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Cognitive deficits in olivopontocerebellar atrophy Implications for the cholinergic hypothesis of Alzheimer's dementia.

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Cognitive Deficits in Olivopontocerebellar
Atrophy: Implications for the Cholinergic
Hypothesis of Alzheimer's Dementia
Stephen J. Ksh, PhD,"IS Munir El-Awar, MD," Lawrence Schut, MD,' Larry Leach, PhD,"
Marlene Oscar-Berrnan, PhD,**ti. and Morris Freedman, MD8
-
A cerebral cortical cholinergic reduction in dominantly inherited olivopontocerebellar atrophy (OPCA) was recently
described. Although the magnitude of the cholinergic reduction was similar to that observed in Alzheimer's disease
(AD), none of the OPCA patients was reported to have been demented. We now describe a comprehensive neuropsychological assessment of 11 patients from cine of the OPCA pedigrees which we examined biochemically. Detailed
neuropsychological testing disclosed previously unrecognized deficits in verbal and nonverbal intelligence, memory,
and frontal system function which were positively correlated with the severity of cerebellar ataxia. However, our
OPCA patients appeared to be at most only mildly disabled by their cognitive impairment and scored within or close
to the normal range on a simple mental statiis screening examination. This, as well as an absence of any aphasia,
apraxia, or agnosia, contrasts with the profile and severity observed in advanced AD dementia, characterized by a
similar cortical cholinergic deficit. This finding also suggests that cholinergic reduction may explain only part of the
pathophysiology underlying the dementia of AD.
Kish SJ, El-Awai. M, Schut L, Leach L, Oscar-Berman M, Freedman M. Lognitive deficits i n
olivopontocerebellar atrophy: implications for the cholinergic hypothesis
of Alzheimer's dementia. Ann Neurol 1988;24:200--206
Much circumstantial evidence suggests that part of the
cognitive dysfunction of patients with Alzheimer's disease (AD) results from reduced cholinergic innervation of the cerebral cortical and limbic brain. This evidence is derived from autopsy and biopsy brain studies
demonstrating reduced activity in A D of the cholinergic enzymes choline acetyltransferase and acetylcholinesterase, as well as a loss of cholinergic neurons
emanating from the nucleus basalis-septum brain area
and terminating in cerebral cortex and limbic structures [cf 251. These findings, together with results of
clinical pharmacological studies demonstrating cognitive impairment after anticholinergic drug administration [lo, 341, and nonhuman experimental studies indicating impaired performance due to lesion of the
cholinergic nucleus basalis of Meynert innervation to
cortex [cf 41, provide the basis for the cholinergic hypothesis of A D dementia [Z,3, 251.
Should the brain cholinergic dysfunction of ,4D actually represent one of the critical biochemical causes
of A D dementia [ 2 5 ] , a cholinergic reduction in brain
of patients without A D would presumably be associated with a cognitive impairment similar t o that observed in AD. We were thus surprised to observe a
group of patients afflicted with a cerebellar ataxia clisorder, dominantly inherited olivopontocerebellar atrophy (OPCA), having a cerebral cortical cholinergic
deficiency as severe as that in A D brain, but without
obvious cognitive impairment 121, 221. As part of
a prospective neurobehaviord-neuropatholo~ical-biochemical study, we examined 14 OPCA patients from
the largest pedigree biochemically studied 1321 t o assess the presence of any cognitive changes. We report
significant though generally mild neuropsychological
deficits in our OPCA patients, with a neurobehavioral
profile and severity differing from those typically observed in AD.
From the 'Huinan B r a n LAboratory, Clarke Institute of Psvchiatry,
Toronto, the Departments of tpsychiatry, $Pharrnacolosy, and
9Medicine (Neurology), Universiry of Toronto, 'Baycrest Center
tor Geriatric Care, Toronto, 'Mount Sinai Hospital Research Insticute, T ~ ~ontarlo,
~ ) VA~ Medical
~ ~ Centers,
,
x~~~~~~~~~ s, MN,
and **Bosron, M A , and the itDepartmrnts of Psychiatry a r d Neurology, Boston Universiry School ot Medicine, Boston, MA
Received Oct 30, 1987, and in revised form Jan 2 7 , 1')XX Acccpttr\
for publication Feb 4 , 1988
Patients and Methods
We examined 14 patients with dominantly inherited OI'<,A
from the Schut [32} pedigree This kindred, which now
spans eight generations, was originally d e x ribeci by Gray 'ind
Address correspondence
to
D r ffish, Human B r a n I.ddhorCitory,
Clarke Institute of Psychiatry, 250 College S r , Toronro. O m r i o
M5T 1R8
200 Copyright 0 1988 by the American Neurological Association
Oliver { 161 and has been followed continuously. The autosoma1 dominant locus resides on a region 15 centimorgans
telomeric of HLA-A on the short arm of chromosome 6
C29l.
The diagnosis of dominantly inherited OPCA was made
on the basis of clinical signs (limb and gait ataxia, dysarthria,
dysphagia). Each patient received a general neurological examination and a bedside mental status assessment. The
neurological severity of the disorder was scored using the
Ataxia Clinical Rating Scale 1271.This scale has been successfully used to assess patients with ataxia, including patients
with OPCA from the Schut pedigree (32). A battery of
standardized neuropsychological tests was administered to
characterize and quantify cognitive deficits in the OPCA patients. To minimize any influence on test performance by
impairment in articulation and motor function, all of the
neuropsychological tests placed minimal or no reliance on
complex motor tasks. The same neurological and neuropsychological tests were administered to 14 control subjects,
equated for age (controls: 32 2 8 years, mean -+ SD;
OPCA: 34 t 8 years), educational status (controls: 12 ? 3
years; OPCA: 13 5 2 years), and sex ratio (8 male, 6 female
for both groups).
The following neuropsychological tests were administered.
First, tests of verbal and nonverbal intellectual ability were
given, including the following:
Mini-Mental State Examination (MMSE) [8, 13): MMSE
scores were prorated for the patients who could not write,
draw, or fold paper.
Wechsler Adult Intelligence Scale-Revised (WAIS-R,
verbal subtest) 1371: there are six verbal subtests of the
WAIS-R-Information,
Digit Span, Vocabulary, Arithmetic, Comprehension, and Similarities.
Peabody Picture Vocabulary Test (PPVT) 1111: the
PPVT measures verbal intellectual ability. After each of a
maximum of 150 words is read aloud by the examiner,
the subject is asked to indicate its meaning by selecting
the correct one of four pictures shown on a plate.
Raven’s Colored Progressive Matrices (RCPM) [28]: the
RCPM measures nonverbal reasoning ability. Subjects are
presented with a series of visual patterns, each with one
part removed, and must select the missing part from a
multiple choice array.
Second, memory was tested with the Wechsler Memory
Scale (MMS) {36]. The WMS consists of sections on Information, Orientation, Mental Control, Digit Span, Logical
Memory (Story Recall), Paired Associate Learning, and Visual Reproductions. The visual reproductions section was not
given to patients whose ataxia interfered with the mechanics
of drawing. Scores of those patients were prorated.
Third, attention was tested with the following:
1. Modified Continuous Performance Test (MCPT) (231
(modified by Kaplan, personal communication). The
MCPT is a test of attention in which the patient raises his
hand every time he hears the letter “A” in a recording of
randomly presented letters of the alphabet.
2. Digit Span Forward.
3. Digit Span Backward.
Fourth, naming was tested with the Boston Naming Test
(BNT) {201. This standardized naming test contains drawings
of 60 items arranged by increasing difficulty.
Fifth, visuospatial function was measured with the Hooper
Visual Organization Test [ 181, which measures visuospatial
organizational ability. Subjects must identify 30 drawings of
fragmented objects.
Sixth, frontal system function was measured with two
tests:
1. Wisconsin Card Sorting (WCS) Test [7, 151 tests concept
formation and provides a sensitive measure of perseveration due to frontal system dysfunction. Subjects sort 128
cards according to a predetermined principle (form. n u n ber, or color) which must be deduced from the e x a m
iner’s feedback. After sorting 10 cards correctly, the principle is changed and must again be deduced by the
subject. Subjects must place each card below the appropriate stimulus card. Where ataxia prevented subjects
from handling cards, the examiner placed the cards where
indicated by the subject.
2. Visual-Verbal Test (VVTI (12). The VVT measures the
ability to sort objects into classes according to a concept,
and then to shift from this concept to another which may
be evolved from the same stimulus item. Subjects are
presented with plates containing four items. O n e subset
of three is alike in some way and a second subset of three
is alike in a different way. Subjects must identify each
group. There are 42 plates.
Finally, depression is tested with ( 1 ) the Hamilton Rating
Scale for Depression 1171, and (2) the Beck Depression Inventory [ S ] .
Results
Neurological Findings
All 14 OPCA patients had clinical features of cerebellar ataxia, cranial nerve involvement, hyperreflexia,
and extensor plantar responses (Table 1). In addition,
most had signs of motor neuron involvement with atrophy and fasciculations. The severity of the disease, as
measured by the Ataxia Clinical Rating Scale 1271
(maximum score = 135), varied considerably among
the patients. Those with scores equal to or greater than
70 (n = 8) were wheelchair-bound or bedridden. Patients scoring 60 o r below (n = 6 ) could walk independently o r with a cane or quad-cane. The severity of the
disease correlated significantly with the estimated duration (Pearson Y = 0.63, p < 0.02).
Despite moderate to severe ataxia, most of the
OPCA patients were able to take care of their personal
hygiene and keep their living places in order. Some
patients, despite severe ataxia, lived alone, required
only parttime help for preparation of meals, and were
able to care for a pet. With the exception of patient S8
(see Table 3 ) who was severely dysarthric, all others
were able to engage in normal conversations, as reported by their spouses or caregivers.
Kish et al: Cognitive Deficits in OPCA
201
Bedside Mental Statzls Examination
Most of the patients showed changes in personhty
and emotion, most commonly inappropri;ne smiling
and laughter, easy tearfulness, an appearance of sadness, and impulsivity. Attention was decreased in
most patients. Spontaneous speech was fluent with no
aphasia, word-finding difficulties, or paraphasias. All
patients had dysarthria ranging from mild to severe.
Auditory comprehension and repetition were normal.
Naming ability was slightly decreased for low frequency words in most patients. Recent arid remote
memory were slightly to moderately decreased in
more than half the patients. In some patients with recent memory impairment, cueing was helpful in recall.
All patients had decreased abstractional abilii:ies, manifested by impaired performance on the similxities test
and on proverb interpretation. The patients gave partial and sometimes concrete answers. It was possible to
examine 12 of the 14 patients for ideomotor limb and
buccofacial praxis. Three tended to use a body part for
objects on one or two commands for ideomotor limb
praxis but corrected readily on verbal explanation. The
other patients showed no evidence of apraxia.
F o m l Neuropsychological Testing
Because of the possible confounding influence of depression upon cognitive test performance, we eliminated from statistical analysis of the neuropsychological data 3 OPCA patients and 1 control subject who
had moderate to severe clinical depression (9eck [ 5 ]
depression score > 15).
Table 2 compares mean neuropsychological test performances in the control and OPCA groups. Individual patient results are shown in Table 3. For each test,
an analysis of covariance determined whether there
was a significant group difference in performance
scores. Because of its possible effects on perfcrmance,
age was used as a covariate in the analyses. The group
by age interaction and the age variable were removed
from analysis if these terms were not significant. Age
was significantly related to performance on the neuropsychological measures on the MMSE, WMS Memory
Quotient, WMS Paired Associates, BNT, WCS number of sorts, and WCS number of perseverative errors.
With the effects of age taken into account, the OPCA
patients were significantly impaired ( p < 0.05) on each
of these tests (see Table 2). Results of the IMMSE,
WMS Memory Quotient, WMS Paired Associates,
WCS number of sorts, and WCS number of perseverative errors revealed a significant group by age interaction, indicating that the OPCA patients were impaired
compared to controls at older age levels. For these
measures, separate analyses were carried out in the
younger patients (< 33 years), using Student's twotailed t tests. The younger patients were significantly
impaired ( p < 0.05) on all measures except the
202
Annals of Neurology Vol 24 N o 2
August 1988
Table I . Mod$ed Ataxia Clinical Rating Scale {25) Scores
in 14 OPCA Patients
No. of
Mean
Patients with
Severity
Difficulty (s) (Maximum)
Function
Cranial Nerves
Speech
Nystagmus
Eye movements
Tongue changes
Cough
Swallowing'
Coordination
Gait
Cerebellar signs
Postural tremor
Increased Tone
Reflexes
Increased muscle
stretch reflexes
Babinski
Peripheral Signs
Atrophy
Fasciculations
Scoliosis and pes cavus
Vibration sensation
Reduced Muscle Strength
Disease Severity
(total score)
6
(18)
14 (100)
1 (7)
8 (57)
1 3 (79)
14 (100)
14 (100)
27.3 (42)
14 (100)
14 (100)
0
(0)
14 (100)
9.3 (18)
14.6 (24)
14 (100)
14 (100)
10 (71)
12 (86)
4 (29)
1 2 (86)
1.2 (86)
4.4
70
(12)
(138)
*Not part of the Ataxia Clinical Rating Scale
OPCA
=
olivopontocerebellar atrophy.
MMSE, the WMS Paired Associates, the WCS number of sorts, and the WCS number of perseverative
errors. O n the B N T we observed a significant group
by age interaction, with the OPCA patients performing more poorly than the controls especially at the
younger age levels.
T o identify which neuropsychological tasks best
identified group differences, we applied a conservative
statistical procedure for multiple comparisons, i.e., the
Bonferoni correction, which sets a conservative level
of confidence for determining significant group differences. In this case, for 17 neuropsychological tests, the
level was determined to be p < 0.0029. Employing
this statistical correction factor, we found that the following tests showed significant group differences: the
WAIS-R Verbal IQ, the WMS Story Recall, the
Hooper Visual Organization test, the WCS number of
perseverative errors, and the VVT.
Expressed as percentage of mean control values,
the OPCA patients scored on average within 20%
of the controls in verbal and nonverbal intellectual
ability (MMSE, WAIS-R, PPV, and RCPM), naming
(BNT), attention (MCPT), and visuo-spatial function
(Hooper). O n the MMSE, a simple screening test for
mental status, all 14 patients scored within o r close to
Table 2. Neuropsychological Behavior in Dominantly Inherited OPCA Versus Control Subjects
Controls
(n = 13)
Mean
Age (yr)
Education (yr)
Sex
Verbal and Nonverbal
Intellectual Ability
Mini-Mental State
WAIS-R Verbal IQ
Peabody Picture Vocabulary Test
Raven's Colored Progressive Matrices
Memory
WMS Memory Quotient
WMS Story Recall
WMS Paired Associates
Attention
Modified Continuous
Performance Test
Digit Span Forward
Digit Span Backward
Naming
Boston Naming Test
Visuospatial Function
Hooper Visual Organization Test
Frontal System Function
WCS number of sorts
WCS number of perseverative errors
Visual-Verbal Test
Depression
Hamilton
Beck
31
12
8M, 5F
OPCA
(n = 11)
SD
7
3
SD
Mean
33
13
6M, 5F
Significance Level
8
2
F(1,20) = 4.63 p < 0.04"
F(1,21) = 28.17p < 0.0001
F(1,20) = 5.40p < 0.03
8.9
28.4
89.1
140.2
1.8
7.8
25.7
34.1
2.3
29.5
6.8
114.4
10.0
17.5
14.1
2.2
2.5
82.9
4.6
11.5
12.5
2.2
5.8
25.7
0.6
21.8
5.2
F(1,21) =
6.6
4.7
1.0
0.9
6.3
4.2
1.0
1.3
NS
NS
95
89
56.2
2.2
49.4
4.2
F(1,19) = 10.62 p < 0.004*
88
26.8
1.9
22.4
2.1
F(1,21) = 27.56p < 0.001
84
8.6
10.5
1.8
1.1
6.1
20.5
4.0
19.8
5.8
4.4
14.6
2.7
2.2
3.2
2.8
8.9
8.5
29.8
109.0
157.9
0.4
9.7
F(1,22)
=
5.20p < 0.03
F(1,20) = 6.02 p < 0.02*
F(1,22) = 35.77 p < 0.0001
F(1,20) = 6.77 p < 0.02"
7.24p < 0.01
95
82
89
87
72
46
66
85
< 0.03"
< 0.001"
71
195
4.5
F(1,21) = 22.32 p < 0.0001
252
3.8
2.8
F(1,22) = 19.07 p < 0.0002
F(1,22) = 29.34 p < 0.0001
330
386
F( 1,20)
F(1,20)
= 5.26 p
= 14.35 p
"A significant age by group interaction (see text for details). OPCA = dominantly inherited olivopontocerebellar atrophy; WAIS-R =
Wechsler. Adult Intelligence Scale-Revised: WMS = Wechsler Memory Scale; WCS = Wisconsin Card Sorting; NS = not significantly
different from controls, p > 0.05.
the lower limit of the standardized score for the normal population ( 2 7 ) 181. However, most of the OPCA
patients were below the limit of our control range.
Quantitatively more severe deficits were observed on
memory tests (WMS Memory Quotient, -28%;
WMS Story Recall, -54%; and WMS Paired Associates, -34%), and on tests of frontal system function (WCS number of sorts, -29%; WCS number of
perseverative errors, + 95%; and VVT, + 152%).
The severity of ataxia (score on the Ataxia Clinical
Rating Scale) significantly correlated with the MMSE
( Y = -0.73,p < 0.006), the WMS Memory Quotient
( Y = -0.76,p < 0.003), and the MCPT ( r = -0.70,
p < 0.0 12). Weaker but statistically significant correlations (0.5-0.7, p < 0.05) were observed between severity of ataxia and duration of illness, PPVT scores,
WMS Story Recall, VVT, Hooper scores, number of
sorts achieved and perseverative errors on the WCS
test, RCPM, and performance on the Digit Span Forward test.
Depression
On the Hamilton and the Beck rating scales for depression, 1 of the 14 OPCA patients showed borderline clinical depression and 3 had moderate to severe
clinical depression. Three others demonstrated mild
mood disturbance. In contrast, only 1 of the controls
was depressed. Within the OPCA group, after exclusion of the 3 patients with moderate to severe depression, the score on the Hamilton Rating Scale for Depression correlated weakly ( r = 0.5 to 0.7, p < 0.05)
with the WMS Memory Quotient, PPVT, and the
Kish et al: Cognitive Deficits in OPCA 203
Table 3. Neurological and NeuropsychologicalBehavior in 1 1 OPCA PatientJ
Patient
S1
Age
Estimated Ataxia Duration (yr)
Disease Severity (maximum 138)
Verbal and Nonverbal Intellectual
Ability
Mini-Mental State
WAIS-R Verbal IQ
Peabody Picture Vocabulary Test
Raven’s Colored Progressive
Matrices
Memory
WMS Memory Quotient
WMS Story Recall
WMS Paired Associates
S2
S3
42
15
60
27
7
72
27.9
30.0
78
96
143
29
133
28
S4
S6
S7
19
7
57
35
17
70
38
10
85
26.9
93
131
29
27.9
80
153
23
27 8
94
160
35
28
7
58
S8
S10
S11
S12
S14
47
20
96
33
10
32
35
17
90
26
3
47
31
30.0 24.7
NE
68
144
13
30
98
87
3.0
9.5
90
5.5
18.5
83
3.5
14.5
76
87
5.0
13.0
83
4.5
11.0
25
17
25
15
24
22
7
5
6
4
8
4
5
3
7
4
7
7
52
45
41
50
56
47
22.0
24.0
19.0
21.0
20.5
1
29
8
13
10
9
3
19
19
17
I5
3
4
1
9
9
12
30.0
99
I60
36
26.8 30.0
85
82
147
150
34
15
98
5
56
30.0
86
153
3%
8.0
20.0
89
3.0
16.0
12
26
26
7
5
6
5
4
3
6
5
52
50
50
51
23.0 NE
24.0
20.5
25.5
24.5
10
11
2
9
0
74
10
34
5
5
10
11
23
13
13
NE
11
17
8
10
8
7
9
10
12
11
16
7
3
4
7
9
9
12
I1
8
5.5
4.5
52
0.0
1.0
94
7.5
11.5
73
NE
26
5
2
NE
5.0
7.0
Attention
Modified Continuous Performance
Test
Digit Span Forward
Digit Span Backward
Naming
Boston Naming Test
Visuospatial Function
Hooper Visual Organization Test
Frontal System
WCS number of sorts
WCS number of perseverative
errors
Visual-Verbal Test
Depression
Hamilton
Beck
9
11
OPCA = ohopontocerebellar atrophy; WAIS-R = Wechsler Adult Intelligence Scale-Revised; WMS = Wechsler Memory Scale; W<:S =
Wisconsin Card Sorting; NE = not examined.
RCPM. There was no correlation between seterity of
depression and the other tests.
Discussion
Cognitive Impairment in OPCA
Our study demonstrates previously unrecognized cognitive impairment in OPCA patients from the Schut
[32] pedigree, one of the largest North American
families afflicted with dominantly inherited OPCA. Intellectual dysfunction has been reported in other
families with familial OPCA Ecf 61. Although cognitive
impairment was found to be related to the severity of
cerebellar ataxia, motor dysfunction alone could not
have caused the test deficits, because neuropsychological tasks were carefully chosen to minimize prcblems
in coordination. Dominantly inherited OPCA in the
Schut family can now be considered one of several
neurodegenerative conditions, including AD [ 2 4 , 26,
30, 311, Parkinson’s disease with dementia 12611, and
Down’s syndrome {38], which manifest cognitive im-
204
Annals of Neurology
Vol 24
No 2 August 1988
pairment and associated loss of cortical cholinergic innervation.
Interestingly, in one of the first descriptions of this
family by Schut (an affected family member) r321, no
mental deterioration was observed. However, as discussed by Schut, the . . disturbances of movement
interfered with tests used to ascertain the actual intellectual capacity.” In our study, cognitive impairment
was assessed by selective neuropsychological tests
which place minimal reliance on motor tasks. A second
likely explanation for previously unrecognized cognitive impairment in this family is that from a functional
standpoint the mental deterioration is mild. The
caregivers (spouses, nurses, social workers) of our
OPCA patients do not regard them as demented or
particularly disabled by cognitive impairment, in contrast to the disability of the cerebellar ataxia. Indeed,
several patients in the advanced stage of OPCA function well with minimal custodial care, despite being
severely disabled by cerebellar ataxia.
I‘.
Although in a restricted environment such as a nursing home, dementia might not be recognized in these
patients, disability due to the cognitive impairment
might be observed in more demanding environments
(e.g., workplace).
Dementia in OPCA and the Cholinergic Hypothesis
We have recently demonstrated in OPCA brain a
marked cortical cholinergic deficiency, evidenced by
reduced activity of the cholinergic marker enzymes
choline acetyltransferase C2 11 and acetylcholinesterase
[223 (7 cases examined), together with a severe loss of
nucleus basalis cholinergic neurones (Kish and
Robitaille, unpublished observations; 5 cases examined). These findings were observed in all affected
family members autopsied who died with ataxia severity and age similar to those of the patients in our present neuropsychological study. Since the magnitude of
the cerebral cortical cholinergic deficit in OPCA
(mean cerebral choline acetyltransferase reduction of
65 to 72%) in the 7 cases biochemically studied was as
severe as that observed in clinically disabling A D dementia 124, 26, 30, 311, we reasoned that, should the
cholinergic dysfunction actually represent a fundamental biochemical cause of the cognitive impairment in
AD, an Alzheimer’s-like dementia in this OPCA family should be uncovered upon comprehensive neuropsychological testing. Our finding of subnormal performance on cognitive testing in this OPCA family
adds circumstantial support for the cholinergic hypothesis of dementia; however, the neuropsychological
profile also suggests that the cognitive impairments in
OPCA differ from those in A D dementia both in severity and behavioral pattern of deficits. Cortical cholinergic deficits in AD of the magnitude previously
observed in the Schut family are associated with a
moderate to severe dementia. These AD individuals
were clearly disabled by their dementia in most aspects
of daily living [31}. In contrast, our patients appeared
to be only mildly demented, with scores on a mental
screening test (MMSE) close to or within control limits, and they did not appear disabled by their cognitive
impairment in daily living skills. Employing DSM-IIIR 171 criteria, the majority of patients would most
likely be considered only mildly demented.
Our neuropsychological data also suggest that the
OPCA patients do not have the behavioral profile of
cognitive changes observed in AD dementia. In this
regard, and as also observed by Tagliavini and Pilleri
{35} in a single case with dominantly inherited OPCA
(and accompanying nucleus basalis cholinergic neurone
loss), none of our patients experienced aphasia,
apraxia, or agnosia, all commonly present in AD. Also,
the OPCA patients scored poorly on the WCS perseverative errors and the VVT, pointing to a prominent
cognitive impairment in the frontal system. In contrast,
most A D patients with MMSE scores similar to those
of our OPCA patients (227) perform within the normal range on the Weigl Test, a test similar to the WCS
{cf 17; Huff, personal communication]. Our patients
have relatively prominent frontal deficits without
aphasia, which more closely resembles “subcortical” or
“frontal-subcortical” dementia [l, cf 141 than A D dementia.
In conclusion, we report previously unrecognized
cognitive impairment in 11 OPCA members of a family previously shown to have a cerebral cortical cholinergic deficiency as severe as that in AD brain. While
our data provide circumstantial support for the cholinergic hypothesis of A D dementia, our observations
also support our working hypothesis, namely, that the
cholinergic reduction explains some but not all of the
AD dementia. From this revised hypothesis we predict
that cholinergic pharmacotherapy in A D will prove to
be of limited use 1331. Prospective comparison of the
neurobehavioral, neurochemical, and neuropathological changes in our OPCA versus AD patients may
help to resolve this clinically important question.
The authors gratefully acknowledge the financial assistance of the
Medical Research Council of Canada (S. K. and M. F.), the National
Ataxia Foundation (U.S.A.) (S. K.), the Ontario Mental Health
Foundation (M. F.), and a scholarship to Dr Freedman from the
Gerontology Research Council of Canada. Dr Oscar-Berman was
supported by the U.S. Veterans Administration and U.S. DHHSNIAAA grant AA07112 to Boston University. Dr Kish is a Career
Scientist of the Ontario Ministry of Health.
We also wish to thank Celia Greenwood, Stephanie Bernstein, and
Reesa Hotz-Sud for assistance with data analysis.
Presented in part at the 112th annual meeting of the American
Neurological Association, San Francisco, CA, October 1787.
References
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