The differential diagnostic dilemma of neuropsychiatric
symptoms in Alzheimer’s disease
A.C.C. Jochems
Master thesis31-07-2017
Student number: 10002722
Supervisor UvA: Dr. F. van Opstal Supervisor Erasmus MC: Dr. J.M. Papma Programme group Brain and Cognition,
Clinical Neuropsychology, Psychology department - University of Amsterdam Research internship Alzheimercentrum zuidwest Nederland – Erasmus MC
1 Abstract
Neuropsychiatric symptoms (NPS) are increasingly recognised as clinical symptoms of Alzheimer’s disease (AD) but not part of the diagnostic criteria. This complicates the diagnostic differentiation between AD and primary psychiatric disorders. Misdiagnosis or a delayed diagnosis negatively influences both patient and caregivers. This study examined how to differentiate between NPS in AD and NPS due to primary psychiatric disorders in a
memory clinic using the Neuropsychiatric inventory (NPI). Therefore, differences between NPS in AD patients and Psychiatry patients, role of age on the diagnosis, and association between NPS and functional disability by means of the Disability Assessment for Dementia (DAD) were examined. Data of 94 AD patients and 86 Psychiatry patients with a 12-item NPI was used.
Agitation, depression, disinhibition, and night-time disturbances were more present in Psychiatry patients than in AD patients. Delusions, depression, euphoria, and disinhibition were also more severe in Psychiatry patients. Depression was more frequent, more Psychiatry patients had clinically relevant depression, and a higher NPI total score. The NPI is not sensitive and specific enough to differentiate AD patients from Psychiatry patients in clinical practice. For AD patients an older age is associated with higher NPI total scores. A negative relationship was found between DAD and high symptom scores, and NPI total score, which indicates an association between decreased functional ability and increased NPS.
Conclusion: Differentiating with the NPI between NPS in AD and NPS due to primary psychiatric disorders is not possible but differences in NPS between AD and psychiatric disorders are found. High depression scores and high NPI total scores might indicate psychiatric problems instead of AD.
2 Introduction
Alzheimer’s disease (AD) is the most prevalent form of dementia. It is associated with progressive cognitive decline, predominantly memory complaints, due to pathophysiological processes affecting the temporal lobe structures and hippocampus early on in the disease (Chang & Silverman, 2004). Current diagnostics of AD are mainly focused on cognitive symptomatology, while neuropsychiatric symptoms (NPS) are increasingly recognised as clinical AD symptoms (Lyketsos et al., 2011). Prevalent NPS in AD are hallucinations, delusions, apathy, agitation, aberrant motor behaviour, anxiety, euphoria, irritability, sleep disturbances, eating disorder, disinhibition, and depression (Borsje, Wetzels, Lucassen, Pot, & Koopmans, 2015). NPS occur in over 80% of AD patients (Lyketsos et al., 2002) at some stage during their disease (Aalten, De Vugt, Jaspers, Jolles, & Verhey, 2005; Gonfrier, Andrieu, Renaud, Vellas, & Robert, 2012; Steinberg et al., 2003). The presence of agitation and psychosis in particular, clinically relevant symptoms in general (Peters et al., 2014), or the increase of any NPS can predict a more rapid progression to a probable AD diagnosis across people with normal cognitive function, subjective cognitive problems, MCI, or mild dementia (David, Lin, Porsteinsson, & Alzheimer's Disease Neuroimaging Initiative, 2016; Rosenberg et al., 2013). The presence of NPS in AD is a source of distress among caregivers (Craig, Mirakhur, Hart, McIlroy, & Passmore, 2005), and negatively affects every day functioning (Haaksma et al., 2017; Rog et al., 2014; Tekin, Fairbanks, O'Connor, Rosenberg, & Cummings, 2002), and the quality of life (QoL) of both caregiver and patient (Banerjee et al., 2006; Shin, Carter, Masterman, Fairbanks, & Cummings, 2005), with earlier
institutionalisation as a consequence (De Vugt et al., 2005). In addition, NPS are related to 30% of the total annual cost of AD (Schnaider Beeri, Werner, Davidson, & Noy, 2002). Despite these severe consequences, NPS are not part of the core diagnostic criteria for AD (McKhann et al., 2011) and are therefore underrecognised and undertreated in daily clinical
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practice. The opposite applies to NPS in frontotemporal dementia (Rascovsky et al., 2011) and Lewy body dementia (LBD; McKeith et al., 2005), in which NPS, such as apathy, disinhibition, hallucinations, delusions, and depression are part of the diagnostic criteria.
A valid measurement for diagnostic purposes of NPS is very useful as NPS in dementia are often mistaken for NPS due to psychiatric disorders. This can cause
misdiagnosis, delayed, or inappropriate treatment. Especially depressive symptoms in elderly, concurring with cognitive problems can cause confusion. Woolley, Khan, Murthy, Miller, and Rankin (2011) found that patients with behavioural frontotemporal dementia (bvFTD) and AD patients received an incorrect psychiatric diagnosis three years before they were correctly diagnosed with dementia. The increased recognition of NPS in AD enabled the proposal of provisional criteria for psychosis of AD (Jeste & Finkel, 2000), apathy in AD (Robert et al., 2009), and Mild Behavioural Impairment (MBI; (Ismail et al., 2016). In the latter, late onset psychiatric symptoms are seen as early manifestations of neurodegeneration. Criteria to distinguish a major depressive episode (MDE) from depression in AD (Olin, Katz, Meyers, Schneider, & Lebowitz, 2002) are mainly based on a higher number of symptoms and a higher frequency of symptoms in a MDE than in depression in AD. Although overlap of symptoms can be found between MDE and AD, symptoms like loss of appetite, loss of weight, suicide, and anxiety are more severe in the depressed patients without dementia (Chemerinski, Petracca, Sabe, Kremer, & Starkstein, 2001). The association of AD with mild depressive symptoms but not with a severe form of depression (Lee et al., 2016) suggests that the differentiation between depression in AD and a primary depression can be based on severity. The criteria for psychosis in AD differ from schizophrenia in elderly based on frequency (Jeste & Finkel, 2000). If the symptom criteria and the severity and frequency of these NPS in AD differ from NPS due to a primary psychiatric disorder, it might be the same for other NPS in AD. As the NPI is used to screen for NPS based on severity and frequency, it
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can be used to look for differences between NPS in AD and NPS due to a primary psychiatric disorder.
More knowledge about possible differences between NPS in AD and primary
psychiatric disorders can improve the recognition of NPS in AD in an earlier stage. An early and correct diagnosis will create possibilities for pharmacological and non-pharmacological interventions. Non-pharmacological interventions for the patients such as music therapy (Livingston et al., 2014) and behavioural management (Abraha et al., 2017), interventions focused on the caregiver (Brodaty & Arasaratnam, 2012), or interventions for both caregiver and patient (Gitlin, 2012) seem to reduce NPS. Appropriate interventions will increase the QoL for patients and their caregivers, hereby extend the moment of institutionalisation, and decrease the costs of care. To distinguish NPS in AD from primary psychiatric symptoms of patients who present themselves in memory clinics with cognitive complaints, it is important to know the differences.
The most frequent NPS in AD are apathy, depression (Aalten et al., 2003; Lyketsos et al., 2011; Steinberg et al., 2004), agitation, anxiety, and irritability (Serra et al., 2010; Suárez-González, Crutch, Franco-Macías, & Gil-Néciga, 2016). A commonly used method to
evaluate these NPS in dementia is the Neuropsychiatric Inventory (NPI), a clinical proxy based measure. For this inventory no official cut-off scores have been set by the author. Only the presence of hallucinations and delusions are always seen as abnormal (J. L. Cummings). However, several cut-off scores for item scores and the total score have been created since (see Table A1, Appendix A, for an overview). In most studies a symptom score of ≥4 per item was considered to be clinically relevant (Schneider et al., 2001). Clinically relevant symptoms are severe, frequently present, and disrupt every day functioning, i.e. at work, at home or socially, and treatment is required (American Psychiatric Association, 2013). Still, it is not clear where these NPI cut-off scores are based on, or if the scores actually represent clinically
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relevant symptoms. This raises the question whether the scores are applicable to the clinical practice and are usable for diagnostic purposes.
NPS in AD might differ from NPS due to primary psychiatric disorders in the way the NPS are reflected in every day live. It is known that NPS in AD negatively influence daily functioning (Haaksma et al., 2017; Rog et al., 2014; Tekin et al., 2002), and clinically relevant NPS disrupt every day functioning (American Psychiatric Association, 2013). While NPS are frequent and persistent in AD patients (Borsje et al., 2015), these symptoms are not always clinically relevant. A finding of Lyketsos et al. (2002) was that 75% of the dementia
participants showed a neuropsychiatric symptom, of which 62% was clinically relevant. If the criteria of NPS differ between AD and primary psychiatric disorders, the symptoms might have different influences on daily functioning. Whether these differences exist is unknown.
Another point of interest is the prevalence of NPS in early onset and late onset AD. NPS are present during every stage of the disease, in both early onset AD (Mulders et al., 2016), developed before the age of 65, and in late onset AD. Whether NPS are relatively fewer in early onset AD than in late onset AD (Toyota et al., 2007; Van Vliet et al., 2012) or not (Barnes et al., 2015) is still unclear.
The overlap between NPS in AD and cognitive complaints due to primary psychiatric disorders complicates the diagnostic differentiation, but all things considered NPS in AD might differ from NPS due to primary psychiatric disorders in many ways. To avoid this diagnostic dilemma, it is necessary to exam how to differentiate between NPS in AD and NPS due to primary psychiatric disorders. This study will 1) identify the differences in NPS
between AD and primary psychiatric disorders based on the presence and number of NPS on NPI, the severity, frequency, symptom score, clinical relevance, NPI total score in AD versus primary psychiatric disorders, 2) examine the potential properties of the NPI to differentiate between NPS in AD versus primary psychiatric disorders, 3) examine the role of the age at
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first visit on the diagnosis, 4) examine the association between NPS and functional disability using the Disability Assessment for Dementia (DAD) in AD patients and psychiatric patients. It is hypothesised that 1) NPS are more prevalent in psychiatric patients. Also higher severity, higher frequency, higher symptom score, and more clinically relevant (cut-off score ≥4) NPS will be seen in psychiatric patients. Also expected are higher NPI total scores for psychiatric patients, 2) separate NPS symptom scores can differentiate between NPS in AD and NPS due to primary psychiatric disorders, 3) a younger age plays a negative role on the presence of NPS, and 4) a stronger association between NPS and functional disability for AD patients compared to psychiatric patients.
Method
Participants
In this study, 191 patients with the clinical diagnosis of possible or probable AD (AD patients, N=94) or a psychiatric diagnosis (Psychiatry patients, N=86) were included. Of the AD patients 85 patients received a probable AD diagnosis, nine patients received a possible AD diagnosis. Most patients had evidence of AD pathophysiology (AD profile in
cerebrospinal fluid, MRI, or PET scan). Patient data was collected from the “Alzheimer Center biobank” study. This concerns clinical data of patients visiting the outpatient memory clinic of the Alzheimer Center seen in 2009-2017. Dutch speaking patients with an NPI were selected. Exclusion criteria were other dementia diagnoses or other causes of cognitive decline.
Procedure
The research was conducted at Alzheimer Center of Erasmus Medical Center where
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or second opinion. The patients underwent standard physical and neurological examinations, and patient and caregiver(s) were interviewed by a neurologist. Thereafter, blood
examination, neuropsychological assessment (NPA), and an MRI (magnetic resonance imaging) scan followed. If deemed necessary the examinations where supplemented with a cerebrospinal fluid examination, or a PET (positron emission tomography) scan followed. Patients were assessed with the Mini-mental State Examination (MMSE). The caregivers were asked by a researcher to fill in additional questionnaires, i.e. NPI and DAD. During the multidisciplinary meeting, the patient received a diagnosis. All patients gave written informed consent to participate and received a copy of the informed consent.
Measures
Demographic information. During a structured interview with the patient and
caregiver(s) information including age, onset of disease (early onset: younger than 65 years of age; late onset: 65 years or older), gender, ethnicity, education, and medical and psychiatric history of the patient and their family were obtained. This interview was part of the dementia screening at the outpatient clinic and collected in a database. If information was missing, that information was gathered from the electronic patient record.
Mini-mental State Examination (MMSE). The MMSE is a global cognitive
screening instrument containing eleven questions with a total test score of 0-30. A score over 24 indicates non-dementia and a score of 24 or lower indicates dementia (Wind et al., 1997).
Neuropsychiatric Inventory - Questionnaire (NPI-Q). Neuropsychiatric symptoms
in dementia are assessed with the Dutch version of the NPI-Q, which has a good validity (De Jonghe, Kat, Kalisvaart, & Boelaarts, 2003). The NPI-Q contains the same twelve NPS as the NPI (Kat et al., 2002): delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, aberrant motor behaviour,
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time behaviour disturbances, eating/appetite abnormalities. For every NPS the presence (yes or no), severity (1-3 Likert scale), and emotional burden (0-5 Likert scale) were determined. The NPI-Q total score is the sum of the severity score with a minimum score of 0 and the maximum score of 36. The NPI-Q is filled out by the patients’ caregiver. This is less time consuming than the NPI which also contains an interview.
Although the NPI-Q was used, the frequency (1-4 Likert scale) of NPS was added and also assessed by caregivers. Because of this, a symptom score could be determined, by
multiplying the severity score and the frequency score (S x F), and calculate a total score ranging from 0 – 144. These scores are comparable to the NPI scoring and not part of the NPI-Q scoring. For the analyses the severity (NPI-Q), frequency (NPI), symptom scores (NPI) and total scores (NPI) were used. The addition of frequency, symptoms score and total score was done to gather extra information and to compare the NPI scores with our NPI-Q version.
Using the NPI-Q with the addition of the frequency score, symptom score and total score of the NPI is comparable to using the NPI. The validity of this NPI-Q version was checked by comparing the NPI-Q scores (N= 152) to the NPI scores (N = 28) for both the AD patients as the Psychiatry patients. Some significant differences were found (see Appendix A, Tables A2 – A9). For almost all the significant differences, the scores were higher in the NPI than the NPI-Q. Only the presence of disinhibition is higher for the NPI-Q than NPI (χ2 (1) = 5.01, p .025). It is expected that future significant differences in the main analyses with the use of the NPI-Q will be even more significant with the use of the NPI. The use of the NPI-Q with added scoring instead of the full NPI does not have negative implications for this study. Although the NPI-Q was used, the scores will be referred to as NPI scores.
Disability Assessment for Dementia (DAD). The DAD measures the functional
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contains 40 items addressing multiple domains: personal hygiene, dressing, urinal and faecal continence, eating, meal preparation, telephoning, outdoor activities, finance and
corresponding, medication, leisure and housework. Every item within the domains is scored based on impairment categories of initiative, planning and organisation, and effective performance. The caregiver indicates for every item whether the patient was able to perform the activities without help or reminder (yes, no or not applicable). High scores represent good abilities. Total score range from 0 (severe disabilities) to 100 (no disabilities). Good interrater and test-retest reliabilities and content validity apply (Gélinas, Gauthier, McIntyre, &
Gauthier, 1999).
Diagnosis. During multidisciplinary meetings, attended by neurologists, geriatricians,
psychiatrists, neuro-radiologists, and neuropsychologists, the diagnoses were determined. These were based on available information i.e. the physical and neurological examination, cognitive assessments, NPA, blood examination, cerebrospinal fluid examination, imaging, and the interview with patient and caregiver. The diagnosis of AD was based on the
NINCDS-ADRDA criteria (McKhann et al., 2011). The criteria for a probable AD diagnosis were a gradual onset; progression of cognitive decline; memory disorder or disorders in other domains: language, visuospatial cognition, or executive functioning; additional cognitive dysfunction in at least one of the following domains: aphasia, apraxia, gnosis, executive functions. Possible AD diagnosis consists of an atypical course of cognitive decline, or an etiologically mixed presentation of the core clinical criteria. Both diagnoses can be supported by evidence of pathophysiological process of AD, e.g. AD profile found in cerebrospinal fluid, disproportionate atrophy (in medial, basal, and lateral temporal lobe, and in the medial parietal cortex) found on the MRI scan or a positive (deposition of amyloid-beta protein in the brain) PET scan. Psychiatric diagnoses were based on the DSM-V criteria (American
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by a psychiatrist as some patients were referred to a psychologist or counsellor. In the Psychiatry patient group not all patients met the full DSM-V criteria for a psychiatric disorder. Their cognitive complaints were not thought to be caused by an underlying neurodegenerative disease, but by NPS, but not on a level of a disorder. This was also
concluded during the multidisciplinary meetings, and potentially during follow-up visits to the Psychiatry outpatient clinic.
Statistical analysis. All information retrieved from the patient was analysed using
SPSS (IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.). Between group analyses for gender, patient’s history of psychiatric disorders, family history of
dementia and psychiatric disorders, early (<65 years) or late (>65 years) onset, and education level were performed by Pearson Chi-square tests. For age (a continuous variable) a Student’s t-test was performed. The other continuous variables, the MMSE scores and DAD scores (non-parametric) were assessed by using Mann-Whitney tests due to non-normal
distributions.
The presence of NPS, yes or no according to the NPI, was assessed by percentages of the number of ‘yes’ answers per symptom. Differences between presence, severity, frequency, symptom scores (SxF), and clinically relevant symptoms (SxF ≥4) for each NPS, and the number of present NPS, were assessed with Pearson Chi-square tests. A non-parametric Mann-Whitney test was used to assess the difference of the total NPI scores between the groups. To examine the differential properties of the NPI, receiver operating characteristic (ROC) curves were generated for the symptoms scores and the total NPI score. For each ROC curve the area under the curve (AUC) was used to find the specificity and sensitivity of each score to differentiate for the AD diagnosis.
A simple regression analyses was used to examine the role of age at first visit (continuous) on the NPI total score. Lastly, Spearman’s Rho correlations were measured
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between symptom scores and the score on the DAD (daily functioning). All analyses, except the ROC analyses, were done for both the AD patients and the Psychiatry patients. A p value of <0.05 was considered statistically significant. Tests have been adjusted for multiple comparisons by Bonferroni corrections.
Results
A total of 180 patients (94 AD patients, 86 Psychiatry patients) were included in the study. The patient’s characteristics are summarised in Table 1. Psychiatry patients significantly differ from AD patients on several characteristics. Psychiatry patients were on average
younger at time of diagnosis (t (178) = 5.45, p <.001), with an onset before 65 years of age (χ2 (1) = 15.01, p <.001), had a higher MMSE score (U = 1008.50, z = -8.26, p <.001, r = -.63) than AD patients. More psychiatry patients had a family history of psychiatry (χ2 (2) = 17.73, p <.001), and psychiatry in their personal medical history (χ2 (2) = 14.95, p =.001) compared to AD patients. An overview of the psychiatric medical history can be found in Table B1 (Appendix B). Depression occurred more in the medical history of Psychiatric patients than in AD patients (χ2
(10) = 32.8, p <.001). Differences in other psychiatric diagnoses did not occur between the groups.
Table 1. Characteristics of the patient groups
AD patients N Psychiatry patients N p value Age (SD) 64.86 (8.56) 94 56.98 (10.79) 86 <.001 Onset <65y, N (%) 51 (54.3) 94 70 (81.4) 86 <.001 Male gender, N (%) 56 (59.6) 94 55 (64.0) 86 .546 Education level, median (IQR) 5.0 (4.0-5.0) 93 5.0 (5.0-6.0) 86 .137 MMSE, mean (SD) 20.41 (5.41) 88 26.69 (2.80) 84 <.001
12 DAD, mean (SD) 74.54 (23.54) 52 83.00 (18.33) 45 .064 Family history of dementia, N (%) 56 (59.6) 94 43 (53.5) 86 .215 Family history of psychiatry, N (%) 10 (10.6) 94 32 (37.2) 86 <.001 Personal history of psychiatry, N (%) 24 (25.5) 94 46 (53.5) 86 .001
Note. AD = Alzheimer’s Disease, MMSE = Mini Mental State Examination, CDR= Clinical Dementia Rating scale, DAD= Disability Assessment for Dementia. Numbers are presented as mean (standard deviation), median (interquartile range; IQR) or stated otherwise. The variables onset, gender, education level, family history of dementia, family history of psychiatry, and personal history of psychiatry have been analysed with the use of Pearson’s Chi- square test. A Student’s t-test was used to analyse age. MMSE and DAD were analysed with Mann-Whitney tests.
Table 2 shows the presence of NPS in AD and Psychiatry patients on the NPI. Symptoms of depression, and apathy are the most prevalent in both AD and Psychiatry patients. The presence of agitation (χ2
(1) = 6.87, p =.009), depression (χ2 (1) = 9.36, p = .002), disinhibition (χ2
(1) = 4.03, p =.045), and night-time disturbances (χ2 (1) = 12.62, p < .001) showed significant differences among the two groups, with a higher presence of these symptoms in Psychiatry patients. Other symptoms did not differ significantly. There is an indication that Psychiatry patients have a higher number of NPS present (M= 5.20), than AD patients (M=4.39; t (173) = -1.97, p =.050) (Figure B1).
Table 2. Presence of NPS(%) in AD patients and Psychiatric patients
AD patients Psychiatry patients p value Delusions 24 (25.5) 22 (25.9) .957 Hallucinations 13 (13.8) 15 (17.4) .504 Agitation 26 (27.7) 40 (46.5) .009* Depression 48 (51.1) 63 (73.3) .002** Anxiety 45 (47.9) 36 (41.9) .418 Euphoria 28 (30.1) 18 (21.2) .174 Apathy 51 (54.3) 53 (62.4) .273 Disinhibition 30 (31.9) 40 (46.5) .045*
13 Irritability 45 (47.9) 58 (67.4) .008* Aberrant motor behaviour 29 (30.9) 22 (25.9) .462 Night-time disturbances 26 (28.0) 46 (54.1) <.001** Eating abnormalities 43 (45.7) 38 (44.7) .889 Presence 1 NPS 8 (8.7) 3 (3.6) .144 2 or more NPS 77 (83.7) 75 (90.4) .133
Note. Number of patients (percentages) who answered ‘yes’. Analysed with the use of Pearson’s Chi- square test. NPS = Neuropsychiatric Symptoms. * Significant at p 0.05. **Significant after Bonferroni correction at p .004.
Table B2 shows the severity score of the NPS. Delusions (χ2 (2) = 8.7, p =.013), depression (χ2
(2) = 7.4, p =.025), euphoria (χ2 (2) = 6.1, p =.047), and disinhibition (χ2 (2) = 7.0, p =.030) were found to be significantly more severe in Psychiatry patients than in AD patients. No significant differences were found for the other NPS. The only significantly different frequency, shown in Table B3, was found for depression (χ2 (3) = 11.36, p =.010), with a higher frequency for Psychiatry patients. Symptom scores (Severity x Frequency) of the NPS are presented in Table 3. Symptom scores of agitation (χ2 (8) = 17.1, p =.029), depression (χ2
(8) = 28.7, p <.001), disinhibition (χ2 (8) = 14.9, p =.037) are significantly higher for Psychiatry patients than AD patients. Other symptoms did not differ significantly. Finally, the NPI total score (U = 2254.0, z = -3.2, p =.001) is also significantly higher for Psychiatry patients. When considering clinically relevant symptoms, i.e. symptom scores of ≥4, AD patients and Psychiatry patients only differed significantly at depression (χ2
(8) = 27.4, p =.001). Of the AD patient and Psychiatry patients respectively 67.0% and 67.4% had two or more clinically relevant symptoms (Table B4). For the AD patients the most prevalent clinically relevant NPS were apathy (30.9%) and eating abnormalities (27.7%). In psychiatry patients, depression (51.2%), apathy, irritability, and night-time disturbances (all 40.7%) were the most prevalent clinically relevant NPS.
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Table 3. Symptom scores of NPS and NPI total score
AD patients Psychiatry patients p value Delusions 0.0 (0.0-0.0) 0.0 (0.0-0.0) .474 Hallucinations 0.0 (0.0-0.0) 0.0 (0.0-0.0) .422 Agitation 0.0 (0.0-1.0) 0.0 (0.0-4.0) .029* Depression 1.0 (0.0-2.5) 4.0 (0.0-9.0) <.001** Anxiety 0.0 (0.0-3.0) 0.0 (0.0-3.0) .886 Euphoria 0.0 (0.0-1.0) 0.0 (0.0-0.0) .117 Apathy 1.0 (0.0-5.0) 2.0 (0.0-8.0) .485 Disinhibition 0.0 (0.0-2.0) 0.0 (0.0-4.0) .037* Irritability 0.0 (0.0-2.0) 2.0 (0.0-6.0) .141 Aberrant motor behaviour 0.0 (0.0-2.0) 0.0 (0.0-0.0) .320 Night-time disturbances 0.0 (0.0-3.0) 1.0 (0.0-8.0) .107 Eating abnormalities 0.0 (0.0-4.0) 0.0 (0.0-4.0) .679 NPI total score, mean
(SD)
20.37 (22.47) 31.58 (24.80) .001**
Note. Numbers are presented as: median (IQR) or otherwise stated. Analysed with the use of Pearson’s Chi- square test. NPIT total score was analysed with a Mann-Whitney test. Symptom scores are based on Severity x Frequency. IQR= Interquartile range, NPS= Neuropsychiatric Symptoms. *Significant at p 0.05. **Significant after Bonferroni correction at p .004.
Statistical significant ROC curves were found (see Table B5, Appendix B) for the symptoms of agitation (AUC = .60, 95% CI [.52 - .68], p = .023), depression (AUC = .68, 95% CI [.60 - .76], p <.001; Figure 1A), irritability (AUC = .63, 95% CI [.55 - .71], p=.023), and night-time disturbances (AUC = .62, 95% CI [.54 - .71], p=.006), though the AUC indicated poor accuracy for the symptom scores on AD diagnosis, i.e. low discrimination between psychiatric diagnosis and AD diagnosis. Also the NPI total score (AUC = .65, 95% CI [.56 - .73], p=.001; Figure 1B), shows a significant ROC curve but with poor accuracy to discriminate between diagnoses. The found cut-off scores for these symptom scores and NPI total score come with relatively low sensitivity and specificity (see Table B6, Appendix B).
15 Figure 1A. ROC Curve depression score Figure 1B. ROC Curve NPI total score
Therefore, the NPI scores are not accurate enough to differentiate between AD and psychiatry in clinical practice. However, it does indicate that the higher the scores on the NPI are, the more likely it is that the scores are positive for a psychiatric diagnosis.
A simple linear regression was conducted to predict total NPI score based on age for both AD patients and Psychiatry patients. For AD patients, age does predict the NPI total score significantly well, F (1,81) = 4.16, p =.045. An older age indicates an increasing NPI total score. However, only 4.9% of the variation of the NPI total score of AD patients can be predicted by age. Age is not a good predictor of the NPI total score for Psychiatry patients, F (1,75) = 0.07, p =.796. Approximately 0.1% (R2 = 0.001) of the variation of the NPI total score of Psychiatry patients can be predicted by age.
Most NPS appear to have a significant relationship with daily functioning of AD patients and Psychiatry patients (see Table 4). Higher symptom scores, and NPI total score indicate a negative relationship with the DAD score. Thus, worse and more NPS are related to a worse functional ability. This includes delusions (rs = .41), anxiety (rs = .55), apathy (rs = -.53), aberrant motor behaviour (rs = -.53), night-time disturbances (rs = -.48), and eating abnormalities (rs = -.48) in AD patients (all ps <.004).
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Table 4. Spearman’s correlation for daily functioning (DAD) and NPS (NPI symptom scores)
AD patients Psychiatry patients
Delusions -.41** -.47** Hallucinations -.14 -.26 Agitation -.30* -.40* Depression -.14 -.42* Anxiety -.55** -.20 Euphoria -.16 .28 Apathy -.53** -.52** Disinhibition -.37* -.36* Irritability -.37* -.34* Aberrant motor behaviour -.53** -.43** Night-time disturbances -.48** -.53** Eating abnormalities -.48** -.29
NPI total score -.76** -.65**
Note. DAD = Disability Assessment for Dementia, NPS= Neuropsychiatric Symptoms, NPI = Neuropsychiatric Inventory. NPI symptom scores: Severity x Frequency. * Significant at 0.05. ** Significant after Bonferroni correction at p .004
For Psychiatry patients a significant relationship was found between daily functioning and delusions (rs = -.47), apathy (rs = -.52), aberrant motor behaviour (rs = -.43), and night-time disturbances (rs = -.53; all ps <.004). Furthermore, a significant relationship was also found between the NPI total score and daily functioning (DAD) score for both AD patients (rs = -.76) and Psychiatry patients (rs = -.65; both ps <.004).
Discussion
In this study it was investigated how to differentiate between NPS in AD and NPS due to primary psychiatric disorders by means of the NPI in a memory clinic. The main findings were that differentiation between NPS in AD and NPS due to primary psychiatric disorders is difficult and in clinical practice not possible with the use of the NPI. Nevertheless, differences
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are found between NPS in AD and NPS due to primary psychiatric disorders. NPS, i.e. agitation, depression, disinhibition, irritability, and night-time disturbances, seem to be more prevalent in psychiatric patients than in AD patients. Some of these symptoms tend to be more severe (delusions, depression, euphoria, and disinhibition), more frequent (depression), and more often clinically relevant (depression) in psychiatric patients compared with AD. It seems that not only NPS are more prevalent in psychiatric patients, but also a higher number of different NPS are present. Although symptomatic differences are found, differentiation with the NPI is not accurate enough and therefore not reliable enough to be used in clinical practice. Agitation, depression, irritability, night-time disturbances, and the NPI total score came forward as items that can potentially differentiate between NPS in AD and NPS due to primary psychiatric disorders. Unfortunately, none of these NPI scores are sensitive and specific enough to actually do so. In addition, a relationship between age and NPS is found in AD patients, where older age is associated with a higher number of NPS, or more severe and frequent NPS. No relationship was found for psychiatric patients. For both AD patients and psychiatric patients decreased functional ability by means of DAD is associated with increased NPS.
The most prevalent NPS in AD that were found are apathy, depression, anxiety, and irritability, these findings are comparable to other studies (Aalten et al., 2007; Benoit et al., 2008; Lyketsos et al., 2002). In this study NPS are highly present, as only 7.6% of the AD patients did not have any NPS and over 80% had two or more NPS. The most present NPS in psychiatry patients are depression, irritability, apathy, and night-time disturbances. There is overlap between NPS in AD and NPS due to primary psychiatric disorders with subtle differences. Some NPS in AD differ from NPS due to primary psychiatric disorders based on frequency, and severity. Noteworthy is depression, which is more prevalent, more severe, and more frequently present in psychiatry patients, also more psychiatry patients have clinically
18
relevant depression. Maybe AD patients can be easier recognised due to the presence of several NPS, particularly depression, apathy, anxiety, and irritability, but not very severe or frequent NPS. Still, the NPS can be clinically relevant. When NPS are present, more in-depth information needs to be gathered in order to comprehend how the NPS are expressed. This can be based on criteria specifically created for NPS in AD (Ismail et al., 2016; Jeste & Finkel, 2000; Olin et al., 2002; Robert et al., 2009). These criteria compare NPS in AD with primary psychiatric symptoms and disorders. By applying these criteria, a more specific view of the NPS can be created and will provided for a better understanding of the symptoms. This will facilitate a better recognition of the NPS. Another difference that needs to be taken into account is the MMSE score, which is lower for AD patients.
As expected, psychiatry patients seem to have more prevalent, severe, and frequently present NPS. These findings correspond to existing criteria for depressive AD (Chemerinski et al., 2001; Lee et al., 2016; Olin et al., 2002), psychotic AD (Jeste & Finkel, 2000), and apathetic AD (Robert et al., 2009). These symptom criteria indicate less severe and less frequent NPS in AD than NPS due to a primary psychiatric disorder. Other NPS like agitation, disinhibition, and night-time disturbances also seem to be more prevalent in psychiatry patients. In addition delusions, euphoria, and disinhibition are more severe in psychiatry patients. These NPS, e.g. euphoria, might not be common in AD (Craig et al., 2005; Lyketsos et al., 2002; Monteiro et al., 2001) or occur only in more severe AD, i.e. delusions (Gauthier et al., 2010; Paulsen et al., 2000). Unfortunately not all psychiatric disorders among the psychiatry patients are known. Because patients with any psychiatric disorder were included, this group is heterogeneous in terms of diagnosis. This might have influenced the found differences in the prevalence, severity, and frequency of NPS that are not that common in AD.
19
During this study, the NPI-Q was used with added frequency scores. This also meant that symptom scores and total scores such as those from the NPI could be used. This provided extra information and did not negatively influence the results. When the scores of the NPI-Q, with added frequency, symptom scores and total score, were compared to the scores of the normal NPI, the scores were comparable to or significantly lower than NPI scores (see Appendix A, tables A2-A9). So there actually might be an underestimation of the presence, severity or frequency of some NPS. Despite the found differences in NPS between AD and psychiatry patients, differentiating with the NPI does not seem possible. The potential differentiating cut-off scores are not accurate enough to be used clinically due to lack of sensitivity and specificity. This might be the result of overlap in scores of the NPI, and in NPS between AD and psychiatric disorders (Landes, Sperry, & Strauss, 2005; Woolley et al., 2011). Also, the NPI is used to screen for NPS in a quantitative manner, e.g. severity and frequency, but not so much qualitatively, e.g. the clinical characteristics of the NPS. For example, some symptoms share common features like apathy and depression (Robert et al., 2009). If there is more specific information available about how e.g. apathy is characterised by a patient, it might be easier to distinguish between apathy and depression. A set of extra questions, like the in-depth question of the NPI (Kat et al., 2002) might be sufficient. More knowledge about clinical characteristics is a factor that could make differentiation more precise and necessary to know in order to create criteria. This is already done to differentiate cognitive deficits in late-life depression from those in AD (King, Cox, Lyness, Conwell, & Caine, 1998). In addition, no cut-off scores were initially created as NPS might have been present premorbid and considered normal for the patient (J. L. Cummings). Therefore, the NPI cannot be used to differentiate in clinical practice. Still, NPI scores (particularly depression scores and NPI total scores) might be taken into account as high scores for depression and high total scores seems to indicate towards psychiatry.
20
Another difference between AD patients and psychiatry patients is the relationship between NPS and age. For AD patients it seems like older age is related to more NPS although not much of the variation in NPS can be explained by age at time of the first visit. Expected was a negative role on the presence of NPS for a younger age (Barnes et al., 2015), but the opposite was found. With these findings it is not clear whether it really is the influence of age. It might also be influenced by a more advanced disease stage as NPS tend to increase over the disease course (Craig et al., 2005; Serra et al., 2010). The onset of the disease was also not taken into account. Older age at first visit might indicate that this concerns late onset (at age 65 or older). However, the relation between onset and NPS cannot be supported by previous studies as they are generally contradictory (Hollingworth et al., 2006; Ropacki & Jeste, 2005; Van Vliet et al., 2012). In this study, a young population of AD patients has been examined as the average age of the AD patients was 64.9 years. Although the relation
between onset and NPS is still unclear, the diagnostic process of early onset AD has shown to be more difficult. Early onset AD has more often an atypical course with more other cognitive impairments besides memory loss than late onset AD patients show (Koedam et al., 2010; Werner, Stein-Shvachman, & Korczyn, 2009), more differential diagnoses are possible as the symptoms seem to be widely varied with psychiatric and behavioural problems (Bentham & La Fontaine, 2005; Haase, 2005). Especially the atypical symptoms and presence of NPS seem to complicate the diagnostic process. As the incidence of early onset AD is low (Garre-Olmo, López-Pousa, Vilalta-Franch, de Gracia Blanco, & Vilarrasa, 2010), and the diagnosis of dementia seems less likely in younger patients, doctors seem to misdiagnose or delay the correct diagnosis (Garre-Olmo et al., 2010; Haase, 2005). This complicated diagnostic process also includes referral to institutions with more expertise like the Alzheimer Center of Erasmus Medical Center. Hence the lower average age of our population than mostly seen in AD patients, and seen in other studies.
21
No relation between age and NPS due to primary psychiatric disorders was found. A discrepancy exists between late onset in AD (onset >65 years of age) and late onset in
psychiatry. Most psychiatric disorders have first occurred before the age of 30 (Jones, 2013). The definition of late life onset differs between psychiatric disorders, e.g. age of onset of late life depression ranges from 50 to 65 years (Aziz & Steffens, 2013; Dols et al., 2017) and late onset of schizophrenia is after the age of 40 - 45 (Colijn, Nitta, & Grossberg, 2015; Sachdev, Mohan, Taylor, & Jeste, 2015). This is clearly younger than late onset in AD. In our study, the average age of the psychiatry patients was around 57.0 years, also just over 50% of these patients had psychiatry in their medical history. This might indicate that the psychiatric disorders were already present at a younger age, as 53.5% of the psychiatry patients had a psychiatric diagnosis in their medical history. This includes late onset psychiatric disorders, as late onset psychiatric disorders can occur at a relatively young age. These disorders do not seem to worsen over time and can be treated with medication or therapy. This indicates that no relationship between age and psychiatry could be found.
As expected a significant association between decreased daily functioning and more NPS was found in both AD patients and psychiatry patients. The association between functional disability and NPS in AD is well known (Haaksma et al., 2017; Rog et al., 2014; Tekin et al., 2002). Psychiatric disorders, especially mood disorders, are also associated with social, emotional and physical disabilities (Bijl & Ravelli, 2000; Bowie et al., 2010; Cuijpers, de Graaf, & van Dorsselaer, 2004). Functional disability can be measured with the DAD for both AD patients and psychiatry even though the DAD is created for dementia (Gélinas et al., 1999). The relationship between NPS in AD and NPS due to primary psychiatric disorders and functional disability seems to be similar.
Differentiation between AD and psychiatry patients is still difficult. Unfortunately, although depression score and NPI total score might be used as indicators, differentiation
22
using the NPI does not seem applicable to clinical practice. A lack of power in this study, but also overlap in NPS between AD and psychiatry patients, and the heterogeneity of psychiatric disorders might all have had an influence on this outcome. Still, the results of this study show which directions need further investigation. A high number of AD patients, just over 90%, experienced NPS. Within these NPS the most differences can be found in the prevalence and some differences were found in severity and frequency. This advocates for provisional criteria of NPS, especially those most prevalent, in AD to specify the expression, severity, and
frequency of NPS in AD compared to those NPS due to primary psychiatric disorders. This will benefit the diagnostic process in a memory clinic with a more complex patient
population.
Some NPS combined might be part of distinct syndromes, like psychosis of AD (Jeste & Finkel, 2000), depression in AD (Olin et al., 2002), apathy in AD (Robert et al., 2009), or MBI (Ismail et al., 2017). This will give more in-depth information about present NPS. In addition to this, there needs to be more focus on a combination of MMSE scores, cognitive profile, presence of different profiles of NPS, and quality and expression of NPS to
distinguish between AD and psychiatry patients.
In this current study, a good comparison has been made between the AD patients and the psychiatry patients in a memory clinic at the beginning of the diagnostic stage. On the presence of NPS most studies have compared several dementias, but AD and psychiatric disorders in a memory clinic have not been compared before. In addition, most studies (Garre-Olmo et al., 2010; Haaksma et al., 2017; Lyketsos et al., 2002) included patients who were already diagnosed and were therefor at the end of the diagnostic stages. In this study, all information of the patients was gathered before they were diagnosed. Thus, they were at the very beginning of the diagnostic process. Also reasonable sample sizes have been used in the current study, and all the information was gathered in a structured manner. Still, the group
23
studied might not be fully representative of the population. For instance, the psychiatric disorders present were heterogeneous. The cohort used also consists of young patients of an average age under 65 years. The relation between age and NPS is now not fully explored as only a small variation of age has been studied. Also the age of onset of AD has not been taken into account. Some studies suggested that the number of NPS does not differ in early and late onset, but the severity and the type of symptom change does (Barnes et al., 2015; D’Onofrio et al., 2016; Zhao et al.). This might suggest that different profiles of NPS exist. Therefore it would be useful to have information from both early and late onset AD patients in different stages of AD. As mentioned before, there might have been a lack of power, and the
psychiatric disorders are heterogeneous. Despite the overlap in NPS which creates difficulties to differentiate using the NPI, maybe it is the NPI itself that makes differentiating impossible. Therefore, it is recommendable to increase the number of patients, to be more selective of the psychiatric disorders of the participating patients, or to use other questionnaires or inventories instead of the NPI.
Another point of interest is that all the patients came to the outpatient memory clinic for dementia screening, including the psychiatry patients presented themselves with cognitive complaints. NPS present in these patients might differ from the NPS present in psychiatry patients without cognitive complaints. The clinical presentation of AD patients referred to the memory clinic of a university hospital might be different from patients who got an AD
diagnosis by their general practitioner or from a specialist in a peripheral hospital. Patients referred to a university hospital might have been difficult to diagnose and referred for a second opinion. This can cause referral bias. Concluding, it would be preferred to collaborate with other institutions to gather information about older AD and psychiatry patients, in different stadia of AD, and so with all possible clinical presentations of AD and psychiatry.
24
Over 90% of the AD patients in this study had one or more NPS, which stresses the importance of the recognition of NPS in AD patients, as well as the potency of early
interventions. The lack of differences, and difficulty to differentiate between NPS in AD and NPS due to primary psychiatric disorders confirm the general believe that NPS in AD are clinical AD symptoms and need different criteria to improve the differentiation between AD and primary psychiatric disorders. The adaption of clinical criteria for AD will increase the recognition of NPS in AD and hereby facilitate the diagnostic differentiation and a diagnosis in an earlier stage, of which patients and their caregivers will benefit due to the possibility for earlier interventions.
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APPENDIX A
Table A1. Scores used as clinical relevant cut-off score in NPI.
Authors Cut-off score Reference
Aalten et al. (2005) ≥4* In line with: Ballard et al. (2001); Lyketsos et al. (2002); Steinberg et al. (2003); Steinberg et al. (2004)
Aalten et al. (2007) >3* Aalten et al. (2005); Ballard et al. (2001); Lyketsos et al. (2002); Steinberg et al. (2003); Steinberg et al. (2004) Lyketsos et al. (2002) ≥4* Schneider et al. (2001) Steinberg et al. (2003) ≥4* Personal communication
CATIE study
Steinberg et al. (2004) ≥4* Schneider et al. (2001) Gonfrier et al. (2012) >3* Cummings (2005)
Peters et al. (2014) ≥4* - No reference mentioned.
Data from Cache County study Caputo et al. (2008) ≥4* Schneider et al. (2001)
Brodaty et al. (2015) ≥4* - No reference mentioned
Koopmans et al. (2014) ≥4* - No reference mentioned
Moon, Moon, Kim, and Han ( 2014)
≥4*
Caputo et al. (2008)
Kwak, Yang, Pyo, and Koo (2014)
≥4*
or total NPI scores 4 or more
Schneider et al. (2001)
Hongisto et al. (2017) NPI total: <20 mild symptoms, 20-50 moderate symptoms, >50 severe symptoms
Bastianetto, 2005 (as cited in Hongisto et al., 2017)
Severity of symptoms based on NPI total score. No clinical relevance. Maust, Langa, Blow, and
Kales (2016)
>4* Okura et al. (2010)
Okura et al. (2010) ≥4* Schneider et al. (2001)
38 Presence of mild symptoms. Score of 0-1 seen as not relevant. Symptoms present: 2-12.
Lange, Hopp, and Kang (2004)
≥9*
- No reference mentioned.
Use of NPI-NH. Spalletta et al. (2010) ≥1 on all symptoms
with at least one symptom ≥4*
Schneider et al. (2001)
Verhey, Aalten, and De Vugt (2003)
≥4*
- No reference found.
Only access to abstract.
Note. * : Severity x Frequency score per symptom. NPI-NH: Neuropsychiatric Inventory – Nursing Home.
Table A2. Comparison NPI-Q and NPI of the presence of NPS in AD patients
NPI-Q (N=75) NPI (N=19) p value
Delusions 18 (24.0) 6 (31.6) .499 Hallucinations 8 (10.7) 5 (26.3) .078 Agitation 19 (25.3) 7 (36.8) .316 Depression 40 (53.3) 8 (42.1) .382 Anxiety 32 (42.7) 13 (68.4) .045* Euphoria 20 (27.0) 8 (42.1) .201 Apathy 39 (52.0) 12 (63.2) .383 Disinhibition 28 (37.3) 2 (10.5) .025* Irritability 36 (48.0) 9 (47.4) .961 Aberrant motor behaviour 24 (32.0) 5 (26.3) .632 Night-time disturbances 20 (26.7) 6 (33.3) .571 Eating abnormalities 35 (46.7) 8 (42.1) .721
Note. Analysed with the use of Pearson’s Chi- square test. Data is presented as median (interquartile range; IQR). NPI-Q = Neuropsychiatric Inventory – Questionnaire, including added frequency scores, symptom scores and total score. NPI= Neuropsychiatric inventory. *Significant at p 0.05.
