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Neuropsychiatric characteristics of PiB-negative subcortical vascular dementia versus behavioral variant frontotemporal dementia
Archives of Gerontology and Geriatrics 67 (2016) 86–91
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Neuropsychiatric characteristics of PiB-negative subcortical vascular dementia versus behavioral variant frontotemporal dementia Na-Yeon Junga,b,c,d, Hee Jin Kima,b , Yeo Jin Kima,b,e, Seonwoo Kimf , Sang Won Seoa,b,g,h , Eun-Joo Kimd,i, Duk L. Na, MD PhDa,b,h,* a
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea Department of Neurology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea d Pusan National University School of Medicine and Medical Research Institute, Pusan, Republic of Korea e Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Republic of Korea f Biostatistics Team, Samsung Biomedical Research Institute, Seoul, Republic of Korea g Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea h Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea i Department of Neurology, Pusan National University Hospital, Pusan, Republic of Korea b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 January 2016 Received in revised form 5 April 2016 Accepted 13 July 2016 Available online 16 July 2016
Background: Neuropsychiatric symptoms of subcortical vascular dementia (SVaD) are mainly associated with damage to frontal-subcortical circuits and may be similar to symptoms of behavioral variant frontotemporal dementia (bvFTD). The aim of this study was to determine whether the neuropsychiatric manifestations of the Pittsburgh compound B (PiB)-negative SVaD and bvFTD groups differ. Methods: We compared the Caregiver-Administered Neuropsychiatry Inventory (CGA-NPI) between 48 patients with PiB() SVaD and 31 patients with bvFTD. A stepwise logistic regression was applied to determine the best model to predict SVaD. Results: The SVaD group showed a higher frequency of depression, whereas the bvFTD group had a higher frequency of elation, aberrant motor behavior and appetite/eating disorders. Regarding NPI subscores, the bvFTD group had greater severity of elation, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders, whereas SVaD did not have significantly higher subscores in any domains. The most predictive models that tend to find suggestions of SVaD, as opposed to bvFTD, are as follows: (1) the presence of depression and the absence of appetite/eating disorders, (2) higher NPI subscores of depression and lower NPI subscores of irritability and aberrant motor behavior. Conclusion: Apart from apathy, SVaD differed from bvFTD in that negative symptoms were more common in SVaD than bvFTD, whereas positive symptoms were predominant in bvFTD compared to SVaD. ã 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Subcortical vascular dementia Frontotemporal dementia Neuropsychiatric symptoms Apathy
1. Introduction Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, are an important part of dementia syndromes in addition to cognitive decline. BPSD poses a significant management challenge for clinicians and contributes to caregiver burden and stress. Patients with behavioral variant frontotemporal dementia (bvFTD) present with insidious changes in personality and
* Corresponding author at: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea. E-mail addresses: [email protected], [email protected] (D.L. Na). http://dx.doi.org/10.1016/j.archger.2016.07.002 0167-4943/ã 2016 Elsevier Ireland Ltd. All rights reserved.
interpersonal conduct that are associated with progressive disintegration of the frontotemporal circuits involved in social cognition, emotion regulation, motivation, decision-making and inhibitory control. All of the behavioral features found in bvFTD can occur in other dementias, but their predominance and early emergence typify bvFTD (Piguet, Hornberger, Mioshi, & Hodges, 2011). Neuropsychiatric abnormalities also account for a considerable portion of the morbidity caused by vascular dementia (AharonPeretz, Kliot, & Tomer, 2000; Gupta et al., 2014; Moretti, Torre, Antonello, & Cazzato, 2006; Srikanth, Nagaraja, & Ratnavalli, 2005). Anatomical correlates for vascular dementia are variable, depending on the affected vascular territories; however, the frontal areas are commonly affected in vascular dementia, and this is especially
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the case with subcortical vascular dementia (SVaD) (Román, Erkinjuntti, Wallin, Pantoni, & Chui, 2002). Therefore, earlier symptoms of vascular dementia can manifest as dysexecutive syndrome and BPSD associated with frontal subcortical circuits (Aharon-Peretz et al., 2000; Duering et al., 2011; Román et al., 2002). Indeed, prior studies have reported that the prevalence of any neuropsychiatric symptoms in patients with vascular dementia are demonstrated in up to 90% of patients, with behavioral symptoms associated with frontal injury being common (AharonPeretz et al., 2000; Srikanth et al., 2005). Although the clinical manifestation of vascular dementia is typically characterized by a stepwise deterioration, fluctuating course, and symptoms and signs suggestive of cerebrovascular disease, the majority of SVaD patients do not have these characteristic symptoms (Erkinjuntti, 2002; Román et al., 2002). Because most ischemia in SVaD patients occurs silently, many SVaD patients have insidious onset and gradual progression of disease, mimicking degenerative dementia. Previous studies demonstrated that neural correlates for SVaD are mainly located in frontal areas (Furuta, Ishii, Nishihara, & Horie, 1991; Tullberg et al., 2004), which largely overlap those of bvFTD. Therefore, initial neuropsychiatric symptoms of SVaD may be similar to those of bvFTD, potentially complicating the differential diagnosis and making it difficult to distinguish between the two disorders. To our knowledge, few studies have compared SVaD with bvFTD in terms of neuropsychiatric symptoms (Moretti et al., 2005; Perri, Monaco, Fadda, Caltagirone, & Carlesimo, 2014). Furthermore, only a few studies are available that investigated neuropsychiatric symptoms in SVaD patients, and these studies did not include patients with “pure” vascular dementia. In other words, although recent studies have shown that vascular and amyloid pathologies coexist in patients with SVaD (Lee et al., 2011) and post-stroke dementia (Mok et al., 2010), prior studies on neuropsychiatric symptoms of vascular dementia did not eliminate patients with mixed vascular and amyloid pathology. The aim of this study is therefore to compare the neuropsychiatric manifestations in patients with Pittsburgh compound B (PiB)-negative SVaD and bvFTD and to determine whether the neuropsychiatric manifestations of the two groups differ.
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has been reported on in a previous study (Kim et al., 2014). One patient without NPI data was excluded from final analysis. The diagnosis of bvFTD was made using the International consensus research criteria for bvFTD (Rascovsky et al., 2011). To fulfill the criteria for probable bvFTD, patients were required to have at least three of the following six behavioral/cognitive symptoms: (1) early behavioral disinhibition, (2) early apathy or inertia, (3) early loss of sympathy or empathy for others, (4) early perseverative, stereotyped or compulsive, ritualistic behavior, (5) hyperorality and dietary changes, and (6) frontal executive deficits with relative sparing of memory and visuospatial functions. Additionally, functional decline and imaging studies (MRI, CT, SPECT or FDG PET) demonstrating focal cerebral atrophy, hypoperfusion, or glucose hypometabolism in the anterior temporal lobe and/or frontal lobe were required. Based on these inclusion criteria, we recruited a total of 32 patients with probable bvFTD from August 2008 to August 2014. One patient without NPI data was excluded from final analysis. Table 1 shows the demographic characteristics of the PiB() SVaD and the bvFTD groups. The two groups did not differ in sex, disease duration, MMSE, CDR, or CDR-SOB. Patients with bvFTD were significantly younger than those with PiB() SVaD. Education level was higher in the bvFTD group than the PiB() SVaD group. 2.2. Standard protocol approval, registration, and patient consent We obtained a written consent from each participant and the institutional review board of Samsung Medical Center approved the study protocol. 2.3. Neuropsychological tests All patients underwent neuropsychological testing using a standardized battery called the Seoul Neuropsychological Screening Battery (Kang & Na, 2003). This battery comprises tests for attention, language, calculation, praxis, visuospatial/constructive function, verbal/visual memory, and frontal/executive function as previously described (Seo et al., 2007). 2.4. Behavior rating scales
2. Methods 2.1. Patients All patients were referred to the Memory Disorders Clinic at Samsung Medical Center for dementia assessment. Patients underwent a detailed clinical interview including behavioral assessment as previously described (Seo et al., 2007), neurologic examinations, a comprehensive neuropsychological test battery, blood tests, and MRI. Blood tests were used to exclude patients with vitamin deficiencies, hypothyroidism, syphilis, and other medical conditions that may cause dementia. MRI excluded patients with intracerebral macrohemorrhage, territorial infarction, head trauma, hydrocephalus, and white matter hyperintensities (WMH) associated with conditions other than ischemia, such as radiation injury, multiple sclerosis, and leukodystrophy. We considered patients with SVaD as having pure SVaD if they fulfilled DSM-IV criteria for vascular dementia, with a “severe” WMH on MRI and if they were negative for PiB retention (Yoon et al., 2013). The severe WMH on MRI was defined as a cap or a band 10 mm as well as a deep white matter lesion 25 mm, as modified from Fazekas ischemia criteria (Fazekas et al., 1993). According to these criteria, we enrolled a total of 49 patients from September 2008 to September 2011 and a subset of these patients
The Caregiver-Administered Neuropsychiatry Inventory (CGANPI) (Kang et al., 2004) was validated the same way as the original NPI (Cummings et al., 1994) except that the CGA-NPI is completed by the patients’ caregivers as a written form of the NPI worksheet. Caregivers who visited the patient at least once a week were given instructions or supervision just before and after filling out the questionnaire. More specifically, 74.7% of our patients lived with the patients, and the frequency of visit in the remaining patients was divided into once a week in 24.1% and more than three times a Table 1 Demographic Characteristics of PiB() SVaD (n = 48) and bvFTD (n = 31) groups. Demographics and cognitive indices
SVaD
bvFTD
p value
Sex (female, %) Age, years Disease duration, months Education, years MMSE CDR CDR-SOB
52.1 71.8 7.2 41.2 23.8 8.5 4.8 21.6 4.4 0.85 0.74 6.03 3.62
45.2 63.7 7.7 34.3 20.2 12.7 4.2 21.0 6.0 0.94 0.89 6.26 3.87
0.644 <0.001 0.189 <0.001 0.619 0.662 0.792
Data are expressed as the mean standard deviation or number of subjects (%); p values were calculated by x2 test or t-test as appropriate. Abbreviations: bvFTD, behavioral variant frontotemporal dementia; CDR, Clinical Dementia Rating; CDRSOB, Clinical Dementia Rating Sum of Boxes; MMSE, Mini Mental State Examination; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
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week in 1.3% of the patients. In a previous study (Kang et al., 2004), the correlation values (k) between the NPI and CGA-NPI scores (severity/frequency/distress of caregiver) were reported to be greater than 0.6 (0.60–0.89). Severity (0 = absent, 1 = mild, 2 = moderate, 3 = severe) and frequency (0 = absent, 1 = occasionally, less than once per week, 2 = often, about once per week, 3 = frequently, several times per week, but less than every day, 4 = very frequently, once or more per day or continuously) are rated for 12 neuropsychiatric domains. The domain score was subsequently calculated as the multiplication of the symptom frequency and severity. The sum of the 12 domain subscores provides the total NPI score. The presence of behavioral and psychological symptoms was defined as a subscore of 1. 2.5. Statistical analysis We used the x2 test or Fisher's exact test to compare categorical variables and the presence of individual BPSD, and used the t-test to compare continuous variables between PiB() SVaD and bvFTD groups. We used the Wilcoxon rank sum test to compare NPI subscores between the two groups. To find variables that were significantly associated with PiB() SVaD group, we performed stepwise regression (entry significant level = 0.1, stay significant level = 0.1) on each potential variable which included age, sex, years of education, and the presence of 12 NPI items. Then, we performed multivariable analysis by logistic regression analysis for PiB() SVaD using significant variables (p < 0.05) in stepwise regression. A model for discriminating PiB() SVaD from bvFTD was generated. Also, we performed stepwise regression using the same method described above, with age, sex, years of education, and 12 NPI subscores as input variables. We generated one more model to discriminate PiB() SVaD from bvFTD. The diagnostic performance of each model was evaluated from the area under the curve (AUC) that was obtained from receiver operating characteristic curve analyses. We used the Youden index to identify a cutoff value for optimal sensitivity and specificity of each model. Statistical analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, NC).
3. Results 3.1. NPI frequency in PiB() SVaD versus bvFTD Of the patients with PiB() SVaD, 83.3% had at least one neuropsychiatric symptom, while 100% of patients in the bvFTD group had at least one neuropsychiatric symptom (p = 0.020). In the PiB() SVaD group, apathy was the commonest BPSD at 58.3%, followed by depression/dysphoria (45.8%), agitation/aggression (41.7%), and anxiety and irritability (37.5%). In the bvFTD group, apathy was also the commonest neuropsychiatric symptom at 77.4%, followed by appetite/eating disorders (71.0%), and agitation/ aggression (61.3%). Comparing the PiB() SVaD and bvFTD groups, the PiB() SVaD group showed a significantly higher frequency of depression/dysphoria compared to the bvFTD group. On the other hand, the bvFTD group had a significantly higher frequency of elation/euphoria, aberrant motor behavior and appetite/eating disorders compared to the PiB() SVaD group (Fig. 1). 3.2. NPI severity based on NPI subscores in PiB() SVaD versus bvFTD Based on NPI subscores, apathy was the most severe symptom in the PiB() SVaD group, followed appetite/eating disorders, sleep and nighttime behavior and agitation. In the bvFTD group, apathy was also the most severe symptom, followed by appetite/eating disorders, aberrant motor behavior and irritability (Fig. 2). When the two groups were compared in terms of NPI subscores, the bvFTD group showed higher scores of elation/euphoria, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders. In contrast, there were no symptoms that had a higher NPI subscore in the PiB() SVaD group than in the bvFTD, and the total NPI scores were significantly higher in the bvFTD group (p < 0.001) (median: 24, interquartile range: 9–36) than the PiB() SVaD group (median: 8.5, interquartile range: 3–15). 3.3. Predicting PiB() SVaD versus bvFTD patients based on NPI Model 1 included four factors independently associated with PiB() SVaD: age, education, the presence of depression/dysphoria
Fig. 1. Frequency of neuropsychiatric symptoms in PiB() SVaD and bvFTD groups. The x2 test or Fisher's exact test shows that the two groups differ significantly in four domains. z Domains where SVaD patients show a significantly higher frequency than bvFTD patients (p < 0.05). * Domains where bvFTD patients show a significantly higher frequency than SVaD patients (p<0.05). Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
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Fig. 2. Mean Neuropsychiatry Inventory (NPI) subscores in PiB() SVaD and bvFTD groups. Wilcoxon rank sum test with Bonferroni's correction shows that the two groups differ significantly in five domains. * Domains where bvFTD patients exhibit higher scores than SVaD patients (p < 0.05). x Domains where bvFTD patients exhibit higher scores than SVaD patients (p<0.001). Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
and appetite/eating disorders. These four factors were selected from stepwise regression among age, sex, education and the presence of 12 NPI items. Sex and other NPI items were excluded from the initial model because they did not contribute significantly. The probability of PiB() SVaD in subjects with depression/ dysphoria was high when controlling for other variables (p = 0.018, OR = 8.26), whereas the probability of PiB() SVaD was low in individuals with appetite/eating disorders (p = 0.001, OR = 0.06). The optimal cut-off point for accuracy on the ROC curve represented a sensitivity of 94% and a specificity of 87% (Fig. 3). The AUC for PiB() SVaD was 0.93 (95% CI, 0.87–0.99) in model 1. Model 2 included five factors independently associated with PiB () SVaD: age, education, NPI subscores of depression/dysphoria, irritability and aberrant motor behavior. These five factors were selected from stepwise regression among age, sex, education and NPI subscores. Sex and other NPI subscores were excluded from the initial model because they did not contribute significantly. The probability of PiB() SVaD in subjects with higher score of depression/dysphoria was higher than that of bvFTD after controlling for other variables (p = 0.047, OR = 1.81), but the probability of PiB() SVaD in individuals with higher scores of irritability (p = 0.020, OR = 0.62) and aberrant motor behavior (P = 0.020, OR = 0.74) was lower. The optimal cut-off point for accuracy on the ROC curve represented a sensitivity of 75% and a specificity of 93% (Fig. 4). The AUC for PiB() SVaD was 0.91 (95% CI, 0.84–0.98) in model 2.
symptom in both the PiB() SVaD and bvFTD groups. (3) PiB() SVaD had a higher frequency of depression compared to bvFTD, while bvFTD presented with more severe elation/euphoria, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders compared to PiB() SVaD. (4) The symptoms that best discriminated PiB() SVaD from bvFTD were depression/dysphoria, appetite/eating disorder, irritability and aberrant motor behavior.
4. Discussion To the best of our knowledge, no previous studies have investigated the neuropsychiatric disturbances in PiB() SVaD, defined as an SUVR ratio on PiB-PET scan <1.5. Furthermore, this is the first study comparing behavioral aspects of PiB() SVaD and bvFTD; only a few studies have looked at differences between SVaD and bvFTD using NPI, but these did not exclude SVaD patients with Alzheimer’s disease (AD) pathology. The four main findings of our study are as follows: (1) The PiB() SVaD group showed a high frequency of neuropsychiatric symptoms, although the percentage of PiB() SVaD patients with neuropsychiatric symptoms was lower than that of bvFTD. (2) Apathy was the most common
Fig. 3. Receiver operating characteristics (ROC) curves for the presence of neuropsychiatric symptoms in the Neuropsychiatry Inventory (NPI) to predict PiB() SVaD compared to bvFTD. Model 1 include the occurrence of depression/ dysphoria and appetite/eating disorders; the area under the curve (AUC) for distinguishing PiB() SVaD from bvFTD is 0.93. Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
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Fig. 4. Receiver operating characteristics (ROC) curves for Neuropsychiatry Inventory (NPI) subscores for the discrimination of PiB() SVaD from bvFTD. Model 2 include NPI subscores for depression/dysphoria, irritability and aberrant motor behavior; the area under the curve (AUC) for PiB() SVaD from bvFTD is 0.91. Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
Regarding the frequency of neuropsychiatric symptoms, 83% of PiB() SVaD patients showed at least one behavioral symptom, which is in agreement with previous reports (Aharon-Peretz et al., 2000; Staekenborg et al., 2010). Apathy was the most common neuropsychiatric symptom in the PiB() SVaD group, followed by depression/dysphoria, agitation/aggression, and anxiety and irritability. Similarly, the most common symptoms in SVaD patients from prior studies were apathy, depression and agitation (AharonPeretz et al., 2000; Moretti et al., 2006; Staekenborg et al., 2010). However, delusion was less frequent in our study (12.5%) compared to previous studies (23–33%) (Gupta et al., 2014; Moretti et al., 2006). This difference may be explained by the fact that our study involved only amyloid negative SVaD patients. A previous study involving patients with subcortical vascular cognitive impairments demonstrated that a greater PiB retention ratio is associated with the presence of delusion (Kim et al., 2013). Another difference between our study and prior studies was that the frequency of appetite/eating disorders in patients with SVaD was 7% in our study as opposed to 30–80% in prior studies (Fuh, Wang, & Cummings, 2005; Gupta et al., 2014). Differences in disease severity may explain this discrepancy: disease severity of our SVaD patients (CDR: 0.85 0.74) was relatively mild compared to the prior studies (Fuh et al., 2005; Gupta et al., 2014) and a previous study (Gupta et al., 2014) showed a positive correlation of CDR with appetite/eating disorders. Apathy was the most common behavioral symptom in both PiB () SVaD and bvFTD groups, which is consistent with overall findings from prior studies that apathy is one of the most frequent behavioral symptoms in patients in all types of dementia, including AD (Casanova, Starkstein, & Jellinger, 2011; Perri et al., 2014; Srikanth et al., 2005). In addition, the present study revealed that bvFTD patients had significantly higher apathy subscores than PiB () SVaD patients (Fig. 2). Previous studies that compared the frequency and severity of apathy between bvFTD and SVaD (or
vascular dementia) produced inconsistent results: one study showed a higher frequency of apathy in SVaD than in bvFTD (Moretti et al., 2005), while other studies did not find a significant difference between the two groups (Perri et al., 2014; Srikanth et al., 2005). These differences may originate from the heterogeneous vascular dementia sample including multi-infarction dementia and mixed dementia with AD. Aside from apathy, PiB() SVaD differed from bvFTD in that depression, a negative symptom, was more predominant in PiB() SVaD than bvFTD patients, whereas positive symptoms such as disinhibition, euphoria, aberrant motor behavior and appetite/ eating disorders were more predominant in bvFTD compared to PiB() SVaD patients. Appetite/eating disorders, aberrant motor behavior and disinhibition are also known to be common in FTD compared to AD (Bozeat, Gregory, Ralph, & Hodges, 2000; Liu et al., 2004) and are associated with atrophy mainly in orbitofrontal regions of bvFTD (Massimo et al., 2009; Woolley et al., 2007). However, PiB() SVaD showed no profound cortical thinning in the orbitofrontal lobes compared with normal controls (Kim et al., 2012). On the other hand, regarding depression, WMH and lacunes in the frontal subcortical areas are known to correlate with the occurrence of depression (Kim et al., 2013), which is compatible with our result showing predominant depressive symptoms in patients with PiB() SVaD. There have been a few studies comparing vascular dementia and bvFTD in terms of neuropsychiatric symptoms. Some of these studies support our findings (Perri et al., 2014; Srikanth et al., 2005): for instance, one study reported that bvFTD patients showed more severe euphoria and disinhibition than other dementia groups (SVaD, AD and dementia with lewy bodies) (Perri et al., 2014). Other studies, however, do not support our findings, showing that anxiety, depression, agitation and psychotic disturbance are more prominent in vascular dementia than FTD (Cherrier et al., 1997; Moretti et al., 2005). Again, these inconsistent results may be due to the heterogeneity of vascular dementia samples, as mentioned above. Our final finding is that depression increased the diagnostic odds of PiB() SVaD compared to bvFTD, whereas appetite/eating disorders, irritability and aberrant motor behavior reduced the odds of PiB() SVaD compared to bvFTD. In addition, we report that the existence of depression and absence of appetite/eating disorders (model 1), and higher depression scores and lower irritability and aberrant motor behavior scores (model 2) can predict PiB() SVaD compared to bvFTD with high sensitivity and specificity (AUC: 0.93 and 0.91, respectively). Our study has some limitations. First, we have not yet performed an external validation study of our models. Second, we included a relatively small number of patients. Therefore, it may be difficult to generalize these findings. Nonetheless, this study has two particular areas of strength. First, our study is the first study to compare PiB() SVaD and bvFTD. Second, we distinguished between specific characteristics of neurobehavioral symptoms, which may be useful for discriminating SVaD from bvFTD. Disclosure statement The authors have no conflicts of interest to declare. Acknowledgements This study was supported by the Samsung Medial Center Clinical Research Development Program grant (CRL108-01-1) and a grant of the Korean Health Technology R&D Project funded by Ministry of Health & Welfare, Republic of Korea (HI14C2746).
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Archives of Gerontology and Geriatrics journal homepage: www.elsevier.com/locate/archger
Neuropsychiatric characteristics of PiB-negative subcortical vascular dementia versus behavioral variant frontotemporal dementia Na-Yeon Junga,b,c,d, Hee Jin Kima,b , Yeo Jin Kima,b,e, Seonwoo Kimf , Sang Won Seoa,b,g,h , Eun-Joo Kimd,i, Duk L. Na, MD PhDa,b,h,* a
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea Department of Neurology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea d Pusan National University School of Medicine and Medical Research Institute, Pusan, Republic of Korea e Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Republic of Korea f Biostatistics Team, Samsung Biomedical Research Institute, Seoul, Republic of Korea g Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea h Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea i Department of Neurology, Pusan National University Hospital, Pusan, Republic of Korea b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 January 2016 Received in revised form 5 April 2016 Accepted 13 July 2016 Available online 16 July 2016
Background: Neuropsychiatric symptoms of subcortical vascular dementia (SVaD) are mainly associated with damage to frontal-subcortical circuits and may be similar to symptoms of behavioral variant frontotemporal dementia (bvFTD). The aim of this study was to determine whether the neuropsychiatric manifestations of the Pittsburgh compound B (PiB)-negative SVaD and bvFTD groups differ. Methods: We compared the Caregiver-Administered Neuropsychiatry Inventory (CGA-NPI) between 48 patients with PiB() SVaD and 31 patients with bvFTD. A stepwise logistic regression was applied to determine the best model to predict SVaD. Results: The SVaD group showed a higher frequency of depression, whereas the bvFTD group had a higher frequency of elation, aberrant motor behavior and appetite/eating disorders. Regarding NPI subscores, the bvFTD group had greater severity of elation, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders, whereas SVaD did not have significantly higher subscores in any domains. The most predictive models that tend to find suggestions of SVaD, as opposed to bvFTD, are as follows: (1) the presence of depression and the absence of appetite/eating disorders, (2) higher NPI subscores of depression and lower NPI subscores of irritability and aberrant motor behavior. Conclusion: Apart from apathy, SVaD differed from bvFTD in that negative symptoms were more common in SVaD than bvFTD, whereas positive symptoms were predominant in bvFTD compared to SVaD. ã 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Subcortical vascular dementia Frontotemporal dementia Neuropsychiatric symptoms Apathy
1. Introduction Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, are an important part of dementia syndromes in addition to cognitive decline. BPSD poses a significant management challenge for clinicians and contributes to caregiver burden and stress. Patients with behavioral variant frontotemporal dementia (bvFTD) present with insidious changes in personality and
* Corresponding author at: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea. E-mail addresses: [email protected], [email protected] (D.L. Na). http://dx.doi.org/10.1016/j.archger.2016.07.002 0167-4943/ã 2016 Elsevier Ireland Ltd. All rights reserved.
interpersonal conduct that are associated with progressive disintegration of the frontotemporal circuits involved in social cognition, emotion regulation, motivation, decision-making and inhibitory control. All of the behavioral features found in bvFTD can occur in other dementias, but their predominance and early emergence typify bvFTD (Piguet, Hornberger, Mioshi, & Hodges, 2011). Neuropsychiatric abnormalities also account for a considerable portion of the morbidity caused by vascular dementia (AharonPeretz, Kliot, & Tomer, 2000; Gupta et al., 2014; Moretti, Torre, Antonello, & Cazzato, 2006; Srikanth, Nagaraja, & Ratnavalli, 2005). Anatomical correlates for vascular dementia are variable, depending on the affected vascular territories; however, the frontal areas are commonly affected in vascular dementia, and this is especially
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the case with subcortical vascular dementia (SVaD) (Román, Erkinjuntti, Wallin, Pantoni, & Chui, 2002). Therefore, earlier symptoms of vascular dementia can manifest as dysexecutive syndrome and BPSD associated with frontal subcortical circuits (Aharon-Peretz et al., 2000; Duering et al., 2011; Román et al., 2002). Indeed, prior studies have reported that the prevalence of any neuropsychiatric symptoms in patients with vascular dementia are demonstrated in up to 90% of patients, with behavioral symptoms associated with frontal injury being common (AharonPeretz et al., 2000; Srikanth et al., 2005). Although the clinical manifestation of vascular dementia is typically characterized by a stepwise deterioration, fluctuating course, and symptoms and signs suggestive of cerebrovascular disease, the majority of SVaD patients do not have these characteristic symptoms (Erkinjuntti, 2002; Román et al., 2002). Because most ischemia in SVaD patients occurs silently, many SVaD patients have insidious onset and gradual progression of disease, mimicking degenerative dementia. Previous studies demonstrated that neural correlates for SVaD are mainly located in frontal areas (Furuta, Ishii, Nishihara, & Horie, 1991; Tullberg et al., 2004), which largely overlap those of bvFTD. Therefore, initial neuropsychiatric symptoms of SVaD may be similar to those of bvFTD, potentially complicating the differential diagnosis and making it difficult to distinguish between the two disorders. To our knowledge, few studies have compared SVaD with bvFTD in terms of neuropsychiatric symptoms (Moretti et al., 2005; Perri, Monaco, Fadda, Caltagirone, & Carlesimo, 2014). Furthermore, only a few studies are available that investigated neuropsychiatric symptoms in SVaD patients, and these studies did not include patients with “pure” vascular dementia. In other words, although recent studies have shown that vascular and amyloid pathologies coexist in patients with SVaD (Lee et al., 2011) and post-stroke dementia (Mok et al., 2010), prior studies on neuropsychiatric symptoms of vascular dementia did not eliminate patients with mixed vascular and amyloid pathology. The aim of this study is therefore to compare the neuropsychiatric manifestations in patients with Pittsburgh compound B (PiB)-negative SVaD and bvFTD and to determine whether the neuropsychiatric manifestations of the two groups differ.
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has been reported on in a previous study (Kim et al., 2014). One patient without NPI data was excluded from final analysis. The diagnosis of bvFTD was made using the International consensus research criteria for bvFTD (Rascovsky et al., 2011). To fulfill the criteria for probable bvFTD, patients were required to have at least three of the following six behavioral/cognitive symptoms: (1) early behavioral disinhibition, (2) early apathy or inertia, (3) early loss of sympathy or empathy for others, (4) early perseverative, stereotyped or compulsive, ritualistic behavior, (5) hyperorality and dietary changes, and (6) frontal executive deficits with relative sparing of memory and visuospatial functions. Additionally, functional decline and imaging studies (MRI, CT, SPECT or FDG PET) demonstrating focal cerebral atrophy, hypoperfusion, or glucose hypometabolism in the anterior temporal lobe and/or frontal lobe were required. Based on these inclusion criteria, we recruited a total of 32 patients with probable bvFTD from August 2008 to August 2014. One patient without NPI data was excluded from final analysis. Table 1 shows the demographic characteristics of the PiB() SVaD and the bvFTD groups. The two groups did not differ in sex, disease duration, MMSE, CDR, or CDR-SOB. Patients with bvFTD were significantly younger than those with PiB() SVaD. Education level was higher in the bvFTD group than the PiB() SVaD group. 2.2. Standard protocol approval, registration, and patient consent We obtained a written consent from each participant and the institutional review board of Samsung Medical Center approved the study protocol. 2.3. Neuropsychological tests All patients underwent neuropsychological testing using a standardized battery called the Seoul Neuropsychological Screening Battery (Kang & Na, 2003). This battery comprises tests for attention, language, calculation, praxis, visuospatial/constructive function, verbal/visual memory, and frontal/executive function as previously described (Seo et al., 2007). 2.4. Behavior rating scales
2. Methods 2.1. Patients All patients were referred to the Memory Disorders Clinic at Samsung Medical Center for dementia assessment. Patients underwent a detailed clinical interview including behavioral assessment as previously described (Seo et al., 2007), neurologic examinations, a comprehensive neuropsychological test battery, blood tests, and MRI. Blood tests were used to exclude patients with vitamin deficiencies, hypothyroidism, syphilis, and other medical conditions that may cause dementia. MRI excluded patients with intracerebral macrohemorrhage, territorial infarction, head trauma, hydrocephalus, and white matter hyperintensities (WMH) associated with conditions other than ischemia, such as radiation injury, multiple sclerosis, and leukodystrophy. We considered patients with SVaD as having pure SVaD if they fulfilled DSM-IV criteria for vascular dementia, with a “severe” WMH on MRI and if they were negative for PiB retention (Yoon et al., 2013). The severe WMH on MRI was defined as a cap or a band 10 mm as well as a deep white matter lesion 25 mm, as modified from Fazekas ischemia criteria (Fazekas et al., 1993). According to these criteria, we enrolled a total of 49 patients from September 2008 to September 2011 and a subset of these patients
The Caregiver-Administered Neuropsychiatry Inventory (CGANPI) (Kang et al., 2004) was validated the same way as the original NPI (Cummings et al., 1994) except that the CGA-NPI is completed by the patients’ caregivers as a written form of the NPI worksheet. Caregivers who visited the patient at least once a week were given instructions or supervision just before and after filling out the questionnaire. More specifically, 74.7% of our patients lived with the patients, and the frequency of visit in the remaining patients was divided into once a week in 24.1% and more than three times a Table 1 Demographic Characteristics of PiB() SVaD (n = 48) and bvFTD (n = 31) groups. Demographics and cognitive indices
SVaD
bvFTD
p value
Sex (female, %) Age, years Disease duration, months Education, years MMSE CDR CDR-SOB
52.1 71.8 7.2 41.2 23.8 8.5 4.8 21.6 4.4 0.85 0.74 6.03 3.62
45.2 63.7 7.7 34.3 20.2 12.7 4.2 21.0 6.0 0.94 0.89 6.26 3.87
0.644 <0.001 0.189 <0.001 0.619 0.662 0.792
Data are expressed as the mean standard deviation or number of subjects (%); p values were calculated by x2 test or t-test as appropriate. Abbreviations: bvFTD, behavioral variant frontotemporal dementia; CDR, Clinical Dementia Rating; CDRSOB, Clinical Dementia Rating Sum of Boxes; MMSE, Mini Mental State Examination; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
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week in 1.3% of the patients. In a previous study (Kang et al., 2004), the correlation values (k) between the NPI and CGA-NPI scores (severity/frequency/distress of caregiver) were reported to be greater than 0.6 (0.60–0.89). Severity (0 = absent, 1 = mild, 2 = moderate, 3 = severe) and frequency (0 = absent, 1 = occasionally, less than once per week, 2 = often, about once per week, 3 = frequently, several times per week, but less than every day, 4 = very frequently, once or more per day or continuously) are rated for 12 neuropsychiatric domains. The domain score was subsequently calculated as the multiplication of the symptom frequency and severity. The sum of the 12 domain subscores provides the total NPI score. The presence of behavioral and psychological symptoms was defined as a subscore of 1. 2.5. Statistical analysis We used the x2 test or Fisher's exact test to compare categorical variables and the presence of individual BPSD, and used the t-test to compare continuous variables between PiB() SVaD and bvFTD groups. We used the Wilcoxon rank sum test to compare NPI subscores between the two groups. To find variables that were significantly associated with PiB() SVaD group, we performed stepwise regression (entry significant level = 0.1, stay significant level = 0.1) on each potential variable which included age, sex, years of education, and the presence of 12 NPI items. Then, we performed multivariable analysis by logistic regression analysis for PiB() SVaD using significant variables (p < 0.05) in stepwise regression. A model for discriminating PiB() SVaD from bvFTD was generated. Also, we performed stepwise regression using the same method described above, with age, sex, years of education, and 12 NPI subscores as input variables. We generated one more model to discriminate PiB() SVaD from bvFTD. The diagnostic performance of each model was evaluated from the area under the curve (AUC) that was obtained from receiver operating characteristic curve analyses. We used the Youden index to identify a cutoff value for optimal sensitivity and specificity of each model. Statistical analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, NC).
3. Results 3.1. NPI frequency in PiB() SVaD versus bvFTD Of the patients with PiB() SVaD, 83.3% had at least one neuropsychiatric symptom, while 100% of patients in the bvFTD group had at least one neuropsychiatric symptom (p = 0.020). In the PiB() SVaD group, apathy was the commonest BPSD at 58.3%, followed by depression/dysphoria (45.8%), agitation/aggression (41.7%), and anxiety and irritability (37.5%). In the bvFTD group, apathy was also the commonest neuropsychiatric symptom at 77.4%, followed by appetite/eating disorders (71.0%), and agitation/ aggression (61.3%). Comparing the PiB() SVaD and bvFTD groups, the PiB() SVaD group showed a significantly higher frequency of depression/dysphoria compared to the bvFTD group. On the other hand, the bvFTD group had a significantly higher frequency of elation/euphoria, aberrant motor behavior and appetite/eating disorders compared to the PiB() SVaD group (Fig. 1). 3.2. NPI severity based on NPI subscores in PiB() SVaD versus bvFTD Based on NPI subscores, apathy was the most severe symptom in the PiB() SVaD group, followed appetite/eating disorders, sleep and nighttime behavior and agitation. In the bvFTD group, apathy was also the most severe symptom, followed by appetite/eating disorders, aberrant motor behavior and irritability (Fig. 2). When the two groups were compared in terms of NPI subscores, the bvFTD group showed higher scores of elation/euphoria, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders. In contrast, there were no symptoms that had a higher NPI subscore in the PiB() SVaD group than in the bvFTD, and the total NPI scores were significantly higher in the bvFTD group (p < 0.001) (median: 24, interquartile range: 9–36) than the PiB() SVaD group (median: 8.5, interquartile range: 3–15). 3.3. Predicting PiB() SVaD versus bvFTD patients based on NPI Model 1 included four factors independently associated with PiB() SVaD: age, education, the presence of depression/dysphoria
Fig. 1. Frequency of neuropsychiatric symptoms in PiB() SVaD and bvFTD groups. The x2 test or Fisher's exact test shows that the two groups differ significantly in four domains. z Domains where SVaD patients show a significantly higher frequency than bvFTD patients (p < 0.05). * Domains where bvFTD patients show a significantly higher frequency than SVaD patients (p<0.05). Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
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Fig. 2. Mean Neuropsychiatry Inventory (NPI) subscores in PiB() SVaD and bvFTD groups. Wilcoxon rank sum test with Bonferroni's correction shows that the two groups differ significantly in five domains. * Domains where bvFTD patients exhibit higher scores than SVaD patients (p < 0.05). x Domains where bvFTD patients exhibit higher scores than SVaD patients (p<0.001). Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
and appetite/eating disorders. These four factors were selected from stepwise regression among age, sex, education and the presence of 12 NPI items. Sex and other NPI items were excluded from the initial model because they did not contribute significantly. The probability of PiB() SVaD in subjects with depression/ dysphoria was high when controlling for other variables (p = 0.018, OR = 8.26), whereas the probability of PiB() SVaD was low in individuals with appetite/eating disorders (p = 0.001, OR = 0.06). The optimal cut-off point for accuracy on the ROC curve represented a sensitivity of 94% and a specificity of 87% (Fig. 3). The AUC for PiB() SVaD was 0.93 (95% CI, 0.87–0.99) in model 1. Model 2 included five factors independently associated with PiB () SVaD: age, education, NPI subscores of depression/dysphoria, irritability and aberrant motor behavior. These five factors were selected from stepwise regression among age, sex, education and NPI subscores. Sex and other NPI subscores were excluded from the initial model because they did not contribute significantly. The probability of PiB() SVaD in subjects with higher score of depression/dysphoria was higher than that of bvFTD after controlling for other variables (p = 0.047, OR = 1.81), but the probability of PiB() SVaD in individuals with higher scores of irritability (p = 0.020, OR = 0.62) and aberrant motor behavior (P = 0.020, OR = 0.74) was lower. The optimal cut-off point for accuracy on the ROC curve represented a sensitivity of 75% and a specificity of 93% (Fig. 4). The AUC for PiB() SVaD was 0.91 (95% CI, 0.84–0.98) in model 2.
symptom in both the PiB() SVaD and bvFTD groups. (3) PiB() SVaD had a higher frequency of depression compared to bvFTD, while bvFTD presented with more severe elation/euphoria, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders compared to PiB() SVaD. (4) The symptoms that best discriminated PiB() SVaD from bvFTD were depression/dysphoria, appetite/eating disorder, irritability and aberrant motor behavior.
4. Discussion To the best of our knowledge, no previous studies have investigated the neuropsychiatric disturbances in PiB() SVaD, defined as an SUVR ratio on PiB-PET scan <1.5. Furthermore, this is the first study comparing behavioral aspects of PiB() SVaD and bvFTD; only a few studies have looked at differences between SVaD and bvFTD using NPI, but these did not exclude SVaD patients with Alzheimer’s disease (AD) pathology. The four main findings of our study are as follows: (1) The PiB() SVaD group showed a high frequency of neuropsychiatric symptoms, although the percentage of PiB() SVaD patients with neuropsychiatric symptoms was lower than that of bvFTD. (2) Apathy was the most common
Fig. 3. Receiver operating characteristics (ROC) curves for the presence of neuropsychiatric symptoms in the Neuropsychiatry Inventory (NPI) to predict PiB() SVaD compared to bvFTD. Model 1 include the occurrence of depression/ dysphoria and appetite/eating disorders; the area under the curve (AUC) for distinguishing PiB() SVaD from bvFTD is 0.93. Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
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Fig. 4. Receiver operating characteristics (ROC) curves for Neuropsychiatry Inventory (NPI) subscores for the discrimination of PiB() SVaD from bvFTD. Model 2 include NPI subscores for depression/dysphoria, irritability and aberrant motor behavior; the area under the curve (AUC) for PiB() SVaD from bvFTD is 0.91. Abbreviations: bvFTD, behavioral variant frontotemporal dementia; PiB, Pittsburgh compound B; SVaD, subcortical vascular dementia.
Regarding the frequency of neuropsychiatric symptoms, 83% of PiB() SVaD patients showed at least one behavioral symptom, which is in agreement with previous reports (Aharon-Peretz et al., 2000; Staekenborg et al., 2010). Apathy was the most common neuropsychiatric symptom in the PiB() SVaD group, followed by depression/dysphoria, agitation/aggression, and anxiety and irritability. Similarly, the most common symptoms in SVaD patients from prior studies were apathy, depression and agitation (AharonPeretz et al., 2000; Moretti et al., 2006; Staekenborg et al., 2010). However, delusion was less frequent in our study (12.5%) compared to previous studies (23–33%) (Gupta et al., 2014; Moretti et al., 2006). This difference may be explained by the fact that our study involved only amyloid negative SVaD patients. A previous study involving patients with subcortical vascular cognitive impairments demonstrated that a greater PiB retention ratio is associated with the presence of delusion (Kim et al., 2013). Another difference between our study and prior studies was that the frequency of appetite/eating disorders in patients with SVaD was 7% in our study as opposed to 30–80% in prior studies (Fuh, Wang, & Cummings, 2005; Gupta et al., 2014). Differences in disease severity may explain this discrepancy: disease severity of our SVaD patients (CDR: 0.85 0.74) was relatively mild compared to the prior studies (Fuh et al., 2005; Gupta et al., 2014) and a previous study (Gupta et al., 2014) showed a positive correlation of CDR with appetite/eating disorders. Apathy was the most common behavioral symptom in both PiB () SVaD and bvFTD groups, which is consistent with overall findings from prior studies that apathy is one of the most frequent behavioral symptoms in patients in all types of dementia, including AD (Casanova, Starkstein, & Jellinger, 2011; Perri et al., 2014; Srikanth et al., 2005). In addition, the present study revealed that bvFTD patients had significantly higher apathy subscores than PiB () SVaD patients (Fig. 2). Previous studies that compared the frequency and severity of apathy between bvFTD and SVaD (or
vascular dementia) produced inconsistent results: one study showed a higher frequency of apathy in SVaD than in bvFTD (Moretti et al., 2005), while other studies did not find a significant difference between the two groups (Perri et al., 2014; Srikanth et al., 2005). These differences may originate from the heterogeneous vascular dementia sample including multi-infarction dementia and mixed dementia with AD. Aside from apathy, PiB() SVaD differed from bvFTD in that depression, a negative symptom, was more predominant in PiB() SVaD than bvFTD patients, whereas positive symptoms such as disinhibition, euphoria, aberrant motor behavior and appetite/ eating disorders were more predominant in bvFTD compared to PiB() SVaD patients. Appetite/eating disorders, aberrant motor behavior and disinhibition are also known to be common in FTD compared to AD (Bozeat, Gregory, Ralph, & Hodges, 2000; Liu et al., 2004) and are associated with atrophy mainly in orbitofrontal regions of bvFTD (Massimo et al., 2009; Woolley et al., 2007). However, PiB() SVaD showed no profound cortical thinning in the orbitofrontal lobes compared with normal controls (Kim et al., 2012). On the other hand, regarding depression, WMH and lacunes in the frontal subcortical areas are known to correlate with the occurrence of depression (Kim et al., 2013), which is compatible with our result showing predominant depressive symptoms in patients with PiB() SVaD. There have been a few studies comparing vascular dementia and bvFTD in terms of neuropsychiatric symptoms. Some of these studies support our findings (Perri et al., 2014; Srikanth et al., 2005): for instance, one study reported that bvFTD patients showed more severe euphoria and disinhibition than other dementia groups (SVaD, AD and dementia with lewy bodies) (Perri et al., 2014). Other studies, however, do not support our findings, showing that anxiety, depression, agitation and psychotic disturbance are more prominent in vascular dementia than FTD (Cherrier et al., 1997; Moretti et al., 2005). Again, these inconsistent results may be due to the heterogeneity of vascular dementia samples, as mentioned above. Our final finding is that depression increased the diagnostic odds of PiB() SVaD compared to bvFTD, whereas appetite/eating disorders, irritability and aberrant motor behavior reduced the odds of PiB() SVaD compared to bvFTD. In addition, we report that the existence of depression and absence of appetite/eating disorders (model 1), and higher depression scores and lower irritability and aberrant motor behavior scores (model 2) can predict PiB() SVaD compared to bvFTD with high sensitivity and specificity (AUC: 0.93 and 0.91, respectively). Our study has some limitations. First, we have not yet performed an external validation study of our models. Second, we included a relatively small number of patients. Therefore, it may be difficult to generalize these findings. Nonetheless, this study has two particular areas of strength. First, our study is the first study to compare PiB() SVaD and bvFTD. Second, we distinguished between specific characteristics of neurobehavioral symptoms, which may be useful for discriminating SVaD from bvFTD. Disclosure statement The authors have no conflicts of interest to declare. Acknowledgements This study was supported by the Samsung Medial Center Clinical Research Development Program grant (CRL108-01-1) and a grant of the Korean Health Technology R&D Project funded by Ministry of Health & Welfare, Republic of Korea (HI14C2746).
N.-Y. Jung et al. / Archives of Gerontology and Geriatrics 67 (2016) 86–91
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