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 symptoms 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 neuropsychiatric 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 distress.
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,21
and the mean total NPI score is similar to the score in patients with Alzheimer's disease recruited for clinical trials with a cholinesterase inhibitor.22
However, 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.23
Firstly, 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,10,24
a 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.21
The cause for this difference may lie in differential pathophysiology, as suggested by recent findings on morphological25
substrates of delusions and hallucinations in dementia with Lewy bodies, a disorder with clinical and neurobiological similarities with PDD.27
Thus, 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.25
These 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.11,28
Several 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.29,30,31
Differential 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.32
Hallucinations in patients with Lewy body disease are associated with Lewy bodies in the temporal cortex,33
and with cholinergic deficits,26
and 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.34
Finally, 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.35
Thus, 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 interactions 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,36
and may thus contribute to the profile of neuropsychiatric symptoms, in particular to the occurrence of visual hallucinations. However, several studies have shown that antiparkinsonian agents are only weakly associated with visual hallucinations, suggesting that disease‐related factors are more important determinants of psychiatric symptoms in patients with PDD.37
Furthermore, 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 antidepressants 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 people18
and 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 validation 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.39,40
Finally, 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 symptoms are remarkably similar to those of a small community‐based cohort of patients with PDD.23
Thus, this group is representative of the overall population with PDD, supporting the validity of the findings.