Journal of the Neurological Sciences 336 (2014) 103–108
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Pharmacological modulation of cognitive and behavioral symptoms in patients with dementia due to Alzheimer's disease☆,☆☆,★ Fabricio Ferreira de Oliveira a,b,⁎, Paulo Henrique Ferreira Bertolucci a, Elizabeth Suchi Chen b, Marilia de Arruda Cardoso Smith b a b
Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
a r t i c l e
i n f o
Article history: Received 9 August 2013 Received in revised form 1 October 2013 Accepted 7 October 2013 Available online 14 October 2013 Keywords: Alzheimer disease Cognitive disorders Dementia Neurodegenerative diseases Neuropsychiatry Drug therapy
a b s t r a c t To evaluate correlations of pharmacological treatment with cognitive and behavioral symptoms in patients with dementia due to Alzheimer's disease with low schooling, subjects were assessed for demographic features, neuropsychiatric symptoms, cognitive decline, functionality, caregiver burden, APOE haplotypes and pharmacological treatment. Among 217 patients, use of cholinesterase inhibitors with or without Memantine was associated with less neuropsychiatric symptoms, while anti-psychotics and/or antiepileptic drugs were associated with lower instrumental functionality. Anti-psychotics were also associated with more neuropsychiatric symptoms in moderately impaired patients, possibly reflecting the greater need for such treatment when behavioral symptoms are present. Patients receiving more medications were usually younger, obese, married, with higher schooling and more neuropsychiatric symptoms. APOE4 + haplotypes were correlated with earlier dementia onset, but not with pharmacological treatment. Higher caregiver burden was associated with more psychotropic drugs. A trend was found for treatment with cholinesterase inhibitors and Memantine to be associated with longer lengths of dementia for moderately impaired but not for severely impaired patients, regardless of APOE haplotypes, translating into a synergistic effect among such medications for slowing cognitive decline but not for prolonging survival. Further longitudinal studies may be required to assess dose–response relationships regarding treatment with psychotropics for patients with dementia. © 2013 Elsevier B.V. All rights reserved.
1. Introduction A progressive decline in cognition and functionality is the hallmark of Alzheimer's disease, with significant impacts over caregiver burden. Established therapies for patients with Alzheimer's disease have shown mild effects over slowing of such decline, but their efficacy for patients with low schooling had not been previously evaluated. Pharmacological treatment for neuropsychiatric symptoms is still controversial in view of the few off-label therapeutic alternatives available, and many studies are subject to financing bias from ☆ All authors have read the paper and agreed to be listed as authors. ☆☆ Supported by CAPES — Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil). ★ This is an original paper; it has not been published before and is not under simultaneous consideration by any other publication. The copyright shall be transferred to the publisher upon acceptance. ⁎ Corresponding author at: Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, Rua Botucatu 740, Vila Clementino, CEP 04023-900 São Paulo, SP, Brazil. Tel.: +55 11 5576 4139; fax: +55 11 5575 5240. E-mail addresses: [email protected] (F.F. de Oliveira), [email protected] (P.H.F. Bertolucci), [email protected] (E.S. Chen), [email protected] (M.A.C. Smith). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.10.015
pharmaceutical companies. Atypical neuroleptics are modestly efficacious but bring serious side effects particularly for the elderly, including venous thromboembolism, stroke and death [1–3]. We sought to assess correlations of pharmacological treatment with cognitive and behavioral symptoms in a university hospital based sample of patients with dementia due to Alzheimer's disease (AD) [4] in several stages and with variable levels of education, with no bias from pharmaceutical corporations. 2. Methods Consecutive outpatients with AD in several levels of clinical evolution were recruited from the Behavioral Neurology Section of Hospital São Paulo, Federal University of São Paulo — UNIFESP, from November 2010 to February 2013 (28 months). After diagnostic confirmation, they were assessed for: gender, age, schooling, estimated age of onset of AD, marital status, quantification of current alcohol consumption or smoking, body mass index, and scores on the Neuropsychiatric Inventory [5], MiniMental State Examination [6], Severe Mini-Mental State Examination [7], Clinical Dementia Rating [8] (CDR), a 15-item Clock Drawing Test [9] (free drawing), the Index of Independence in Activities of Daily Living [10], Lawton's Scale for Instrumental Activities of Daily Living [11], and
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the Brazilian Version of the Zarit Caregiver Burden Interview [12]. Current use of any medications, but particularly cholinesterase inhibitors (ChEis), Memantine, anti-depressants, anti-psychotics and anti-epileptic drugs, was also quantified considering that patients had been receiving them for at least three months before the evaluation. All cognitive assessments and body mass index measurements were conducted on weekdays at morning time, by the same examiner (FFO). Diagnosis of AD was in accordance with the National Institute on Aging–Alzheimer's Association criteria [4]. Obesity was diagnosed when body mass index was over 30 kg/m2. For the validated version of the Clock Drawing Test [9] that was used in this study, patients were instructed to freely draw a clock that marked 11:10, setting the hands and numbers on the face (repetition was allowed). Scoring comprised 15 items, each scored as zero or one: outer circle present and closed; acceptable circle diameter; intact sequence 1–12, with no omissions or intrusions; only Arabic numerals; correct sequential order of the numerals; paper is not rotated for number placement; proper symmetrical spacing; all numbers inside the circle; only two hands present; any mark to indicate the hour; any mark to indicate the minute; minute hand longer than hour hand; no pointless intrusions; both hands connected, or up to 2 mm space between them; and center of the clock drawn or inferred where hands meet. The Index of Independence in Activities of Daily Living [10] reflects behavioral levels of six sociobiological functions: bathing, dressing, toileting, transfer, continence, and feeding. Each function was scored as zero for dependency or one for independence, according to information from caregivers, with an index total of zero to six. A trichotomous version (1=unable; 2=able with help; 3=able without help) of Lawton's Scale for Instrumental Activities of Daily Living [11] was employed, with scores for using the telephone, getting to places beyond walking distance, grocery shopping, meal preparation, housekeeping, doing handyman work, doing laundry, taking own medications, and handling finances; information had to be obtained from caregivers, with a total score of 9 to 27. The Brazilian Version of the Zarit Caregiver Burden Interview [12] comprises 14 questions graded on a scale of zero to four. It was adapted from the original version, with comparable reliability for assessing caregiver burden in AD. After blood samples were collected from all patients in tubes with EDTA 0.1%, genomic DNA was extracted for genotyping. APOE haplotypes were determined for all patients (SNPs rs7412 and rs429358 assessed by way of Real-Time Polymerase Chain Reactions using TaqMan® SNP Genotyping Assays). Real-Time Polymerase Chain Reactions were undertaken on the Applied Biosystems 7500 Fast Real-Time PCR System (Applied Biosystems®, USA) following the standard protocols of the manufacturer. Statistical comparisons for continuous variables were conducted by way of Mann–Whitney test when two groups were compared, or Kruskal–Wallis test for three or more groups. Linear regression models were employed for comparisons regarding medication intake and independent variables (test results, body mass index, alcohol consumption). Spearman correlations were estimated for age at examination, schooling, and medication intake. The threshold of significance was set at ρ b 0.05. This study is part of the research project 1067/10 (CAAE 0540.0.174.000-10) approved by the Ethics Committee of Hospital São Paulo, Federal University of São Paulo — UNIFESP, on August 2010. All invited patients and their legal representatives agreed to participate on the research and signed the Informed Consent Form before the evaluation, with no exceptions. 3. Results A total of 217 patients were included; 147 were female (67.7%) and 70 were male (32.3%); 109 (50.23%) were married, while 6 (2.76%) were divorced, 19 (8.76%) were single, and 83 (38.25%) were widowers;
56 (25.8%) had history of alcohol consumption, whereas 11 (5.1%) were regularly drinking at survey time; 79 (36.4%) had smoking history, whereas 14 (6.5%) were regular smokers at survey time. Obesity was diagnosed in 36 patients (16.6%). Table 1 shows full demographic data and test results. Overall, 170 patients (78.34%) were using ChEis at survey time: among these, 60 used Rivastigmine (35.3%), 58 used Donepezil (34.1%), and 52 used extended-release Galantamine (30.6%); 52 patients (23.96%) were treated with Memantine, while 88 (40.55%) used anti-depressants; 53 patients used anti-psychotics (24.42%), namely Quetiapine (n = 42), Risperidone (n = 10) and Olanzapine (n = 1), while 19 used anti-epileptic drugs (8.76%), mostly Carbamazepine (n = 7) and Valproic Acid (n = 6). Use of ChEis had no differential impact over scores on the Clock Drawing Test [9] (ρ = 0.116), Index of Independence in Activities of Daily Living [10] (ρ = 0.474), Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ = 0.472), or the Brazilian Version of the Zarit Caregiver Burden Interview [12] (ρ = 0.491). However, when caregiver burden scores were higher, patients were more likely to use Memantine with or without ChEis (ρ =0.015). Patients with higher global scores on the Neuropsychiatric Inventory [5] were also more likely to use Memantine (ρ = 0.001). Treatment with any anti-depressants had no differential impact over scores on the Clock Drawing Test [9] (ρ = 0.458), Neuropsychiatric Inventory [5] (ρ N 0.26), Index of Independence in Activities of Daily Living [10] (ρ = 0.696), Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ = 0.395), or the Brazilian Version of the Zarit Caregiver Burden Interview [12] (ρ = 0.642), regardless of CDR scores. Treatment with anti-psychotics and/or anti-epileptic drugs had no impact over the Clock Drawing Test [9] (ρ = 0.095) or the Index of Independence in Activities of Daily Living [10] (ρ = 0.586), but had highly significant associations with lower scores on Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ b 0.001) and with higher scores on the Brazilian Version of the Zarit Caregiver Burden Interview [12] (ρ = 0.018). Table 2 shows the distribution of neuropsychiatric symptoms according to each dementia stage, while Table 3 shows comparisons of neuropsychiatric symptoms according to pharmacological treatment in different dementia stages. With the exception of scores for anxiety, all other items from the Neuropsychiatric Inventory [5] had higher scores for more impaired patients, but more remarkably apathy and
Table 1 Demographic data and test results. Variable (units), n = 217
Mean SDa
Age at examination (years-old) Age of dementia onset (years-old) Length of the dementia syndrome (years) Schooling (years) Body mass index (kg/m2) Daily amount of different medications Daily amount of pills/injections Lifetime alcoholic drinking load (liters per year) Current alcoholic drinking load (liters per year) Lifetime smoking load (packs per year) Current smoking load (packs per year) Neuropsychiatric Inventory (0–120 points) Mini-Mental State Examination (0–30 points) Severe Mini-Mental State Examination (0–30 points) Clock Drawing Test (0–15 points) Index of Independence in Activities of Daily Living (0–6 points) Lawton's Scale for Instrumental Activities of Daily Living (9–27 points) Brazilian Version of the Zarit Caregiver Burden Interview (0–56 points)
78 6.2 60–95 73.19 6.8 52–88 5.4 2.9 0.5–14.5 4.21 3.7 0–15 25.75 4.3 14.28–41.62 4.52 2.5 0–12 6.21 3.6 0–16 17.26 50.8 0–315 1.67 11.3 0–120 48.75 103.7 0–700 14.38 62.1 0–365 22.6 16.6 0–87 15.64 5.8 0–29 26.43 4.9 0–30 6.26 4.5 0–15 5 1.6 0–6
a
SD = standard deviation.
Range
14.21
4.7
9–27
16.58
10.7
0–54
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Table 2 Frequency and mean scores of neuropsychiatric symptoms according to each dementia stage. Neuropsychiatric symptoma
Agitation Hallucinations Anxiety Apathy Delusions Disinhibition Dysphoria Euphoria Irritability Aberrant motor behavior a b
All stages (n = 217)
CDRb = 1.0 (n = 83)
CDRb = 2.0 (n = 104)
CDRb = 3.0 (n = 30)
Frequency
Mean scores
Frequency
Mean scores
Frequency
Mean scores
Frequency
Mean scores
60.8% 36.9% 53.5% 68.7% 40.1% 29.5% 59.0% 24.9% 61.8% 34.6%
2.576 1.212 3.074 4.604 1.590 1.184 2.323 1.124 2.687 2.258
51.8% 18.1% 63.9% 61.5% 25.3% 21.7% 53.0% 18.1% 65.1% 27.7%
2.265 0.410 3.735 3.458 1.024 0.470 1.747 0.783 2.386 1.422
65.4% 43.3% 50.0% 67.3% 45.2% 30.8% 58.7% 27.9% 58.7% 39.4%
2.712 1.269 2.721 4.894 1.808 1.375 2.375 1.279 2.721 2.760
70.0% 66.7% 36.7% 93.3% 63.3% 46.7% 76.7% 33.3% 63.3% 36.7%
2.967 3.233 2.467 6.767 2.400 2.500 3.733 1.533 3.400 2.833
According to the Neuropsychiatric Inventory. CDR = Clinical Dementia Rating.
hallucinations. Anxiety was the only behavioral symptom presenting lower scores for more impaired patients. Table 4 shows results from simple linear regression models. Patients with higher scores on the Mini-Mental State Examination [6] showed propensity for more daily intake of different medications (ρ = 0.017). For patients with CDR = 1.0 (n = 83), higher scores on the Neuropsychiatric Inventory [5] were associated with more need for pharmacological treatment (ρ = 0.029), according to Fig. 1. Also for patients with CDR = 1.0, higher scores in anxiety (squared multiple R = 0.078; F-ratio = 6.822, ρ = 0.011) and irritability (squared multiple R = 0.080; F-ratio = 7.057, ρ = 0.010) were related with more daily intake of different medications. Regarding daily intake of pills/ injections, a positive association with anxiety (squared multiple R =
0.076; F-ratio = 6.686, ρ = 0.012) and irritability (squared multiple R = 0.093; F-ratio = 8.296, ρ = 0.005) was also shown for patients with CDR = 1.0. These analyses were also conducted for other neuropsychiatric symptoms in each stage of the dementia syndrome, but results were non-significant. Marital status had no overall impact over the total amount of daily medications or pills/injections, except for patients with CDR = 1.0 (n = 83), for whom there was a tendency for married patients to use a larger variety of medications (ρ = 0.033) and more pills/injections (ρ = 0.039) than the non-married ones. Nonetheless, marital status had no relations with overall scores on the Neuropsychiatric Inventory [5] (ρ = 0.653) or length of the dementia syndrome, regardless of CDR scores (ρ N 0.32). Use of anti-psychotics and/or anti-epileptic drugs
Table 3 Kruskal–Wallis test results for neuropsychiatric symptoms according to pharmacological treatment. Variable 1
Neuropsychiatric Inventory total scores Neuropsychiatric Inventory total scores Neuropsychiatric Inventory total scores Agitation Agitation Agitation Hallucinations Hallucinations Hallucinations Anxiety Anxiety Anxiety Apathy Apathy Apathy Delusions Delusions Delusions Disinhibition Disinhibition Disinhibition Dysphoria Dysphoria Dysphoria Euphoria Euphoria Euphoria Irritability Irritability Irritability Aberrant motor behavior Aberrant motor behavior Aberrant motor behavior a b
Variable 2
ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs
CDRa = 1.0 (n = 83)
CDRa = 2.0 (n = 104)
CDRa = 3.0 (n = 30)
Kruskal–Wallis test statistic
ρ-Value
Kruskal–Wallis test statistic
ρ-Value
Kruskal–Wallis test statistic
ρ-Value
1.543 7.820 4.488 5.490 5.902 6.014 7.020 2.070 5.150 2.739 0.085 2.079 1.862 1.715 2.840 1.297 5.639 4.961 4.253 9.400 3.162 8.820 6.665 9.318 2.707 4.289 7.591 3.799 6.250 3.972 2.351 8.903 7.882
0.672 0.020 0.344 0.139 0.052 0.198 0.071 0.355 0.272 0.434 0.958 0.721 0.602 0.424 0.585 0.730 0.060 0.291 0.235 0.009 0.531 0.032 0.036 0.054 0.439 0.117 0.108 0.284 0.044 0.410 0.503 0.012 0.096
8.377 4.931 2.594 8.612 7.029 1.664 1.085 12.365 1.296 6.573 1.856 3.272 3.245 2.970 1.449 6.151 7.362 0.820 5.846 1.065 3.717 3.560 1.059 1.342 6.320 2.560 1.549 3.382 0.337 2.980 10.757 0.943 2.215
0.039 0.085 0.459 0.035 0.030 0.645 0.781 0.002 0.730 0.087 0.395 0.352 0.355 0.226 0.694 0.105 0.025 0.845 0.119 0.587 0.294 0.313 0.589 0.719 0.097 0.278 0.671 0.336 0.845 0.395 0.013 0.624 0.529
5.026 5.314 2.570 7.472 4.643 2.366 4.145 6.555 1.414 4.888 6.164 0.682 1.138 4.212 0.518 2.211 4.751 2.574 6.140 2.778 5.315 4.281 4.495 0.280 3.576 2.909 3.291 11.053 3.302 3.592 0.808 3.696 0.635
0.170 0.150 0.277 0.058 0.200 0.306 0.246 0.088 0.493 0.180 0.104 0.711 0.768 0.239 0.772 0.530 0.191 0.276 0.105 0.427 0.070 0.233 0.213 0.869 0.311 0.406 0.193 0.011 0.347 0.166 0.848 0.296 0.728
CDR = Clinical Dementia Rating. ChEis = Cholinesterase inhibitors (Donepezil or Galantamine or Rivastigmine).
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Table 4 Results from simple linear regression models. Variablea
Mini-Mental State Examination Severe Mini-Mental State Examination Neuropsychiatric Inventory (CDR = 3.0) Neuropsychiatric Inventory (CDR = 2.0) Neuropsychiatric Inventory (CDR = 1.0) Agitation Hallucinations Anxiety Apathy Delusions Disinhibition Dysphoria Euphoria Irritability Aberrant motor behavior Lifetime alcoholic drinking load (CDR = 3.0) Lifetime alcoholic drinking load (CDR = 2.0) Lifetime alcoholic drinking load (CDR = 1.0) Current alcoholic drinking load Body mass index Length of the dementia syndrome Clock Drawing Test Index of Independence in Activities of Daily Living Lawton's Scale for Instrumental Activities of Daily Living Brazilian Version of the Zarit Caregiver Burden Interview a
Daily amount of different medications
Daily amount of pills/injections
Squared multiple R
t
F-ratio
ρ-Value
Squared multiple R
t
F-ratio
ρ-Value
0.026 b0.001 0.013 b0.001 0.057 0.003 b0.001 0.009 0.025 0.016 0.007 0.001 0.001 0.005 0.019 0.004 0.001 0.005 b0.001 0.092 0.020 0.001 0.002 0.001 0.006
2.416 0.109 −0.600 −0.143 2.222 0.769 −0.134 1.406 2.359 −1.868 1.266 −0.508 −0.471 1.034 −2.064 0.348 −0.324 0.636 −0.248 4.655 2.100 0.480 −0.606 −0.367 1.105
5.838 0.012 0.360 0.020 4.938 0.592 0.018 1.978 5.567 3.488 1.603 0.258 0.222 1.069 4.259 0.121 0.105 0.405 0.061 21.668 4.411 0.230 0.367 0.135 1.221
0.017 0.913 0.553 0.887 0.029 0.443 0.894 0.161 0.019 0.063 0.207 0.612 0.638 0.302 0.040 0.731 0.747 0.526 0.805 b0.001 0.037 0.632 0.545 0.714 0.270
0.013 0.001 0.012 b0.001 0.099 0.009 0.001 0.007 0.027 0.009 0.008 0.001 b0.001 0.006 0.018 0.013 b0.001 0.004 b0.001 0.095 0.027 b0.001 0.007 0.005 0.018
1.694 −0.423 −0.592 −0.183 2.984 1.406 0.398 1.264 2.440 −1.372 1.315 −0.339 0.158 1.101 −1.997 0.609 −0.002 0.550 −0.235 4.762 2.428 −0.094 −1.271 −1.009 1.961
2.870 0.179 0.351 0.034 8.905 1.977 0.159 1.597 5.955 1.882 1.729 0.115 0.025 1.213 3.989 0.371 b0.001 0.302 0.055 22.677 5.893 0.009 1.615 1.018 3.847
0.092 0.673 0.558 0.855 0.004 0.161 0.691 0.208 0.015 0.171 0.190 0.735 0.875 0.272 0.047 0.547 0.998 0.584 0.815 b0.001 0.016 0.925 0.205 0.314 0.051
n = 217 except where otherwise noted CDR = 3.0 (n = 30), CDR = 2.0 (n = 104), or CDR = 1.0 (n = 83).
was also unrelated with length of AD (ρ = 0.509). Use of antidepressants was marginally related with longer lengths of AD for patients with CDR = 3.0 (n = 30, ρ = 0.079), but not for patients in earlier stages (ρ N 0.19). However, for patients with CDR = 2.0 (n = 104), use of any of the ChEis was associated with longer lengths of AD (ρ = 0.007), according to Fig. 2, and even longer when Memantine was added to the pharmacological treatment (ρ b 0.001), according to Fig. 3, relations that were not found for patients with CDR = 3.0 (n = 30, ρ N 0.23). Gender was unrelated with daily use of different medications (ρ = 0.106), but a marginally significant association was found for male patients to take more pills/injections per day than female patients (ρ = 0.059). Spearman correlations were significant (ρ b 0.0001) between daily medication intake and number of pills/injections taken per day (rs = 0.9444), between daily medication intake and both age at examination (rs = −0.1637) and schooling (rs = 0.0375), and between number of pills/injections taken per day and both age at examination (rs = −0.2289) and schooling (rs = 0.0396). With regard to APOE haplotypes, 26 were ε4/ε4, 81 were ε4/ε3, 7 were ε4/ε2, 93 were ε3/ε3, and 10 were ε3/ε2; in other words, 114 were APOE4+, and 103 were APOE4−. Earlier onset of AD was correlated
with APOE4+ in patients with CDR = 2.0 (n = 104, ρ = 0.019) and with the ε4/ε4 haplotype in patients with CDR = 1.0 (n = 83, ρ b 0.007). APOE haplotypes had no influence over the daily amount of different medications (ρ N 0.19) or pills/injections (ρ N 0.25) taken by patients, or scores on the Neuropsychiatric Inventory [5] (ρ N 0.19), Index of Independence in Activities of Daily Living [10] (ρ N 0.26) or Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ N 0.27), regardless of CDR scores.
Fig. 1. Impact of scores on the Neuropsychiatric Inventory over daily use of medications for patients with CDR = 1.0.
Fig. 2. Influence of treatment with different cholinesterase inhibitors over the length of the dementia syndrome for patients with CDR = 2.0.
4. Discussion The cross-sectional nature of this study does not allow for causal relations to be inferred. Therefore, only associations may be deduced from the results. Overall daily use of different medications was correlated with the number of pills/injections taken per day. Older patients with less schooling would use fewer medications than younger patients with high schooling, possibly because of differences in seeking medical attention or following prescriptions. APOE haplotypes had an impact over the age of onset of AD, but not over pharmacological treatment, behavior or functionality. An earlier study [13] with a smaller sample showed that APOE4+ carriers had more neuropsychiatric symptoms, particularly hallucinations and aberrant motor behavior, but its
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Fig. 3. Influence of treatment with cholinesterase inhibitors and/or Memantine over the length of the dementia syndrome for patients with CDR = 2.0.
longitudinal design might have favored the observation of more severe psychopathology. ChEis were associated with lower total scores on the Neuropsychiatric Inventory [5] only for moderately impaired patients. While no association was found between such scores and use of anti-epileptic drugs, an association with higher total scores was found for mildly impaired patients who used anti-psychotics, a result that could represent more need for psychotropic treatment when behavioral symptoms are present. Besides controversy still regarding the clinical efficacy of these drugs, it has been demonstrated that adverse effects offset advantages of atypical anti-psychotics for treatment of neuropsychiatric symptoms in AD [2], while the benefits of combined behavioral management techniques have not been entirely proven as well [14]. When caregiver burden was higher, patients were more likely to use anti-psychotics and/or anti-epileptic drugs, and Memantine with or without ChEis. This may reflect caregiver pressure on physicians for prescription of such medications in view of the impact of functional progression over caregivers' abilities to manage patients [15]. However, the benefits of Memantine for patients in moderate-to-severe stages of AD have been controversial. Some studies have shown that, for patients already receiving Donepezil, Memantine slowed memory, language and praxis decline [16], and helped stabilize functional independence [17]. Other studies have shown stabilization of cognition, functionality, behavior and caregiver distress [18] with use of Memantine in moderate-to-severe AD [19], even without concomitant use of ChEis [20]. Nonetheless, the combination of ChEis with Memantine has been considered to be neuroprotective when undertaken for at least two years, and superior to treatment with ChEis without Memantine [21] or to suspension of ChEis [22]. A delay in nursing home admission with no significant difference in survival rates has also been demonstrated for patients treated with ChEis, and even more significantly for those who received ChEis with Memantine [23]. In spite of these results, a recent study showed that Donepezil with or without Memantine had the same cognitive effects, but a mild benefit of Memantine over Neuropsychiatric Inventory [24] scores was observed [22]. Anyhow, Memantine is indicated only for moderate-to-severe AD, whereas ChEis and Memantine may lead to faster cognitive decline and progression to dementia when given to patients with mild cognitive impairment [25]. Patients with more behavioral symptoms were also more likely to use Memantine; it is difficult to identify whether this result predicts dementia progression or defines an outcome, a possible consequence of the impression that prescription of Memantine may help alleviate such manifestations of dementia [26,27]. Among neuropsychiatric symptoms, Memantine has been shown to reduce mostly frontally mediated behavioral disturbances, but particularly worsening and development of agitation [18,28]. While overall behavioral symptoms had an increasing tendency with higher CDR scores, with more notable escalations for apathy and hallucinations, anxiety was the only neuropsychiatric symptom
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presenting lower scores for more impaired patients. These results contrast an earlier study [29] with a smaller sample, which showed rising anxiety and, more significantly, disinhibition, agitation and irritability in later stages; however, severely impaired patients were rare in that study, and they were not stratified according to pharmacological treatment, which could have lessened such symptoms. Also, overall neuropsychiatric symptoms tend to correlate better with functional independence than with cognitive decline [18]. Treatment with ChEis was associated with lower scores for dysphoria in mildly impaired patients, agitation and/or aberrant motor behavior in moderately impaired patients, and irritability in severely impaired patients. Other studies have shown that disinhibition, anxiety and apathy tend to show greater improvement with such treatment [24]. While treatment with Galantamine has been associated with significantly lower agitation, an earlier 12-week trial showed that Donepezil was not more effective than placebo for treatment of agitation in AD [30]. In agreement with other studies [31], Quetiapine was the most widely prescribed anti-psychotic in this sample. Treatment with antipsychotics was associated with higher scores for disinhibition, dysphoria, irritability and aberrant motor behavior in mildly impaired patients, and also with higher scores for agitation, hallucinations and delusions in moderately impaired patients. No such associations were found for severely impaired patients. Considering that hallucinations are strong predictors of functional decline [15,32], these results might reflect a greater need for psychotropic treatment when a faster progression of dementia is perceived, while agitation tends to respond poorly to atypical anti-psychotics in the long term [26]. Despite the fact that this is a cross-sectional study, these results could also suggest a lack of effectiveness of anti-psychotics for behavioral symptoms in patients with AD. Patients with lesser degrees of independence for instrumental activities of daily living would also use anti-psychotics and/or antiepileptic drugs more frequently, a possible outcome related with more sensitivity of such activities to cognitive and behavioral change [31]. Apathy, aberrant motor behavior, higher body mass index, longer lengths of the dementia syndrome and higher scores on the MiniMental State Examination [6] were associated with daily use of more medications. Mildly impaired patients were also more likely to use a larger amount of daily medications when they were married, with more irritability or anxiety, and when total scores on the Neuropsychiatric Inventory [5] were higher — however, a plateau was reached for scores over 20. Caregiver burden was marginally significant for daily use of more pills/injections. It is possible that married or obese patients who have higher scores on the Mini-Mental State Examination [6] or longer lengths of AD tend to seek medical assistance more often, consequently leading to more pharmacological treatment. Use of anti-depressants did not impact overall behavioral symptoms or functionality, but was marginally related with longer lengths of AD for severely impaired patients. Moderately impaired patients had longer lengths of AD when they were using ChEis, and even longer when Memantine was also prescribed. This is an original result that may reflect a previously described synergistic effect among such medications for slowing cognitive decline [27], translating into a longer length of the moderate dementia stage for patients with AD. Since ChEis and Memantine had no effect over length of dementia for severely impaired patients, we conclude that such medications were not able to prolong life and neither to stop cognitive decline, despite their effect in slowing cognitive decline of moderately impaired patients. In a retrospective study [33], patients with mild-to-moderate AD who received treatment with Galantamine for up to seven years exhibited attenuated decline in Mini-Mental State Examination [6] scores, while it has been shown that patients who stop treatment with Galantamine or Donepezil experience subsequent faster cognitive decline. In conclusion, we have shown that pharmacological therapy with ChEis with or without Memantine, but not therapy with anti-psychotics and/or anti-epileptic drugs, was associated with lower scores in the Neuropsychiatric Inventory [5] in moderately impaired subjects from
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this sample of patients with low mean schooling. A trend was found for use of ChEis with Memantine to be associated with longer lengths of the dementia syndrome for moderately impaired patients, regardless of APOE haplotypes. The strengths of this study include the wide diversity in levels of schooling, frequent use of psychotropic medications, and the fact that records of a large sample of patients were evaluated by way of brief cognitive instruments. Nevertheless, recruitment was carried out in a single center; therefore, results may not be generalizable to the whole population of São Paulo. Also, dose–response relationships were not investigated in view of the low variability of all drug regimens. Considering that a wide diversity of anti-depressants was found and a specific scale for assessment of depression was not employed, a deeper evaluation of the effects of such medications was not possible. Further longitudinal studies may be required to corroborate our results and ascertain the roles of ChEis, Memantine, and psychotropics in general for modulation of cognition and behavior in patients with AD. Disclosures Fabricio F Oliveira, MD, MSc, is a PhD student at the Federal University of São Paulo — UNIFESP in São Paulo, Brazil; he receives a scholarship for academic research from CAPES — Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, a governmental agency in Brazil, and receives personal compensation for acting as a Healthcare Council Member for Gerson Lehrman Group. Paulo H F Bertolucci, MD, MSc, PhD, is a professor at the Department of Neurology and Neurosurgery of the Federal University of São Paulo — UNIFESP in São Paulo, Brazil; he has received personal compensation for acting as a consultant for Novartis, Lilly, Pfizer, Janssen and Support. Elizabeth S Chen, MSc, PhD, is a professor at the Department of Morphology and Genetics of the Federal University of São Paulo — UNIFESP in São Paulo, Brazil. Marilia A C Smith, MSc, PhD, is a full professor at the Department of Morphology and Genetics of the Federal University of São Paulo — UNIFESP in São Paulo, Brazil; she receives support for scholarly activities from the following Brazilian public agencies for research: FAPESP — The State of São Paulo Research Foundation, CNPq — Conselho Nacional de Desenvolvimento Científico e Tecnológico, and CAPES — Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Conflict of interest There is no conflict of interest. References [1] Liperoti R, Pedone C, Lapane KL, Mor V, Bernabei R, Gambassi G. Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents. Arch Intern Med 2005;165:2677–82. [2] Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355:1525–38. [3] Shin J-Y, Choi N-K, Jung S-Y, Lee J, Kwon JS, Park B-J. Risk of ischemic stroke with the use of risperidone, quetiapine and olanzapine in elderly patients: a population-based, case-crossover study. J Psychopharmacol 2013;27:638–44. [4] McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 2011;7:263–9. [5] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–14.
[6] Folstein MF, Folstein S, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. [7] Harrell LE, Marson D, Chatterjee A, Parrish JA. The Severe Mini-Mental State Examination: a new neuropsychologic instrument for the bedside assessment of severely impaired patients with Alzheimer disease. Alzheimer Dis Assoc Disord 2000;14:168–75. [8] Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43:2412–4. [9] Freedman M, Leach L, Kaplan E, Winocur G, Shulman KI, Delis DC. Clock drawing: a neuropsychological analysis. New York: Oxford University Press; 1994. [10] Katz S, Akpom CA. A measure of primary socio-biological functions. Int J Health Serv 1976;6:493–508. [11] Lawton MP. Instrumental Activities of Daily Living (IADL) scale: self-reported version. Psychopharmacol Bull 1988;24:789–91. [12] Taub A, Andreoli SB, Bertolucci PHF. Dementia caregiver burden: reliability of the Brazilian version of the Zarit Caregiver Burden Interview. Cad Saude Publica 2004;20:372–6. [13] Del Prete M, Spaccavento S, Craca A, Fiore P, Angelelli P. Neuropsychiatric symptoms and the APOE genotype in Alzheimer's disease. Neurol Sci 2009;30:367–73. [14] Weiner MF, Tractenberg RE, Sano M, Logsdon R, Teri L, Galasko D, et al. No long-term effect of behavioral treatment on psychotropic drug use for agitation in Alzheimer's disease patients. J Geriatr Psychiatry Neurol 2002;15:95–8. [15] Mortimer JA, Ebbitt B, Jun SP, Finch MD. Predictors of cognitive and functional progression in patients with probable Alzheimer's disease. Neurology 1992;42:1689–96. [16] Schmitt FA, van Dyck CH, Wichems CH, Olin JT. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord 2006;20:255–62. [17] Feldman HH, Schmitt FA, Olin JT. Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Dis Assoc Disord 2006;20:263–8. [18] Cummings JL, Schneider E, Tariot PN, Graham SM. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006;67:57–63. [19] Winblad B, Jones RW, Wirth Y, Stöffler A, Möbius HJ. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007;24:20–7. [20] Clerici F, Vanacore N, Elia A, Spila-Alegiani S, Pomati S, Da Cas R, et al. Memantine effects on behaviour in moderately severe to severe Alzheimer's disease: a postmarketing surveillance study. Neurol Sci 2012;33:23–31. [21] Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer's disease. Alzheimer Dis Assoc Disord 2008;22:209–21. [22] Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012;366:893–903. [23] Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600–7. [24] Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997;48:S10–6. [25] Schneider LS, Insel PS, Weiner MW. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol 2011;68:58–66. [26] Ballard C, Corbett A, Chitramohan R, Aarsland D. Management of agitation and aggression associated with Alzheimer's disease: controversies and possible solutions. Curr Opin Psychiatry 2009;22:532–40. [27] Gauthier S, Molinuevo JL. Benefits of combined cholinesterase inhibitor and memantine treatment in moderate–severe Alzheimer's disease. Alzheimers Dement 2013;9:326–31. [28] Gauthier S, Wirth Y, Möbius HJ. Effects of memantine on behavioural symptoms in Alzheimer's disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies. Int J Geriatr Psychiatry 2005;20:459–64. [29] Srikanth S, Nagaraja AV, Ratnavalli E. Neuropsychiatric symptoms in dementiafrequency, relationship to dementia severity and comparison in Alzheimer's disease, vascular dementia and frontotemporal dementia. J Neurol Sci 2005;236:43–8. [30] Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, et al. Donepezil for the treatment of agitation in Alzheimer's disease. N Engl J Med 2007;357:1382–92. [31] Barnes TRE, Banerjee S, Collins N, Treloar A, McIntyre S, Paton C. Antipsychotics in dementia: prevalence and quality of antipsychotic drug prescribing in UK mental health services. 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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Pharmacological modulation of cognitive and behavioral symptoms in patients with dementia due to Alzheimer's disease☆,☆☆,★ Fabricio Ferreira de Oliveira a,b,⁎, Paulo Henrique Ferreira Bertolucci a, Elizabeth Suchi Chen b, Marilia de Arruda Cardoso Smith b a b
Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
a r t i c l e
i n f o
Article history: Received 9 August 2013 Received in revised form 1 October 2013 Accepted 7 October 2013 Available online 14 October 2013 Keywords: Alzheimer disease Cognitive disorders Dementia Neurodegenerative diseases Neuropsychiatry Drug therapy
a b s t r a c t To evaluate correlations of pharmacological treatment with cognitive and behavioral symptoms in patients with dementia due to Alzheimer's disease with low schooling, subjects were assessed for demographic features, neuropsychiatric symptoms, cognitive decline, functionality, caregiver burden, APOE haplotypes and pharmacological treatment. Among 217 patients, use of cholinesterase inhibitors with or without Memantine was associated with less neuropsychiatric symptoms, while anti-psychotics and/or antiepileptic drugs were associated with lower instrumental functionality. Anti-psychotics were also associated with more neuropsychiatric symptoms in moderately impaired patients, possibly reflecting the greater need for such treatment when behavioral symptoms are present. Patients receiving more medications were usually younger, obese, married, with higher schooling and more neuropsychiatric symptoms. APOE4 + haplotypes were correlated with earlier dementia onset, but not with pharmacological treatment. Higher caregiver burden was associated with more psychotropic drugs. A trend was found for treatment with cholinesterase inhibitors and Memantine to be associated with longer lengths of dementia for moderately impaired but not for severely impaired patients, regardless of APOE haplotypes, translating into a synergistic effect among such medications for slowing cognitive decline but not for prolonging survival. Further longitudinal studies may be required to assess dose–response relationships regarding treatment with psychotropics for patients with dementia. © 2013 Elsevier B.V. All rights reserved.
1. Introduction A progressive decline in cognition and functionality is the hallmark of Alzheimer's disease, with significant impacts over caregiver burden. Established therapies for patients with Alzheimer's disease have shown mild effects over slowing of such decline, but their efficacy for patients with low schooling had not been previously evaluated. Pharmacological treatment for neuropsychiatric symptoms is still controversial in view of the few off-label therapeutic alternatives available, and many studies are subject to financing bias from ☆ All authors have read the paper and agreed to be listed as authors. ☆☆ Supported by CAPES — Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil). ★ This is an original paper; it has not been published before and is not under simultaneous consideration by any other publication. The copyright shall be transferred to the publisher upon acceptance. ⁎ Corresponding author at: Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, Rua Botucatu 740, Vila Clementino, CEP 04023-900 São Paulo, SP, Brazil. Tel.: +55 11 5576 4139; fax: +55 11 5575 5240. E-mail addresses: [email protected] (F.F. de Oliveira), [email protected] (P.H.F. Bertolucci), [email protected] (E.S. Chen), [email protected] (M.A.C. Smith). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.10.015
pharmaceutical companies. Atypical neuroleptics are modestly efficacious but bring serious side effects particularly for the elderly, including venous thromboembolism, stroke and death [1–3]. We sought to assess correlations of pharmacological treatment with cognitive and behavioral symptoms in a university hospital based sample of patients with dementia due to Alzheimer's disease (AD) [4] in several stages and with variable levels of education, with no bias from pharmaceutical corporations. 2. Methods Consecutive outpatients with AD in several levels of clinical evolution were recruited from the Behavioral Neurology Section of Hospital São Paulo, Federal University of São Paulo — UNIFESP, from November 2010 to February 2013 (28 months). After diagnostic confirmation, they were assessed for: gender, age, schooling, estimated age of onset of AD, marital status, quantification of current alcohol consumption or smoking, body mass index, and scores on the Neuropsychiatric Inventory [5], MiniMental State Examination [6], Severe Mini-Mental State Examination [7], Clinical Dementia Rating [8] (CDR), a 15-item Clock Drawing Test [9] (free drawing), the Index of Independence in Activities of Daily Living [10], Lawton's Scale for Instrumental Activities of Daily Living [11], and
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the Brazilian Version of the Zarit Caregiver Burden Interview [12]. Current use of any medications, but particularly cholinesterase inhibitors (ChEis), Memantine, anti-depressants, anti-psychotics and anti-epileptic drugs, was also quantified considering that patients had been receiving them for at least three months before the evaluation. All cognitive assessments and body mass index measurements were conducted on weekdays at morning time, by the same examiner (FFO). Diagnosis of AD was in accordance with the National Institute on Aging–Alzheimer's Association criteria [4]. Obesity was diagnosed when body mass index was over 30 kg/m2. For the validated version of the Clock Drawing Test [9] that was used in this study, patients were instructed to freely draw a clock that marked 11:10, setting the hands and numbers on the face (repetition was allowed). Scoring comprised 15 items, each scored as zero or one: outer circle present and closed; acceptable circle diameter; intact sequence 1–12, with no omissions or intrusions; only Arabic numerals; correct sequential order of the numerals; paper is not rotated for number placement; proper symmetrical spacing; all numbers inside the circle; only two hands present; any mark to indicate the hour; any mark to indicate the minute; minute hand longer than hour hand; no pointless intrusions; both hands connected, or up to 2 mm space between them; and center of the clock drawn or inferred where hands meet. The Index of Independence in Activities of Daily Living [10] reflects behavioral levels of six sociobiological functions: bathing, dressing, toileting, transfer, continence, and feeding. Each function was scored as zero for dependency or one for independence, according to information from caregivers, with an index total of zero to six. A trichotomous version (1=unable; 2=able with help; 3=able without help) of Lawton's Scale for Instrumental Activities of Daily Living [11] was employed, with scores for using the telephone, getting to places beyond walking distance, grocery shopping, meal preparation, housekeeping, doing handyman work, doing laundry, taking own medications, and handling finances; information had to be obtained from caregivers, with a total score of 9 to 27. The Brazilian Version of the Zarit Caregiver Burden Interview [12] comprises 14 questions graded on a scale of zero to four. It was adapted from the original version, with comparable reliability for assessing caregiver burden in AD. After blood samples were collected from all patients in tubes with EDTA 0.1%, genomic DNA was extracted for genotyping. APOE haplotypes were determined for all patients (SNPs rs7412 and rs429358 assessed by way of Real-Time Polymerase Chain Reactions using TaqMan® SNP Genotyping Assays). Real-Time Polymerase Chain Reactions were undertaken on the Applied Biosystems 7500 Fast Real-Time PCR System (Applied Biosystems®, USA) following the standard protocols of the manufacturer. Statistical comparisons for continuous variables were conducted by way of Mann–Whitney test when two groups were compared, or Kruskal–Wallis test for three or more groups. Linear regression models were employed for comparisons regarding medication intake and independent variables (test results, body mass index, alcohol consumption). Spearman correlations were estimated for age at examination, schooling, and medication intake. The threshold of significance was set at ρ b 0.05. This study is part of the research project 1067/10 (CAAE 0540.0.174.000-10) approved by the Ethics Committee of Hospital São Paulo, Federal University of São Paulo — UNIFESP, on August 2010. All invited patients and their legal representatives agreed to participate on the research and signed the Informed Consent Form before the evaluation, with no exceptions. 3. Results A total of 217 patients were included; 147 were female (67.7%) and 70 were male (32.3%); 109 (50.23%) were married, while 6 (2.76%) were divorced, 19 (8.76%) were single, and 83 (38.25%) were widowers;
56 (25.8%) had history of alcohol consumption, whereas 11 (5.1%) were regularly drinking at survey time; 79 (36.4%) had smoking history, whereas 14 (6.5%) were regular smokers at survey time. Obesity was diagnosed in 36 patients (16.6%). Table 1 shows full demographic data and test results. Overall, 170 patients (78.34%) were using ChEis at survey time: among these, 60 used Rivastigmine (35.3%), 58 used Donepezil (34.1%), and 52 used extended-release Galantamine (30.6%); 52 patients (23.96%) were treated with Memantine, while 88 (40.55%) used anti-depressants; 53 patients used anti-psychotics (24.42%), namely Quetiapine (n = 42), Risperidone (n = 10) and Olanzapine (n = 1), while 19 used anti-epileptic drugs (8.76%), mostly Carbamazepine (n = 7) and Valproic Acid (n = 6). Use of ChEis had no differential impact over scores on the Clock Drawing Test [9] (ρ = 0.116), Index of Independence in Activities of Daily Living [10] (ρ = 0.474), Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ = 0.472), or the Brazilian Version of the Zarit Caregiver Burden Interview [12] (ρ = 0.491). However, when caregiver burden scores were higher, patients were more likely to use Memantine with or without ChEis (ρ =0.015). Patients with higher global scores on the Neuropsychiatric Inventory [5] were also more likely to use Memantine (ρ = 0.001). Treatment with any anti-depressants had no differential impact over scores on the Clock Drawing Test [9] (ρ = 0.458), Neuropsychiatric Inventory [5] (ρ N 0.26), Index of Independence in Activities of Daily Living [10] (ρ = 0.696), Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ = 0.395), or the Brazilian Version of the Zarit Caregiver Burden Interview [12] (ρ = 0.642), regardless of CDR scores. Treatment with anti-psychotics and/or anti-epileptic drugs had no impact over the Clock Drawing Test [9] (ρ = 0.095) or the Index of Independence in Activities of Daily Living [10] (ρ = 0.586), but had highly significant associations with lower scores on Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ b 0.001) and with higher scores on the Brazilian Version of the Zarit Caregiver Burden Interview [12] (ρ = 0.018). Table 2 shows the distribution of neuropsychiatric symptoms according to each dementia stage, while Table 3 shows comparisons of neuropsychiatric symptoms according to pharmacological treatment in different dementia stages. With the exception of scores for anxiety, all other items from the Neuropsychiatric Inventory [5] had higher scores for more impaired patients, but more remarkably apathy and
Table 1 Demographic data and test results. Variable (units), n = 217
Mean SDa
Age at examination (years-old) Age of dementia onset (years-old) Length of the dementia syndrome (years) Schooling (years) Body mass index (kg/m2) Daily amount of different medications Daily amount of pills/injections Lifetime alcoholic drinking load (liters per year) Current alcoholic drinking load (liters per year) Lifetime smoking load (packs per year) Current smoking load (packs per year) Neuropsychiatric Inventory (0–120 points) Mini-Mental State Examination (0–30 points) Severe Mini-Mental State Examination (0–30 points) Clock Drawing Test (0–15 points) Index of Independence in Activities of Daily Living (0–6 points) Lawton's Scale for Instrumental Activities of Daily Living (9–27 points) Brazilian Version of the Zarit Caregiver Burden Interview (0–56 points)
78 6.2 60–95 73.19 6.8 52–88 5.4 2.9 0.5–14.5 4.21 3.7 0–15 25.75 4.3 14.28–41.62 4.52 2.5 0–12 6.21 3.6 0–16 17.26 50.8 0–315 1.67 11.3 0–120 48.75 103.7 0–700 14.38 62.1 0–365 22.6 16.6 0–87 15.64 5.8 0–29 26.43 4.9 0–30 6.26 4.5 0–15 5 1.6 0–6
a
SD = standard deviation.
Range
14.21
4.7
9–27
16.58
10.7
0–54
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Table 2 Frequency and mean scores of neuropsychiatric symptoms according to each dementia stage. Neuropsychiatric symptoma
Agitation Hallucinations Anxiety Apathy Delusions Disinhibition Dysphoria Euphoria Irritability Aberrant motor behavior a b
All stages (n = 217)
CDRb = 1.0 (n = 83)
CDRb = 2.0 (n = 104)
CDRb = 3.0 (n = 30)
Frequency
Mean scores
Frequency
Mean scores
Frequency
Mean scores
Frequency
Mean scores
60.8% 36.9% 53.5% 68.7% 40.1% 29.5% 59.0% 24.9% 61.8% 34.6%
2.576 1.212 3.074 4.604 1.590 1.184 2.323 1.124 2.687 2.258
51.8% 18.1% 63.9% 61.5% 25.3% 21.7% 53.0% 18.1% 65.1% 27.7%
2.265 0.410 3.735 3.458 1.024 0.470 1.747 0.783 2.386 1.422
65.4% 43.3% 50.0% 67.3% 45.2% 30.8% 58.7% 27.9% 58.7% 39.4%
2.712 1.269 2.721 4.894 1.808 1.375 2.375 1.279 2.721 2.760
70.0% 66.7% 36.7% 93.3% 63.3% 46.7% 76.7% 33.3% 63.3% 36.7%
2.967 3.233 2.467 6.767 2.400 2.500 3.733 1.533 3.400 2.833
According to the Neuropsychiatric Inventory. CDR = Clinical Dementia Rating.
hallucinations. Anxiety was the only behavioral symptom presenting lower scores for more impaired patients. Table 4 shows results from simple linear regression models. Patients with higher scores on the Mini-Mental State Examination [6] showed propensity for more daily intake of different medications (ρ = 0.017). For patients with CDR = 1.0 (n = 83), higher scores on the Neuropsychiatric Inventory [5] were associated with more need for pharmacological treatment (ρ = 0.029), according to Fig. 1. Also for patients with CDR = 1.0, higher scores in anxiety (squared multiple R = 0.078; F-ratio = 6.822, ρ = 0.011) and irritability (squared multiple R = 0.080; F-ratio = 7.057, ρ = 0.010) were related with more daily intake of different medications. Regarding daily intake of pills/ injections, a positive association with anxiety (squared multiple R =
0.076; F-ratio = 6.686, ρ = 0.012) and irritability (squared multiple R = 0.093; F-ratio = 8.296, ρ = 0.005) was also shown for patients with CDR = 1.0. These analyses were also conducted for other neuropsychiatric symptoms in each stage of the dementia syndrome, but results were non-significant. Marital status had no overall impact over the total amount of daily medications or pills/injections, except for patients with CDR = 1.0 (n = 83), for whom there was a tendency for married patients to use a larger variety of medications (ρ = 0.033) and more pills/injections (ρ = 0.039) than the non-married ones. Nonetheless, marital status had no relations with overall scores on the Neuropsychiatric Inventory [5] (ρ = 0.653) or length of the dementia syndrome, regardless of CDR scores (ρ N 0.32). Use of anti-psychotics and/or anti-epileptic drugs
Table 3 Kruskal–Wallis test results for neuropsychiatric symptoms according to pharmacological treatment. Variable 1
Neuropsychiatric Inventory total scores Neuropsychiatric Inventory total scores Neuropsychiatric Inventory total scores Agitation Agitation Agitation Hallucinations Hallucinations Hallucinations Anxiety Anxiety Anxiety Apathy Apathy Apathy Delusions Delusions Delusions Disinhibition Disinhibition Disinhibition Dysphoria Dysphoria Dysphoria Euphoria Euphoria Euphoria Irritability Irritability Irritability Aberrant motor behavior Aberrant motor behavior Aberrant motor behavior a b
Variable 2
ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs ChEisb Anti-psychotics Anti-epileptic drugs
CDRa = 1.0 (n = 83)
CDRa = 2.0 (n = 104)
CDRa = 3.0 (n = 30)
Kruskal–Wallis test statistic
ρ-Value
Kruskal–Wallis test statistic
ρ-Value
Kruskal–Wallis test statistic
ρ-Value
1.543 7.820 4.488 5.490 5.902 6.014 7.020 2.070 5.150 2.739 0.085 2.079 1.862 1.715 2.840 1.297 5.639 4.961 4.253 9.400 3.162 8.820 6.665 9.318 2.707 4.289 7.591 3.799 6.250 3.972 2.351 8.903 7.882
0.672 0.020 0.344 0.139 0.052 0.198 0.071 0.355 0.272 0.434 0.958 0.721 0.602 0.424 0.585 0.730 0.060 0.291 0.235 0.009 0.531 0.032 0.036 0.054 0.439 0.117 0.108 0.284 0.044 0.410 0.503 0.012 0.096
8.377 4.931 2.594 8.612 7.029 1.664 1.085 12.365 1.296 6.573 1.856 3.272 3.245 2.970 1.449 6.151 7.362 0.820 5.846 1.065 3.717 3.560 1.059 1.342 6.320 2.560 1.549 3.382 0.337 2.980 10.757 0.943 2.215
0.039 0.085 0.459 0.035 0.030 0.645 0.781 0.002 0.730 0.087 0.395 0.352 0.355 0.226 0.694 0.105 0.025 0.845 0.119 0.587 0.294 0.313 0.589 0.719 0.097 0.278 0.671 0.336 0.845 0.395 0.013 0.624 0.529
5.026 5.314 2.570 7.472 4.643 2.366 4.145 6.555 1.414 4.888 6.164 0.682 1.138 4.212 0.518 2.211 4.751 2.574 6.140 2.778 5.315 4.281 4.495 0.280 3.576 2.909 3.291 11.053 3.302 3.592 0.808 3.696 0.635
0.170 0.150 0.277 0.058 0.200 0.306 0.246 0.088 0.493 0.180 0.104 0.711 0.768 0.239 0.772 0.530 0.191 0.276 0.105 0.427 0.070 0.233 0.213 0.869 0.311 0.406 0.193 0.011 0.347 0.166 0.848 0.296 0.728
CDR = Clinical Dementia Rating. ChEis = Cholinesterase inhibitors (Donepezil or Galantamine or Rivastigmine).
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Table 4 Results from simple linear regression models. Variablea
Mini-Mental State Examination Severe Mini-Mental State Examination Neuropsychiatric Inventory (CDR = 3.0) Neuropsychiatric Inventory (CDR = 2.0) Neuropsychiatric Inventory (CDR = 1.0) Agitation Hallucinations Anxiety Apathy Delusions Disinhibition Dysphoria Euphoria Irritability Aberrant motor behavior Lifetime alcoholic drinking load (CDR = 3.0) Lifetime alcoholic drinking load (CDR = 2.0) Lifetime alcoholic drinking load (CDR = 1.0) Current alcoholic drinking load Body mass index Length of the dementia syndrome Clock Drawing Test Index of Independence in Activities of Daily Living Lawton's Scale for Instrumental Activities of Daily Living Brazilian Version of the Zarit Caregiver Burden Interview a
Daily amount of different medications
Daily amount of pills/injections
Squared multiple R
t
F-ratio
ρ-Value
Squared multiple R
t
F-ratio
ρ-Value
0.026 b0.001 0.013 b0.001 0.057 0.003 b0.001 0.009 0.025 0.016 0.007 0.001 0.001 0.005 0.019 0.004 0.001 0.005 b0.001 0.092 0.020 0.001 0.002 0.001 0.006
2.416 0.109 −0.600 −0.143 2.222 0.769 −0.134 1.406 2.359 −1.868 1.266 −0.508 −0.471 1.034 −2.064 0.348 −0.324 0.636 −0.248 4.655 2.100 0.480 −0.606 −0.367 1.105
5.838 0.012 0.360 0.020 4.938 0.592 0.018 1.978 5.567 3.488 1.603 0.258 0.222 1.069 4.259 0.121 0.105 0.405 0.061 21.668 4.411 0.230 0.367 0.135 1.221
0.017 0.913 0.553 0.887 0.029 0.443 0.894 0.161 0.019 0.063 0.207 0.612 0.638 0.302 0.040 0.731 0.747 0.526 0.805 b0.001 0.037 0.632 0.545 0.714 0.270
0.013 0.001 0.012 b0.001 0.099 0.009 0.001 0.007 0.027 0.009 0.008 0.001 b0.001 0.006 0.018 0.013 b0.001 0.004 b0.001 0.095 0.027 b0.001 0.007 0.005 0.018
1.694 −0.423 −0.592 −0.183 2.984 1.406 0.398 1.264 2.440 −1.372 1.315 −0.339 0.158 1.101 −1.997 0.609 −0.002 0.550 −0.235 4.762 2.428 −0.094 −1.271 −1.009 1.961
2.870 0.179 0.351 0.034 8.905 1.977 0.159 1.597 5.955 1.882 1.729 0.115 0.025 1.213 3.989 0.371 b0.001 0.302 0.055 22.677 5.893 0.009 1.615 1.018 3.847
0.092 0.673 0.558 0.855 0.004 0.161 0.691 0.208 0.015 0.171 0.190 0.735 0.875 0.272 0.047 0.547 0.998 0.584 0.815 b0.001 0.016 0.925 0.205 0.314 0.051
n = 217 except where otherwise noted CDR = 3.0 (n = 30), CDR = 2.0 (n = 104), or CDR = 1.0 (n = 83).
was also unrelated with length of AD (ρ = 0.509). Use of antidepressants was marginally related with longer lengths of AD for patients with CDR = 3.0 (n = 30, ρ = 0.079), but not for patients in earlier stages (ρ N 0.19). However, for patients with CDR = 2.0 (n = 104), use of any of the ChEis was associated with longer lengths of AD (ρ = 0.007), according to Fig. 2, and even longer when Memantine was added to the pharmacological treatment (ρ b 0.001), according to Fig. 3, relations that were not found for patients with CDR = 3.0 (n = 30, ρ N 0.23). Gender was unrelated with daily use of different medications (ρ = 0.106), but a marginally significant association was found for male patients to take more pills/injections per day than female patients (ρ = 0.059). Spearman correlations were significant (ρ b 0.0001) between daily medication intake and number of pills/injections taken per day (rs = 0.9444), between daily medication intake and both age at examination (rs = −0.1637) and schooling (rs = 0.0375), and between number of pills/injections taken per day and both age at examination (rs = −0.2289) and schooling (rs = 0.0396). With regard to APOE haplotypes, 26 were ε4/ε4, 81 were ε4/ε3, 7 were ε4/ε2, 93 were ε3/ε3, and 10 were ε3/ε2; in other words, 114 were APOE4+, and 103 were APOE4−. Earlier onset of AD was correlated
with APOE4+ in patients with CDR = 2.0 (n = 104, ρ = 0.019) and with the ε4/ε4 haplotype in patients with CDR = 1.0 (n = 83, ρ b 0.007). APOE haplotypes had no influence over the daily amount of different medications (ρ N 0.19) or pills/injections (ρ N 0.25) taken by patients, or scores on the Neuropsychiatric Inventory [5] (ρ N 0.19), Index of Independence in Activities of Daily Living [10] (ρ N 0.26) or Lawton's Scale for Instrumental Activities of Daily Living [11] (ρ N 0.27), regardless of CDR scores.
Fig. 1. Impact of scores on the Neuropsychiatric Inventory over daily use of medications for patients with CDR = 1.0.
Fig. 2. Influence of treatment with different cholinesterase inhibitors over the length of the dementia syndrome for patients with CDR = 2.0.
4. Discussion The cross-sectional nature of this study does not allow for causal relations to be inferred. Therefore, only associations may be deduced from the results. Overall daily use of different medications was correlated with the number of pills/injections taken per day. Older patients with less schooling would use fewer medications than younger patients with high schooling, possibly because of differences in seeking medical attention or following prescriptions. APOE haplotypes had an impact over the age of onset of AD, but not over pharmacological treatment, behavior or functionality. An earlier study [13] with a smaller sample showed that APOE4+ carriers had more neuropsychiatric symptoms, particularly hallucinations and aberrant motor behavior, but its
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Fig. 3. Influence of treatment with cholinesterase inhibitors and/or Memantine over the length of the dementia syndrome for patients with CDR = 2.0.
longitudinal design might have favored the observation of more severe psychopathology. ChEis were associated with lower total scores on the Neuropsychiatric Inventory [5] only for moderately impaired patients. While no association was found between such scores and use of anti-epileptic drugs, an association with higher total scores was found for mildly impaired patients who used anti-psychotics, a result that could represent more need for psychotropic treatment when behavioral symptoms are present. Besides controversy still regarding the clinical efficacy of these drugs, it has been demonstrated that adverse effects offset advantages of atypical anti-psychotics for treatment of neuropsychiatric symptoms in AD [2], while the benefits of combined behavioral management techniques have not been entirely proven as well [14]. When caregiver burden was higher, patients were more likely to use anti-psychotics and/or anti-epileptic drugs, and Memantine with or without ChEis. This may reflect caregiver pressure on physicians for prescription of such medications in view of the impact of functional progression over caregivers' abilities to manage patients [15]. However, the benefits of Memantine for patients in moderate-to-severe stages of AD have been controversial. Some studies have shown that, for patients already receiving Donepezil, Memantine slowed memory, language and praxis decline [16], and helped stabilize functional independence [17]. Other studies have shown stabilization of cognition, functionality, behavior and caregiver distress [18] with use of Memantine in moderate-to-severe AD [19], even without concomitant use of ChEis [20]. Nonetheless, the combination of ChEis with Memantine has been considered to be neuroprotective when undertaken for at least two years, and superior to treatment with ChEis without Memantine [21] or to suspension of ChEis [22]. A delay in nursing home admission with no significant difference in survival rates has also been demonstrated for patients treated with ChEis, and even more significantly for those who received ChEis with Memantine [23]. In spite of these results, a recent study showed that Donepezil with or without Memantine had the same cognitive effects, but a mild benefit of Memantine over Neuropsychiatric Inventory [24] scores was observed [22]. Anyhow, Memantine is indicated only for moderate-to-severe AD, whereas ChEis and Memantine may lead to faster cognitive decline and progression to dementia when given to patients with mild cognitive impairment [25]. Patients with more behavioral symptoms were also more likely to use Memantine; it is difficult to identify whether this result predicts dementia progression or defines an outcome, a possible consequence of the impression that prescription of Memantine may help alleviate such manifestations of dementia [26,27]. Among neuropsychiatric symptoms, Memantine has been shown to reduce mostly frontally mediated behavioral disturbances, but particularly worsening and development of agitation [18,28]. While overall behavioral symptoms had an increasing tendency with higher CDR scores, with more notable escalations for apathy and hallucinations, anxiety was the only neuropsychiatric symptom
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presenting lower scores for more impaired patients. These results contrast an earlier study [29] with a smaller sample, which showed rising anxiety and, more significantly, disinhibition, agitation and irritability in later stages; however, severely impaired patients were rare in that study, and they were not stratified according to pharmacological treatment, which could have lessened such symptoms. Also, overall neuropsychiatric symptoms tend to correlate better with functional independence than with cognitive decline [18]. Treatment with ChEis was associated with lower scores for dysphoria in mildly impaired patients, agitation and/or aberrant motor behavior in moderately impaired patients, and irritability in severely impaired patients. Other studies have shown that disinhibition, anxiety and apathy tend to show greater improvement with such treatment [24]. While treatment with Galantamine has been associated with significantly lower agitation, an earlier 12-week trial showed that Donepezil was not more effective than placebo for treatment of agitation in AD [30]. In agreement with other studies [31], Quetiapine was the most widely prescribed anti-psychotic in this sample. Treatment with antipsychotics was associated with higher scores for disinhibition, dysphoria, irritability and aberrant motor behavior in mildly impaired patients, and also with higher scores for agitation, hallucinations and delusions in moderately impaired patients. No such associations were found for severely impaired patients. Considering that hallucinations are strong predictors of functional decline [15,32], these results might reflect a greater need for psychotropic treatment when a faster progression of dementia is perceived, while agitation tends to respond poorly to atypical anti-psychotics in the long term [26]. Despite the fact that this is a cross-sectional study, these results could also suggest a lack of effectiveness of anti-psychotics for behavioral symptoms in patients with AD. Patients with lesser degrees of independence for instrumental activities of daily living would also use anti-psychotics and/or antiepileptic drugs more frequently, a possible outcome related with more sensitivity of such activities to cognitive and behavioral change [31]. Apathy, aberrant motor behavior, higher body mass index, longer lengths of the dementia syndrome and higher scores on the MiniMental State Examination [6] were associated with daily use of more medications. Mildly impaired patients were also more likely to use a larger amount of daily medications when they were married, with more irritability or anxiety, and when total scores on the Neuropsychiatric Inventory [5] were higher — however, a plateau was reached for scores over 20. Caregiver burden was marginally significant for daily use of more pills/injections. It is possible that married or obese patients who have higher scores on the Mini-Mental State Examination [6] or longer lengths of AD tend to seek medical assistance more often, consequently leading to more pharmacological treatment. Use of anti-depressants did not impact overall behavioral symptoms or functionality, but was marginally related with longer lengths of AD for severely impaired patients. Moderately impaired patients had longer lengths of AD when they were using ChEis, and even longer when Memantine was also prescribed. This is an original result that may reflect a previously described synergistic effect among such medications for slowing cognitive decline [27], translating into a longer length of the moderate dementia stage for patients with AD. Since ChEis and Memantine had no effect over length of dementia for severely impaired patients, we conclude that such medications were not able to prolong life and neither to stop cognitive decline, despite their effect in slowing cognitive decline of moderately impaired patients. In a retrospective study [33], patients with mild-to-moderate AD who received treatment with Galantamine for up to seven years exhibited attenuated decline in Mini-Mental State Examination [6] scores, while it has been shown that patients who stop treatment with Galantamine or Donepezil experience subsequent faster cognitive decline. In conclusion, we have shown that pharmacological therapy with ChEis with or without Memantine, but not therapy with anti-psychotics and/or anti-epileptic drugs, was associated with lower scores in the Neuropsychiatric Inventory [5] in moderately impaired subjects from
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this sample of patients with low mean schooling. A trend was found for use of ChEis with Memantine to be associated with longer lengths of the dementia syndrome for moderately impaired patients, regardless of APOE haplotypes. The strengths of this study include the wide diversity in levels of schooling, frequent use of psychotropic medications, and the fact that records of a large sample of patients were evaluated by way of brief cognitive instruments. Nevertheless, recruitment was carried out in a single center; therefore, results may not be generalizable to the whole population of São Paulo. Also, dose–response relationships were not investigated in view of the low variability of all drug regimens. Considering that a wide diversity of anti-depressants was found and a specific scale for assessment of depression was not employed, a deeper evaluation of the effects of such medications was not possible. Further longitudinal studies may be required to corroborate our results and ascertain the roles of ChEis, Memantine, and psychotropics in general for modulation of cognition and behavior in patients with AD. Disclosures Fabricio F Oliveira, MD, MSc, is a PhD student at the Federal University of São Paulo — UNIFESP in São Paulo, Brazil; he receives a scholarship for academic research from CAPES — Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, a governmental agency in Brazil, and receives personal compensation for acting as a Healthcare Council Member for Gerson Lehrman Group. Paulo H F Bertolucci, MD, MSc, PhD, is a professor at the Department of Neurology and Neurosurgery of the Federal University of São Paulo — UNIFESP in São Paulo, Brazil; he has received personal compensation for acting as a consultant for Novartis, Lilly, Pfizer, Janssen and Support. Elizabeth S Chen, MSc, PhD, is a professor at the Department of Morphology and Genetics of the Federal University of São Paulo — UNIFESP in São Paulo, Brazil. Marilia A C Smith, MSc, PhD, is a full professor at the Department of Morphology and Genetics of the Federal University of São Paulo — UNIFESP in São Paulo, Brazil; she receives support for scholarly activities from the following Brazilian public agencies for research: FAPESP — The State of São Paulo Research Foundation, CNPq — Conselho Nacional de Desenvolvimento Científico e Tecnológico, and CAPES — Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Conflict of interest There is no conflict of interest. References [1] Liperoti R, Pedone C, Lapane KL, Mor V, Bernabei R, Gambassi G. Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents. Arch Intern Med 2005;165:2677–82. [2] Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355:1525–38. [3] Shin J-Y, Choi N-K, Jung S-Y, Lee J, Kwon JS, Park B-J. Risk of ischemic stroke with the use of risperidone, quetiapine and olanzapine in elderly patients: a population-based, case-crossover study. J Psychopharmacol 2013;27:638–44. [4] McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 2011;7:263–9. [5] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–14.
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