered the Purdue Pegboard Test21 to estimate motor dexter¬ ity. A third measure of motor ability tested was speed of speech. This was measured by having a subject repeat the word "hospital" as fast and accurately as possible in a 10-second period. The total number of times was
pronounced accurately
was
recorded. A fourth measure used was the Mazes subtest from the Wechsler Intelli¬ gence Scale for Children22 that estimates route finding. The scale score from this subtest was used. Finally, we used the Northwestern Gait Scale23 and the modified Columbia Scale24 to provide clinical indexes of motor ability. Conceptual Flexibility.—The Trail Making Test25 was administered to estimate the subjects' ability to follow within and across set categorical sequences. The Wisconsin Card Sorting Test (WCST)2' was adminis¬ tered to evaluate the ability of patients to form and to shift concepts based on reason¬ ing and responsiveness to the examiner's feedback. Fluency.—Verbal fluency was assessed by means of the FAS,27 animal (subjects were required to produce as many animal names as they could in 1 minute), and supermarket (subjects had to produce names of items that could be found in a typical supermar¬ ket in 1 minute) fluency tasks. Visuospatial fluency was evaluated by the drawing flu¬ ency task28 in which subjects were required to draw as many different geometric de¬ signs as possible in 1 minute. Attention.—We used the " -Test" to esti¬
simple vigilance.29 Subjects were re¬ quired to identify the letter A when they heard it among a long series of letters. The mate
number of errors was recorded. The Paced Auditory Serial Addition Test (PASAT) was used to estimate attention and infor-
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The first set of comparisons presented below represent the baseline evaluation. Statistical procedures used include t tests
(signified by a simple value), repeated analysis of variance, and correla¬ tions. The small number of subjects in each group and the large number of comparisons made precluded the appropriate use of mulmeasures
tivariate statistics. We ran correlational analyses to determine the relationship be¬ tween symptom duration, current mood state, and overall degree of dementia and performance on tests of executive and at¬ tentional processes; the findings are pre¬ sented only when the Spearman's rank or¬ der correlations reached .50. Due to multi¬ ple comparisons, we used a Bonferroni correction procedure that set the value significance level at .001. The Bonferroni correction was obtained by dividing the al¬ pha level by the total number of compari¬ .001. The numerator is the sons, ie, .50/40 overall alpha adapted by us. This is divided by the number of comparisons actually made. This adjusted significance level (P < .001) is used to judge the significance of all comparisons made. The second set of comparisons presented represent the effects of placebo and drug treatment conditions on PSP patient test performance compared with baseline (8 of 12 patients participated in the drug study). Only the PSP patient performance is con¬ sidered, since the control subjects did not receive physostigmine. Statistical proce¬ dures were similar to those described above. =
RESULTS General Cognitive Functioning and Mood State (Table 2)
Patients with PSP had significantly diminished WAIS-R IQ scores when compared with control subjects. Their performance scale score was particu¬ larly low. The MDRS total score of the
patients with PSP places them in the mildly impaired range. Finally, the Wechsler Memory Scale Memory Quo¬ tient of the patients with PSP is sig¬ nificantly diminished when compared with that of the control subjects but is consistent with their WAIS-R verbal IQ score. Patients with PSP, as a group,
were
marginally depressed
based on their Hamilton and Beck De¬ pression Scale scores. However, many of the endorsed items on these depres¬ sion scales reflected somatic com¬ plaints or changes in cognitive func¬ tioning and did not indicate increased sadness or other depressive symptoms.
Table 2.—General Cognitive Functioning and Mood State* Control Subjects (SD)
Tests Wechsler Adult
Full Scale IQ
90.14(7.93) -9.23 .0001 94.58(9.11) -7.56 .0001 125.66(10.89) 86.41(8.41) -9.18 .0001 Wechsler Memory Scale, Memory Quotient 134.08(14.11) 96.33(9.41) -6.64 .0001 Mattis Dementia Rating Scale 142.75(1.85) 122.33(7.77) -8.03 .0001 Beck Depression Inventory 2.50 (2.23) 4.68 .0007 13.08 (8.00) Hamilton Depression Scale 1.58(1.88) 7.08(5.77) 2.89 .01 This table indicates severity of general cognitive abilities in the patients with progressive supranuclear palsy (PSP). The significance level was set at P< .001. Most scores, while significantly different than from control subjects, fell into the low to below-average range. Patients with PSP reported being mildly depressed.
_126.83 (13.71)
particularly impaired
—
speech). We also performed an explor¬ atory correlation analysis between the Columbia Scale score of patients with PSP and their scores on the cognitive tasks. Except for the WAIS-R perfor¬ mance IQ score (r .47), which de¬ pends on speeded performance and the number of categories achieved on the WCST (r .72), all other correlations were less than .35 suggesting a limited influence of motor impairment on the cognitive performance of patients with =
=
PSP.
Concept Formation and Reasoning Processes (Table 4) The performance of patients with PSP on the Trail Making Test demon¬ strated the pronounced difficulty they have when a simple visuomotor task becomes complicated by an additional
conceptual step [F(l,22) 36.72; < .0001]. On part A of the Trail Making Test, patients with PSP were
Control Subjects (SD)
Tests Purdue Pegboard Right hand Left hand Bilateral
PSP (SD)
9.83
(.38)
4.66
12.08
(1.83)
(1.50) (3.09) 7.50 (3.68) 11.16 (3.35) 14.58 (2.19)
Luria tests
on
the Luria tasks requiring an extended sequence of coordinated motor move¬ ments. On the Purdue Pegboard Test, patients with PSP demonstrated bilat¬ erally slowed (more pronounced for the dominant hand) coordination. Speed of speech was mildly slowed. The Mazes subtest scale score achieved by the patients with PSP fell within the normal range (ie, the oldest age range provided on this children's test) but was impaired relative to the con¬ trol subjects. The Northwestern Gait Scale score of the patients with PSP indicated moderate severity of motor impairment. Although PSP patient performance was diminished across motor tasks, it appeared that the mo¬ tor impairment of patients with PSP was most pronounced on those tasks requiring sequential coordinated movements (eg, Luria tests) rather than simple motor tasks (eg, speed of
=
Motor Processes*
Table 3.
Patients with PSP were signifi¬ cantly impaired on the Luria tasks. were
t Test
130.16(12.73)
Verbal IQ Performance IQ
Motor Processes (Table 3)
They
PSP (SD)
Intelligence Scale-Revised
(2.46)
f Test
-7.95
.0001
-6.98
.0001
5.91
13.25 (1.76)
5.16
-10.30 (2.84) WISC-R Mazes -4.22 .0007 16.75 (1.65) -5.52 .0001 20.08 (1.88) Speed of speech * WISC-R indicates Wechsler Intelligence Scale for Children-Revised. The data on motor performance con¬ firm the observed slowing of motor processes in patients with progressive supranuclear palsy (PSP). The sig¬ nificance level
was
set at
20.58
< .001.
significantly slower than the control (P < .0001), but it was on part (which requires shifting between a numerical and alphabetical set) that patients with PSP demonstrated their most dramatic slowing [F(l) 21.78; < .0001]. Their difficulty in shifting conceptual sets was reinforced by the performance of the patients with PSP group
=
the MDRS and the WCST. Patients with PSP were significantly impaired compared with control subjects on the concept formation subscale of the MDRS. Control subjects averaged close to achieving five categories, whereas patients with PSP barely av¬ eraged three categories on the WCST. Patients with PSP attained as many correct responses as control subjects but had over twice as many errors. When we looked at the type of errors made, we saw that almost all of the control subjects' errors were of the "conceptual type," whereas patients with PSP made fewer conceptual but on
more
perseverative
errors
(P < .007).
Patients with PSP required almost twice as many trials as control sub¬ jects to achieve the first category on the WCST, but this difference did not reach significance. Visual (picture ar¬ rangement task) and verbal (similari¬ ties) reasoning were also difficult for patients with PSP. Even though PSP patient performance on the picture arrangement task and WCST was not significantly impaired based on the adjusted values, they still indicated
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trend toward impaired problem solv¬ ing by patients with PSP. a
Lexical Production and
Drawing
(Table 5)
Patients with PSP (x 9.8) pro¬ duced significantly fewer original line drawings compared with control sub¬ jects (x 21.9) on the design fluency task (although their performance on this task was relatively no worse than on the animal fluency task). The draw¬ ings they did complete were often per¬ severatile and such perseverations were drawn significantly more fre¬ quently by patients with PSP than by control subjects. Patients with PSP were signifi¬ cantly more impaired than were con¬ trol subjects in producing words that start with a specific letter or belong to =
=
specific category (eg,_animal fluency: patients with PSP, 8.8; control 21.6). The PSP patients' subjects, performance deficits on verbal fluency tasks was similar to their performance òn a drawing fluency task but included proportionally fewer perseverative re¬ a
=
=
sponses. These results stand in con¬ trast to their relatively better perfor¬
the Boston Naming Test, suggesting that patients with PSP can more easily retrieve names of pictured objects than initiate a conscious mance on
search for the
same names in lieu of The PSP patients' per¬ formance on the initiation and perseveration subscale of the MDRS com-
pictorial
cues.
plemented the above findings regard¬ ing increased latency of response and perseverative responses.
Table Tests Trail A
Attention (Table 6)
On the -Test, which estimates sim¬ ple vigilance and selective attention ability, the control subjects made no errors, while patients with PSP omit¬ ted responding to only a few stimuli. On the PASAT, patients with PSP made significantly more errors than control subjects at all rates of presen¬ tation [F(l,22) 67.75; < .0001], al¬ though the slope of the PSP patients' performance across rates of presenta¬ tion was similar to that of the control subjects [F(3) .70; < .54], indicat¬ ing that they were sensitive to the in¬ creasing difficulty of the task. On the < Stroop test, [F(l,22) 130.16; .0001] patients with PSP read signifi¬ cantly fewer color words and named significantly fewer colors than the con¬ trol subjects. In the interference con¬ dition, patients with PSP read slightly fewer words than control subjects but the difference was minimal compared with the word-reading and colornaming conditions [F(2) 53.13; < .0001]. In fact, the group interfer¬ ence scores were relatively close (P < .02), indicating similar sensitiv¬ ity to interference mechanisms. That is, patients with PSP were only mar¬ ginally different than control subjects in automatic processing of linguistic information in contrast to what has been reported in patients with frontal lobe lesions.32·33 =
=
4.—Concept Formation Control
and
Reasoning Processes*
Subjects (SD)
PSP (SD)
Making Test 31.58 65.33
Wisconsin Card
(7.56) (20.33)
117.41 (42.77) 391.25(203.15)
6.54
.0001
5.71
.0001
Sorting Test
Categories
3.00 (1.90) .002 -3.51 (1.07) NSD 66.41 (17.64) -.696 (10.08) 24.91 (20.18) 56.41 (25.05) 11.37 (6.50) 24.61 (14.05) 2.89 .007 70.31 (15.79) 41.03 (22.88) Conceptual errors, % No. of trials to first category 14.66 (9.35) 23.81 (21.50) 1.29 NSD 39 (0) 34.58 (3.55) -4.30 .001 Concept formation subscale (MDRS) Picture arrangement subtest (WAIS-R) 13.16 (2.82) 7.83 (2.08) -4.05 .001 Similarities subtest (WAIS-R) 14.08 (1.24) 9.41 (2.74) -5.29 .0003 *MDRS indicates Mattis Dementia Rating Scale; WAIS-R, Wechsler Adult Intelligence Scale-Revised. We show the difficulty patients with progressive supranuclear palsy (PSP) have on tests evaluating concept forma¬ tion and reasoning. The significance level was set at < .001. Note the disproportionate difficulty that patients with PSP had completing part of the Trail Making Test. On the Wisconsin Card Sorting Test, patients with PSP committed relatively more perseverative than conceptual errors, while control subjects had the opposite pattern. 5.33
Total correct Total errors Perseverative errors, %
71.25
=
=
Table 5.—Performance of Patients With PSP and Control Naming, and Initiation* Tests
Control
PSP (SD)
on
Tests of
Fluency,
/Test
Design fluency Total
Perseverations FAS
21.90
(6.83) (1.21)
9.83
.54
5.08
(12.34) (2.06)
16.16
(4.40) (5.08)
-6.37
.0001
(7.57) (2.31)
-8.06
.0001
fluency
Total Perseverations
48.08 1.19
2.08
NS
Category fluency Animals
21.63 (4.36) 8.83 (2.29) 26.58 (5.19) 12.25 (3.95) Supermarket Boston Naming Test 81.66 (3.00) 70.22 (9.44) -4.37 .002 Initiation and perseveration 36.83 (.389) 27.83 (4.60) subscale (MDRS) PSP indicates progressive supranuclear palsy; NS, not significant; and MRDS, Mattis Dementia Rating Scale. The significance level was set at < .001.
Time Estimation
Patients with PSP demonstrated sensitivity to time perception on the basis of their performance estimating the duration of time passed while lis¬ tening to a tapping sound. However, across conditions (ie, varying the num¬ ber of taps per minute), their estima¬ tion of the number of taps they heard in a selective attention task was mar¬ ginally underestimated compared with control subjects (P < .02 to < .04). Patients with PSP also slightly underestimated the current time when asked, as well as the dura¬ tion of the testing session, but in these estimates their performance was sim¬ ilar to control subjects.
Subjects (SD)
Subjects
Table 6.—Attention* Tests
Stroop
Control Subjects (SD)
PSP (SD)
/Test
(15.80) (10.50) 24.00 (4.71)
-9.43
.0001
-7.73
.0001
test
Words
(13.18) (9.46) 43.91 (8.15)
Colors Colorword interference Interference
111.00
46.33
74.58
33.50
-12.3
score
-3.25
Auditory Serial Addition Test, second 14.66 (6.05) 43.33(12.65) 2.0 43.25 (10.67) 13.41 (6.25) -8.73 .0001 40.08 (10.92) 12.16 (5.20) 1.2 35.33 (11.61) 8.58 (4.58) -7.26 .0001 A-Test 0.00 (0) 2.00 (1.70) * Patients with progressive supranuclear palsy (PSP) made relatively few errors on a simple bedside test of attention, while (controlling for speed) performing similarly as control subjects across conditions on two tradi¬ tional tests of attention. Patients with PSP were slower than control subjects when reading words or naming col¬ ors but they were relatively equally affected by the interference condition. In addition, even though patients with PSP made more errors on the Paced Auditory Serial Addition Test, they were equally sensitive as control sub¬ jects when task difficulty was manipulated. The significance level was set at < .001. Paced 2.4
Correlational Analyses
Severity of cognitive deficit as esti¬ by the MDRS, total score was highly correlated with performance on the majority of cognitive tests admin¬ istered with the exception of the verbal fluency tests and the indexes of depres¬ sion. On the other hand, only one cormated
relation between mood state (Hamil¬ ton Depression Scale score) and cogni¬ tive functioning (drawing fluency) reached criteria (r .50). Moreover, duration of illness was only correlated with PSP patient performance on the Luria motor tests (r .60) and the =
=
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Stroop test interference condition (r .68). =
Effects of Drug and Placebo on Executive and Attentional Processes
Following baseline testing, the pa¬ tients with PSP received either phy-
sostigmine or a placebo in a doubleblind crossover design. The results in¬ dicated that neither physostigmine
placebo produced a significant change in executive and attentional performance in patients with PSP. At best, patients showed a slight overall improvement in performance due to practice but this change was not sig¬ nificant. Drug treatment also had no clinically significant effect on extrapyr¬ amidal motor function (modified Co¬ lumbia Rating Scale score akinesia 7 ± 1 during baseline and placebo and 6.5 ± 1 during physostigmine; rigidity .6 ± .2 throughout the study). The levels of cerebrospinal fluid con¬ stituents did not significantly change during physostigmine administration. Acetylcholinesterase and butyrylchonor
linesterase levels were 15 ± 2 and 10 ± 1.5 nmol/min per milliliter, re¬ spectively, during both placebo and
drug
treatment
periods, respectively.
Homovanillic acid was 17 ± 2 and 18 ± 3 ng/mL, and 5-hydroxyindoleacetic acid was 15 ± 1 and 17 ± 2 during the placebo and physo¬
stigmine phases.
There were no clinically significant adverse effects associated with physo¬
stigmine treatment.
COMMENT
The results of our study confirm that patients with PSP are generally im¬ paired when compared with matched control subjects across a wide range of cognitive and motor tasks. Slowed mo¬ tor performance in these patients can affect scores on cognitive tasks. For example, patients with PSP were oc¬ casionally penalized on the WAIS-R performance scale subtests because of how slowly they solved a problem even though they achieved the correct solu¬ tion. Despite controlling for motor speed by administering tasks where cognitive-processing conditions are manipulated independent of response speed, slowed motor processes remain a possible confound in the interpreta¬ tion of cognitive test results in PSP. For example, several of the less cognitively demanding timed tests varied in "cognitive load" (eg, the PASAT and Stroop test) and although patients
with PSP
were
slower than control
subjects across conditions on these tasks, they were not additionally slowed by greater cognitive load (eg, speeding presentation rate or intro¬ ducing an interference condition), sug¬ gesting that at least some of the pa¬ tients' performance on response-time tasks can be explained by slowed and/ or
inhibited execution of motor re¬ However, on other timed
sponses.
(eg, subtests from the WAIS-R WCST), patients did not improve their problem-solving performance even when additional (but nonscorable) time was allowed. Physostigmine (at the doses administered) did not improve PSP patient performance. tasks or
Of more interest is the finding that patients with PSP are particularly impaired when a task requires sequen¬ tial movements, reasoning, conceptual shifting, monitoring the frequency with which stimuli are presented, and rapid retrieval of verbal knowledge.
These deficits indicate that above and beyond a general slowing of cognitive processes, the patient with PSP finds it difficult to perform on some tasks tra¬ ditionally associated with prefrontal lobe functioning. Although we found that patients with PSP were slower and made more errors than control subjects on tests of automatic and ef¬ fortful attentional processing such as the Stroop test and the PASAT, pa¬ tients with PSP were nearly as sen¬ sitive as control subjects to the con¬ ditions of these tests. This finding suggests a slowing of the effortful cog¬
nitive processes associated with selec¬ tive attention but not a deficit in auto¬ matic processes. Mood state and dura¬ tion of illness were generally not associated with performance on se¬ lected tests of executive and atten¬ tional processes. However, perform¬ ance on a dementia severity scale was indicative of the level of PSP patient
performance on attentional and exec¬ utive functioning tasks. The sugges¬ tion that patients with PSP have im¬ paired performance on tasks measur¬ ing frontal lobe functions has been made before.8·5 However, caution is ad¬ vised before attributing the cognitive deficits of patients with PSP primarily to prefrontal lobe dysfunction. Rather, a deafferenting process, as has been suggested by some,8 would mean that relatively intact frontal processing would be deprived of input from basal ganglia, basal forebrain, and collicular, and mediodorsal thalamus. In cog¬ nitive terms, this suggests that knowl¬ edge representation in the form of "higher-order" memory storage would be relatively intact in the frontal lobe while cognitive processes that affect the speed of processing representa¬ tional knowledge, the sequencing of knowledge during encoding and re¬ trieval, and the sequencing and coor¬ dination of learned motor movements would be affected by PSP. These im¬ paired cognitive processes have been more associated with basal ganglia functioning than prefrontal lobe func¬ tioning. Yet, without the collaboration
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of such processes, the prefrontal rep¬ resentational systems would be de¬ prived of the processes that help acti¬ vate and organize them in a timely fashion. The representational systems in the frontal lobe recently described as managerial knowledge units are rel¬ atively spared in patients with PSP.34 The managerial knowledge unit is viewed as a schema or scriptlike rep¬ resentation of a set of related events that are structured to achieve a behav¬ ioral goal. Basal ganglia lesions could result in only weakly activated frontal lobe representations that would be prone to inhibition or disinhibition depending on environmental or task constraints. While this explanation is speculative, it does predict sparing of certain kinds of cognitive and social knowledge in these patients. Social and problem-solving behaviors ap¬ peared relatively intact in the patients with PSP we studied, although their performance on both the WCST and picture arrangement task was im¬
paired.
Slowed processing of information by patients with PSP is likely to com¬ pound the basic deficits described
above.35 It would have detrimental ef¬ fects on memory tests, tests where in¬ formation was presented rapidly, and tests that required greater cognitive effort. Tests more carefully designed to control for speed of processing, knowl¬ edge retrieval, and organization of knowledge should aid in teasing apart the cognitive deficits observed in pa¬ tients with PSP. In addition, direct comparison of patients with PSP with other patients who have contrasting subcortical damage (eg, Huntington's disease) will help disambiguate the various contributions of subcortical structures to cognition. The cognitive processes impaired in patients with PSP have their effect across a wide range of reasoning, memory, atten¬ tional, and linguistic tasks and may take the appearance of a "subcortical dementia." However, the implication in our study is that cognitive tasks properly controlled for such processes as
motor
execution, staged planning,
and speed of stimulus presentation will allow for relatively improved PSP
patient performance. Physostigmine did not improve pa¬ tient performance on tests of attention and executive functioning. Brain me¬ tabolism studies have indicated hypometabolic flow in prefrontal brain regions in patients with PSP.9·10 Some authors have described increased blood flow in prefrontal cortex follow¬ ing physostigmine administration in the patients with PSP we studied (I.L.,
T.N.C., Daniel R. Weinberger, MD, Karen Berman, MD, unpublished data, 1989). Thus, increases in prefrontal cortex blood flow during physostig¬ mine administration in patients with
PSP does not necessarily indicate im¬ provement in cognitive functioning on tasks sensitive to frontal lobe dysfunc¬ tion. We thank
Marjorie Risher for her administra-
tive expertise and her invaluable assistance in preparing the manuscript; and the National In¬ stitute of Neurological Disorders and Stroke and the Medical Neurology Branch, Bethesda, Md, for providing the facilities that allowed us to prepare the manuscript.
References 1. Kristensen MO. Progressive supranuclear palsy: 20 years later. Acta Neurol Scand. 1985;71:177-189. 2. Albert M, Feldman RG, Willis AL. The subcortical dementia of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 1974;
37:121-130. 3. Steele
JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. Arch Neurol. 1964;
10:333-359. 4. Maher ER, Lees AJ. The clinical features and natural history of the Steele-Richardson-Olszewski syndrome (progressive supranuclear pal-
sy). Neurology. 1986;36:1005-1008. 5. Cambier J, Masson M, Viader F, Limodin J, Strube A. Le syndrome frontal de la maladie de Steele-Richardson-Olszewski. Rev Neurol. 1985;
141:528-535. 6. Rafal RD, Posner MI, Friedman JH, Inhoff AW, Bernstein E. Orienting of visual attention in
progressive supranuclear palsy. Brain. 1988;
111:267-280. 7. Maher ER, Smith EM, Lees AJ. Cognitive deficits in the Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). J Neurol
Neurosurg Psychiatry. 1985;48:1234-1239. 8. Pillon B, Dubois B, Lhermitte F, Agid Y. Heterogeneity of cognitive impairment in progressive supranuclear palsy, Parkinson's disease, and Alzheimer's disease. Neurology. 1986;36:1179\x=req-\
1185. 9. Leenders KL, Frackowiak RSJ, Lees AJ. Steele-Richardson-Olszewski syndrome: brain energy metabolism, blood flow, and fluorodopa uptake measured by positron emission tomography. Brain. 1988;111:615-630. 10. Goffinet AM, De Voider AG, Gillain C, et al. Positron tomography demonstrates frontal lobe hypometabolism in progressive supranuclear palsy. Ann Neurol. 1989;25:131-139. 11. Ruberg M, Javoy-Agid F, Hirsch E, et al. Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann Neurol. 1985;18:523\x=req-\
536. 12. Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci USA. 1987;84:5976-5980. 13. Agid Y, Javoy-Agid F, Ruberg M, et al. Progressive supranuclear palsy: anatomoclinical and biochemical considerations. In: Yahr MD, Bergmann KJ, eds. Advances in Neurology. New York, NY: Raven Press; 1986; vol 45. 14. Jellinger K. The pedunculopontine nucleus in Parkinson's disease, progressive supranuclear palsy, and Alzheimer's disease. J Neurol Neurosurg
Psychiatry. 1988;51:540-543.
15. Litvan I, Gomez C, Atack JR, et al. Physostigmine treatment of progressive supranuclear palsy. Ann Neurol. In press. 16. Wechsler DA. WAIS-R Manual. New York, NY: Psychological Corp; 1981. 17. Wechsler DA. A standardized memory scale for clinical use. J Psychol. 1945;19:87-95. 18. Litvan I, Grafman J, Gomez C, Chase TN. Memory impairment in patients with progressive supranuclear palsy. Arch Neurol. 1989;46:765-767. 19. Mattis S. Mental status examination for organic mental syndrome in the elderly patient. In: Bellak L, Karasu TB, eds. Geriatric Psychiatry. New York, NY: Grune & Stratton; 1976. 20. Christensen AL. Luria's Neuropsychological Investigation. 2nd ed. Copenhagen, Denmark: Munksgaard International Publishers Ltd; 1979. 21. Purdue Research Foundation. Examiner's Manual for the Purdue Pegboard. Chicago, Ill: Science Research Associates; 1948. 22. Wechsler D. WISC-R Manual: Wechsler Intelligence Scale for Children-Revised. New York, NY: Psychological Corp; 1974. 23. Canter GJ, DeLa Torre R, Mier M. A method for evaluating disability in patients with Parkinson's disease. J Nervous Mental Disorders.
1961;133:143-147. 24. Montgomery GK, Reynolds NC, Warren
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Qualitative assessment of Parkinson's disstudy of reliability and data reduction with an abbreviated Columbia Scale. Neuropharmacology. 1985;8:83-92. 25. Army Individual Test Battery. Manual of Direction and Scoring. Washington, DC: Ward Department, Adjutant General's Office; 1944. 26. Grant DA, Berg EA. A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. J Exp Psychol. 1948;38:404-411. 27. Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuropsychologia. RM.
ease:
1967;5:135-140.
28. Jones-Gotman M, Milner B. Design fluency: the invention of nonsense drawings after focal cortical lesions. Neuropsychologia. 1977;15:653\x=req-\ 674. 29. Strub RL, Black FW. The Mental Status Examination in Neurology. Philadelphia, Pa: FA Davis Co Publishers; 1985. 30. Gronwall DMA. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills. 1977;44:367-373. 31. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643-662. 32. Perret E. The left frontal lobe of man and the suppression of habitual responses in verbal categorical behavior. Neuropsychologia. 1974; 12:323-330. 33. Stuss DT, Benson DF. The Frontal Lobes. New York, NY: Raven Press; 1986. 34. Grafman J. Plans, actions, and mental sets: managerial knowledge units in the frontal lobes. In: Perecman E, ed. Integrating Theory and Practice in Neuropsychology. Hillsdale, NJ: Lawrence Erlbaum Associates; 1989. 35. Dubois B, Pillon B, Legault F, Agid Y, Lhermitte F. Slowing of cognitive processing in progressive supranuclear palsy. Arch Neurol.
1988;45:1194-1199.
Progressive Supranuclear Palsy Jordan Grafman, PhD; Irene Litvan, MD; Claudia Gomez, MA; Thomas N. Chase, MD
\s=b\ Performance on tasks evaluating "executive and attentional" processes presumably subserved by prefrontal cortex were compared in patients with progressive supranuclear palsy and with age- and education-matched control subjects. The results indicated that patients with pro-
gressive supranuclear palsy were particularly impaired when a task required sequential movements, conceptual shifting, monitoring the frequency with which stimuli are presented, or rapid retrieval of verbal knowledge. These deficits could not simply be accounted for by slowed information processing or by a deficit in representational knowledge. Conceivably, "weak activation" of frontal lobe representational knowledge characterized by an observed attentional deficit results in the neuropsychological impairments noted in patients with progressive supra\x=req-\ nuclear palsy. The oral administration of physostigmine, under double-blind placebo-controlled conditions, did not facilitate executive or attentional performance as evaluated by our tasks. (Arch Neurol. 1990;47:553-558)
Accepted for publication September 29, 1989. From the Cognitive Neuroscience Unit, Medical Neurology Branch (Dr Grafman) and Experimental Therapeutics Branch (Drs Litvan and Chase and Ms Gomez), National Institute of Neurological Disorders and Stroke, Bethesda, Md. The opinions and assertions contained herein are the private views of the authors, and are not to be construed as official or necessarily reflecting the views of the National Institutes of Health, the United States Public Health Service, the Department of Health and Human Services, or the Uniformed Services University of the Health Sciences.
Reprint requests to the Cognitive Neuroscience Unit, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg 10, Room 5C422, Bethesda, MD 20892 (Dr Grafman).
Qîubcortical
dementia is often ineluded in the clinical description of patients suffering from progressive su¬ pranuclear palsy (PSP).1 This demen¬ tia has been characterized by forgetfulness, slowing of information pro¬ cessing, mood changes, and difficulty in manipulating learned knowledge.23 The difficulty in manipulating learned knowledge may be attributable to frontal lobe dysfunction,4·5 while an associated deficit in orienting visual attention in the vertical plane appears independent of any impairment in ef¬ fortful manipulation of learned knowl¬ edge and may relate to the midbrain lesions found in this disorder.6 On the basis of poor performance by patients with PSP on tasks requiring effortful manipulation of learned knowledge, flexible thinking, and attention,7 spec¬ ulation has centered on the possible role that basal ganglia and basal fore¬ brain lesions have on frontal lobe func¬ tioning. Conceivably, degeneration of afferent fibers projecting from basal ganglia and basal forebrain structures to the frontal lobe may isolate prefron¬ tal cortex from subcortical structures (and/or cause some minor transneural degeneration in prefrontal cortex re¬ sulting in partially dysfunctional cor¬ tical tissue).8 Recent positron emission tomographic scan studies of patients with PSP910 have described decreased metabolism and regional blood flow in the area of the prefrontal cortex. The findings to date suggest that patients with PSP may be impaired on tasks used to assess "executive and at¬ tentional" processes presumably sub¬ served by prefrontal cortex. To test this hypothesis, we examined patients
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with PSP and matched control sub¬ on tests of executive and atten¬ tional processes. Next, we compared the performance of patients with PSP during baseline, placebo, and drug con¬ ditions on these same tests to deter¬ mine whether the administration of a cholinesterase inhibitor facilitated PSP cognitive performance.
jects
PATIENTS AND METHODS
Twelve patients with PSP were strati¬ fied, matched with 12 normal control sub¬ jects (Table 1). The diagnosis of PSP was based on the presence of all the following features: (1) age of onset, 50 years or older; (2) parkinsonian signs including bradykinesia, postural or gait disorder, axial rigidity, and no resting tremor; (3) pseudobulbar signs including dysarthria and dysphagia; (4) extraocular movement abnor¬ malities characterized by supranuclear ver¬ tical (with or without horizontal) palsy; (5) progressive course; and (6) no roentgenographic abnormalities other than subcortical and/or midbrain atrophy. All patients with PSP had magnetic resonance imaging scans except one who received a computed tomographic scan (the magnetic resonance imaging was contraindicated in his case because he had a pacemaker). Most, but not all, magnetic resonance imagings described mild subcortical and/or midbrain atrophy and third ventricle enlargement. All pa¬
tients with PSP also underwent electro-oculographic studies that demonstrated ver¬ tical gaze palsy with preservation of oculocephalic reflexes. Except for one patient who continued to receive a constant dose of levodopa-carbidopa (Sinemet, 600 mg/d), none of the patients took other centrally active drugs during the course of this clin¬ ical trial. There were no significant age or education differences between groups. To participate in this study, patients with PSP were required to show evidence that they
Subject Table*
Table 1. —
Control
PSP Characteristics Years of education
Age
(SD) (5.9) 15.1 (3.6)
63.4
Age at onset
60.3
(5.6)
35.0
(11.9)
Subjects (SD) 63.8 (5.5) 16.3 (2.9)
of disease
Duration of disease Hoehn-Yahr
Scale *
3.2
(.39)
score
progressive supranuclear palsy (PSP) (n 12) and control subjects (n 12) were as closely matched as possible for age and years of education. Patients with PSP were mild to moderately affected by their disease. The subjects' age is given Patients with =
=
in years and illness duration in months.
read, write, understand instructions, comprehend written and spoken language, and express themselves clearly. Cholinergic nuclei, including the pedunculopontine tegmental nucleus, are affected along with dopamine-producing neurons in PSP.1112 It has been suggested that some of the cognitive symptoms described in PSP may be due to cholinergic rather than dopaminergic deficiencies.1314 On this basis, an experimental trial of physostigmine (an acetylcholinesterase inhibitor) was offered to patients with PSP in the hopes of ame¬ liorating some of their cognitive deficits.15 Following their baseline evaluation, pa¬ tients first received 4 days of open-label dose finding. Physostigmine was adminis¬ tered orally every 2 hours, six times daily at doses that increased from 0.5 mg per dose (3 mg/d) on the first day to 2 mg per dose (12 mg/d) on the fourth day. Verbal memory was evaluated by alternate versions of the Selective Reminding Test5 administered twice daily, 30 minutes after taking the first and last daily doses of physostigmine. Mean performance on both tests at each dose was could
used to determine the best dose for each in¬ dividual. For the second part of this study, patients were randomized to a 10-day cross¬ over, placebo-controlled double-blind trial of physostigmine, at their previously deter¬ mined best dose (1.25 ± 0.2 mg per dose; range, 0.5 to 2.0 mg) orally administered every 2 hours, six times per day. There was a 3-day washout period between baseline and initiation of the crossover trial; while on the crossover trial, there was no washout period between phases. Patients received neuropsychological testing only after the third day of initiation of each phase (phy¬
sostigmine or placebo). The following neuropsychological tests were performed once during the third and fourth days of each study phase (baseline, placebo, and drug), starting 30 minutes af¬ ter the second daily dose of drug or placebo and lasting 1 to 2 hours. Tests
Wechsler Adult
Intelligence Scale-Revised
(WAIS-R).16-This test, WAIS-R, was ad¬ ministered to provide general indexes of intellectual performance. The full-scale,
verbal, and performance IQ scores are pre¬ sented. In addition, the age-corrected scale score for the similarities subtest is reported as a measure of verbal reasoning and the age-corrected scale score for the picture ar¬
rangement subtest is described sure
of
as a mea¬
pictorial reasoning.
Wechsler Memory Scale.17—Wechsler Memory Scale was used to obtain a general level of memory functioning. This test is composed of several subtests whose scores can be combined to produce a single mem¬ ory quotient that can be directly compared with the WAIS-R IQ scores. In this article, we present the memory quotient only. A companion article discusses the memory performance of patients with PSP in much more
detail.18
Mattis Dementia Rating Scale (MDRS).19— The MDRS was used to estimate the sever¬ ity of the PSP patient's cognitive decline. In addition, two subscales (conceptual think¬ ing and initiation and perseveration), which are often found diminished in pa¬ tients with frontal lobe dysfunction is de¬
mation-processing capacity.30 We also ad¬ ministered the Stroop color word test31 to obtain an estimate of automatic processing. Time Estimation.—Subjects were required to estimate the correct time during the testing session and the duration of the en¬ tire testing session. A tapping task was also used to assess the subject's estimation of time duration. The subjects heard 60,30,15, or 6 taps for 1 minute. They were then asked to estimate the number of taps they heard as well as the time that elapsed. Beck and Hamilton Depression Scales
used to estimate mood state. The tests were administered over several sessions in a set order for all subjects. No single testing session exceeded 2 hours. Pa¬ tients with PSP performance did not reveal specific effects of fatigue for the last few tests administered within a session. In¬ formed consent was obtained from all sub¬ jects after the procedures were explained. Other neurobehavioral data collected dur¬ ing the physostigmine trial will be pre¬ sented in separate articles. were
scribed.
Motor
hospital
Analysis Methods
Ability.—Manual dexterity was as¬
sessed by a set of 10 tests described by Luria20 as sensitive to frontal lobe lesions. Many of these tests require sequential mo¬ tor movements. A single score was used to estimate the number of tests "passed" by a subject. We also administered the Purdue Pegboard Test21 to estimate motor dexter¬ ity. A third measure of motor ability tested was speed of speech. This was measured by having a subject repeat the word "hospital" as fast and accurately as possible in a 10-second period. The total number of times was
pronounced accurately
was
recorded. A fourth measure used was the Mazes subtest from the Wechsler Intelli¬ gence Scale for Children22 that estimates route finding. The scale score from this subtest was used. Finally, we used the Northwestern Gait Scale23 and the modified Columbia Scale24 to provide clinical indexes of motor ability. Conceptual Flexibility.—The Trail Making Test25 was administered to estimate the subjects' ability to follow within and across set categorical sequences. The Wisconsin Card Sorting Test (WCST)2' was adminis¬ tered to evaluate the ability of patients to form and to shift concepts based on reason¬ ing and responsiveness to the examiner's feedback. Fluency.—Verbal fluency was assessed by means of the FAS,27 animal (subjects were required to produce as many animal names as they could in 1 minute), and supermarket (subjects had to produce names of items that could be found in a typical supermar¬ ket in 1 minute) fluency tasks. Visuospatial fluency was evaluated by the drawing flu¬ ency task28 in which subjects were required to draw as many different geometric de¬ signs as possible in 1 minute. Attention.—We used the " -Test" to esti¬
simple vigilance.29 Subjects were re¬ quired to identify the letter A when they heard it among a long series of letters. The mate
number of errors was recorded. The Paced Auditory Serial Addition Test (PASAT) was used to estimate attention and infor-
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The first set of comparisons presented below represent the baseline evaluation. Statistical procedures used include t tests
(signified by a simple value), repeated analysis of variance, and correla¬ tions. The small number of subjects in each group and the large number of comparisons made precluded the appropriate use of mulmeasures
tivariate statistics. We ran correlational analyses to determine the relationship be¬ tween symptom duration, current mood state, and overall degree of dementia and performance on tests of executive and at¬ tentional processes; the findings are pre¬ sented only when the Spearman's rank or¬ der correlations reached .50. Due to multi¬ ple comparisons, we used a Bonferroni correction procedure that set the value significance level at .001. The Bonferroni correction was obtained by dividing the al¬ pha level by the total number of compari¬ .001. The numerator is the sons, ie, .50/40 overall alpha adapted by us. This is divided by the number of comparisons actually made. This adjusted significance level (P < .001) is used to judge the significance of all comparisons made. The second set of comparisons presented represent the effects of placebo and drug treatment conditions on PSP patient test performance compared with baseline (8 of 12 patients participated in the drug study). Only the PSP patient performance is con¬ sidered, since the control subjects did not receive physostigmine. Statistical proce¬ dures were similar to those described above. =
RESULTS General Cognitive Functioning and Mood State (Table 2)
Patients with PSP had significantly diminished WAIS-R IQ scores when compared with control subjects. Their performance scale score was particu¬ larly low. The MDRS total score of the
patients with PSP places them in the mildly impaired range. Finally, the Wechsler Memory Scale Memory Quo¬ tient of the patients with PSP is sig¬ nificantly diminished when compared with that of the control subjects but is consistent with their WAIS-R verbal IQ score. Patients with PSP, as a group,
were
marginally depressed
based on their Hamilton and Beck De¬ pression Scale scores. However, many of the endorsed items on these depres¬ sion scales reflected somatic com¬ plaints or changes in cognitive func¬ tioning and did not indicate increased sadness or other depressive symptoms.
Table 2.—General Cognitive Functioning and Mood State* Control Subjects (SD)
Tests Wechsler Adult
Full Scale IQ
90.14(7.93) -9.23 .0001 94.58(9.11) -7.56 .0001 125.66(10.89) 86.41(8.41) -9.18 .0001 Wechsler Memory Scale, Memory Quotient 134.08(14.11) 96.33(9.41) -6.64 .0001 Mattis Dementia Rating Scale 142.75(1.85) 122.33(7.77) -8.03 .0001 Beck Depression Inventory 2.50 (2.23) 4.68 .0007 13.08 (8.00) Hamilton Depression Scale 1.58(1.88) 7.08(5.77) 2.89 .01 This table indicates severity of general cognitive abilities in the patients with progressive supranuclear palsy (PSP). The significance level was set at P< .001. Most scores, while significantly different than from control subjects, fell into the low to below-average range. Patients with PSP reported being mildly depressed.
_126.83 (13.71)
particularly impaired
—
speech). We also performed an explor¬ atory correlation analysis between the Columbia Scale score of patients with PSP and their scores on the cognitive tasks. Except for the WAIS-R perfor¬ mance IQ score (r .47), which de¬ pends on speeded performance and the number of categories achieved on the WCST (r .72), all other correlations were less than .35 suggesting a limited influence of motor impairment on the cognitive performance of patients with =
=
PSP.
Concept Formation and Reasoning Processes (Table 4) The performance of patients with PSP on the Trail Making Test demon¬ strated the pronounced difficulty they have when a simple visuomotor task becomes complicated by an additional
conceptual step [F(l,22) 36.72; < .0001]. On part A of the Trail Making Test, patients with PSP were
Control Subjects (SD)
Tests Purdue Pegboard Right hand Left hand Bilateral
PSP (SD)
9.83
(.38)
4.66
12.08
(1.83)
(1.50) (3.09) 7.50 (3.68) 11.16 (3.35) 14.58 (2.19)
Luria tests
on
the Luria tasks requiring an extended sequence of coordinated motor move¬ ments. On the Purdue Pegboard Test, patients with PSP demonstrated bilat¬ erally slowed (more pronounced for the dominant hand) coordination. Speed of speech was mildly slowed. The Mazes subtest scale score achieved by the patients with PSP fell within the normal range (ie, the oldest age range provided on this children's test) but was impaired relative to the con¬ trol subjects. The Northwestern Gait Scale score of the patients with PSP indicated moderate severity of motor impairment. Although PSP patient performance was diminished across motor tasks, it appeared that the mo¬ tor impairment of patients with PSP was most pronounced on those tasks requiring sequential coordinated movements (eg, Luria tests) rather than simple motor tasks (eg, speed of
=
Motor Processes*
Table 3.
Patients with PSP were signifi¬ cantly impaired on the Luria tasks. were
t Test
130.16(12.73)
Verbal IQ Performance IQ
Motor Processes (Table 3)
They
PSP (SD)
Intelligence Scale-Revised
(2.46)
f Test
-7.95
.0001
-6.98
.0001
5.91
13.25 (1.76)
5.16
-10.30 (2.84) WISC-R Mazes -4.22 .0007 16.75 (1.65) -5.52 .0001 20.08 (1.88) Speed of speech * WISC-R indicates Wechsler Intelligence Scale for Children-Revised. The data on motor performance con¬ firm the observed slowing of motor processes in patients with progressive supranuclear palsy (PSP). The sig¬ nificance level
was
set at
20.58
< .001.
significantly slower than the control (P < .0001), but it was on part (which requires shifting between a numerical and alphabetical set) that patients with PSP demonstrated their most dramatic slowing [F(l) 21.78; < .0001]. Their difficulty in shifting conceptual sets was reinforced by the performance of the patients with PSP group
=
the MDRS and the WCST. Patients with PSP were significantly impaired compared with control subjects on the concept formation subscale of the MDRS. Control subjects averaged close to achieving five categories, whereas patients with PSP barely av¬ eraged three categories on the WCST. Patients with PSP attained as many correct responses as control subjects but had over twice as many errors. When we looked at the type of errors made, we saw that almost all of the control subjects' errors were of the "conceptual type," whereas patients with PSP made fewer conceptual but on
more
perseverative
errors
(P < .007).
Patients with PSP required almost twice as many trials as control sub¬ jects to achieve the first category on the WCST, but this difference did not reach significance. Visual (picture ar¬ rangement task) and verbal (similari¬ ties) reasoning were also difficult for patients with PSP. Even though PSP patient performance on the picture arrangement task and WCST was not significantly impaired based on the adjusted values, they still indicated
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trend toward impaired problem solv¬ ing by patients with PSP. a
Lexical Production and
Drawing
(Table 5)
Patients with PSP (x 9.8) pro¬ duced significantly fewer original line drawings compared with control sub¬ jects (x 21.9) on the design fluency task (although their performance on this task was relatively no worse than on the animal fluency task). The draw¬ ings they did complete were often per¬ severatile and such perseverations were drawn significantly more fre¬ quently by patients with PSP than by control subjects. Patients with PSP were signifi¬ cantly more impaired than were con¬ trol subjects in producing words that start with a specific letter or belong to =
=
specific category (eg,_animal fluency: patients with PSP, 8.8; control 21.6). The PSP patients' subjects, performance deficits on verbal fluency tasks was similar to their performance òn a drawing fluency task but included proportionally fewer perseverative re¬ a
=
=
sponses. These results stand in con¬ trast to their relatively better perfor¬
the Boston Naming Test, suggesting that patients with PSP can more easily retrieve names of pictured objects than initiate a conscious mance on
search for the
same names in lieu of The PSP patients' per¬ formance on the initiation and perseveration subscale of the MDRS com-
pictorial
cues.
plemented the above findings regard¬ ing increased latency of response and perseverative responses.
Table Tests Trail A
Attention (Table 6)
On the -Test, which estimates sim¬ ple vigilance and selective attention ability, the control subjects made no errors, while patients with PSP omit¬ ted responding to only a few stimuli. On the PASAT, patients with PSP made significantly more errors than control subjects at all rates of presen¬ tation [F(l,22) 67.75; < .0001], al¬ though the slope of the PSP patients' performance across rates of presenta¬ tion was similar to that of the control subjects [F(3) .70; < .54], indicat¬ ing that they were sensitive to the in¬ creasing difficulty of the task. On the < Stroop test, [F(l,22) 130.16; .0001] patients with PSP read signifi¬ cantly fewer color words and named significantly fewer colors than the con¬ trol subjects. In the interference con¬ dition, patients with PSP read slightly fewer words than control subjects but the difference was minimal compared with the word-reading and colornaming conditions [F(2) 53.13; < .0001]. In fact, the group interfer¬ ence scores were relatively close (P < .02), indicating similar sensitiv¬ ity to interference mechanisms. That is, patients with PSP were only mar¬ ginally different than control subjects in automatic processing of linguistic information in contrast to what has been reported in patients with frontal lobe lesions.32·33 =
=
4.—Concept Formation Control
and
Reasoning Processes*
Subjects (SD)
PSP (SD)
Making Test 31.58 65.33
Wisconsin Card
(7.56) (20.33)
117.41 (42.77) 391.25(203.15)
6.54
.0001
5.71
.0001
Sorting Test
Categories
3.00 (1.90) .002 -3.51 (1.07) NSD 66.41 (17.64) -.696 (10.08) 24.91 (20.18) 56.41 (25.05) 11.37 (6.50) 24.61 (14.05) 2.89 .007 70.31 (15.79) 41.03 (22.88) Conceptual errors, % No. of trials to first category 14.66 (9.35) 23.81 (21.50) 1.29 NSD 39 (0) 34.58 (3.55) -4.30 .001 Concept formation subscale (MDRS) Picture arrangement subtest (WAIS-R) 13.16 (2.82) 7.83 (2.08) -4.05 .001 Similarities subtest (WAIS-R) 14.08 (1.24) 9.41 (2.74) -5.29 .0003 *MDRS indicates Mattis Dementia Rating Scale; WAIS-R, Wechsler Adult Intelligence Scale-Revised. We show the difficulty patients with progressive supranuclear palsy (PSP) have on tests evaluating concept forma¬ tion and reasoning. The significance level was set at < .001. Note the disproportionate difficulty that patients with PSP had completing part of the Trail Making Test. On the Wisconsin Card Sorting Test, patients with PSP committed relatively more perseverative than conceptual errors, while control subjects had the opposite pattern. 5.33
Total correct Total errors Perseverative errors, %
71.25
=
=
Table 5.—Performance of Patients With PSP and Control Naming, and Initiation* Tests
Control
PSP (SD)
on
Tests of
Fluency,
/Test
Design fluency Total
Perseverations FAS
21.90
(6.83) (1.21)
9.83
.54
5.08
(12.34) (2.06)
16.16
(4.40) (5.08)
-6.37
.0001
(7.57) (2.31)
-8.06
.0001
fluency
Total Perseverations
48.08 1.19
2.08
NS
Category fluency Animals
21.63 (4.36) 8.83 (2.29) 26.58 (5.19) 12.25 (3.95) Supermarket Boston Naming Test 81.66 (3.00) 70.22 (9.44) -4.37 .002 Initiation and perseveration 36.83 (.389) 27.83 (4.60) subscale (MDRS) PSP indicates progressive supranuclear palsy; NS, not significant; and MRDS, Mattis Dementia Rating Scale. The significance level was set at < .001.
Time Estimation
Patients with PSP demonstrated sensitivity to time perception on the basis of their performance estimating the duration of time passed while lis¬ tening to a tapping sound. However, across conditions (ie, varying the num¬ ber of taps per minute), their estima¬ tion of the number of taps they heard in a selective attention task was mar¬ ginally underestimated compared with control subjects (P < .02 to < .04). Patients with PSP also slightly underestimated the current time when asked, as well as the dura¬ tion of the testing session, but in these estimates their performance was sim¬ ilar to control subjects.
Subjects (SD)
Subjects
Table 6.—Attention* Tests
Stroop
Control Subjects (SD)
PSP (SD)
/Test
(15.80) (10.50) 24.00 (4.71)
-9.43
.0001
-7.73
.0001
test
Words
(13.18) (9.46) 43.91 (8.15)
Colors Colorword interference Interference
111.00
46.33
74.58
33.50
-12.3
score
-3.25
Auditory Serial Addition Test, second 14.66 (6.05) 43.33(12.65) 2.0 43.25 (10.67) 13.41 (6.25) -8.73 .0001 40.08 (10.92) 12.16 (5.20) 1.2 35.33 (11.61) 8.58 (4.58) -7.26 .0001 A-Test 0.00 (0) 2.00 (1.70) * Patients with progressive supranuclear palsy (PSP) made relatively few errors on a simple bedside test of attention, while (controlling for speed) performing similarly as control subjects across conditions on two tradi¬ tional tests of attention. Patients with PSP were slower than control subjects when reading words or naming col¬ ors but they were relatively equally affected by the interference condition. In addition, even though patients with PSP made more errors on the Paced Auditory Serial Addition Test, they were equally sensitive as control sub¬ jects when task difficulty was manipulated. The significance level was set at < .001. Paced 2.4
Correlational Analyses
Severity of cognitive deficit as esti¬ by the MDRS, total score was highly correlated with performance on the majority of cognitive tests admin¬ istered with the exception of the verbal fluency tests and the indexes of depres¬ sion. On the other hand, only one cormated
relation between mood state (Hamil¬ ton Depression Scale score) and cogni¬ tive functioning (drawing fluency) reached criteria (r .50). Moreover, duration of illness was only correlated with PSP patient performance on the Luria motor tests (r .60) and the =
=
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Stroop test interference condition (r .68). =
Effects of Drug and Placebo on Executive and Attentional Processes
Following baseline testing, the pa¬ tients with PSP received either phy-
sostigmine or a placebo in a doubleblind crossover design. The results in¬ dicated that neither physostigmine
placebo produced a significant change in executive and attentional performance in patients with PSP. At best, patients showed a slight overall improvement in performance due to practice but this change was not sig¬ nificant. Drug treatment also had no clinically significant effect on extrapyr¬ amidal motor function (modified Co¬ lumbia Rating Scale score akinesia 7 ± 1 during baseline and placebo and 6.5 ± 1 during physostigmine; rigidity .6 ± .2 throughout the study). The levels of cerebrospinal fluid con¬ stituents did not significantly change during physostigmine administration. Acetylcholinesterase and butyrylchonor
linesterase levels were 15 ± 2 and 10 ± 1.5 nmol/min per milliliter, re¬ spectively, during both placebo and
drug
treatment
periods, respectively.
Homovanillic acid was 17 ± 2 and 18 ± 3 ng/mL, and 5-hydroxyindoleacetic acid was 15 ± 1 and 17 ± 2 during the placebo and physo¬
stigmine phases.
There were no clinically significant adverse effects associated with physo¬
stigmine treatment.
COMMENT
The results of our study confirm that patients with PSP are generally im¬ paired when compared with matched control subjects across a wide range of cognitive and motor tasks. Slowed mo¬ tor performance in these patients can affect scores on cognitive tasks. For example, patients with PSP were oc¬ casionally penalized on the WAIS-R performance scale subtests because of how slowly they solved a problem even though they achieved the correct solu¬ tion. Despite controlling for motor speed by administering tasks where cognitive-processing conditions are manipulated independent of response speed, slowed motor processes remain a possible confound in the interpreta¬ tion of cognitive test results in PSP. For example, several of the less cognitively demanding timed tests varied in "cognitive load" (eg, the PASAT and Stroop test) and although patients
with PSP
were
slower than control
subjects across conditions on these tasks, they were not additionally slowed by greater cognitive load (eg, speeding presentation rate or intro¬ ducing an interference condition), sug¬ gesting that at least some of the pa¬ tients' performance on response-time tasks can be explained by slowed and/ or
inhibited execution of motor re¬ However, on other timed
sponses.
(eg, subtests from the WAIS-R WCST), patients did not improve their problem-solving performance even when additional (but nonscorable) time was allowed. Physostigmine (at the doses administered) did not improve PSP patient performance. tasks or
Of more interest is the finding that patients with PSP are particularly impaired when a task requires sequen¬ tial movements, reasoning, conceptual shifting, monitoring the frequency with which stimuli are presented, and rapid retrieval of verbal knowledge.
These deficits indicate that above and beyond a general slowing of cognitive processes, the patient with PSP finds it difficult to perform on some tasks tra¬ ditionally associated with prefrontal lobe functioning. Although we found that patients with PSP were slower and made more errors than control subjects on tests of automatic and ef¬ fortful attentional processing such as the Stroop test and the PASAT, pa¬ tients with PSP were nearly as sen¬ sitive as control subjects to the con¬ ditions of these tests. This finding suggests a slowing of the effortful cog¬
nitive processes associated with selec¬ tive attention but not a deficit in auto¬ matic processes. Mood state and dura¬ tion of illness were generally not associated with performance on se¬ lected tests of executive and atten¬ tional processes. However, perform¬ ance on a dementia severity scale was indicative of the level of PSP patient
performance on attentional and exec¬ utive functioning tasks. The sugges¬ tion that patients with PSP have im¬ paired performance on tasks measur¬ ing frontal lobe functions has been made before.8·5 However, caution is ad¬ vised before attributing the cognitive deficits of patients with PSP primarily to prefrontal lobe dysfunction. Rather, a deafferenting process, as has been suggested by some,8 would mean that relatively intact frontal processing would be deprived of input from basal ganglia, basal forebrain, and collicular, and mediodorsal thalamus. In cog¬ nitive terms, this suggests that knowl¬ edge representation in the form of "higher-order" memory storage would be relatively intact in the frontal lobe while cognitive processes that affect the speed of processing representa¬ tional knowledge, the sequencing of knowledge during encoding and re¬ trieval, and the sequencing and coor¬ dination of learned motor movements would be affected by PSP. These im¬ paired cognitive processes have been more associated with basal ganglia functioning than prefrontal lobe func¬ tioning. Yet, without the collaboration
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of such processes, the prefrontal rep¬ resentational systems would be de¬ prived of the processes that help acti¬ vate and organize them in a timely fashion. The representational systems in the frontal lobe recently described as managerial knowledge units are rel¬ atively spared in patients with PSP.34 The managerial knowledge unit is viewed as a schema or scriptlike rep¬ resentation of a set of related events that are structured to achieve a behav¬ ioral goal. Basal ganglia lesions could result in only weakly activated frontal lobe representations that would be prone to inhibition or disinhibition depending on environmental or task constraints. While this explanation is speculative, it does predict sparing of certain kinds of cognitive and social knowledge in these patients. Social and problem-solving behaviors ap¬ peared relatively intact in the patients with PSP we studied, although their performance on both the WCST and picture arrangement task was im¬
paired.
Slowed processing of information by patients with PSP is likely to com¬ pound the basic deficits described
above.35 It would have detrimental ef¬ fects on memory tests, tests where in¬ formation was presented rapidly, and tests that required greater cognitive effort. Tests more carefully designed to control for speed of processing, knowl¬ edge retrieval, and organization of knowledge should aid in teasing apart the cognitive deficits observed in pa¬ tients with PSP. In addition, direct comparison of patients with PSP with other patients who have contrasting subcortical damage (eg, Huntington's disease) will help disambiguate the various contributions of subcortical structures to cognition. The cognitive processes impaired in patients with PSP have their effect across a wide range of reasoning, memory, atten¬ tional, and linguistic tasks and may take the appearance of a "subcortical dementia." However, the implication in our study is that cognitive tasks properly controlled for such processes as
motor
execution, staged planning,
and speed of stimulus presentation will allow for relatively improved PSP
patient performance. Physostigmine did not improve pa¬ tient performance on tests of attention and executive functioning. Brain me¬ tabolism studies have indicated hypometabolic flow in prefrontal brain regions in patients with PSP.9·10 Some authors have described increased blood flow in prefrontal cortex follow¬ ing physostigmine administration in the patients with PSP we studied (I.L.,
T.N.C., Daniel R. Weinberger, MD, Karen Berman, MD, unpublished data, 1989). Thus, increases in prefrontal cortex blood flow during physostig¬ mine administration in patients with
PSP does not necessarily indicate im¬ provement in cognitive functioning on tasks sensitive to frontal lobe dysfunc¬ tion. We thank
Marjorie Risher for her administra-
tive expertise and her invaluable assistance in preparing the manuscript; and the National In¬ stitute of Neurological Disorders and Stroke and the Medical Neurology Branch, Bethesda, Md, for providing the facilities that allowed us to prepare the manuscript.
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