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Neuropsychiatric predictors of conversion to dementia both in patients with amnestic mild cognitive impairment and those with subcortical vascular MCI
Clinical Neurology and Neurosurgery 115 (2013) 1264–1270
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Neuropsychiatric predictors of conversion to dementia both in patients with amnestic mild cognitive impairment and those with subcortical vascular MCI Sook Hui Kim a , Hyun Seok Kang b , Hee Jin Kim a , Hui Jin Ryu a , Min young Kim a , Sang Won Seo c , Duk L. Na c , Seol-Heui Han a,∗ a
Department of Neurology, Konkuk University Hospital, Konkuk University School of Medicine, Seoul, Republic of Korea Department of Neurology, Bundang Jesaeng General Hospital, Gyeonggi-do, Republic of Korea c Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 2 August 2011 Received in revised form 21 October 2012 Accepted 27 November 2012 Available online 3 January 2013 Keywords: Neuropsychiatric Inventory Amnestic mild cognitive impairment Subcortical vascular mild cognitive impairment
a b s t r a c t Objective: The aim of this study was to investigate whether specific neuropsychiatric domains could predict a conversion to dementia in those patients either with amnestic subtype of mild MCI (aMCI) or subcortical vascular MCI (svMCI). Methods: At baseline, all subjects underwent neuropsychological tests, Neuropsychiatric Inventory (NPI), and MRI. We compared the baseline NPI scores between converters (CV) and non-converters (NCV) both in the aMCI and svMCI groups. Results: The mean follow-up duration was 16.74 ± 8.02 months (range: 4.2–43.9). At the second time point, about 30% of aMCI and svMCI patients converted to dementia with 7.5% of aMCI patients exhibiting improvement to normal cognitive state. In female aMCI patients, those who later improved to normal cognition exhibited higher baseline depression scores than the CV group. However, baseline depression scores were higher in the CV group than the NCV group in svMCI patients, and this difference was significant only in males. Conclusion: Our results suggest that depression might serve as a predictive marker of conversion to dementia in patients with svMCI, albeit only in males. On the other hand, patients who later improved to normal cognition showed higher scores of depression at baseline in female aMCI patients, suggesting that longer follow-ups are warranted in female patients with aMCI and depression. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Patients with dementia present not only cognitive impairment but also neuropsychiatric symptoms including behavioral and mood changes. Neuropsychiatric symptoms often have a more serious impact on the performance of daily activities than do cognitive deficits, therefore they lead to an increase in caregiver burden. Organic changes in the specific neural structures may mediate the genesis of neuropsychiatric symptoms in dementia [1,2] and thus, the more the disease progresses, the more likely patients present abnormal behaviors. Up to now, neuropsychiatric symptoms have been the most extensively investigated in patients with dementia; however, those symptoms could also be present in patients with mild cognitive impairment (MCI) which is a
∗ Corresponding author at: Department of Neurology, Konkuk University Hospital, 4-12 Hwayanag-dong, Gwangjin-gu 143-729, Seoul, Republic of Korea. Tel.: +82 2 2030 6221; fax: +82 2 2049 6192. E-mail address: [email protected] (S.-H. Han). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2012.11.029
preclinical stage of dementia [3]. In fact, Apostolova and Cummings summarized the studies of neuropsychiatric symptoms in MCI patients and argued that neuropsychiatric symptoms are more prevalent than expected, existing in about 35–75% of MCI populations [4]. Mild cognitive impairment comprises heterogeneous subgroups according to clinical characteristics and etiologies [5], being divided into amnestic and non-amnestic types, and degenerative and vascular etiologies. Of those, amnestic subtype of MCI (aMCI) may represent a forme fruste of Alzheimer’s disease (AD) [6], especially when patients with aMCI do not exhibit white matter ischemia or lacunes on magnetic resonance imaging (MRI). On the other hand, subcortical vascular MCI (svMCI) may refer to a preclinical stage of subcortical vascular dementia (SVaD) [7]. Neuropsychiatric symptoms of SVaD may differ from those of AD such that vascular depression [8,9], agitation, anxiety, and apathy are more prevalent features in patients with SVaD than in those with AD [10,11]. In addition, sometimes non-cognitive behavioral problems precede the cognitive impairment in those patients. Likewise neuropsychiatric symptoms of aMCI may differ from those of svMCI, however, this has seldom been studied.
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Many investigators have attempted to find biological markers which can predict the conversion to dementia in MCI patients, given that early detection and treatment in order to halt the progression to dementia would be invaluable. Those studies, however, mainly have focused on neuropsychological or imaging findings. On the other hand, there have been only a few studies that have tried to assess the predictability of neuropsychiatric symptoms in patients with MCI [12,13]. A previous study compared the baseline differences of neuropsychiatric symptoms in MCI patients using the Neuropsychiatric Inventory (NPI) and demonstrated that patients who would later develop dementia had higher frequencies of depression and apathy than those patients who remained stable at follow-up [12]. However, that study included only a small number of patients and subsequent subgroup analyses with regard to etiology (degenerative vs. vascular MCI) were not conducted. Another study involving a larger number of patients also did not consider the etiologies of MCI and did not delineate the specific NPI domains [13]. Adding to neuropsychological and imaging biomarkers, neuropsychiatric markers may serve as a complementary modality predicting the progression to dementia both in patients with aMCI and those with svMCI. Thus, the purposes of the current study were, from a large hospital-based cohort, (1) to find baseline differences in NPI characteristics between aMCI and svMCI groups and (2) to investigate whether specific neuropsychiatric domains could predict the conversion to dementia in patients either with aMCI or svMCI, and if so, whether there were differences in predictable NPI domains between the two groups. Since, a difference between males and females with respect to the prevalence of neuropsychiatric symptoms has been widely reported across various studies [14,15], we considered a sub-analysis according to gender in all analyses.
2. Materials and methods 2.1. Participants Patients were extracted from the CREDOS (Clinical Research Center for Dementia of South Korea) study which was a large hospital-based cohort for epidemiological and clinical studies of patients with cognitive impairment. Of the total, we enrolled patients either with aMCI or svMCI. Diagnosis of aMCI in the CREDOS study met the following criteria: (1) patients met the criteria for MCI proposed by Petersen et al. including the followings: memory problems, objective memory disorder, absence of other cognitive disorders or repercussions on daily life, normal general cogntive function and absence of dementia [16]; (2) they had no focal neurological symptoms or signs to suggest focal brain lesions or parkinsonism on neurological examination; (3) they had no structural lesions on brain MRI such as brain tumor, hemorrhage, or hydrocephalus, nor did they exhibit significant cortical/subcortical vascular ischemia. Patients with only mild degree of ischemia were included based on the CREDOS rating scales of white matter changes [17]. To be more specific regarding Petersen’s criteria, we applied the following principles in addition to the general principles stated above: (1) subjective memory complaint by the patient or his/her caregiver; (2) objective memory decline below one standard deviation (SD) on neuropsychological tests, in which delayed recall performance was used; (3) normal general cognitive function; (4) normal activities of daily living (ADL) both clinically and on an ADL scale; and (5) not demented. As for svMCI, we applied Petersen criteria with the following modifications: (1) “subjective cognitive complaint by the patient or his/her caregiver” was used instead of “subjective memory complaint by the patient of his/her caregiver”; (2) in “objective memory
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decline below the 1 SD on neuropsychological tests,” we used “objective cognitive decline. . ..” Instead; (3) normal general cognitive function; (4) normal Activity of Daily Living (ADL) score both judged clinically and on ADL scales; (5) not having dementia; and (6) a subcortical vascular feature defined as both focal neurological symptom/sign and the severe degree of ischemia on MRI defined as a cap or band ≥10 mm as well as a deep white matter lesion ≥25 mm. Patients were excluded if they had cortical lesions, cortico-subcortical non lacunar territorial infarcts, hemorrhage, or normal pressure hydrocephalus. For the evaluation of ADL, we used the Barthel Index [18], and the Seoul-Instrumental Activities of Daily Living (S-IADL) [19]. The S-IADL was a caregiveradministered instrument designed to measure IADL. It contained 15 items: using the telephone, shopping, preparing food/cooking, household chores, using transportation, going out for a short distance, taking medications, managing finances, grooming, using household appliances, managing belongings, securing a door, keeping appointments, talking about recent events, and participating in leisure/hobbies. All items were scored on a four-point Likert scale ranging from 0 to 3, with higher scores indicating lower functioning. All the patients underwent laboratory tests to exclude other possible causes that can affect cognition including complete blood counts (CBC), chemistry and electrolytes, lipid profile, urinalysis, venereal disease research laboratory (VDRL), thyroid function test, vitamin B12/folate, fibrinogen, and homocysteine. From August 2005 to December 2008, there were 1135 aMCI and 286 svMCI patients that were registered. As of December 2009, 238 patients received at least one follow-up evaluation and the data from baseline and the most recent follow-up visits were used for our evaluation (174 patients had only one follow-up visit, 52 had two, 11 had three and 1 had four follow-up visits). The remaining 1183 were supposed to be followed up or had been lost. In the CREDOS cohort, subjects included in the current study were older and had on average higher educational levels than those who were not included (71.08 ± 7.00 vs. 69.73 ± 7.96, p = 0.013 for age; 8.73 ± 5.07 vs. 7.35 ± 5.17, p < 0.001 for educational level; 25.06 ± 3.42 vs. 24.82 ± 3.66, p = 0.330 for MMSE score). Two out of the 238 were excluded because they did not perform the NPI questionnaire. Thus, a final total of 236 (187 MCI and 49 svMCI) were included in this study (Fig. 1). The mean duration from diagnosis to follow-up was 16.74 ± 8.02 months (range: 4.2–43.9). Detailed demographics are displayed in Table 1. The diagnosis of AD at follow-up was based on National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria for probable AD [20]. As for SVaD, patients had to meet the diagnostic criteria for the vascular dementia as proposed by the DSM IV and had to have a subcortical vascular feature defined as in the svMCI. Some patients met both of the full diagnostic criteria for AD and SVaD, which meant mixed cases. We considered these patients to have AD with or without white matter changes. At the time of the second follow-up, 70 of 236 patients (29.7%) converted to dementia and 166 (70.3%) remained stable. Of patients who did not convert to dementia, fourteen improved to a normal cognitive state at follow-up, all of whom were aMCI patients at baseline. Patients were informed in detail and informed consents were received. The study was approved by the Institutional Review Board of Konkuk University Hospital. 2.2. Assessment of neuropsychiatric symptoms Neuropsychiatric symptoms were assessed using the caregiveradministered NPI (CGA-NPI) [21]. The CGA-NPI worksheet was identical to the NPI version. The CGA-NPI procedures, including the scoring method, did not differ from those of the NPI. After the
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Fig. 1. Participants flow chart. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; SVaD = subcortical vascular dementia; NPI = Neuropsychiatric Inventory; F/U = follow-up.
caregivers completed the CGA-NPI unassisted, they were briefly interviewed by the examiners (post supervision), who checked if the caregivers had completed the form appropriately. The NPI was composed of 12 domain caregiver-based ratings including delusion, hallucination, agitation, depression, anxiety, elation, apathy, disinhibition, irritability, aberrant motor behavior, sleep disorder, and eating disorder [22]. Scores on each domain were determined by multiplying the frequency (range from 1 to 4) and severity (range
from 1 to 3) scores. The total NPI score was determined by the sum of all domain scores. 2.3. Neuropsychological evaluation The Seoul Neuropsychological Screening Battery (SNSB), a standardized neuropsychological battery [23], included tests for attention, language, praxis, four elements of Gerstmann syndrome,
Table 1 Demographic characteristics and results of NPI scores in aMCI and svMCI patients. aMCI
N Age Sex, female (%) Education CDR, sum of box MMSE Time from diagnosis to F/U (months) NPI scores NPI total Delusion Hallucination Aggression Depression Anxiety Euphoria Apathy Disinhibition Anger Aberrant motor behaviors Sleep disorder Eating disorder
svMCI
Total
Male
Female
Total
Male
Female
187 70.39 ± 7.06 64.71% 8.86 ± 5.02 1.54 ± 0.85 25.01 ± 3.42 16.09 ± 7.72
66 70.43 ± 6.93
121 70.32 ± 7.36
22 74.05 ± 6.28
27 71.48 ± 6.86
12.30 ± 3.96 1.49 ± 0.93 25.82 ± 2.95 15.43 ± 7.39
6.99 ± 4.54† 1.56 ± 0.81 24.56 ± 3.58† 16.45 ± 7.90
49 72.63 ± 6.66* 55.10% 8.14 ± 5.39 1.48 ± 0.86 25.18 ± 3.60 19.21 ± 8.21*
10.45 ± 5.60 1.30 ± 0.70 26.41 ± 3.38 18.83 ± 8.18
6.26 ± 4.49† 1.63 ± 0.96 24.19 ± 3.53† 19.52 ± 9.27
5.00 ± 7.06 0.14 ± 0.80 0.07 ± 0.45 0.21 ± 0.81 0.66 ± 1.49 0.50 ± 1.16 0.04 ± 0.28 0.73 ± 1.76 0.16 ± 0.51 0.78 ± 1.64 0.20 ± 0.97 0.62 ± 1.56 0.90 ± 2.12
3.88 ± 5.48 0.02 ± 0.12 0.02 ± 0.12 0.27 ± 1.09 0.26 ± 0.83 0.45 ± 1.04 0.09 ± 0.45 0.61 ± 1.21 0.12 ± 0.37 0.89 ± 1.59 0.27 ± 1.27 0.41 ± 1.01 0.41 ± 1.69
5.61 ± 7.74 0.21 ± 0.98 0.11 ± 0.54† 0.18 ± 0.61 0.88 ± 1.71 0.53 ± 1.22 0.01 ± 0.09 0.79 ± 2.00 0.17 ± 0.57 0.72 ± 1.67 0.16 ± 0.76 0.73 ± 1.78 1.17 ± 2.28†
4.49 ± 6.42 0.06 ± 0.24 0 0.31 ± 1.34 0.76 ± 1.68 0.37 ± 0.78 0.02 ± 0.14 1.00 ± 2.31 0.29 ± 0.94 0.59 ± 1.21 0 0.59 ± 1.41 0.51 ± 1.42
4.18 ± 6.66 0.09 ± 0.29 0 0.14 ± 0.47 0.91 ± 2.33 0.36 ± 0.66 0 1.36 ± 2.85 0.18 ± 0.50 0.50 ± 1.10 0 0.32 ± 0.89 0.32 ± 1.29
4.74 ± 6.33 0.04 ± 0.19 0 0.44 ± 1.76 0.63 ± 0.88 0.37 ± 0.88 0.04 ± 0.19 0.70 ± 1.75 0.37 ± 1.18 0.67 ± 1.30 0 0.81 ± 1.71 0.67 ± 1.52
NPI total score = frequency × severity. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; CDR = Clinical Dementia Rating scale; MMSE = Mini-Mental State Examination; F/U = follow-up; NPI = Neuropsychiatric Inventory. * p < 0.05 vs. total aMCI. † p < 0.05 vs. male.
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visuoconstructive function, verbal and visual memory and frontal/executive function. Memory function was considered abnormal when the score for the delayed recall on the Seoul Verbal learning test (SVLT; three learning-free recall trials of 12 words, 20min delayed recall trial for these 12 items, and a recognition test) or Rey–Osterrieth Complex Figure Test (RCFT) was below the 1 SD of the norm. The detailed elements of the test have been presented elsewhere [24]. 2.4. Statistical analysis Statistical analysis was conducted using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). Demographic characteristics between the two groups were compared using independent-samples t-test for continuous variables and a Chi-square test for categorical variables. The NPI scores were compared between the groups using an analysis of covariance (ANCOVA) to control variables which differ between groups (age, education, MMSE, and follow-up duration). The value of p < 0.05 was set as a significance threshold and when post hoc multiple comparisons were applied, p-values were adjusted using the Bonferroni correction. 3. Results 3.1. Comparison of the baseline neuropsychiatric symptoms between aMCI and svMCI Patients with svMCI were older and had longer follow-up periods than those with aMCI (Table 1). About 67% of the aMCI and 61% of svMCI patients exhibited at least one neuropsychiatric symptom. In aMCI patients, the most frequent neuropsychiatric abnormalities were depression (33.2%), irritability (33.2%), apathy (26.7%), anxiety (25.7%), and eating disorder (23.1%). The most frequent neuropsychiatric symptoms exhibited by svMCI patients were depression (34.7%), apathy (30.6%), irritability (30.6%), anxiety (24.5%), and sleep disorder (20.4%). In baseline NPI scores, the aMCI group exhibited higher scores on hallucination and aberrant motor behavior than the svMCI group,
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but the statistical significance was lost after adjusting for age and follow-up period. When each group was further subdivided according to gender, male patients had higher MMSE scores and educational level compared with female patients both in aMCI and svMCI groups. After adjusting MMSE scores and educational levels, females exhibited higher scores on hallucination (F = 5.455, p = 0.001) and eating disorder (F = 3.278, p = 0.022) than males in the aMCI group, while no significant difference was found between males and females in the svMCI group (Table 1). 3.2. Comparison of the baseline neuropsychiatric symptoms between converters and non-converters in patients with aMCI At the follow-up examination, 117 out of 187 aMCI patients (62.6%) turned out to be non-converters (NCV) who remained in an aMCI state, whereas 56 out of 187 patients (29.9%) were designated as converters (CV) who progressed to dementia. The remaining 14 patients improved to normal cognitive status, which will be described later. The time between the baseline and the follow-up test averaged 16.1 ± 7.7 months, and therefore, the annual conversion rate in our aMCI patients was 22.4%. When comparing NPI scores between CV and NCV groups, there were no significant differences in the total and subscores of baseline NPI items after adjusting MMSE scores (Table 2). We further divided the aMCI patients into subgroups according to gender. However, there were no significant differences in the NPI scores between CV and NCV groups both in males and females. In our sample, 14 patients improved to a normal cognitive state at the follow-up (IMP; n = 14/187, 7.5%), thus we conducted an additional analysis of baseline demographics and NPI scores among three groups including the IMP group (NCV, CV and IMP groups). There was no significant difference of the female ratio among three subgroups: IMP (n = 8, 57.14%); NCV (n = 77, 65.81%); CV (n = 36, 64.29%). Significant differences were found in age (F = 6.611, p = 0.02) and MMSE scores (F = 12.138, p < 0.001) among the three groups. In the post hoc analysis with Bonferroni’s correction for multiple comparison, the IMP group was younger (66.5 ± 6.14) and
Table 2 Demographic characteristics and NPI scores in non-converters and converters. aMCI (n = 187)
N Age Sex, female (%) Education (years) CDR, sum of box MMSE F/U duration NPI scores NPI total Delusion Hallucination Aggression Depression Anxiety Euphoria Apathy Disinhibition Anger Aberrant motor behaviors Sleep disorder Eating disorder
svMCI (n = 49)
NCV
CV
NCV
CV
117 71.16 ± 6.93 65.81% 8.22 ± 5.16 1.44 ± 0.73 25.33 ± 3.10 16.09 ± 7.71
56 70.37 ± 9.71 64.29% 9.81 ± 4.80* 1.88 ± 1.03* 23.57 ± 3.68* 16.40 ± 8.39
35 71.74 ± 6.39 65.71% 7.21 ± 4.71 1.43 ± 0.91 25.34 ± 3.52 19.44 ± 9.19
14 74.86 ± 7.05 28.57%* 10.46 ± 6.43 1.61 ± 0.74 24.79 ± 3.91 18.63 ± 7.70
5.50 ± 6.52 0.27 ± 0.94 0.07 ± 0.53 0.29 ± 0.73 0.66 ± 1.24 0.55 ± 1.04 0.05 ± 0.30 0.80 ± 1.88 0.1 ± 0.46 0.96 ± 1.65 0.16 ± 0.71 0.68 ± 1.94 0.86 ± 2.08
4.54 ± 6.21 0.06 ± 0.24 0 0.06 ± 0.24 0.89 ± 1.92 0.37 ± 0.81 0.03 ± 0.17 1.23 ± 2.66 0.20 ± 0.47 0.54 ± 0.95 0 0.63 ± 1.35 0.54 ± 1.36
4.36 ± 7.16 0.07 ± 0.27 0 0.93 ± 2.43 0.43 ± 0.76 0.36 ± 0.74 0 0.43 ± 0.85 0.5 ± 1.61 0.71 ± 1.73 0 0.50 ± 1.61 0.43 ± 4.60
4.71 ± 7.21 0.09 ± 0.77 0.09 ± 0.43 0.21 ± 0.89 0.58 ± 1.48 0.44 ± 1.15 0.03 ± 0.29 0.65 ± 1.55 0.17 ± 0.56 0.69 ± 1.70 0.24 ± 1.13 0.60 ± 1.39 0.91 ± 2.15
NPI total score = frequency × severity. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; CDR = Clinical Dementia Rating scale; MMSE = Mini-Mental State Examination; F/U = follow-up; NPI = Neuropsychiatric Inventory. * p < 0.05.
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Fig. 2. A comparison of the baseline depression scores between CV and NCV groups in aMCI and svMCI patients. In aMCI patients, the IMP group exhibited higher baseline depression scores than the NCV group with regard to females, while in svMCI patients, the CV group exhibited higher depression scores compared to the NCV group with respect to males. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; IMP = patients who improved to a normal cognitive state; NCV = non-converters; CV = converters; *p values < 0.05.
had higher MMSE scores (28.00 ± 2.11) than NCV (p = 0.004 for age, p = 0.011 for MMSE) and CV groups (p = 0.001 for age, p < 0.001 for MMSE). After adjustment for the age and MMSE scores, no significant differences were found in NPI scores among the three groups. However, some differences were found when sub-analyzing patients according to gender. In females, the IMP group was younger (64.38 ± 5.48) than NCV (70.69 ± 6.28, p = 0.036) and CV (71.22 ± 7.98, p = 0.030) groups, and the MMSE scores were higher in the IMP group as compared to that of the CV group (27.13 ± 2.30 vs. 23.47 ± 4.14, p = 0.023). After adjusting for age and MMSE scores, the IMP group showed higher depression scores than the NCV group (2.38 ± 2.56 vs. 0.73 ± 1.67, p = 0.018, after Bonferroni’s correction). Although it did not reach statistical significance, there was a trend toward relatively higher depression scores in the IMP group than in the CV group (2.38 ± 2.56 vs. 0.89 ± 1.45, p = 0.064, after Bonferroni’s correction). In males, the results of the comparison in demographic variables were similar to those of females (IMP group with younger age than CV group: 64.0 ± 7.51 vs. 72.35 ± 8.63, p = 0.038, and higher MMSE scores than NCV and CV groups: IMP 29.17 ± 1.17; NCV 26.35 ± 2.53, p = 0.034; CV 23.75 ± 2.75, p = 0.001). However, no items exhibited significant differences among the three groups after correcting for age and MMSE scores as confounding factors. The results have been displayed in Fig. 2. 3.3. Comparison of the baseline neuropsychiatric symptoms between converters and non-converters in patients with svMCI With regard to the svMCI group, no patients have recuperated to normal cognitive levels and therefore, patients were classified only into non-converters (n = 35/49, 71.4%) and converters (n = 14/49, 28.6%). The baseline and the second tests spanned 19.2 ± 8.7 months, therefore the annual conversion rate in our svMCI patients was 17.9%. There were no significant differences in demographic variables except for the gender ratio which revealed a higher proportion of females in the NCV group than in the CV group (65.71% vs. 28.57%). After adjusting the gender ratio, the scores of total and each NPI domain did not differ between two groups (Table 2). Therefore, as with the aMCI group, we conducted subgroup analyses according to gender. In males, the CV group exhibited a higher score of depression compared to the NCV group
(3.90 ± 4.07 vs. 0.50 ± 0.80, p = 0.027, after Bonferroni’s correction). However, in females, there were no significant differences between NCV and CV groups in the total and subscores of the NPI domains. The results have been displayed in Fig. 2. 4. Discussion The overall prevalence of neuropsychiatric symptoms in our MCI sample was rather high (67%) as compared to previous reports (35–75%) [3,4,25], which may be attributed to the fact that the study population was drawn from a hospital-based cohort. The higher annual conversion rate (22% for aMCI and 17% for svMCI) in our study compared to previous study (12%) [16] also supported the fact that our MCI patients included more impending dementia. To our knowledge, there have been no studies that compared neuropsychiatric symptom between aMCI and svMCI. We expected neuropsychiatric symptoms to be more common in svMCI than in aMCI. However, the frequency of each neuropsychiatric symptom did not differ between the two. In a previous study performed on AD and VaD, it was reported that patients with VaD had higher NPI scores in all domains than AD patients [26]. One plausible explanation for our result is that, at least in their early stages, there are few or no differences between aMCI and svMCI. In addition, most previous studies comparing neuropsychiatric symptoms in AD and VaD showed only minor difference [11,27,28] which was in line with our result. Although the frequency of each neuropsychiatric symptom did not differ between aMCI and svMCI, when the groups were further divided according to gender, some differences remained in aMCI, but not in svMCI. That is, in aMCI patients, hallucination and eating disorder were more common in females than in males. Women are more likely than men to have eating disorders in the general society as well. In previous studies focusing on neuropsychiatric symptoms in MCI, the difference in the prevalence of neuropsychiatric symptoms between males and females was inconsistent [29,30]. Our finding that a genderrelated difference existed in aMCI suggests that neuropsychiatric abnormalities in aMCI may be driven both by neurobiological and socio-environmental factors. This finding is consistent with previous report that socio-demographic variables such as age, sex, education, and financial status influence neuropsychiatric symptoms in MCI patients [31].
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One of the major goals of this study was to determine if NPI could serve as a marker to predict the conversion to dementia. Previous studies have shown that MCI patients with higher total NPI score or those with depression or apathy were more likely to convert to dementia [12,13]. Unlike these studies, converters and non-converters in the current study did not differ with respect to the total and domain-specific NPI scores in aMCI patients. On the other hand, in svMCI patients, especially in male patients, depression was a predictive marker of conversion to dementia, suggesting that vascular depression is more closely related to organic brain lesions such as ischemic brain damage. This is supported by the fact that in elderly patients with depression, researchers have identified an increase of hyperintensities in the white matter and deep gray matter [32,33]. However, it is unclear why this is the case only for males and not for females. More interestingly, depression served as a good prognostic factor for female aMCI patients. That is, a significant number of female aMCI patients may represent cognitive deficits secondary to depression, implying that these patients seem to have had a higher chance of improving to normal cognition. These finding are contrary to recent studies that found MCI patients with depression were at higher risk of developing AD [12,34]. However, this finding was not replicated in other studies [35,36]. These differences may be derived from the difference in study population and social characteristics in each culture. In our study population, female aMCI patients seem to have a closer relationship with so-called pseudo-cognitive deficits from depression. This postulate may be supported by the fact that so-called “Hwabyung”, a unique Korean culture bound syndrome expressing depression, is more prevalent in women than in men [37]. Thus, this finding suggests that longer follow-ups are warranted in female patients with aMCI and depression. There were a couple of limitations related to the current study. First, we did not control for the effects of anti-dementia or other medications that might have an impact on neuropsychiatric symptoms, possibly confounding the results. Second, another major limitation of this study was relatively small sample size and short follow-up period in the follow-up studies, thus future study with a large number of patients and longer follow-up period is needed. Third, we could not check whether the patients have been received work-up for depression and treatment after diagnosed with depression. 5. Conclusions Our data suggested that depression might serve as a potential marker of conversion to dementia in patients with svMCI, although the result was significant only in male patients. In addition, female aMCI patients with depression need to be carefully followed due to possible chance of improving to normal cognition. However, given the small number for these gender subanalyses, further study involving a large number of patients is required. Conflicts of interest The authors have no conflicts of interest to disclose. Acknowledgments This study was supported by a grant from the Korea Health 21 R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A102065, A090609). References
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Neuropsychiatric predictors of conversion to dementia both in patients with amnestic mild cognitive impairment and those with subcortical vascular MCI Sook Hui Kim a , Hyun Seok Kang b , Hee Jin Kim a , Hui Jin Ryu a , Min young Kim a , Sang Won Seo c , Duk L. Na c , Seol-Heui Han a,∗ a
Department of Neurology, Konkuk University Hospital, Konkuk University School of Medicine, Seoul, Republic of Korea Department of Neurology, Bundang Jesaeng General Hospital, Gyeonggi-do, Republic of Korea c Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 2 August 2011 Received in revised form 21 October 2012 Accepted 27 November 2012 Available online 3 January 2013 Keywords: Neuropsychiatric Inventory Amnestic mild cognitive impairment Subcortical vascular mild cognitive impairment
a b s t r a c t Objective: The aim of this study was to investigate whether specific neuropsychiatric domains could predict a conversion to dementia in those patients either with amnestic subtype of mild MCI (aMCI) or subcortical vascular MCI (svMCI). Methods: At baseline, all subjects underwent neuropsychological tests, Neuropsychiatric Inventory (NPI), and MRI. We compared the baseline NPI scores between converters (CV) and non-converters (NCV) both in the aMCI and svMCI groups. Results: The mean follow-up duration was 16.74 ± 8.02 months (range: 4.2–43.9). At the second time point, about 30% of aMCI and svMCI patients converted to dementia with 7.5% of aMCI patients exhibiting improvement to normal cognitive state. In female aMCI patients, those who later improved to normal cognition exhibited higher baseline depression scores than the CV group. However, baseline depression scores were higher in the CV group than the NCV group in svMCI patients, and this difference was significant only in males. Conclusion: Our results suggest that depression might serve as a predictive marker of conversion to dementia in patients with svMCI, albeit only in males. On the other hand, patients who later improved to normal cognition showed higher scores of depression at baseline in female aMCI patients, suggesting that longer follow-ups are warranted in female patients with aMCI and depression. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Patients with dementia present not only cognitive impairment but also neuropsychiatric symptoms including behavioral and mood changes. Neuropsychiatric symptoms often have a more serious impact on the performance of daily activities than do cognitive deficits, therefore they lead to an increase in caregiver burden. Organic changes in the specific neural structures may mediate the genesis of neuropsychiatric symptoms in dementia [1,2] and thus, the more the disease progresses, the more likely patients present abnormal behaviors. Up to now, neuropsychiatric symptoms have been the most extensively investigated in patients with dementia; however, those symptoms could also be present in patients with mild cognitive impairment (MCI) which is a
∗ Corresponding author at: Department of Neurology, Konkuk University Hospital, 4-12 Hwayanag-dong, Gwangjin-gu 143-729, Seoul, Republic of Korea. Tel.: +82 2 2030 6221; fax: +82 2 2049 6192. E-mail address: [email protected] (S.-H. Han). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2012.11.029
preclinical stage of dementia [3]. In fact, Apostolova and Cummings summarized the studies of neuropsychiatric symptoms in MCI patients and argued that neuropsychiatric symptoms are more prevalent than expected, existing in about 35–75% of MCI populations [4]. Mild cognitive impairment comprises heterogeneous subgroups according to clinical characteristics and etiologies [5], being divided into amnestic and non-amnestic types, and degenerative and vascular etiologies. Of those, amnestic subtype of MCI (aMCI) may represent a forme fruste of Alzheimer’s disease (AD) [6], especially when patients with aMCI do not exhibit white matter ischemia or lacunes on magnetic resonance imaging (MRI). On the other hand, subcortical vascular MCI (svMCI) may refer to a preclinical stage of subcortical vascular dementia (SVaD) [7]. Neuropsychiatric symptoms of SVaD may differ from those of AD such that vascular depression [8,9], agitation, anxiety, and apathy are more prevalent features in patients with SVaD than in those with AD [10,11]. In addition, sometimes non-cognitive behavioral problems precede the cognitive impairment in those patients. Likewise neuropsychiatric symptoms of aMCI may differ from those of svMCI, however, this has seldom been studied.
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Many investigators have attempted to find biological markers which can predict the conversion to dementia in MCI patients, given that early detection and treatment in order to halt the progression to dementia would be invaluable. Those studies, however, mainly have focused on neuropsychological or imaging findings. On the other hand, there have been only a few studies that have tried to assess the predictability of neuropsychiatric symptoms in patients with MCI [12,13]. A previous study compared the baseline differences of neuropsychiatric symptoms in MCI patients using the Neuropsychiatric Inventory (NPI) and demonstrated that patients who would later develop dementia had higher frequencies of depression and apathy than those patients who remained stable at follow-up [12]. However, that study included only a small number of patients and subsequent subgroup analyses with regard to etiology (degenerative vs. vascular MCI) were not conducted. Another study involving a larger number of patients also did not consider the etiologies of MCI and did not delineate the specific NPI domains [13]. Adding to neuropsychological and imaging biomarkers, neuropsychiatric markers may serve as a complementary modality predicting the progression to dementia both in patients with aMCI and those with svMCI. Thus, the purposes of the current study were, from a large hospital-based cohort, (1) to find baseline differences in NPI characteristics between aMCI and svMCI groups and (2) to investigate whether specific neuropsychiatric domains could predict the conversion to dementia in patients either with aMCI or svMCI, and if so, whether there were differences in predictable NPI domains between the two groups. Since, a difference between males and females with respect to the prevalence of neuropsychiatric symptoms has been widely reported across various studies [14,15], we considered a sub-analysis according to gender in all analyses.
2. Materials and methods 2.1. Participants Patients were extracted from the CREDOS (Clinical Research Center for Dementia of South Korea) study which was a large hospital-based cohort for epidemiological and clinical studies of patients with cognitive impairment. Of the total, we enrolled patients either with aMCI or svMCI. Diagnosis of aMCI in the CREDOS study met the following criteria: (1) patients met the criteria for MCI proposed by Petersen et al. including the followings: memory problems, objective memory disorder, absence of other cognitive disorders or repercussions on daily life, normal general cogntive function and absence of dementia [16]; (2) they had no focal neurological symptoms or signs to suggest focal brain lesions or parkinsonism on neurological examination; (3) they had no structural lesions on brain MRI such as brain tumor, hemorrhage, or hydrocephalus, nor did they exhibit significant cortical/subcortical vascular ischemia. Patients with only mild degree of ischemia were included based on the CREDOS rating scales of white matter changes [17]. To be more specific regarding Petersen’s criteria, we applied the following principles in addition to the general principles stated above: (1) subjective memory complaint by the patient or his/her caregiver; (2) objective memory decline below one standard deviation (SD) on neuropsychological tests, in which delayed recall performance was used; (3) normal general cognitive function; (4) normal activities of daily living (ADL) both clinically and on an ADL scale; and (5) not demented. As for svMCI, we applied Petersen criteria with the following modifications: (1) “subjective cognitive complaint by the patient or his/her caregiver” was used instead of “subjective memory complaint by the patient of his/her caregiver”; (2) in “objective memory
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decline below the 1 SD on neuropsychological tests,” we used “objective cognitive decline. . ..” Instead; (3) normal general cognitive function; (4) normal Activity of Daily Living (ADL) score both judged clinically and on ADL scales; (5) not having dementia; and (6) a subcortical vascular feature defined as both focal neurological symptom/sign and the severe degree of ischemia on MRI defined as a cap or band ≥10 mm as well as a deep white matter lesion ≥25 mm. Patients were excluded if they had cortical lesions, cortico-subcortical non lacunar territorial infarcts, hemorrhage, or normal pressure hydrocephalus. For the evaluation of ADL, we used the Barthel Index [18], and the Seoul-Instrumental Activities of Daily Living (S-IADL) [19]. The S-IADL was a caregiveradministered instrument designed to measure IADL. It contained 15 items: using the telephone, shopping, preparing food/cooking, household chores, using transportation, going out for a short distance, taking medications, managing finances, grooming, using household appliances, managing belongings, securing a door, keeping appointments, talking about recent events, and participating in leisure/hobbies. All items were scored on a four-point Likert scale ranging from 0 to 3, with higher scores indicating lower functioning. All the patients underwent laboratory tests to exclude other possible causes that can affect cognition including complete blood counts (CBC), chemistry and electrolytes, lipid profile, urinalysis, venereal disease research laboratory (VDRL), thyroid function test, vitamin B12/folate, fibrinogen, and homocysteine. From August 2005 to December 2008, there were 1135 aMCI and 286 svMCI patients that were registered. As of December 2009, 238 patients received at least one follow-up evaluation and the data from baseline and the most recent follow-up visits were used for our evaluation (174 patients had only one follow-up visit, 52 had two, 11 had three and 1 had four follow-up visits). The remaining 1183 were supposed to be followed up or had been lost. In the CREDOS cohort, subjects included in the current study were older and had on average higher educational levels than those who were not included (71.08 ± 7.00 vs. 69.73 ± 7.96, p = 0.013 for age; 8.73 ± 5.07 vs. 7.35 ± 5.17, p < 0.001 for educational level; 25.06 ± 3.42 vs. 24.82 ± 3.66, p = 0.330 for MMSE score). Two out of the 238 were excluded because they did not perform the NPI questionnaire. Thus, a final total of 236 (187 MCI and 49 svMCI) were included in this study (Fig. 1). The mean duration from diagnosis to follow-up was 16.74 ± 8.02 months (range: 4.2–43.9). Detailed demographics are displayed in Table 1. The diagnosis of AD at follow-up was based on National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria for probable AD [20]. As for SVaD, patients had to meet the diagnostic criteria for the vascular dementia as proposed by the DSM IV and had to have a subcortical vascular feature defined as in the svMCI. Some patients met both of the full diagnostic criteria for AD and SVaD, which meant mixed cases. We considered these patients to have AD with or without white matter changes. At the time of the second follow-up, 70 of 236 patients (29.7%) converted to dementia and 166 (70.3%) remained stable. Of patients who did not convert to dementia, fourteen improved to a normal cognitive state at follow-up, all of whom were aMCI patients at baseline. Patients were informed in detail and informed consents were received. The study was approved by the Institutional Review Board of Konkuk University Hospital. 2.2. Assessment of neuropsychiatric symptoms Neuropsychiatric symptoms were assessed using the caregiveradministered NPI (CGA-NPI) [21]. The CGA-NPI worksheet was identical to the NPI version. The CGA-NPI procedures, including the scoring method, did not differ from those of the NPI. After the
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Fig. 1. Participants flow chart. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; SVaD = subcortical vascular dementia; NPI = Neuropsychiatric Inventory; F/U = follow-up.
caregivers completed the CGA-NPI unassisted, they were briefly interviewed by the examiners (post supervision), who checked if the caregivers had completed the form appropriately. The NPI was composed of 12 domain caregiver-based ratings including delusion, hallucination, agitation, depression, anxiety, elation, apathy, disinhibition, irritability, aberrant motor behavior, sleep disorder, and eating disorder [22]. Scores on each domain were determined by multiplying the frequency (range from 1 to 4) and severity (range
from 1 to 3) scores. The total NPI score was determined by the sum of all domain scores. 2.3. Neuropsychological evaluation The Seoul Neuropsychological Screening Battery (SNSB), a standardized neuropsychological battery [23], included tests for attention, language, praxis, four elements of Gerstmann syndrome,
Table 1 Demographic characteristics and results of NPI scores in aMCI and svMCI patients. aMCI
N Age Sex, female (%) Education CDR, sum of box MMSE Time from diagnosis to F/U (months) NPI scores NPI total Delusion Hallucination Aggression Depression Anxiety Euphoria Apathy Disinhibition Anger Aberrant motor behaviors Sleep disorder Eating disorder
svMCI
Total
Male
Female
Total
Male
Female
187 70.39 ± 7.06 64.71% 8.86 ± 5.02 1.54 ± 0.85 25.01 ± 3.42 16.09 ± 7.72
66 70.43 ± 6.93
121 70.32 ± 7.36
22 74.05 ± 6.28
27 71.48 ± 6.86
12.30 ± 3.96 1.49 ± 0.93 25.82 ± 2.95 15.43 ± 7.39
6.99 ± 4.54† 1.56 ± 0.81 24.56 ± 3.58† 16.45 ± 7.90
49 72.63 ± 6.66* 55.10% 8.14 ± 5.39 1.48 ± 0.86 25.18 ± 3.60 19.21 ± 8.21*
10.45 ± 5.60 1.30 ± 0.70 26.41 ± 3.38 18.83 ± 8.18
6.26 ± 4.49† 1.63 ± 0.96 24.19 ± 3.53† 19.52 ± 9.27
5.00 ± 7.06 0.14 ± 0.80 0.07 ± 0.45 0.21 ± 0.81 0.66 ± 1.49 0.50 ± 1.16 0.04 ± 0.28 0.73 ± 1.76 0.16 ± 0.51 0.78 ± 1.64 0.20 ± 0.97 0.62 ± 1.56 0.90 ± 2.12
3.88 ± 5.48 0.02 ± 0.12 0.02 ± 0.12 0.27 ± 1.09 0.26 ± 0.83 0.45 ± 1.04 0.09 ± 0.45 0.61 ± 1.21 0.12 ± 0.37 0.89 ± 1.59 0.27 ± 1.27 0.41 ± 1.01 0.41 ± 1.69
5.61 ± 7.74 0.21 ± 0.98 0.11 ± 0.54† 0.18 ± 0.61 0.88 ± 1.71 0.53 ± 1.22 0.01 ± 0.09 0.79 ± 2.00 0.17 ± 0.57 0.72 ± 1.67 0.16 ± 0.76 0.73 ± 1.78 1.17 ± 2.28†
4.49 ± 6.42 0.06 ± 0.24 0 0.31 ± 1.34 0.76 ± 1.68 0.37 ± 0.78 0.02 ± 0.14 1.00 ± 2.31 0.29 ± 0.94 0.59 ± 1.21 0 0.59 ± 1.41 0.51 ± 1.42
4.18 ± 6.66 0.09 ± 0.29 0 0.14 ± 0.47 0.91 ± 2.33 0.36 ± 0.66 0 1.36 ± 2.85 0.18 ± 0.50 0.50 ± 1.10 0 0.32 ± 0.89 0.32 ± 1.29
4.74 ± 6.33 0.04 ± 0.19 0 0.44 ± 1.76 0.63 ± 0.88 0.37 ± 0.88 0.04 ± 0.19 0.70 ± 1.75 0.37 ± 1.18 0.67 ± 1.30 0 0.81 ± 1.71 0.67 ± 1.52
NPI total score = frequency × severity. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; CDR = Clinical Dementia Rating scale; MMSE = Mini-Mental State Examination; F/U = follow-up; NPI = Neuropsychiatric Inventory. * p < 0.05 vs. total aMCI. † p < 0.05 vs. male.
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visuoconstructive function, verbal and visual memory and frontal/executive function. Memory function was considered abnormal when the score for the delayed recall on the Seoul Verbal learning test (SVLT; three learning-free recall trials of 12 words, 20min delayed recall trial for these 12 items, and a recognition test) or Rey–Osterrieth Complex Figure Test (RCFT) was below the 1 SD of the norm. The detailed elements of the test have been presented elsewhere [24]. 2.4. Statistical analysis Statistical analysis was conducted using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). Demographic characteristics between the two groups were compared using independent-samples t-test for continuous variables and a Chi-square test for categorical variables. The NPI scores were compared between the groups using an analysis of covariance (ANCOVA) to control variables which differ between groups (age, education, MMSE, and follow-up duration). The value of p < 0.05 was set as a significance threshold and when post hoc multiple comparisons were applied, p-values were adjusted using the Bonferroni correction. 3. Results 3.1. Comparison of the baseline neuropsychiatric symptoms between aMCI and svMCI Patients with svMCI were older and had longer follow-up periods than those with aMCI (Table 1). About 67% of the aMCI and 61% of svMCI patients exhibited at least one neuropsychiatric symptom. In aMCI patients, the most frequent neuropsychiatric abnormalities were depression (33.2%), irritability (33.2%), apathy (26.7%), anxiety (25.7%), and eating disorder (23.1%). The most frequent neuropsychiatric symptoms exhibited by svMCI patients were depression (34.7%), apathy (30.6%), irritability (30.6%), anxiety (24.5%), and sleep disorder (20.4%). In baseline NPI scores, the aMCI group exhibited higher scores on hallucination and aberrant motor behavior than the svMCI group,
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but the statistical significance was lost after adjusting for age and follow-up period. When each group was further subdivided according to gender, male patients had higher MMSE scores and educational level compared with female patients both in aMCI and svMCI groups. After adjusting MMSE scores and educational levels, females exhibited higher scores on hallucination (F = 5.455, p = 0.001) and eating disorder (F = 3.278, p = 0.022) than males in the aMCI group, while no significant difference was found between males and females in the svMCI group (Table 1). 3.2. Comparison of the baseline neuropsychiatric symptoms between converters and non-converters in patients with aMCI At the follow-up examination, 117 out of 187 aMCI patients (62.6%) turned out to be non-converters (NCV) who remained in an aMCI state, whereas 56 out of 187 patients (29.9%) were designated as converters (CV) who progressed to dementia. The remaining 14 patients improved to normal cognitive status, which will be described later. The time between the baseline and the follow-up test averaged 16.1 ± 7.7 months, and therefore, the annual conversion rate in our aMCI patients was 22.4%. When comparing NPI scores between CV and NCV groups, there were no significant differences in the total and subscores of baseline NPI items after adjusting MMSE scores (Table 2). We further divided the aMCI patients into subgroups according to gender. However, there were no significant differences in the NPI scores between CV and NCV groups both in males and females. In our sample, 14 patients improved to a normal cognitive state at the follow-up (IMP; n = 14/187, 7.5%), thus we conducted an additional analysis of baseline demographics and NPI scores among three groups including the IMP group (NCV, CV and IMP groups). There was no significant difference of the female ratio among three subgroups: IMP (n = 8, 57.14%); NCV (n = 77, 65.81%); CV (n = 36, 64.29%). Significant differences were found in age (F = 6.611, p = 0.02) and MMSE scores (F = 12.138, p < 0.001) among the three groups. In the post hoc analysis with Bonferroni’s correction for multiple comparison, the IMP group was younger (66.5 ± 6.14) and
Table 2 Demographic characteristics and NPI scores in non-converters and converters. aMCI (n = 187)
N Age Sex, female (%) Education (years) CDR, sum of box MMSE F/U duration NPI scores NPI total Delusion Hallucination Aggression Depression Anxiety Euphoria Apathy Disinhibition Anger Aberrant motor behaviors Sleep disorder Eating disorder
svMCI (n = 49)
NCV
CV
NCV
CV
117 71.16 ± 6.93 65.81% 8.22 ± 5.16 1.44 ± 0.73 25.33 ± 3.10 16.09 ± 7.71
56 70.37 ± 9.71 64.29% 9.81 ± 4.80* 1.88 ± 1.03* 23.57 ± 3.68* 16.40 ± 8.39
35 71.74 ± 6.39 65.71% 7.21 ± 4.71 1.43 ± 0.91 25.34 ± 3.52 19.44 ± 9.19
14 74.86 ± 7.05 28.57%* 10.46 ± 6.43 1.61 ± 0.74 24.79 ± 3.91 18.63 ± 7.70
5.50 ± 6.52 0.27 ± 0.94 0.07 ± 0.53 0.29 ± 0.73 0.66 ± 1.24 0.55 ± 1.04 0.05 ± 0.30 0.80 ± 1.88 0.1 ± 0.46 0.96 ± 1.65 0.16 ± 0.71 0.68 ± 1.94 0.86 ± 2.08
4.54 ± 6.21 0.06 ± 0.24 0 0.06 ± 0.24 0.89 ± 1.92 0.37 ± 0.81 0.03 ± 0.17 1.23 ± 2.66 0.20 ± 0.47 0.54 ± 0.95 0 0.63 ± 1.35 0.54 ± 1.36
4.36 ± 7.16 0.07 ± 0.27 0 0.93 ± 2.43 0.43 ± 0.76 0.36 ± 0.74 0 0.43 ± 0.85 0.5 ± 1.61 0.71 ± 1.73 0 0.50 ± 1.61 0.43 ± 4.60
4.71 ± 7.21 0.09 ± 0.77 0.09 ± 0.43 0.21 ± 0.89 0.58 ± 1.48 0.44 ± 1.15 0.03 ± 0.29 0.65 ± 1.55 0.17 ± 0.56 0.69 ± 1.70 0.24 ± 1.13 0.60 ± 1.39 0.91 ± 2.15
NPI total score = frequency × severity. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; CDR = Clinical Dementia Rating scale; MMSE = Mini-Mental State Examination; F/U = follow-up; NPI = Neuropsychiatric Inventory. * p < 0.05.
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Fig. 2. A comparison of the baseline depression scores between CV and NCV groups in aMCI and svMCI patients. In aMCI patients, the IMP group exhibited higher baseline depression scores than the NCV group with regard to females, while in svMCI patients, the CV group exhibited higher depression scores compared to the NCV group with respect to males. aMCI = amnestic subtype of mild cognitive impairment; svMCI = subcortical vascular mild cognitive impairment; IMP = patients who improved to a normal cognitive state; NCV = non-converters; CV = converters; *p values < 0.05.
had higher MMSE scores (28.00 ± 2.11) than NCV (p = 0.004 for age, p = 0.011 for MMSE) and CV groups (p = 0.001 for age, p < 0.001 for MMSE). After adjustment for the age and MMSE scores, no significant differences were found in NPI scores among the three groups. However, some differences were found when sub-analyzing patients according to gender. In females, the IMP group was younger (64.38 ± 5.48) than NCV (70.69 ± 6.28, p = 0.036) and CV (71.22 ± 7.98, p = 0.030) groups, and the MMSE scores were higher in the IMP group as compared to that of the CV group (27.13 ± 2.30 vs. 23.47 ± 4.14, p = 0.023). After adjusting for age and MMSE scores, the IMP group showed higher depression scores than the NCV group (2.38 ± 2.56 vs. 0.73 ± 1.67, p = 0.018, after Bonferroni’s correction). Although it did not reach statistical significance, there was a trend toward relatively higher depression scores in the IMP group than in the CV group (2.38 ± 2.56 vs. 0.89 ± 1.45, p = 0.064, after Bonferroni’s correction). In males, the results of the comparison in demographic variables were similar to those of females (IMP group with younger age than CV group: 64.0 ± 7.51 vs. 72.35 ± 8.63, p = 0.038, and higher MMSE scores than NCV and CV groups: IMP 29.17 ± 1.17; NCV 26.35 ± 2.53, p = 0.034; CV 23.75 ± 2.75, p = 0.001). However, no items exhibited significant differences among the three groups after correcting for age and MMSE scores as confounding factors. The results have been displayed in Fig. 2. 3.3. Comparison of the baseline neuropsychiatric symptoms between converters and non-converters in patients with svMCI With regard to the svMCI group, no patients have recuperated to normal cognitive levels and therefore, patients were classified only into non-converters (n = 35/49, 71.4%) and converters (n = 14/49, 28.6%). The baseline and the second tests spanned 19.2 ± 8.7 months, therefore the annual conversion rate in our svMCI patients was 17.9%. There were no significant differences in demographic variables except for the gender ratio which revealed a higher proportion of females in the NCV group than in the CV group (65.71% vs. 28.57%). After adjusting the gender ratio, the scores of total and each NPI domain did not differ between two groups (Table 2). Therefore, as with the aMCI group, we conducted subgroup analyses according to gender. In males, the CV group exhibited a higher score of depression compared to the NCV group
(3.90 ± 4.07 vs. 0.50 ± 0.80, p = 0.027, after Bonferroni’s correction). However, in females, there were no significant differences between NCV and CV groups in the total and subscores of the NPI domains. The results have been displayed in Fig. 2. 4. Discussion The overall prevalence of neuropsychiatric symptoms in our MCI sample was rather high (67%) as compared to previous reports (35–75%) [3,4,25], which may be attributed to the fact that the study population was drawn from a hospital-based cohort. The higher annual conversion rate (22% for aMCI and 17% for svMCI) in our study compared to previous study (12%) [16] also supported the fact that our MCI patients included more impending dementia. To our knowledge, there have been no studies that compared neuropsychiatric symptom between aMCI and svMCI. We expected neuropsychiatric symptoms to be more common in svMCI than in aMCI. However, the frequency of each neuropsychiatric symptom did not differ between the two. In a previous study performed on AD and VaD, it was reported that patients with VaD had higher NPI scores in all domains than AD patients [26]. One plausible explanation for our result is that, at least in their early stages, there are few or no differences between aMCI and svMCI. In addition, most previous studies comparing neuropsychiatric symptoms in AD and VaD showed only minor difference [11,27,28] which was in line with our result. Although the frequency of each neuropsychiatric symptom did not differ between aMCI and svMCI, when the groups were further divided according to gender, some differences remained in aMCI, but not in svMCI. That is, in aMCI patients, hallucination and eating disorder were more common in females than in males. Women are more likely than men to have eating disorders in the general society as well. In previous studies focusing on neuropsychiatric symptoms in MCI, the difference in the prevalence of neuropsychiatric symptoms between males and females was inconsistent [29,30]. Our finding that a genderrelated difference existed in aMCI suggests that neuropsychiatric abnormalities in aMCI may be driven both by neurobiological and socio-environmental factors. This finding is consistent with previous report that socio-demographic variables such as age, sex, education, and financial status influence neuropsychiatric symptoms in MCI patients [31].
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One of the major goals of this study was to determine if NPI could serve as a marker to predict the conversion to dementia. Previous studies have shown that MCI patients with higher total NPI score or those with depression or apathy were more likely to convert to dementia [12,13]. Unlike these studies, converters and non-converters in the current study did not differ with respect to the total and domain-specific NPI scores in aMCI patients. On the other hand, in svMCI patients, especially in male patients, depression was a predictive marker of conversion to dementia, suggesting that vascular depression is more closely related to organic brain lesions such as ischemic brain damage. This is supported by the fact that in elderly patients with depression, researchers have identified an increase of hyperintensities in the white matter and deep gray matter [32,33]. However, it is unclear why this is the case only for males and not for females. More interestingly, depression served as a good prognostic factor for female aMCI patients. That is, a significant number of female aMCI patients may represent cognitive deficits secondary to depression, implying that these patients seem to have had a higher chance of improving to normal cognition. These finding are contrary to recent studies that found MCI patients with depression were at higher risk of developing AD [12,34]. However, this finding was not replicated in other studies [35,36]. These differences may be derived from the difference in study population and social characteristics in each culture. In our study population, female aMCI patients seem to have a closer relationship with so-called pseudo-cognitive deficits from depression. This postulate may be supported by the fact that so-called “Hwabyung”, a unique Korean culture bound syndrome expressing depression, is more prevalent in women than in men [37]. Thus, this finding suggests that longer follow-ups are warranted in female patients with aMCI and depression. There were a couple of limitations related to the current study. First, we did not control for the effects of anti-dementia or other medications that might have an impact on neuropsychiatric symptoms, possibly confounding the results. Second, another major limitation of this study was relatively small sample size and short follow-up period in the follow-up studies, thus future study with a large number of patients and longer follow-up period is needed. Third, we could not check whether the patients have been received work-up for depression and treatment after diagnosed with depression. 5. Conclusions Our data suggested that depression might serve as a potential marker of conversion to dementia in patients with svMCI, although the result was significant only in male patients. In addition, female aMCI patients with depression need to be carefully followed due to possible chance of improving to normal cognition. However, given the small number for these gender subanalyses, further study involving a large number of patients is required. Conflicts of interest The authors have no conflicts of interest to disclose. Acknowledgments This study was supported by a grant from the Korea Health 21 R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A102065, A090609). References
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