Keywords
Parkinson's disease - dementia - cognition
Palavras-chave
doença de Parkinson - demência - cognição
Parkinson's disease (PD) is a degenerative disorder in which motor changes are mainly
as a result of the death of dopaminergic neurons in the substantia nigra. However,
the changes are not restricted to this brain region and can be found in other nuclei
of the brainstem, in the cerebral cortex and even in peripheral neurons, such as those
in the myoenteric plexus. The presence of degenerative processes in the dopaminergic
system and in different brain areas, for example the frontal lobe, can explain a series
of non-motor signs and symptoms such as cognitive impairment and dementia[1].
Parkinson's disease dementia (PDD) is a dysexecutive syndrome characterized by impaired
planning, a deficit in executive function (including organization of goal-directed
activities), dyspraxia, bradyphrenia, reduced problem-solving ability, learning difficulty
and short-term memory loss. Most patients also present with concomitant fluctuations
in attention, mood and personality, as well as hallucinations and psychoses[2],[3]. Parkinson's disease dementia has a prevalence of 40% to 80%[4], and the annual increase in risk is between 6% and 15%[5]. Cognitive decline is not limited to advanced PD stages and has been identified
in 20% to 35% of patients recently diagnosed with PD or in the initial stages of the
disease. This high prevalence and the major impact the condition has on the patient
and family members make it essential to detect and diagnose cognitive changes in PD
patients as early as possible[6]. Risk factors for PDD are mild cognitive deficit, advanced age, late-onset PD, more
severe motor symptoms, depression, long disease duration, akinetic-rigid syndrome
and psychoses[5],[6]. Parkinson's disease dementia is the most important risk factor for admission of
PD patients to a nursing home. In addition, the risk of mortality for patients with
PDD is higher than for patients without the condition[7].
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological
battery was created in 1986 by the National Institute on Aging for the clinical assessment
of cognitive changes in Alzheimer's disease (AD), including diagnosis and longitudinal
assessment of cognitive deficits. Since it was created, the CERAD battery has been
used to assess not only cognitive changes exclusive to AD but also a broad spectrum
of other cognitive changes, PD, frontotemporal dementia and vascular dementia, for
example [7],[8],[9],[10],[11],[12]. The widespread use of this scale can be attributed to its very good inter-rater
agreement, its retest reliability and its reliability when used for longitudinal follow-up
assessments[8],[9]. We have been able to corroborate these findings in another study with AD patients[13].
In light of the above, the present study sought to investigate the efficacy of using
this tool in the PD patients' diagnosis and assessment.
METHODS
Forty-nine patients who had been seen at the neurology service, Campos Gerais Regional
University Hospital, and INOVARE Serviços de Saúde Ltda., and who agreed to take part
in the study, were selected in accordance with the Parkinson's Disease Society Brain
Bank diagnostic criteria[14]. The ratio of males to females was 1.88:1. All the participants signed a voluntary
informed-consent form.
The exclusion criteria, which were intended to exclude patients whose signs and symptoms
made it impossible for them to perform a cognitive assessment or apply the proposed
tests, were as follows: 1) advanced PD stage with severe motor impairment; 2) severe
psychotic symptoms; 3) another dementia not associated with PD; and 4 patients who
had cognitive changes that had started at least one year before motor symptoms (possible
dementia with Lewy bodies)[2]. The study was approved by the State University of Ponta Grossa Research Ethics
Committee (reference FA631.285).
All the patients were assessed during the ON phase of levodopa therapy; preferably
two hours after the medication had been administered (ON phase = stage with the effect
of levodopa; OFF phase = stage without effect of levodopa). A team trained in movement
disorders carried out the clinical assessment. A semi-structured questionnaire was
applied to collect epidemiologic data, data about disease progression, previous and
current treatment. Patients were classified according to motor changes on the Hoehn
and Yahr scale[15] and the Unified Parkinson's Disease Rating Scale III (UPDRS-III)[16].
After the confirmation of diagnosis, the patients' cognition was assessed. All patients
were assessed during the ON phase of levodopa and while they were using acetylcholinesterase
inhibitors. The Clinical Dementia Rating Scale (CDR) was used to assess cognitive
impairment in six areas: memory, orientation, judgement and problem solving, community
affairs, home and hobbies, and personal care[17]. Patients scoring ≥ 1 in at least two of the six CDR domains or those receiving
a CDR-SOB (sum of boxes) score ≥ 3 were classified as having cognitive impairment;
patients scoring below these cutoff scores were classified as cognitively intact[18]. Among the patients with cognitive decline, PDD was diagnosed using the Movement
Disorders Society criteria[2],[19].
A trained team also applied the CERAD neuropsychological battery[8],[9],[10]. This consists of seven subtests that together give a maximum score of 100 as follows:
1) verbal fluency; 2) modified Boston naming; 3) word list learning; 4) constructional
praxis; 5) word list recall; 6) word list recognition; and 7) constructional praxis
recall. In this study, unlike most authors, the Mini-Mental State Examination (MMSE)
or clock drawing test were not added to the CERAD battery.
For the analysis, PD patients were divided into two groups, one with dementia and
the other without. The data for both groups of patients were compared and tested to
determine whether they had a normal or non-normal distribution pattern in the Shapiro-Wilk
test. Statistical differences between the means of the groups were determined using
the one-tailed Students t-test for normal distributions and the Mann-Whitney test
for non-normal distributions. Fisher's exact test was used to analyze the differences
between the expected and observed values on two qualitative variables. All the statistical
analysis was performed with Statistica for Windows (ver. 99) and Microsoft Office
Excel 2010. The receiver operating characteristic (ROC) curve in Med Calc for Windows
was used to calculate the sensitivity, specificity, and cutoff of the CERAD neuropsychological
battery. The area under the curve (AUC) is equal to the probability that a variable
will correctly classify a pair of individuals randomly chosen from two groups as belonging
to their true category. An AUC = 1.0 indicates no overlap between groups and that
the individuals will always be correctly classified, whereas AUC = 0.500 indicates
chance-level accuracy. Differences were considered significant when p < 0.05.
RESULTS
When using the Movement Disorders Society criteria, 33 (67.3%) of the 49 patients
were diagnosed with PDD and 16 (32.7%) without. When the clinical and epidemiologic
characteristics of the patients with dementia and those without were compared, the
PDD patients had a lower schooling and a worse motor score on the UPDRS-III ([Table 1]).
Table 1
Clinical and epidemiologic characteristics of Parkinson's disease patients with and
without dementia.
|
Variable
|
Total (n = 49)
|
With dementia (n = 33)
|
Without dementia (n = 16)
|
p-value
|
|
Gender
|
49 (100%)
|
33 (67.3%)
|
16 (32.6%)
|
|
|
Female
|
18 (36.7%)
|
13 (39.4%)
|
5 (31.3%)
|
0.7541
|
|
Male
|
31 (63.3%)
|
20 (60.6%)
|
11 (68.7%)
|
|
|
Age at onset of symptoms
|
60.6 ± 12.3
|
62.3 ± 11.6
|
57.1 ± 12.8
|
0.0827
|
|
Disease duration
|
8.9 ± 8.3
|
9.6 ± 9.5
|
7.7 ± 4.2
|
0.239
|
|
Duration of levodopa therapy
|
5.5 ± 5.1
|
5.3 ± 5.0
|
6.7 ± 5.8
|
0.4326
|
|
Hoehn and Yahr
|
2.3 ± 1.2
|
2.4 ± 1.3
|
2.1 ± 1.0
|
0.2382
|
|
UPDRS -III
|
21.4 ± 11.4
|
24.4 ± 11.4
|
14.9 ± 8.1
|
0.002*
|
|
Schooling
|
7.0 ± 4.9
|
5.9 ± 4.6
|
9.4 ± 4.7
|
0.0105*
|
Age, age at onset of symptoms, schooling, disease duration and duration of levodopa
therapy are all expressed in years. UPDRS-III: Unified Parkinson's Disease Rating
Scale III.
*Statistically significant value.
Using the CDR for dementia diagnosis as the gold standard, the ROC curve for the CERAD
battery had an AUC = 0.989 (95% CI = 0.967 − 1, p < 0.0001) ([Figure]). [Table 2] shows the sensitivity and specificity results for different CERAD cutoffs. The Youden
index determined the score of 57 as an optimum cutoff for the CERAD (Figure).
Figure Comparison of Parkinson's disease patients by CERAD through the ROC Curve with Younden's
J Index.
Table 2
Cutoffs for the CERAD.
|
Cutoff
|
Sensitivity (%)
|
Specificity (%)
|
|
52
|
78.8
|
100
|
|
53
|
87.9
|
93.7
|
|
54
|
90.9
|
93.7
|
|
55
|
97.0
|
93.7
|
|
57*
|
100
|
93.7
|
*Younden's J Index; CERAD: Consortium to Establish a Registry for Alzheimer's Disease
An analysis of the ROC curve for accuracy showed a moderate accuracy (AUC = 0.7 -
0.9) in three CERAD subtests, and a high accuracy (AUC > 0.9) in seven subtests. Verbal
fluency had the worst AUC, 0.754 (95% CI = 0.610 – 0.866), and word list learning
had the best, 0.937 (95% CI = 0.828 – 0,986). The AUC and cutoff for each CERAD subtest
were also calculated ([Table 3]).
Table 3
Comparison of PD patients, with and without dementia, by CERAD subtests.
|
Test (Maximum score)
|
With dementia (n = 33)
|
Without dementia (n = 16)
|
p-value
|
AUC*
|
Cutoff**
|
|
Verbal Fluency (13)
|
9.97 ±3.1
|
12.25 ± 1.7
|
0.0002
|
0.754 (95% CI = 0.610-0.866)
|
12
|
|
Modified Boston Naming (15)
|
8.73 ±2.9
|
12.06 ± 1.7
|
< 0.0001
|
0.841 (95% CI = 0.708-0.930)
|
9
|
|
Word List Learning (30)
|
9.12 ±3.7
|
15.75 ± 2.9
|
< 0.0001
|
0.937 (95% CI = 0.828-0,986)
|
12
|
|
Constructional Praxis (11)
|
4.70 ±2.7
|
8.16 ± 2.0
|
< 0.0001
|
0.836 (95% CI = 0.703-0.926)
|
5
|
|
Word List Recall (10)
|
1.89 ±1.6
|
5.06 ± 1.4
|
< 0.0001
|
0.929 (95% CI = 0.818-0,983)
|
4
|
|
Word List Recognition (10)
|
4.97 ±3.0
|
7.5 ± 1.5
|
0.0001
|
0.759 (95% CI = 0.615-0.869)
|
5
|
|
Constructional Praxis Recall (10)
|
2.94 ±2.5
|
7.44 ± 2.2
|
< 0.0001
|
0.903 (95% CI = 0.785-0.969)
|
4
|
*Area under the curve (AUC);
**Cutoff to maximise Youden's J Index (p < 0.05); PD: Parkinson's disease; CERAD:
Consortium to Establish a Registry for Alzheimer's Disease
DISCUSSION
Overall, 67.3% of the patients in this study were diagnosed with PDD. This number
is close to the upper limit of the prevalence of PDD found in various earlier studies
(25% to 83%)[4],[20],[21]. This high prevalence in a cross-sectional study may be explained by the fact that
the patients were followed up in a tertiary care hospital and that their mean disease
duration and complexity were greater than in other patient series.
Low schooling had a statistical correlation with dementia. This corroborates the findings
reported in the literature, according to which a lack of education is a risk factor
for dementia[22]. Old age, disease duration and progression of motor symptoms did not have a correlation
with PDD. The Hoehn & Yahr stage did not show significant differences between the
patients with dementia and without dementia, unlike that in the UPDRS scale. These
findings do not concur with the results of a study by Zhu et al.[23], in which patients with dementia were older and had a longer disease duration and
higher Hoehn & Yahr stage[7],[24]. Karrasch et al.[18] found patients with cognitive decline with worse motor scores in the UPDRS and Hoeh
& Yahr, and with a longer disease duration, but there was no difference in schooling
between patients with PD with and without dementia. These contradictory findings may
be due to the small number of patients without dementia in our study, most of whom
were an advanced age (69.3 ± 11.4 years). In addition, a very important factor was
the time when the patients were assessed. In our series, this was done during the
ON phase (with the effect of levodopa), when the patients' motor skills were at their
best. If the patients were evaluated during the OFF phase, the results may have been
similar to those of other studies.
The results suggest that the CERAD may have the necessary efficacy and accuracy for
the evaluation of cognition in PD patients. This neuropsychological battery has been
used worldwide, not only in AD, but also for various types of dementias, as it includes
a wide range of subtests[18],[25],[26],[27]. The cognitive functions most affected in PD are executive functions, attention
and memory. However, other cortical functions such as visuospatial functions, orientation
and perception are also affected[25]. Although the seven main subtests are almost always present, there are variations
in the CERAD battery. In the CERAD Brazilian validation with AD patients, Bertolucci
et al.[10] added the MMSE (cutoff = 85, and 59 without MMSE). In the version used by Karrasch
et al.[18] for PD patients, the clock drawing test was added. We preferred to test using the
version without the MMSE or clock drawing test. Our cutoff was 57, very close to the
Brazilian study with AD patients[10].
One of the difficulties in using the traditional seven subtests of the CERAD in PD
patients is that the only CERAD subtest for executive functions assessment is the
verbal fluency test. These cognitive domains are affected in PDD, quite often more
severely than in AD[28]. Verbal fluency was the subtest with the worst accuracy in our study. Tedrus et
al.[27] reported similar findings. In the study by Karrash et al.[18], the authors attempted to overcome the lack of tests assessing frontostriatal functions
in the CERAD by adding the clock drawing test. However, the accuracy of both subtests
was also lower[18]. Like executive functions, visuospatial functions are compromised in PDD, a finding
that tends to be more frequent in PDD patients than in AD patients[28]. Visuospatial function was assessed by the constructional praxis test in the CERAD;
however, this subtest had moderate accuracy and it was poorly sensitive for visuospatial
deficits. Karrash et al.[18] also showed moderate accuracy for this subtest.
The CERAD naming test assesses language function, which has already been shown to
be impaired in PD patients, although to a lesser extent than in AD patients[7]. The difference in the results of the naming test for the two groups was statistically
significant, despite the moderate accuracy, unlike in the study by Karrasch et al[18]. Initially, these discordant findings could be attributed to social and cultural
differences in the populations studied, because some images are not familiar to some
Brazilian subjects (e.g., ice tongs). However, in the study by Bertolucci et al.[10], in which the CERAD battery was validated for Brazilian Portuguese, the control
group displayed good performance in identifying the images, achieving a mean of 13.1
out of a maximum score of 15 in the naming test. We tried to find differences other
than the cultural backgrounds between our patients and those of Karrasch et al.[18], but the samples from the two studies were similar in age and level of symptom progression.
Nevertheless, the level of education was considerably lower in the Brazilian group.
Thus, the combination of advanced age and, mainly, low school level may help in the
understanding of these scores.
In the CERAD subtests that assess memory (word list learning, word list recall, word
list recognition and constructional praxis recall), patients with PDD performed worse
than those without dementia. In the study by Karrasch et al.[18]
, only the result for word list learning was statistically significant, and in the
study by Tedrus et al.[27]
, none of the differences in the results of the subtests were statistically significant.
These subtests are extremely sensitive to changes in episodic verbal memory[29]. A decline in episodic verbal memory may be the strongest indication of incipient
dementia in PD patients[6]. Memory abilities have already been reported to be impaired in PDD patients, although
to a lesser extent than in AD patients. The CERAD battery provides a more accurate
assessment of memory deficits than specific tests for PD patients, such as the Scales
for Outcomes in Parkinson's disease-Cognition[28],[29].
We have reported a number of limitations of our study; however, we can state that
our data suggest the possibility of the CERAD neuropsychological battery being used
to evaluate PD patients with cognitive deficits. The large number of cognitive domains
comprised in this battery makes it a powerful diagnostic tool. We would like to see
further studies, with a greater number of patients, being able to prove the issues
that our study introduces.
