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Electrophysiological dfierences between demented and nondemented patients with Parkinson's disease.

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Electrophysiological Dfierences Between
Demented and Nondemented Patients
with Parhnson’s Disease
Douglas S. Goodin, MD, and Michael J. Aminoff, MD
~
Long-latency auditory evoked potentials were studied in demented and nondemented patients with Parkinson’s disease
who were matched for age, stage of disease, duration of illness, and amount and nature of antiparkinsonian medication.
We found clear electrophysiological differences between the two groups of patients in that the N1, N2, and P3 peak
latencies were prolonged in the demented group compared both to the nondemented group and to normal controls.
Moreover, the N1 latency but not the N2 and P3 latency prolongation distinguished the demented parkinsonian
patients from demented patients with Alzheimer’s disease. These results provide strong evidence for the existence of
different subtypes of dementia and suggest that electrophysiological recordings may be helpful in establishing the
underlying pathogenesis of a dementia syndrome when there is clinical uncertainty.
Goodin DS, Aminoff MJ: Electrophysiological differences between demented and nondemented patients
with Parkinson’s disease. Ann Neurol 2190-94, 1987
Some authors have suggested that there are clinically
distinct types of dementia reflecting, in part, different
sites of neuropathological involvement. For instance,
some have distinguished cortical from subcortical dementias 11, 3 , 5, 141, although this has not met with
universal acceptance El9f. We have recently reported
differences in long-latency auditory evoked potentials
among patients with dementia caused by Huntington’s,
Alzheimer’s, and Parkinson’s diseases 191. Although
the N 2 and P3 components of the cerebral responses
were prolonged in latency in all three groups, the
latencies of the N l and P2 components differed
among the groups. The N1 latencies were prolonged
in those with Huntington’s and Parkinson’s diseases,
whereas P2 was prolonged only in the group with
Huntington’s disease. These earlier components were
normal in latency in the group with Alzheimer’s disease. Using electrophysiological criteria alone, we
were able to classify correctly most of ouf patients into
one of these three diagnostic groups, thereby lending
support to the notion of different subtypes of dementia. However, we could not completely exclude the
possibility that these electrophysiological differences
were related to the underlying disease rather than to
the dementia itself. Accordingly, we have studied the
long-latency auditory evoked potentials in both demented and nondemented patients with Parkinson’s
From the Department of Neurology, University of California, San
Francisco, CA.
Received Apr 24, 1986, and in revised form June 18. Accepted for
publication June 19, 1986.
disease, matched for age, stage of disease, and duration
of illness.
Patients
Twenty-eight patients with clinically definite Parkinson’s disease participated in the study. All had at least two of its
cardinal features (bradykinesia,tremor, rigidity, and postural
instability), which had developed insidiously. Patients were
excluded who had parkinsonism that was due to other causes
or was part of a more widespread neurological illness. Fourteen of these patients met the criteria for dementia of the
Diagnostic and Statistical Manual of Mental Disorders of the
American Psychiatric Association, 1980. The remaining 14
patients had clinically normal mental function.
All patients were evaluated with the Mini Mental State
examination 171 to measure the severity of intellectual deterioration. The severity of their motor disability was rated on
the Hoehn and Yahr scale [13].
Electrophysiological Studies
Each patient was presented binaurally with a predetermined
sequence of 420 tones (65 dBHL, 50-msec duration, 5-msec
rise and fall times) at a rate of one tone every 1.5 seconds.
The frequency of the tones was 1,000 Hz in 86% of trials
and 2,000 Hz in the remaining 14%. The order of tones was
pseudorandom, with the constraint that no two rare (2,000
Hz) tones occurred consecutively. Subjects were instructed
to keep a mental record of the number of rare tones. Responses were recorded (bandpass, 1 to 40 Hz) from F,, C,,
Address reprint requests to Dr Goodin, Room 794-M, Department
of Neurology, University of California, San Francisco, CA 94143.
and P, electrode placements on the scalp (International
10:20 system), referred to linked mastoids. Eye movements
were monitored with an electrode placed infraorbitally and
also referred to linked mastoids. Cerebral responses to the
rare and frequent stimuli were averaged separately, and at
least two trials were performed to ensure reproducibility.
Statistical analysis was performed using t tests to assess
intergroup differences. Both the demented and nondemented patients were also compared to patients with Alzheimer’s disease (n = 18) and normal controls (n = lo),
selected solely on the basis of an age of 59 or more years to
match the age of the patients with Parkinson’s disease. These
control subjects and patients with Alzheimer’s disease were
derived from our previously published series 191. For this
analysis, intergroup differences were also assessed using t
tests. However, to be sure that the results were significant,
given the large number of comparisons, an ANOVA was
also performed, and when significant interactions were detected, the significance of intergroup differences was confirmed using Tukey’s post hoc test (a = 0.05).
Results
The clinical features of the two groups of patients with
Parkinson’s disease are shown in Table 1. There was
no difference in age, stage of the disease, or duration
of illness between the demented and nondemented
patients, or in the amount and nature of antiparkinsonian drugs that they received. The demented patients
did, however, score significantly lower on the Mini
Mental State examination than did the patients who
were mentally normal (Table 1).
Evoked potential waveforms recorded from the vertex in both a demented and nondemented patient with
Parkinson’s disease are shown in the Figure. Cerebral
responses to both rare and frequent tones for each
subject are displayed. In both subjects the response to
the frequent tone consists of a negative (N 1)-positive
(P2) complex constituting the auditory “vertex” potential. The response to the rare tone, in contrast, is more
complex, consisting of a negative (N1)-positive (apparent P2)-negative (N2)-positive (P3) complex [lo].
It can be seen that the relative timing of the peaks is
different in the 2 patients. Table 2 shows the mean
latencies for each of these components in the two
groups of patients, as well as the expected latencies in
comparably aged persons based on our findings in a
series of 40 normal controls aged 20 to 80 years [9].In
the demented parkinsonian patients, the peak latencies
of the N1, N2, and P3 components of the response
are delayed relative to those in nondemented parkinsonian patients, whereas the latency of the P2 component is unchanged. No significant latency differences
for any component were noted between the nondemented parkinsonian patients and the normal subjects,
whereas the demented patients with Parkinson’s disease differed from normals and nondemented parkinsonian patients in exactly the same way.
Our findings in demented parkinsonian patients resemble those in patients with Alzheimer’s disease, in
that N2 and P3 latencies were delayed relative to normal, but the N 1 component was delayed only in demented patients with Parkinson’s disease (Table 3).
Despite the fact that the Mini Mental State score was
significantly reduced and the N2 and P3 latencies were
significantly prolonged in both groups of demented
subjects, there w g no significant correlation in either
group between these electrophysiological measures
and the Mini Mental State score. In contrast, the N 1
latency correlated significantly with the Mini Mental
State score in the demented parkinsonian patients ( r =
-0.678; p = 0.022) but not in the patients with Alzheimer’s disease.
Discussion
These results, in combination with those we reported
earlier, provide strong evidence for the existence of
Table 1. Clinical Features of Demented and Nondemented Patients with Parkinson’s Disease“
Feature
Age (yr)
Hoehn and Yahr stage
Duration of illness (yr)
Medicationsb
Carbidopa (mg/day)’
Levodopa (mglday)’
Mini Mental State score
Demented
Group
71.4 (7.5)
2.5 (0.5)
4.8 (2.9)
87.2 (101.9)
826.9 (1018.7)
23.2 (3.8)
Nondemented
Group
Significance
of Difference
between Groups
67.2 (4.8)
2.7 (0.5)
5.0 (2.7)
NS
NS
NS
58.4 (52.7)
450.0 (418.3)
27.9 (1.2)
NS
NS
p < 0.0005
“Mean values of the measure are given with SD in parentheses.
bAmantadine was taken by 1 nondemented patient and 2 demented patients in standard doses of 200 mg daily or less. Bromocripune was taken
by 4 nondemented patients (in doses of 37.5, 20, 7.5, and 5 mg daily, respectively) and by 1 demented patient (27.5 mg daily). Anticholinergic
medication was taken by 5 nondemented patients and by 3 demented patients. There was no significant difference in the mean dose of my of
these medications between the two groups.
‘The difference between the demented and nondemented groups was not significant. The mean difference appears large because one of the
demented patients was referred to us while taking 400 mg of carbidopa and 4,000 mg of levodopa per day, without apparent evidence of toxicity.
Goodin and Aminoff: Dementia in PD
91
*
Rare Tone
Frequent Tone
P3
P2
Non-demented Patient
with Parkinson‘s Disease
............. ......................
+
......
. ...
. .......
. . ......
Demented Patient
with Parkinson’s Dlsease
......
N1
N1
0
400
800
0
N2
800
400
TIME (msec)
Evoked potentials, recorded at C,, from a nonukmented subject
aged 59 years (top trace) and a demented subject aged 69 years
(bottom trace), both with Parkinson’s disea.re.Traces o n the left
are the response to the frequent tone and those on the right are t o
the rare tone. Individual trials are shown in dotted lines and the
sum of the trials is shown in a solid line.
distinct subtypes of dementia. In our earlier paper, we
found clear electrophysiological differences in the
long-latency auditory evoked potentials between patients with Parkinson’s disease and both normal controls and patients with Alzheimer’s disease. The present findings confirm that these differences relate to the
dementia that sometimes accompanies Parkinson’s disease, rather than to the disease itself. Our subjects
were well matched for age, stage of disease, duration
of illness, and amount of antiparkinsonian medication.
Nevertheless, we found exactly the same differences
between demented and nondemented parkinsonian
patients that we found between demented patients
with Paskinson’s disease and healthy controk
Although our results support the notion that the
intellectual decline in patients with Parkinson’s disease
is distinct from that resulting from other conditions
such as Alzheimer’s disease, they do not necessarily
support the concept of bradyphrenia. This term has
been used to suggest that the intellectual decline of
some parkinsonian patients is analogous to the
slowness of movement (bradykinesia) that occurs in
this disease, and is possibly related to similar neuropathological mechanisms 11, 3, 13, 22, 241. The concept of bradyphrenia has recently attracted considerable interest as a way of explaining the cognitive
deficits in parkinsonism 13, 13, 22). In the same way
Table 2. Mean Component Latencies (msec) for Demented and Nondemented Patients with Parkinson’s Disease”
Evoked Potential Component
Nondemented parkinsonian patients
Demented parkinsonian patients
Significance of difference between
demented and nondemented patients
Expected latencyb
N1
P2
N2
P3
90 (6)
103 (10)
p = 0.001
182 (20)
186 (13)
NS
245 (23)
293 ( 2 5 )
p < 0.0005
361 (28)
399 (40)
p = 0.019
90
178
242
340
“Numbers in parentheses are SD.
bThe expected latency of each component lor a subject of comparable age (69 years) computed from
c91.
92 Annals of Neurology Vol 21 No 1 January 1987
OUT
normal age-latency regression 1ine.s
Table 3. Comparison of the Mean N l Latency’ in Demented and Nondemented Parkinsonian Patients,
Patients with Alzheimer’s Disease, and Normal Controls of Comparable Age
Significance of the Intergroup N1 Latency Difference
Group
Normal subjects
Nondemented parkinsonian
patients
Demented parkinsonian
patients
Patients with Alzheimer’s
disease
Mean
Age (Yr)
N 1 Latency
(msec)
Normal
Subjects
Nondemented
Parkinsonian
Patients
Demented
Parkinsonian
Patients
67 (7.0)
67 (4.8)
72 (9)
...
90 (6)
NS
...
...
...
...
7 1 (7.5)
103 (10)
p
p
...
70 (7.5)
89 (7)
= 0.011
NS
= 0.001
NS
p < 0.0005
”Numbers in parentheses are SD.
that bradykmesia occurs without actual weakness, the
slowness of thought (bradyphrenia) is thought to occur
without true intellectual decline (i.e., dementia). This
implies that, although parkinsonian patients will take
more time to complete a cognitive task (because of
their bradykinesia or bradyphrenia, or both), they will
be able to accomplish the task if given sufficient time.
In support of the concept of bradyphrenia, several
authors have reported a correlation between bradykmesia and intellectual difficulties in parkinsonian patients 18, 16, 18, 211; others have reported improved
mental function after successful pharmacological treatment of bradykinesia [2,4,6, 15, 171. Indeed, Hansch
and co-workers 112) have reported a prolongation of
the P3 latency in a mixed group of demented and
nondemented parkinsonian patients, and interpreted
this finding as supportive evidence of bradyphrenia in
the disease. Clearly, however, this conclusion is untenable as the P3 latency is prolonged in a wide variety of
dementia not thought to be characterized by bradyphrenia 19, 11, 231, and thus this finding is nonspecific.
Evidence can be marshalled against the concept of
bradyphrenia and its putative association with bradykinesia. Thus, Rafal and associates 122) were unable to
demonstrate any slowness of thought in nondemented
parkinsonian patients made more bradykinetic by
withdrawal of medication. Moreover, we found electrophysiological abnormalities suggestive of dementia
in parkinsonian patients who were considered intellectually impaired based on clinical observations, but
these abnormalities were not seen in those with apparently preserved intellect, despite similar motor disturbances (Table 1). Thus, both our findings and those of
Rafal and associates 122) suggest, at the very least, that
bradykinesia and bradyphrenia are not obligatorily
coupled. Further, several studies have documented
cognitive impairment in parkinsonian patients using
cognitive tasks without time constraints 116, 211,
thereby suggesting that a true dementia, distinct from
bradyphrenia, does occur in this disease.
Nevertheless, our findings do indicate that this dementia is electrophysiologically distinct from the dementias occurring in certain other conditions. The prolongations of the N1, N2, and P3 latencies seen in the
demented parkinsonian patients clearly relate to the
intellectual impairment and not to the motor disability
(Table 2), and yet this electrophysiological pattern is
distinct from that seen in Alzheimer’s disease, in which
the N1 latency is normal (Table 3), and from that seen
in Huntington’s disease, in which the P2 latency is also
prolonged {9].
Our results indicate that subtypes of dementia can
be distinguished electrophysiologically. The electrophysiological characteristics of the dementia may thus
provide clues as to the underlying pathogenesis when
it is otherwise clinically inapparent. Some patients with
presumed Alzheimer’s disease have conspicuous extrapyramidal features 1201, and patients with dementia
and Parkinson’s disease are often also at an age when
they are at risk to develop Alzheimer’s disease. In such
a context, the electrophysiological features of the dementia may help to define its basis and to select more
homogeneous groups for therapeutic and other clinical
trials.
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