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Journal of Alzheimer’s Disease 45 (2015) 599–608 DOI 10.3233/JAD-141044 IOS Press

Clinical and Neuropsychological Comparisons of Early-Onset Versus Late-Onset Frontotemporal Dementia: A CREDOS-FTD Study Byoung Seok Yea , Seong Hye Choib , Seol-Heui Hanc , SangYun Kimd , Dong-Won Yange Kee Hyung Parkf , Hyun Jeong Hang , Young Chul Younh , Byung-Ok Choii , Seung H. Kimj , Sook-young Wook , Duk L. Nai and Eun-Joo Kiml,∗ a Department

of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea of Neurology, Inha University School of Medicine, Incheon, Republic of Korea c Department of Neurology, Konkuk University College of Medicine, Seoul, Republic of Korea d Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea e Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea f Department of Neurology, Gachon University Gil Hospital, Incheon, Republic of Korea g Department of Neurology, Myongji Hospital, College of Medicine, Kwandong University, Goyang, Republic of Korea h Department of Neurology, Chung-Ang University, Seoul, Republic of Korea i Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea j Department of Neurology, Hanyang University College of Medicine, Seoul, Korea k Biostatistics team, Samsung Biomedical Research Institute, Seoul, Korea l Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea b Department

Handling Associate Editor: John Hodges

Accepted 17 December 2014

Abstract. Background: Cognitive performance changes with chronological aging. Previous studies investigating clinical heterogeneity in frontotemporal dementia (FTD) according to the age of symptom onset did not consider the effect of chronological aging on cognition. Objective: We compared cognitive and behavioral symptoms in patients with early-onset (EO) and late-onset (LO) FTD with consideration of chronological aging effect.

∗ Correspondence to: Eun-Joo Kim, MD, Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, 1-10 Ami-dong,

Seo-gu, Busan, 602-739 Korea. Tel.: +82 51 240 7829; Fax: +82 51 245 2783; E-mail: [email protected].

ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved

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B.S. Ye et al. / Clinical Differences between EO-FTD and LO-FTD

Methods: A total of 166 FTD patients were enrolled consecutively from multi-center memory clinics using a nationwide FTD register. To control for the effects of chronological aging on neuropsychological scores, seven hundred and two subjects with normal cognition were also enrolled and regression models were set up. Neuropsychological scores that were detrended with the regression models and the behavioral symptoms of the EO-FTD and LO-FTD groups were compared. Subgroup analyses were performed for three main subtypes of FTD, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). Results: Among 166 FTD patients, there were 76 bvFTD, 57 SD, and 33 PNFA patients who met new diagnostic criteria for bvFTD or primary progressive aphasia, respectively. LO-FTD (48.2%) was more common than previously thought and the proportions of EO and LO groups differed across FTD subtypes. EO-FTD patients had lower memory and frontal/executive scores and more prominent frontal/behavioral symptoms than LO-FTD patients. Conclusion: Our study suggested that FTD could be heterogeneous with respect the age of symptom onset. After controlling for the effects of chronological aging, EO-FTD patients exhibited more profound memory and frontal/executive dysfunction and more behavioral symptoms than LO-FTD patients. Keywords: Age at symptom onset, behavior, frontotemporal dementia, neuropsychology

INTRODUCTION Frontotemporal dementia (FTD) is a progressive neurodegenerative disease characterized by prominent atrophy in the frontal and/or temporal lobes and progressive, variable deterioration in behavior and/or language. The three distinctive clinical types of FTD are behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). FTD is known as a predominantly pre-senile dementia with an arbitrary age of onset less than 65 years. However some epidemiological studies have suggested that late-onset (LO) FTD (onset at 65 years or older) is more common than previously thought [1–3]. Age at symptom onset may be one of factors associated with differences in the clinical phenotype and progression of neurodegenerative dementia. For example, patients with early-onset Alzheimer’s disease (EOAD) show more impaired cortical dysfunctions, more rapid progression, more severe metabolic deficits, and greater cortical atrophy than patients with late-onset Alzheimer’s disease (LOAD) [4–7]. To date, however, there have been only a few studies comparing the clinical characteristics of early (EO) and lateonset (LO) FTD [8–10]. In this study, we compared the demographic characteristics, cognitive functions, and neuropsychiatric symptoms of patients with EOFTD and LO-FTD on the Clinical Research Center for Dementia of South Korea (CREDOS) FTD register. Cognitive performance can change with age; this can be regarded as a chronological aging effect on cognition [11]. In this study, we compared the cognition and behavioral symptoms associated with EO-FTD and LO-FTD using a linear detrending method with general linear models to eliminate the confounding effects of

chronological aging. In parallel with the results from previous studies for EOAD and LOAD, more severe pathological changes would be necessary for EO-FTD patients to exhibit similar clinical symptoms to those of LO-FTD patients; we therefore hypothesized that EO-FTD patients might have more profound cognitive impairments than LO-FTD patients after controlling for the effects of chronological aging. MATERIALS AND METHODS Subjects The CREDOS-FTD register was started in 2010, as a part of CREDOS, a government-funded dementia research project conducted by dementia specialists from neurological and psychiatric clinics [12]. Patients with FTD were enrolled consecutively from 16 neurological clinics across South Korea that had participated in the CREDOS-FTD study. All participants met the following research criteria for FTD proposed by Knopman et al. [13]: 1) predominant frontal and/or temporal lobe dysfunction manifested as a cognitive/behavioral syndrome; 2) absent or insignificant impairment in anterograde memory and visuospatial function within the first two years following symptom onset; and 3) focal cerebral atrophy of at least one of the following areas: anterior temporal lobes, frontal lobes, insula, and caudate nuclei. Participants were classified as bvFTD, SD, or PNFA based on cognitive and behavioral symptoms [13]. In 2011, new consensus diagnostic criteria for bvFTD [14], SD (or semantic variant primary progressive aphasia) [15], and PNFA (or nonfluent/agrammatic variant primary progressive aphasia) [15] were developed, which were additionally applied to our samples. Patients with clinical and

B.S. Ye et al. / Clinical Differences between EO-FTD and LO-FTD

electrophysiological evidence of motor neuron disease (motor neuron disease-plus syndrome) and patients who could not be clearly classified as one of FTD subtypes due to their uncertain clinical presentations were excluded from the current study. Disease severity was assessed by the FTD-Clinical Dementia Rating (FTD-CDR) including two additional domains (behavior and language) in addition to the six domains of the standardized CDR [13]. All patients underwent comprehensive interviews, neurological examination, and neuropsychological assessment as described elsewhere [16]. In brief, caregivers were interviewed in depth by neurologists and neuropsychologists. Patients with current or past neurological or psychiatric illnesses such as schizophrenia, epilepsy, brain tumors, encephalitis, or severe head trauma were excluded. Patients with physical illnesses that might interfere with the study, such as hearing or vision loss, severe cardiac disorders, severe respiratory illnesses, malignancy, or hepatic or renal disorders, were excluded. Blood tests to exclude secondary causes of dementia included a complete blood count, blood chemistry tests, vitamin B12, folate, syphilis serology, and thyroid function tests. Conventional brain MRI scans confirmed the absence of structural lesions such as tumors, traumatic brain injuries, hydrocephalus, and severe white matter hyperintensities.

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(FEDAS) [27]. In addition to the family history of dementia, family history of Parkinson’s disease, motor neuron disease, and psychiatric disorders was further investigated. A committee consisting of five to ten dementia specialists held a quarterly meeting to review the clinical histories and brain imaging results of all participants to reach consensus on the clinical diagnosis. The institutional review boards at all participating centers approved this study, and informed consent was obtained from all patients and caregivers. Neuropsychological assessments All patients underwent a specialized neuropsychological test battery for FTD (FTD-Cog), providing separate subscores for items assessing attention, language and related functions, visuospatial functions, memory, and frontal/executive functions. A detailed description for FTD-Cog is available in a previous publication [28]. A total of 702 age- and gender-matched normal control (NC) subjects who had no history of neurological or psychiatric illnesses and exhibited normal performance in a battery of neuropsychological tests were selected from the CREDOS register to control for the effects of chronological aging on neuropsychological test scores. More detailed information of NC is described in Supplementary Method 1.

Clinical evaluations Statistical analysis We used the FTD Evaluation Package developed by CREDOS, which is composed of the Clinical Evaluation Form and the Caregiver Questionnaire Form. The Clinical Evaluation Form includes the following: 1) a history of cognitive decline from the caregiver; 2) a Mini-Mental State Examination (MMSE) [17]; 3) an FTD-CDR Sum of Boxes score (FTD-CDR SB) [13]; 4) a Global Deterioration Scale score [18]; 5) a Hachinski ischemia scale score [19]; 6) a neurological examination; 7) a Geriatric Depression Scale score [20]; and 8) an Unified Parkinson Disease Rating Scale part III score [21]. The Caregiver Questionnaire Form asks for the following information: 1) basic demographic data about the patient and caregiver; 2) lifestyle and family history; 3) past medical history including vascular risk factors; 4) Korean Dementia Screening Questionnaire [22]; 5) Barthel activities of daily living index score [23]; 6) Seoul Instrumental Activities of Daily Living [24]; 7) Caregiver administered Neuropsychiatric Inventory (CGA-NPI) [25]; 8) Frontal Behavioral Inventory [26]; and 9) Frontal Executive dysfunction, Disinhibition, and Apathy Scale

EO and LO groups were compared across the whole sample of FTD patients as well across each subtype of FTD (bvFTD, SD, and PNFA). Student’s t-test and chi-square test were used as appropriate to compare the demographic and clinical characteristics of the groups. To control for the effect of chronological aging on neuropsychological performance, we used a linear detrending method with general linear models to remove the confounding effects of chronological aging on the scorable neuropsychological tests, based on the data from the NC subjects (detailed detrending formula is provided in the Supplementary Method 2). We also tested the quadratic effects of age on neuropsychological test scores in NC subjects and included them in the detrending formula when they were significant. Because of the ceiling effect of the Rey-Osterrieth Complex Figure Test (RCFT) copy in NC subjects, negative skewness was observed and could not be corrected by exponential or power transformation. Therefore, we could not derive detrending formula for the RCFT copy. Detrended (i.e., corrected for

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confounding effects of chronological aging) neuropsychological scores were computed from the original neuropsychological test scores for all FTD patients based on the age of 65 years which is an arbitrary cut-off but most widely used in the studies related to age at symptom onset of neurodegenerative disease for determining classification into EO and LO groups. Detrended neuropsychological test scores for the EO and LO subgroups were compared using analysis of covariance after controlling for the clinical factors (other than age, gender, and education) which were significantly different in the two groups. To compare neuropsychiatric and behavioral symptoms, which were not routinely tested in NC subjects, analysis of covariance was performed after controlling for factors which were significantly different in the EO and LO subgroups. RESULTS Demographic characteristics A total of 166 patients with a clinical diagnosis of FTD were enrolled consecutively. The mean age of symptom onset was 63.0 ± 8.9 years. Of 166 FTD patients, 86 (51.8%) had age of onset of less than 65 years and 80 (48.2%) patients were aged 65 years or older. One hundred and sixty-six FTD patients consisted of 76 bvFTD (45.8%), 57 SD (34.3%), and 33 PNFA (19.9%). Of the patients suffering from one of the three main clinical variants of FTD, 47 of 76 bvFTD patients (61.8%), 27 of 57 SD patients (47.4%), and 12 of 33 PNFA patients (36.4%) had symptom onset before 65 years of age (chi-square test, p = 0.036). As shown in Table 1, hypertension was more common in the LO-FTD group than in the EO-FTD group, and EO-bvFTD group had a longer history of FTD than the LO-bvFTD group. Otherwise, there were no demographic differences between the EO- and LO-FTD subgroups. Comparison of neuropsychological performance After detrending at the age of 65 years, an arbitrary cut-off for determining classification into EO and LO groups, the EO-FTD patients scored lower in the Seoul Verbal Learning Test delayed recall test, phonemic Controlled Oral Word Association Test, and Stroop color reading test than LO-FTD patients (Table 2). EO-bvFTD patients were more significantly impaired in the phonemic Controlled Oral Word Association Test and Stroop color reading tests than LO-bvFTD

patients. EO-SD patients also performed significantly worse on the Seoul Verbal Learning Test delayed recall and Stroop color reading tests. EO-PNFA patients performed worse on the Stroop color reading test than LO-PNFA patients. Comparison of neuropsychiatric and behavioral symptoms Comparison of the CGA-NPI scores showed that more patients in the EO-FTD group than in the LOFTD group were rated as depressive, apathetic, and impulsive. The EO-FTD group also had a significantly higher total CGA-NPI score than LO-FTD group (Table 3). Subgroup analysis demonstrated that hallucination was more common and severe in the EO-bvFTD group than the LO-bvFTD group, and depression was more common in the EO-SD group than the LO-SD group. While total FEDAS score was comparable between EO- and LO-groups, EO-bvFTD group had higher FEDAS executive score than LObvFTD group. The caregivers for the EO-FTD group reported more Frontal Behavioral Inventory symptoms than caregivers for the LO-FTD group. DISCUSSION In this study we compared the demographic characteristics, neuropsychological performance, and behavioral and psychiatric symptoms of a large cohort of carefully phenotyped FTD patients according to their age at symptom onset. The major findings are as follows: first, LO-FTD was more common than previously thought and the proportions of EO and LO groups differed across FTD subtypes; second, EO-FTD patients performed worse in tests of memory and frontal/executive functions than the LO-FTD group; and third, depression, apathy, impulsivity, and frontal/behavioral symptoms were more common in EO-FTD. Taken together, these data provide evidence that the heterogeneity of neuropsychological and behavioral symptoms in FTD may be accounted for by age at symptom onset. Our first major finding was that LO-FTD patients accounted for over 40% of all FTD patients, which was in line with previous studies reporting similar proportions of LO-FTD [1, 2, 8]. Analysis of subtypes of FTD revealed that EO-bvFTD was more common than LO-bvFTD whereas LO-PNFA was more common than EO-PNFA. There were almost equal numbers of EO and LO patients in the SD group. These findings are partly consistent with several studies which have

86 56.2 (5.9) 59.9 (6.0) 38 (44.2) 9.9 (5.1) 3.3 (2.4) 4 (4.7) 8 (9.3) 25 (29.1) 10 (11.6) 3 (3.5) 2.0 (2.2) 14.6 (7.4) 18.6 (2.7) 16.1 (12.1) 5.7 (11.1) 8.5 (5.8) 19.3 (7.3) 5.5 (4.3)

Number of patients Age at onset, years Age at diagnosis Female, n (%) Education, years Disease duration Familial history Diabetes mellitus Hypertension Hyperlipidemia Ischemic heart disease Hachinski ischemia scale KDSQ Barthel index S-IADL UPDRS score FTD CDR Sum of Boxes MMSE CDR Sum of Boxes

p 47 55.8 (6.8) 59.8 (6.9) 21 (44.7) 9.9 (5.5) 3.7 (2.6) 3 (6.4) 6 (12.8) 17 (36.2) 7 (14.9) 2 (4.3) 2.0 (2.0) 16.9 (7.5) 17.7 (3.4) 21.1 (12.3) 5.8 (10.2) 10.0 (6.0) 18.7 (7.5) 6.9 (4.8)

29 71.1 (6.3) 73.5 (6.3) 11 (37.9) 9.2 (6.4) 2.1 (1.3) 0 7 (24.1) 15 (51.7) 7 (24.1) 3 (10.3) 1.8 (1.9) 12.9 (6.9) 18.6 (2.4) 17.2 (10.4) 6.3 (9.3) 7.0 (3.3) 21.0 (5.4) 4.1 (2.8)

bvFTD (n = 76) EO-bvFTD LO-bvFTD < 0.001 < 0.001 0.563 0.616 0.001 0.283 0.224 0.182 0.313 0.364 0.703 0.022† 0.197 0.165 0.823 0.007∗ 0.154 0.005

p 27 57.8 (3.7) 61.1 (4.2) 12 (44.4) 10.2 (5.0) 3.0 (2.0) 1 (3.7) 1 (3.7) 6 (22.2) 2 (7.4) 1 (3.7) 1.9 (2.8) 11.5 (6.0) 19.8 (0.7) 9.0 (7.3) 1.7 (3.1) 5.8 (4.2) 21.3 (6.9) 2.9 (1.8)

30 69.3 (3.6) 73.3 (3.7) 14 (46.7) 9.0 (5.3) 3.7 (1.9) 1 (3.3) 4 (13.3) 12 (40.0) 5 (16.7) 2 (6.7) 1.3 (1.4) 15.3 (6.5) 18.9 (2.2) 17.2 (11.0) 7.8 (19.5) 9.6 (5.3) 15.4 (8.1) 5.5 (2.6)

SD (n = 57) EO-SD LO-SD < 0.001 < 0.001 0.866 0.387 0.147 0.940 0.211 0.149 0.427 > 0.999 0.448 0.032 0.050 0.002∗ 0.140 0.004 0.005 0.001

p 12 54.4 (5.9) 57.6 (5.0) 5 (41.7) 9.6 (4.1) 2.8 (2.3) 0 1 (8.3) 2 (16.7) 1 (8.3) 0 2.0 (2.1) 12.5 (7.6) 19.5 (1.2) 11.6 (10.4) 15.2 (19.4) 8.8 (6.6) 17.2 (6.9) 4.6 (3.7)

21 70.7 (4.3) 73.3 (3.8) 10 (47.6) 9.8 (6.3) 2.4 (2.2) 0 4 (19.0) 10 (47.6) 1 (4.8) 1 (4.8) 2.3 (1.8) 10.2 (9.3) 17.7 (4.6) 14.1 (14.2) 17.1 (23.6) 7.4 (6.3) 17.8 (9.7) 3.6 (2.8)

PNFA (n = 33) EO-PNFA LO-PNFA

0.630 0.133 > 0.999 > 0.999 0.804 0.507 0.137 0.631 0.830 0.552 0.839 0.530

< 0.001 < 0.001 0.741 0.897 0.639

p

Data are expressed in mean (standard deviation). p values are results of independent t-tests or chi-square tests as appropriate. ∗ Not significant after controlling for the disease duration. bvFTD, behavioral variant frontotemporal dementia; CDR, Clinical Dementia Rating; EO, early-onset; FTD, frontotemporal dementia; KDSQ, Korean Dementia Screening Questionnaire; LO, late-onset; MMSE, Mini-Mental State Examination; PNFA, progressive non-fluent aphasia; S-IADL, Seoul Instrumental Activities of Daily Living; SD, semantic dementia; UPDRS, Unified Parkinson Disease Rating Scale.

80 70.3 (4.9) < 0.001 73.4 (4.7) < 0.001 35 (43.8) 0.955 9.3 (5.9) 0.447 2.8 (1.9) 0.113 1 (1.2) 0.207 15 (18.8) 0.078 37 (46.2) 0.022 13 (16.2) 0.389 6 (7.5) 0.213 1.7 (1.7) 0.437 13.1 (7.5) 0.221 18.5 (3.0) 0.866 16.5 (11.5) 0.816 9.5 (18.0) 0.131 8.1 (5.0) 0.644 18.1 (7.9) 0.323 4.5 (2.8) 0.152

Total FTD (n = 166) EO-FTD LO-FTD

Variables

Table 1 Comparison of demographic factors and clinical scales of patients according to their age of symptom onset B.S. Ye et al. / Clinical Differences between EO-FTD and LO-FTD 603

3.1 (5.6) 22.6 (17.2) 21.5 (11.4) 9.2 (5.2) 1.9 (1.8) 4.7 (4.2) 6.7 (5.3) 4.6 (3.5) 15.0 (9.3)

2.3 (1.7) 22.7 (17.6) 24.0 (11.5) 8.6 (5.4) 1.2 (1.9) 3.9 (3.8) 5.9 (4.4) 2.3 (3.9) 4.1 (7.6)

Total FTD EO-FTD LO-FTD

0.390 0.002 < 0.001

0.669 0.045 0.319

0.259

0.696

0.314

p

7.2 (4.5) 1.7 (2.9) 4.1 (7.2)

10.1 (5.4) 1.8 (2.0) 4.3 (4.2)

20.6 (12.3)

32.9 (16.0)

2.1 (1.8)

9.1 (5.5) 6.0 (4.6) 17.3 (12.8)

11.4 (5.3) 2.2 (1.6) 6.2 (4.1)

21.6 (11.8)

35.8 (13.4)

4.4 (9.1)

bvFTD EO-bvFTD LO-bvFTD

0.088 < 0.001 < 0.001

0.180 0.470 0.078

0.477

0.748

0.051

p

4.6 (3.7) 3.5 (4.4) 6.2 (8.3)

6.8 (4.7) 0.3 (1.1) 3.5 (3.4)

31.4 (2.6)

8.2 (7.2)

3.1 (1.2)

EO-SD

8.1 (6.2)

2.5 (1.4)

LO-SD

4.1 (4.3) 3.6 (2.4) 14.1 (6.4)

6.8 (3.9) 1.1 (0.9) 3.1 (3.7)

24.3 (9.3)

SD

0.618 0.919 0.001

0.993 0.006 0.707

< 0.001

0.983

0.099

p

3.5 (3.8) 1.5 (5.3) –1.1 (4.8)

7.0 (5.4) 1.0 (1.8) 3.0 (3.3)

19.6 (13.8)

18.2 (14.8)

1.2 (1.5)

7.0 (4.7) 4.1 (2.3) 13.1 (5.7)

9.7 (5.5) 2.8 (2.7) 5.0 (4.3)

16.8 (13.0)

26.5 (17.0)

2.2 (1.3)

PNFA EO-PNFA LO-PNFA

0.052 0.143 < 0.001

0.212 0.079 0.207

0.597

0.202

0.098

p

Data are expressed in mean (standard deviation) of detrended neuropsychological scores based on age 65. p values are results of analyses of covariance after controlling factors showing different distribution between EO- and LO-groups. Hypertension was controlled for comparison between EO-FTD and LO-FTD groups, while disease duration was controlled for comparison between EO-bvFTD and LO-bvFTD groups. ∗ RCFT copy was expressed in raw score. bvFTD, behavioral variant of frontotemporal dementia; COWAT, Controlled Oral Word Association Test; EO, early-onset; FTD, frontotemporal dementia; K-BNT, Korean version of the Boston Naming Test; LO, late-onset; PNFA, progressive non-fluent aphasia; RCFT, Rey-Osterrieth Complex Figure Test; SD, semantic dementia; SVLT, Seoul Verbal Learning Test.

Attention Digit span backward Language K-BNT (60) Visuospatial function RCFT copy (36)∗ Memory SVLT immediate recall (36) SVLT delayed recall (12) SVLT recognition score (24) Frontal/executive function COWAT supermarket COWAT phonemic Stroop color reading test (112)

Neuropsychological test (possible maximum score)

Table 2 Comparison of neuropsychological test scores between early-onset and late-onset subgroups among total frontotemporal dementia and among each subtype of frontotemporal dementia

604 B.S. Ye et al. / Clinical Differences between EO-FTD and LO-FTD

1.0 (3.0) 0.1 (0.4) 2.0 (2.6) 0.5 (0.9) 1.4 (2.8) 0.6 (1.7) 3.2 (3.8) 1.3 (2.8) 2.2 (3.4) 1.7 (3.4) 1.3 (2.7) 2.4 (3.3) 17.8 (19.8) 20.2 (13.2) 10.0 (9.9) 19.9 (12.0) 50.2 (30.6) 23.9 (15.6)

0.7 (2.4) 0.5 (1.9) 2.2 (3.1) 1.2 (1.8) 1.6 (2.6) 1.0 (2.6) 4.6 (4.5) 2.4 (3.6) 3.1 (4.1) 2.8 (4.4) 1.6 (3.3) 3.1 (3.6) 24.7 (21.4)

23.8 (12.4) 12.2 (8.7) 21.8 (12.8) 57.9 (28.8) 29.2 (15.9)

Total FTD EO-FTD LO-FTD

0.082 0.136 0.346 0.110 0.044

0.495 0.073 0.606 0.007 0.543 0.210 0.037 0.040 0.175 0.089 0.514 0.187 0.043

p

28.4 (10.4) 13.8 (8.4) 25.4 (12.2) 67.6 (23.3) 33.4 (15.6)

1.2 (3.1) 0.9 (2.6) 2.9 (3.6) 1.1 (1.5) 1.8 (2.9) 1.3 (2.8) 5.5 (4.6) 3.5 (4.2) 3.5 (4.3) 4.1 (4.7) 2.4 (3.9) 3.7 (3.8) 31.8 (22.6) 22.8 (11.9) 15.5 (11.3) 23.0 (11.9) 61.6 (29.3) 27.3 (15.4)

1.9 (3.9) 0.04 (0.2) 3.2 (3.3) 0.7 (1.1) 1.8 (3.3) 0.4 (1.4) 4.6 (4.6) 1.9 (3.5) 3.6 (4.3) 2.4 (4.4) 2.1 (3.7) 3.4 (4.1) 26.2 (25.0)

bvFTD EO-bvFTD LO-bvFTD

0.040 0.463 0.409 0.343 0.116

0.407 0.033 0.733 0.243 0.957 0.090 0.429 0.103 0.938 0.134 0.751 0.697 0.336

p

18.8 (11.9) 11.1 (9.4) 17.4 (11.6) 47.5 (30.1) 23.6 (15.6)

0.2 (1.2) 0.04 (0.2) 1.8 (2.2) 1.6 (2.3) 1.6 (2.2) 0.9 (2.7) 4.0 (4.1) 1.5 (2.5) 2.8 (4.1) 1.0 (3.2) 0.7 (2.1) 2.4 (3.2) 18.6 (16.9)

EO-SD

SD

20.9 (13.4) 8.1 (7.9) 19.3 (11.1) 48.3 (28.3) 24.7 (14.7)

0.3 (1.5) 0.2 (0.5) 1.7 (1.8) 0.5 (0.9) 1.1 (2.7) 0.9 (2.3) 2.8 (3.3) 1.3 (2.7) 1.8 (2.8) 1.5 (2.5) 0.7 (1.2) 1.9 (2.5) 14.6 (13.7)

LO-SD

0.540 0.204 0.525 0.915 0.799

0.737 0.213 0.921 0.022 0.457 0.968 0.229 0.803 0.263 0.529 0.980 0.444 0.332

p

17.2 (14.1) 8.6 (6.8) 18.1 (15.0) 43.9 (33.3) 24.6 (14.1)

0 0 0.2 (0.6) 0.4 (0.7) 0.9 (1.9) 0 1.9 (3.7) 0 1.7 (2.2) 1.8 (4.1) 0.7 (1.3) 2.3 (3.9) 9.9 (14.7) 14.6 (14.1) 4.2 (5.1) 15.9 (13.1) 34.7 (30.8) 17.7 (16.1)

0.8 (3.1) 0.1 (0.3) 0.3 (0.8) 0.4 (0.7) 1.1 (2.4) 0.2 (0.8) 1.3 (1.5) 0.3 (1.0) 0.9 (2.1) 0.9 (2.6) 1.1 (2.7) 1.8 (2.9) 8.9 (13.7)

PNFA EO-PNFA LO-PNFA

0.638 0.057 0.691 0.461 0.253

0.426 0.440 0.708 0.898 0.804 0.440 0.554 0.343 0.350 0.514 0.692 0.685 0.868

p

Data are expressed in mean (standard deviation). p values are results of analyses of covariance after controlling factors showing different distribution between EO- and LO-groups. Hypertension was controlled for comparison between EO-FTD and LO-FTD groups, while disease duration was controlled for comparison between EO-bvFTD and LO-bvFTD groups. bvFTD, behavioral variant of frontotemporal dementia; EO, early-onset; FEDAS, frontal executive, dysfunction, disinhibition, apathy scale; FTD-FBI, frontotemporal dementia frontal behavioral inventory; FTD, frontotemporal dementia; LO, late-onset; NPI, neuropsychiatric inventory; PNFA, progressive non-fluent aphasia; SD, semantic dementia.

NPI Delusion Hallucination Aggression Depression Anxiety Euphoria Apathy Impulsivity Anger Repetitive behavior Sleep problem Eating problem NPI Total score FEDAS FEDAS Executive score FEDAS Disinhibition score FEDAS Apathy score FEDAS Total score FTD-FBI total score

Items

Table 3 Comparison of neuropsychiatric and frontal behavioral symptom scores between early-onset and late-onset subgroups among total frontotemporal dementia and among each subtype of frontotemporal dementia B.S. Ye et al. / Clinical Differences between EO-FTD and LO-FTD 605

606

B.S. Ye et al. / Clinical Differences between EO-FTD and LO-FTD

reported that patients with bvFTD and SD are usually younger at age of onset than patients with PNFA [3, 29]. The second finding was that after controlling for the effects of chronological aging, EO-FTD patients had more severe deficits in overall neuropsychological performance, and specifically more significant impairments in memory and frontal/executive functions than LO-FTD group. However, two previous studies which compared cognitive symptoms in EO-bvFTD and LObvFTD groups reported inconsistent results [8, 9]. One study reported that the LO-bvFTD patients performed significantly worse in tests of memory and visuospatial function than EO-bvFTD patients [9]. The number of patients in that study was relatively small and the authors only presented data for MMSE recall and construction and Raven’s colored progressive matrices, so direct comparison between their study and ours may not be appropriate. The other study did not detect any specific differences in neuropsychological performance associated with age of onset in bvFTD [8]. The reason for this discrepancy is not entirely clear. However, these authors did not consider the effects of chronological aging when comparing EO- and LObvFTD; when the EO- and LO-bvFTD groups in our study were compared directly without detrending to control for the effects of chronological aging there was no significant group difference in neuropsychological performance (Supplementary Table 1), suggesting that the results of the other study might have been confounded by the effects of chronological aging. Our finding of worse neuropsychological performances in EO-FTD than in LO-FTD is reminiscent of results from previous research on AD in which EOAD patients were found to be more impaired in tests of overall cognitive function [4, 30] than LOAD patients. This effect might be explained by the agerelated cognitive reserve [5, 7, 31], i.e., a higher pathological burden might be required to produce the same severity of dementia in younger patients with a greater functional reserve. Further studies comparing the pathological burdens, topographical pattern of structural changes, metabolic deterioration, and amount and location of cortical and subcortical tissue loss in EO- and LO-FTD groups would address this hypothesis. The third finding was that EO-FTD patients had more prominent frontal/behavioral symptoms than LO-FTD patients. In general, EO-FTD patients were reported to have more symptoms across all the behavioral assessments administered in our study. Specifically, the EO-FTD group had more symptoms

of depression, apathy, and impulsivity on the CGANPI than the LO-FTD group and EO-bvFTD group had more dysexecutive symptoms than the LO-bvFTD group. Apathy and executive dysfunction are known to be the most prominent behavioral and neuropsychological symptoms in FTD, and have been reported in numerous studies of EO-FTD [14, 32, 33]. However, in contrast to our study, previous studies reported higher [9] or comparable [10] total CGA-NPI scores in LO-FTD patients than in EO-FTD patients. These differences might be explained by the relatively smaller sample size [10] and higher level of general cognition (total MMSE score) [9] in the EO-FTD patients in the previous studies. Only the hallucination subscore on the CGA-NPI was significantly higher in EO-bvFTD group than the LO-bvFTD group. Hallucination, along with other psychotic symptoms, is generally recognized to be an uncommon feature of FTD [34, 35]. Several previous studies have reported that hallucination was relatively common in bvFTD patients with abnormal expansion of C9orf72 [36, 37] and that carriers of the C9orf72 repeat expansion generally had early age onset. However, this hypothesis is rendered less plausible by our previous investigation into the frequency of repeat expansion of C9orf72 in Korean FTD patients which found negative results [38]. An alternative explanation is that FTD patients who suffer hallucinations have a mixed pathology with characteristics associated with both AD and FTD. Previous studies have reported that about 20% of bvFTD patients exhibit AD pathology as the primary neuropathological finding, and these patients were more likely to experience delusions and hallucinations than patients for whom the main neuropathological finding was FTD pathology [39]. Since AD pathology increases sharply as a function of age, this hypothesis does not account for the greater prevalence of hallucinations in the EObvFTD group in our study. Our study has limitations. First, we could not pathologically confirm the diagnosis of FTD. Second, age at symptom onset was based on interviews with caregivers, which might raise uncertainties about defining clear-cut onset age. Third, there might be a generalization issue, because all 16 centers which participated in the CREDOS-FTD study were neurological clinics. Patients with FTD who visit a psychiatric clinic might have different clinical, neuropsychological, and behavioral features from those treated in a neurological clinic. Fourth, cut-off point of 65 years old used to divide FTD patients into EO- and LO-groups in the current study was arbitrary. However, when we regrouped our FTD patients according to the mean age

B.S. Ye et al. / Clinical Differences between EO-FTD and LO-FTD

of symptom onset (63 years old), and compared the newly defined EO- and LO-FTD groups, the pattern of neuropsychological difference was similar to that from groups based on arbitrary cut-off age of 65 (Supplementary Table 2). Finally, we used a linear detrending method with general linear models to remove the confounding effects of chronological normal aging on the scorable neuropsychological tests, based on the data from the age- and gender-matched NC subjects. However, we could not derive a detrending formula for the RCFT copy for ceiling effect of the RCFT copy in NC subjects. Thus, we acknowledge that there may be a possibility that effects from chronological aging might be represented better by other regression models than our linear regression models. These limitations notwithstanding, this study has strengths, namely that given the rarity of FTD, this is a relatively larger sample in which to examine clinical differences associated with age of onset in FTD and even in subtypes of FTD. Our findings suggest that FTD is clinically heterogeneous and that at least part of this heterogeneity can be related to age at symptom onset. After controlling for the effects of chronological aging in most neuropsychological results, EO-FTD patients exhibited more profound memory and frontal/executive dysfunctions and more severe behavioral symptoms than LO-FTD patients. ACKNOWLEDGMENTS This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020) and a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120182). Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/14-1044r2).

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SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/ 10.3233/JAD-141044. [13]

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