Neuropsychiatric symptoms in patients with Parkinson's disease and dementia: frequency, profile and associated care giver stress.
ABSTRACT To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson's disease (PDD).
537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed.
89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score > or = 4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson's disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson's Disease Rating Scale and care giver distress scores.
Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.
- SourceAvailable from: Yannick Vermeiren[Show abstract] [Hide abstract]
ABSTRACT: Depression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Both NPS have negative effects on cognitive performance and life expectancy. The current study aimed to investigate and compare monoaminergic etiologies between both neurodegenerative conditions, given the lack of an efficient pharmacological treatment until present. Eleven behaviorally relevant brain regions of the left frozen hemisphere of 10 neuropathologically confirmed AD patients with/without depression (AD + D/-D; 5 were psychotic within AD + D), 10 confirmed DLB patients, all of whom were depressed (DLB + D; 5 psychotic patients), and, finally, 10 confirmed control subjects were regionally dissected. All patients were retrospectively assessed before death using the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) and Cornell Scale for Depression in Dementia amongst others. The concentrations of dopamine (DA), serotonin (5-HT), (nor)adrenaline and respective metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), 5-hydroxy-3-indoleacetic acid (5-HIAA), and, 3-methoxy-4-hydroxyphenylglycol (MHPG), were determined using reversed-phase high-performance liquid chromatography with electrochemical detection. DLB subjects had the overall lowest monoamine and metabolite concentrations regarding 33 out of 41 significant monoaminergic group alterations. Moreover, MHPG levels were significantly decreased in almost 8 out of 11 brain regions of DLB- compared to AD patients. We also observed the lowest 5-HT and 5-HIAA levels, and 5-HIAA/5-HT turnover ratios in DLB + D compared to AD + D subjects. Additionally, a 4- and 7-fold increase of DOPAC/DA and HVA/DA turnover ratios, and, a 10-fold decrease of thalamic DA levels in DLB + D compared to AD + D patients and control subjects was noticed. Regarding psychosis, hippocampal DA levels in the overall DLB group significantly correlated with Behave-AD AB scores. In the total AD group, DA levels and HVA/DA ratios in the amygdala significantly correlated with Behave-AD AB scores instead. Monoaminergic neurotransmitter alterations contribute differently to the pathophysiology of depression and psychosis in DLB as opposed to AD, with a severely decreased serotonergic neurotransmission as the main monoaminergic etiology of depression in DLB. Similarly, psychosis in DLB might, in part, be etiologically explained by dopaminergic alterations in the hippocampus, whereas in AD, the amygdala might be involved.Alzheimer's Research and Therapy 02/2015; 7(7). · 3.50 Impact Factor
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ABSTRACT: Resumo: A doença de Alzheimer (DA) tem como expressão fundamental a demência enquanto a do-ença de Parkinson (DP) apresenta manifestações essencialmente motoras neuropsi-quiátrico. Houve diferenças significativas entre os grupos DA,DP e GC em relação a 6 comportamen-tos. Na comparação direta entre os grupos DA e DP houve diferença significativa em relação a 2 questões e entre os grupos DP e GC em relação a 4 questões. Os resultados obtidos podem ser de extrema rele-vância na condução da terapêutica e reabilitação in-dividuais dos pacientes. Palavras-chave: Parkinson; Alzheimer; comporta-mento. Área do Conhecimento: Ciências da Saúde – Medi-cina – CNPq. 1. INTRODUÇÃO À medida que a expectativa de vida torna-se mais elevada, sobretudo nos países desenvolvidos e em desenvolvimento, tem-se observado um crescimento da prevalência de doenças neurodegenerativas, tais como a doença de Alzheimer (DA) e a doença de Parkinson (DP), acompanhadas de intensas reper-cussões biopsicossociais. A DA é a principal causa de demência, a qual é defi-nida como uma síndrome clínica caracterizada declí-nio cognitivo e/ou comportamental crônico e geral-mente progressivo, de início insidioso. A DP, por sua vez, cursa com manifestações essen-cialmente motoras, tais como tremor de repouso, rigidez muscular, bradicinesia e anormalidade postu-ral. No entanto, a ocorrência de distúrbios cognitivos é frequente, e a prevalência média de demência está em torno de 31% [1, 37]. O Inventário Neuropsiquiátrico (INP) foi desenvolvido para avaliar dez distúrbios comportamentais que po-dem ocorrer em pacientes acometidos por doenças neurodegenerativas: delírios, alucinações, agita-ção/agressão, disforia, ansiedade, euforia, apatia, desinibição, irritabilidade/labilidade, agitação motora . É composto por dez questões, tendo cada uma o conteúdo referente a um dos dez comportamentos citados. A informação é obtida através do acompanhante do paciente, o qual é questionado a classificar o com-portamento de acordo com sua gravidade (ausente, discreto, moderado/grave) e de acordo com sua fre-quência de acometimento (ausente, ocasional, maior ou igual uma vez por semana). O INP é fonte importante de informações sobre o estado psicológico e comportamental do paciente, ambos determinantes do percurso clínico da doença, da melhor abordagem terapêutica a ser utilizada e, consequentemente, da saúde do cuidador. O objetivo desse estudo é comparar os sintomas comportamentais e neuropsiquiátricos nas doenças de Alzheimer e de Parkinson.
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ABSTRACT: Apathy, characterized by lack of motivation and loss of initiative, is a non-cognitive symptom that affects a high proportion, but not all, of patients with all forms of dementia. To explore the phenomenon of apathy in people with dementia, we searched the PubMed and Google Scholar electronic databases for original research and review articles on apathetic behaviors in patients with dementia using the search terms "apathy, behavioral and psychological symptoms, dementia, Alzheimer's disease, Frontotemporal dementia, Dementia associated with Parkinson's disease, Huntington's disease, Vascular dementia". Some nosological aspects, neurobiological basis, and assessment of, as well as, potential benefits of non-pharmacologic and pharmacologic interventions for apathy in dementia are discussed. Greater understanding of apathy will improve the identification, intervention, and treatment of this ubiquitous and pernicious syndrome.Journal of Nervous & Mental Disease 10/2014; 202(10):718-724. · 1.81 Impact Factor
Neuropsychiatric symptoms in patients with Parkinson’s
disease and dementia: frequency, profile and associated care
D Aarsland, K Brønnick, U Ehrt, P P De Deyn, S Tekin, M Emre, J L Cummings
............................................................... ............................................................... .....
See end of article for
D Aarsland, Centre for
Received 28 October 2005
Revised version received
6 May 2006
Accepted 9 May 2006
Published Online First
4 July 2006
J Neurol Neurosurg Psychiatry 2007;78:36–42. doi: 10.1136/jnnp.2005.083113
Objective: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with
Parkinson’s disease (PDD).
Methods: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were
assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the
inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables
Results: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and
64% had at least one symptom with a score >4. The most common symptoms were depression (58%), apathy
(54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced
Parkinson’s disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least
one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with
few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy
(24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI
score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation
clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson’s Disease
Rating Scale and care giver distress scores.
Conclusion: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms
differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified.
These subgroups may be associated with distinct neurobiological changes, which should be explored in future
to reduced quality of life,3distress for the care giver4and
increased risk for admission to nursing home5 6in patients with
Parkinson’s disease. Most patients with Parkinson’s disease
will eventually develop dementia,7and neuropsychiatric symp-
toms are more common in those with Parkinson’s disease with
dementia (PDD).1 8Knowledge of the wide variety of psychia-
tric symptoms and diagnostic skills to identify and implement
optimal treatment of these symptoms are thus of major
importance in the management of patients with Parkinson’s
disease and those with PDD.
The multiple psychiatric symptoms in patients with dementia
tend to cluster into discrete psychiatric syndromes,9 10indicating
that the underlying pathophysiological constructs may explain
the relationship between observed variables. Identifying these
underlying constructs is important, as it may prove to be more
valuable to correlate neurochemical measures with syndromes
rather than with individual symptoms. Also, from the clinical
point of view, treatment might be best directed towards
syndromes rather than towards each specific, individual
behavioural symptom. Finally, there is emerging evidence of
subtypes within the major neurodegenerative disorders, includ-
ing Parkinson’s disease,11and exploring psychiatric syndromes
may help in distinguishing such subtypes.
Statistical methods such as factor analysis, cluster analysis and
latent class analysis have been used to identify empirically based
classifications of neuropsychiatric clusters in patients with
neurodegenerative disorders, with high face validity.9 10 12These
wide range of neuropsychiatric disturbances commonly
Neuropsychiatric disturbances contribute considerably
of the heterogeneity of patients with dementia, and lead to clearer
treatment strategies for different subgroups. Although factor
analysis can provide information on how symptoms correlate in a
sample, it is of limited value in understanding how the symptoms
occur in groups of patients, and is thus of limited value in
identifying groups of patients on the basis of symptoms. Rather,
classification of individual patients is possible using cluster
analysis, a data-driven, exploratory classification method.13
Five different clusters of neuropsychiatric symptoms were
recently identified in patients with Parkinson’s disease.12
However, to the best of our knowledge, no studies have
explored how neuropsychiatric symptoms cluster in patients
with PDD. Therefore, to explore whether natural subgroups of
patients with Parkinson’s disease can be identified on the basis
Neuropsychiatric Inventory (NPI) to a large sample of patients
with PDD, and used cluster analysis to identify the inter-
relationship of neuropsychiatric symptoms. The analysis is
based on the baseline data obtained in a large phase III clinical
trial evaluating the safety and efficacy of rivastigmine in PDD.14
Men and women at least 50 years old, with a clinical diagnosis
of Parkinson’s disease according to the UK Parkinson’s Disease
Abbreviations: MMSE, Mini-Mental State Examination; NPI,
Neuropsychiatric Inventory; PDD, dementia associated with Parkinson’s
disease; UPDRS, Unified Parkinson’s Disease Rating Scale
See Editorial Commentary, p 2
Society Brain Bank clinical diagnostic criteria,15and of PDD
according to the fourth edition of the Diagnostic and statistical
manual of mental disorders (Code 294.1),16were recruited from
research centres in Austria, Belgium, Canada, France, Germany,
Italy, The Netherlands, Norway, Portugal, Spain, Turkey and
the UK.14Patients were required to have mild to moderately
severe dementiaas defined
Examination (MMSE)17score of 10–24 inclusive, with the
onset of dementia at least 2 years after the first diagnosis of
idiopathic Parkinson’s disease. Patients were required to have
contact with a responsible care giver on at least 3 days a week.
For ambulatory patients receiving professional care (eg, living
in a nursing home), the care giver could be a designated
member of the medical team. Exclusion criteria included any
primary neurodegenerative disorder other than Parkinson’s
disease or any other causes of dementia; a major depressive
episode; active, uncontrolled seizure disorder; any disability or
unstable disease that might prevent the patient from complet-
ing all study requirements; and a known hypersensitivity to
drugs similar to rivastigmine in structure or pharmacological
The study was approved by local properly constituted
institutional review boards. Participants and their care givers
gave written informed consent. All procedures were in
accordance with ethical standards of the responsible committee
on human experimentation and with the Helsinki declaration.
Neuropsychiatric symptoms were assessed using the 10-item
NPI18by a trained rater following standard procedures. The
validity of the NPI has been established,18and high reliability in
Parkinson’s disease has been reported.1Firstly, screening
questions for each of the 10 neuropsychiatric symptoms were
asked. Positive responses were probed with structured ques-
tions focusing on specific features of the neuropsychiatric
symptom. The informant rated the frequency of each symptom
on a scale from 1 to 4, and the severity of the symptom on a
scale from 1 to 3. A composite score, defined as the product of
frequency and severity, yielding a score ranging from 1 to 12 for
each item, was used in the analysis. A care giver distress item is
also included, where the care giver is requested to score the
level of emotional distress experienced by the care giver caused
by each symptom (level of distress: not at all, 1; minimal, 2;
moderate, 3; severe, 4; very severe or extreme distress, 5).
Cognition was assessed by means of MMSE scores17; motor
symptoms were evaluated with the Unified Parkinson’s Disease
Rating Scale (UPDRS) and motor subscale (part III)19; and
staging of Parkinson’s disease by the Hoehn and Yahr scale.20
Descriptive statistics were applied first (mean, standard
deviation (SD), rates). Student’s t test was used for compar-
isons of normally distributed continuous data and x2test for
categorical variables. Non-parametric tests were used for
comparison of the NPI scores owing to the skewness and
non-linearity of these data.
NPI subscores of each patient with a positive score on at least
one NPI item were standardised to z score values based on the
mean and SD of each NPI variable, to ensure equal weighting of
the different symptoms in the clustering procedure. A similarity
matrix was calculated using an euclidian distance measure. K-
means cluster analysis was used on the similarity matrix. For
validation purposes, we used a split-sample validation proce-
dure. The sample was divided into two, using the randomisa-
tion procedure in SPSS V.12.01. Separate similarity matrices
were computed for each sample and subjected to a K-means
clustering procedure. The resulting clusters were compared
with the clusters from the full-sample analysis regarding
The clusters were analysed regarding the Hoehn and Yahr
stage, MMSE and NPI care giver distress scale scores. One-way
analysis of variance was used for statistical comparisons of the
five clusters for continuous variables, with retrospective
corrections where appropriate, using Scheffe’s test. A value of
p,0.05 was considered significant. In addition, a multinomial
logistic regression analysis was carried out to study the effect of
clinical features on the allocation of a patient to a particular
cluster, with cluster number as the dependent variable and
clinical and demographic variables as predictors.
NPI was completed for 537 patients (65% men and 35%
women). The mean (SD) age of the sample was 72.64
(6.61) years, and they had 9.00 (4.06) years of formal educa-
tion. The mean (SD) duration since onset of Parkinson’s disease
was 10.03 (5.9) years, and that since diagnosis of dementia was
2.15 (1.7) years. The mean MMSE score was 19.33 (3.90),
UPDRS motor score 33.32 (14.07) and Hoehn and Yahr stage
2.78 (0.83). All patients received antiparkinsonian agents,
26.6% used an antidepressant, 27.4% used an antipsychotic
Neuropsychiatric Inventory item and care giver distress scores in the total group and in those showing symptoms
All patients Patients showing symptoms
MeanSDMeanSDn (%)n (%)*
of allMean SDMean SD
1.052.400.461.1 118 (22.0)68 (58)12.64.7188.8.131.522 (44) 9.7
12.9312.047.30 6.7480 (89.4)345 (72)64.114.2711.98.05 8.7315 (66)58.6
*Percentage of patients showing symptoms.
Neuropsychiatric symptoms in Parkinson’s disease 37
agent and 19.5% used an anxiolytic agent; 13.1% used more
than one type of psychotropic drug.
Table 1 shows the mean score and proportion of patients with a
non-zero score on the NPI items. The mean (SD) total NPI score
was 12.9 (12.0). The most common symptoms were depression,
apathy, anxiety and hallucinations, and the least common were
euphoria and disinhibition. Only 10.6% were without any
symptoms, whereas 89.4% presented at least one symptom.
Seventy three per cent of those who presented with at least one
symptom, or 64% of the total group, had at least one symptom
with a score >4. The mean number of symptoms present was
3.3 (2.2), and 60% displayed >3 symptoms. Among those
patients who had symptoms, the highest scores were found for
apathy, delusions, anxiety and depression.
Associations between NPI and clinical characteristics
The total NPI score did not differ between male and female
patients (p=0.55), and we found no association with age
(r=20.08; p=0.06). However, we found significant associa-
tions between total NPI score and cognitive impairment and
stage of Parkinson’s disease. Patients with an MMSE score
below the median score of 20 had more neuropsychiatric
symptoms than those with MMSE score .20: mean total NPI
15.02 (13.23) v 11.19 (10.71); number of symptoms 3.7 (2.3) v
3.0 (2.0); Mann–Whitney test; p=0.001 for both). Comparing
individual items, patients with MMSE score ,20 had higher
mean scores and a higher proportion of non-zero scores for the
variables delusions, hallucinations, aberrant motor behaviour
(p,0.001 for all three) and apathy (p=0.006).
A similar pattern was found for the relationship between NPI
items and Hoehn and Yahr stage. Those with a Hoehn and Yahr
stage at or above the median stage of 3 had a total NPI score of
15.06 (13.14) compared with 10.79 (10.50) in those with a
Hoehn and Yahr score ,3 (p,0.001). Patients with more
advanced Parkinson’s disease had higher scores and a higher
proportion ofnon-zero scores
(p,0.001), hallucinations (p,0.001), apathy (p=0.001) and
aberrant motor behaviour (p=0.008).
on theitems delusions
NPI cluster analysis
The cluster analysis classified the patients in five clusters on the
basis of a judgement of the interpretability of the solution
(fig 1). The split-sample validation procedure gave a total
classification agreement of 85%. The agreement between the
cluster classification in the first and second half of the sample
versus the full-sample solution was 91% and 79%, respectively.
The patients in cluster 1, the largest group (n=279; 52.1%),
consisted principally of participants reporting few and mild
neuropsychiatric symptoms. The mean (SD) total NPI score of
this group was 5.2 (4.6), and 64.3% showed ,3 symptoms.
Cluster 2 (n=58; 10.8%) was characterised by patients with
high scores on depression, anxiety and apathy, and low scores
on the other items. Owing to their symptom profile, we refer to
this as the ‘‘mood’’ group. Cluster 3 (n=126; 23.5%), had high
scores on apathy (mean 6.6 (2.1)) and low scores on the
remaining items, including depression, thus labelled the
‘‘apathy’’ group. A small group (n=29; 5.4%), cluster 4,
consisted of patients with moderate or severe subscores on
most items, including irritability and agitation items. Scores on
irritability and agitation were low in the other clusters. This
group was labelled the ‘‘agitation’’ group, with a total NPI score
of 39.2, and with 55.2% showing >6 symptoms. The final
cluster, cluster 5 (n=45; 8.4%), was characterised by high
scores on visual hallucinations (5.9 (2.9)) and delusions (6.4
(2.7)), in combination with lower scores on most other items,
and was labelled the ‘‘psychosis’’ group. The differences in total
NPI score between the groups were significant (F=285,
df=4532, p,0.001; post-hoc Tukey test, all p values ,0.001),
with the exception of clusters 2 and 5, not significant (fig 2).
We found slight differences between the clusters with regard
to sex distribution (p,0.05): the proportion of men was lowest
in the mood group (50.9%) and highest in the apathy group
Aberrant motor behaviour
scores in the five clusters.
The final cluster solution: mean Neuropsychiatric Inventory item
Mean NPI score
neuropsychiatric clusters. N, mean score. Error bars show 95% confidence
interval of mean.
Total Neuropsychiatric Inventory (NPI) scores in the five
38Aarsland, Brønnick, Ehrt, et al
(74.6%). The set of one-way analyses of variance showed that
the five clusters did not differ regarding age (F=1.9, df=4,
p=0.12) or duration of Parkinson’s disease (F=1.3, df=4,
p=0.25). The psychosis group had the highest mean UPDRS
motor subscore (fig 3), but there were no significant between-
group differences (F=2.3, df=4, p=0.06). We found, how-
ever, highly significantdifferences
regarding MMSE (F=6.1, df=4, p,0.001; fig 4): cluster 1,
with minimal neuropsychiatric disturbances, and the Mood and
Apathy clusters had the highest MMSE scores, and had
significantly higher scores than the patients in cluster 4, the
Agitation cluster. The MMSE score in the Psychosis cluster was
lower than in clusters 1–3, but these differences did not reach
significance, although the difference between clusters 5 and 2
approached significance (p=0.057). Table 2 shows the odds
ratios for effects of these clinical and demographic features on
cluster allocation. A low score on the MMSE predicted
allocation to clusters 4 and 5 compared with cluster 1, and
male sex was associated with a higher likelihood of being
placed in cluster 3 and lower likelihood of being in cluster 2
than in cluster 1. More advanced disease stage was associated
with a significantly higher likelihood of being placed in all
clusters with neuropsychiatric symptoms (ie, clusters 2–5) than
in cluster 1. The frequency of using antidepressants did not
differ among the clusters, but we found a significant difference
in the use of antipsychotics (x2=28.7, df=4, p,0.001). The
highest proportion using antipsychotic agents was in cluster 5
(56%), intermediate in clusters 4 (34%) and 3 (33%), and
lowest in clusters 2 (21%) and 1 (19%).
NPI care giver distress scores
As expected, the mean care giver distress score was highest for
those items with the highest frequency. In patients with a
positive score for that item, the highest care giver distress score
was found for delusions, apathy, agitation, depression and
irritability (table 1). Moderately severe distress—that is, a score
(UPDRS III) motor subscores in the five neuropsychiatric clusters. N, mean
score. Error bars show 95% confidence interval of mean.
Mean Unified Parkinson’s Disease Rating Scale—third edition
neuropsychiatric clusters. N, mean score. Error bars show 95% confidence
interval of mean.
Mean Mini-Mental State Examination (MMSE) scores in the five
Association of age, sex, disease stage and cognition with cluster allocation
Cluster Variablep Value Odds ratio
Hoehn and Yahr stage
Hoehn and Yahr stage
Hoehn and Yahr stage
Hoehn and Yahr stage
0.916 to 1.001
1.109 to 3.579
1.076 to 2.271
0.993 to 1.178
0.970 to 1.038
0.363 to 0.946
1.088 to 1.867
0.924 to 1.037
0.869 to 0.977
0.523 to 2.636
1.072 to 2.746
0.772 to 0.935
0.920 to 1.016
0.467 to 1.795
1.077 to 2.347
0.844 to 0.993
MMSE, Mini-Mental State Examination.
Results from the multivariable multinomial logistic regression analysis, using cluster 1 as reference cluster.
Neuropsychiatric symptoms in Parkinson’s disease 39
of >3—was reported by .20% of carers for several symptoms,
and 58.6% of the carers reported at least one neuropsychiatric
symptom to be causing at least moderately severe distress.
Among the five clusters, the highest total care giver distress
total score was found for the agitation, psychosis and mood
clusters, but even the distress score for the apathy cluster was
significantly higher than the distress score for the cluster,
showing no or few NPI symptoms (fig 5).
We describe the neuropsychiatric symptoms in the largest
sample of patients with PDD reported to date. At least one
neuropsychiatric symptom was present in nearly 90% of the
included participants. Although most patients had few symp-
toms and low scores, a considerable number of patients had
many symptoms, and 64% had a composite score of >4 for at
least one item, indicating at least moderate severity. The most
common symptoms were depression, anxiety, apathy and
hallucinations. The symptoms tended to occur in a specific
pattern, and five symptom clusters were identified, dominated
by mood symptoms, apathy, psychosis, a small group with
predominant agitation accompanied by several other, marked
symptoms, and a group with few and mild symptoms. In
addition to being common, the clinical relevance of neuropsy-
chiatric symptoms in patients with PDD is further underlined
by the finding that nearly 60% of the care givers reported at
least one NPI symptom to be a cause of moderate or severe
The frequency and severity of psychiatric symptoms in this
PDD group are higher than those reported in a community-
based cohort of patients with Alzheimer’s disease,21and the
mean total NPI score is similar to the score in patients with
Alzheimer’s disease recruited for clinical trials with a cholines-
terase inhibitor.22However, the distribution and clustering of
psychiatric symptoms differ markedly between patients with
Alzheimer’s disease and those with PDD, supporting the
findings in a previous smaller study.23Firstly, although the
identification of groups dominated by mood symptoms,
psychosis and agitation in patients with PDD is similar to
those in patients with Alzheimer’s disease,10 24a substantial
group (24%) with predominantly apathy but with low scores on
mood symptoms was identified in patients with PDD, which
has not been reported in those with Alzheimer’s disease.
Secondly, in the psychosis group, hallucinations were twice as
common as delusions in patients with PDD, whereas the
reverse is true in Alzheimer’s disease. The proportion with
delusions is similar in patients with Alzheimer’s disease and in
those with PDD, whereas hallucinations were present in 44% of
patients with PDD compared with only 13% in those with
Alzheimer’s disease.21The cause for this difference may lie in
differential pathophysiology, as suggested by recent findings on
morphological25and neurochemical26substrates of delusions
and hallucinations in dementia with Lewy bodies, a disorder
with clinical and neurobiological similarities with PDD.27Thus,
the brain changes underlying psychosis in Alzheimer’s disease
may differ from those in PDD, as has previously been shown for
dementia with Lewy bodies and Alzheimer’s disease.25These
findings of different clustering of neuropsychiatric symptoms in
Alzheimer’s disease and PDD extend previous clinical and
neurobiological observations suggesting that dementia in
patients with Parkinson’s disease is not mainly due to
concomitant Alzheimer’s disease.
The identification of neuropsychiatric clusters supports and
extends previous findings indicating clinical subgroups in
patients with Parkinson’s disease.11 28Several studies have
suggested subgroups according to the profile of cognitive
impairment, with some patients showing a pattern compatible
with frontostriatal deficits and others more with a temporal–
limbic deficit.29–31Differential neurochemical deficits underlying
different motor subtypes have also been previously reported.28
On the basis of the current study, we propose subgroups of
patients with PDD based on the neuropsychiatric symptom
profile, with potential treatment implications. We hypothesise
specific neurobiological changes underlying the different
neuropsychiatric clusters. Apathy has been linked to pathology
of the anterior cingulum, and to disturbances in the medial
frontostriatal circuitry, probably mediated by dopaminergic
deficits.32Hallucinations in patients with Lewy body disease are
associated with Lewy bodies in the temporal cortex,33and with
cholinergic deficits,26and thus cholinergic deficits may be
particularly pronounced in these patients. Depression in
Parkinson’s disease has been associated with serotonergic
deficits, but also noradrenergic changes.34Finally, agitation is
common in Alzheimer’s disease, and neuropathological studies
have found that neurofibrillar burden in the left orbitofrontal
cortex correlates considerably with agitation scores.35Thus, in
patients with PDD with agitation, Alzheimer’s disease-like
changes may be particularly pronounced, although other
pathologies in the orbitofrontal cortex may also contribute. In
summary, the neuropsychatric profile of patients with PDD may
provide information on the differential use of dopaminergic,
serotonergic, noradrenergic and cholinergic drugs. However,
given the complex anatomical and neurotransmitter interac-
tions in the brain, linking complex behaviours such as
psychiatric symptoms to one specific brain area or one
transmitter system is clearly an oversimplification, although
major anatomical and chemical contributors can be identified.
In addition, the MMSE score differed significantly between
clusters, and so it is possible that the neuropsychiatric
syndromes to some extent may represent different stages of
the dementia. Nevertheless, our findings do provide an
empirical basis for testing the neurochemical hypotheses in
future clinical trials.
Dopaminergic agents may have behavioural effects,36and
may thus contribute to the profile of neuropsychiatric
symptoms, in particular to the occurrence of visual hallucina-
tions. However, several studies have shown that antiparkinso-
nianagents areonly weaklyassociated with visual
NPI caregiver sum score
Inventory (NPI) clusters. N, mean score. Error bars show 95% confidence
interval of mean.
Sum of care giver distress scores in the five Neuropsychiatric
40 Aarsland, Brønnick, Ehrt, et al
hallucinations, suggesting that disease-related factors are more
important determinants of psychiatric symptoms in patients
with PDD.37Furthermore, antipsychotic drugs were used by 20–
30% of patients without or with only mild neuropsychiatric
symptoms, indicating that these drugs may have influenced the
observed symptom profile, and that psychotic symptoms are
even more common than observed in this study. A proportion of
patients used antidepressants. Although the use of antidepres-
sants did not differ among clusters, it is possible that the use of
such drugs might have influenced the NPI profile and the
distribution of patients to the different clusters.
We note some methodological limitations of this study.
Firstly, as this was a multicentre clinical trial, the inter-rater
reliability of NPI may be lower and thus some important
associations might have been lost. However, NPI is a highly
structured instrument with proved high reliability, and the
raters participated in training sessions before the study.
Secondly, recording of neuropsychiatric symptoms was
observer based only, and some neuropsychiatric symptoms
with more subjective character may have been missed. In
addition, some symptoms, such as obsessive–compulsive
symptoms, were not assessed.
Thirdly, this was a cross-sectional study, and a longitudinal
approach may more accurately reflect the frequency and
clustering of neuropsychiatric disturbances. The diagnosis was
clinical without autopsy confirmation, and misdiagnosis may
occur. However, established diagnostic criteria for Parkinson’s
disease and standardised assessments of motor symptoms were
used. Fourthly, a control group was not included. However,
there is evidence that the frequency and severity of NPI items is
low in healthy elderly people18and in those without dementia.38
With regard to statistical methods, cluster analysis can be
criticised because of the subjective nature of several decisions
affecting the final outcome. However, the split-sample valida-
tion procedure showed an agreement of 85% between the
cluster classification in the subsamples and the full sample, far
higher than the 20% agreement expected if the classification
was random. The patterns of relationships with the other
clinical variables provide further support for the validity of our
clustering solution, as does the face validity and similarity with
previous cluster analyses.
The patients were recruited for a clinical trial with
rivastigmine. The patients had fairly low NPI scores, and this
is typical for trial populations as very disturbed patients cannot
participate in trials. Trial participants also tend to be better
educated and have better general health, and this may affect
the generalisability to other PDD populations. In addition,
patients with major depression were not included. However,
major depression is rare in Parkinson’s disease.39 40Finally, only
patients with a carer who must be in contact with the patient
for a minimum of 3 days a week were included. Thus, a
selection bias may have been introduced. However, the age,
severity of motor symptoms, level of cognitive impairment and
prevalence, and distribution and severity of psychiatric symp-
toms are remarkably similar to those of a small community-
based cohort of patients with PDD.23Thus, this group is
representative of the overall population with PDD, supporting
the validity of the findings.
This study was based on baseline data from a drug trial sponsored by
the Novartis Pharmaceuticals Corporation.
D Aarsland, K Brønnick, U Ehrt, Centre for Clinical Neuroscience
Research, Stavanger University Hospital, Stavanger, Norway
P P De Deyn, Department of Neurology, Middelheim Hospital, Laboratory
of Neurochemistry and Behavior, Born-Bunge Foundation, University of
Antwerp, Antwerp, Belgium
S Tekin, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey,
M Emre, Istanbul Faculty of Medicine, Istanbul, Turkey
J L Cummings, UCLA Alzheimer’s Disease Center, Los Angeles, California,
Competing interests: None declared.
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ECHO ............................................................... ........................................................
Misdiagnosis of epilepsy in children
centre of its kind in Denmark—were examined. Their median age was 8 years 6 months (range
8 months to 17 years 8 months) and 54% were boys.
The referrals were made from local hospitals’ paediatric departments in 51%, other
departments in 27%, and from general or specialist practitioners in 22%. Doubt regarding the
diagnosis of epilepsy was expressed in the referral note in 17%. On admission, 86% of the
children were on antiepileptic drug treatment. During admission all children were subjected to a
comprehensive intensive observation and 62% had EEG monitoring.
In total, 87 children (39%) were found not to have epilepsy. In 30% of children referred
without any doubts about their epilepsy, the diagnosis was found to be wrong. Of the 159
children admitted for the first time, 75 (47%) were discharged with a diagnosis of non-epileptic
seizures. Of 125 admitted for the first time with no doubts about the diagnosis of epilepsy, 44
(35%) did not have epilepsy. Staring episodes were the most frequently encountered non-
epileptic paroxysmal event. Psychogenic non-epileptic seizures were found in 12 children.
The study shows that the treating physician should be cautious in diagnosis, especially of
staring episodes. A diagnostic re-evaluation should be undertaken in difficult cases with
continuing paroxysmal events in order to avoid unnecessary drug treatment and restrictions on
the child’s lifestyle.
m Uldall P, et al. Archives of Diseases in Children 2006;91:219–21
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survey of children admitted to a tertiary epilepsy centre with difficult to treat paroxysmal
events found that 39% of the children did not have epilepsy. In the retrospective study,
case notes of 233 children admitted to the Dianalund Epilepsy Centre—the only tertiary
42Aarsland, Brønnick, Ehrt, et al