Clinical Effects of Frontal Behavioral Impairment: Cortical Thickness and Cognitive Decline in Individuals with Subjective Cognitive Decline and Amnestic Mild Cognitive Impairment

Abstract

Background:

Frontal behavioral impairment (FrBI) is commonly observed in various degenerative diseases and refers to various behavioral symptoms.

Objective:

We investigated the effects of the presence of FrBI on cortical thickness, and the longitudinal neuropsychological changes in people in the predementia stage.

Methods:

A total of 794 individuals completed neuropsychological tests and the Frontal Behavioral Inventory (FBI) Questionnaire, and underwent magnetic resonance (MR) scanning. Participants were analyzed and grouped into non-FrBI (FBI = 0) or FrBI (FBI≥1). Cortical thickness was measured on MR images using a surface-based method.

Results:

In total, 281 people with subjective cognitive decline (SCD) and 513 with amnestic mild cognitive impairment (aMCI) were assessed for FrBI. Relative to people without FrBI, those with FrBI presented reduced cortical thickness in the frontal, anterior temporal and lateral parietal regions (p < 0.05, FDR corrected). People with FrBI developed Alzheimer’s disease, rather than behavioral variant frontotemporal dementia, as observed over seven years. Mixed effects models reported that people with FrBI have greater cognitive decline than those with non-FrBI in multiple domains, including language, memory, and executive functions (p < 0.05, FDR corrected). Furthermore, while negative FrBI symptoms (e.g., deficit behaviors) were associated with greater declines in multiple domains, positive FrBI symptoms (e.g., disinhibition symptoms) were related to declines in visuospatial function and verbal memory. Finally, the occurrence of both types of symptoms correlated with multi-domain cognitive decline.

Conclusions:

FrBI predicted worse clinical outcomes, including reduced cortical thickness and cognitive decline, which are not necessarily specific to frontal dysfunction.

Keywords

Cognitive decline cortical thickness frontotemporal dementia neuropsychiatric symptoms neuropsychological tests

INTRODUCTION

Behavioral variant frontotemporal dementia (bvFTD) is characterized by the symptoms associated with frontal behavioral impairment (FrBI), which include disinhibition, apathy, loss of sympathy, and perseveration [1]. Furthermore, people with bvFTD often exhibit cortical atrophy limited to the frontal and anterior temporal regions [2]. In contrast, Alzheimer’s disease (AD) is initially characterized by memory impairments, followed by language, visuospatial, and executive dysfunction [3]. Given that the prompt detection of dementia could lead to early treatment and affect disease progression, the concept of mild cognitive impairment (MCI) has emerged [4, 5]. For instance, previous studies have shown that most people with MCI, especially those with the amnestic type (aMCI), develop AD within five years, suggesting that aMCI may be an early manifestation of AD [6]. Recently, both the International Working Group and the National Institute on Aging-Alzheimer’s Association proposed some MCI research criteria by the presence of biomarker evidence, referred to as prodromal AD [7], or MCI due to AD [8]. In addition, previous studies suggested that cognitively normal individuals with memory impairment concerns (i.e., subjective cognitive decline; SCD) presented more conversion to dementia than those without such concerns [9]. Therefore, aMCI and SCD were combined into a new category, which is referred to as the predementia stage. Similarly, a predementia stage of bvFTD may exist, given that bvFTD exhibits a characteristic degenerative disease course, with an insidious onset which is followed by slow progression.

The Frontal Behavior Inventory (FBI) [10] was developed as a screening questionnaire for distinguishing between bvFTD and other types of dementia. Specifically, it consists of several items that assess both the positive and negative behavioral symptoms commonly observed in bvFTD. Therefore, expecting people with FrBI detected by the FBI to be in a predementia stage of bvFTD is reasonable. Alternatively, FrBI might be characterized by the non-specific predementia stage of degenerative dementia, considering that it is also frequently observed in AD. Indeed, several previous studies have indicated the presence of behavioral dysfunction, such as agitation, depression, and disinhibition, in both MCI and AD [11 –14].

In the present study, we sought to investigate the effects of FrBI (detected by the FBI) on the clinical outcomes (measured by cortical thickness and longitudinal neuropsychological changes) of people with aMCI and SCD. First, we hypothesized the presence of FrBI to predict worse clinical outcomes, including decreased cortical thickness and cognitive decline, as opposed to non-FrBI. Second, the pattern of worse clinical outcomes was proposed to be decreased cortical thickness and cognitive impairment as seen in bvFTD. Specifically, we hypothesized the cortical thickness reductions associated with FrBI to be most prominent in the frontal and anterior temporal regions. Finally, we hypothesized that people with FrBI would also predominantly develop dementia of the bvFTD type.

Methods

Study participants

A total of 794 individuals who underwent high-resolution 3.0-Tesla brain magnetic resonance imaging (MRI), neuropsychological tests, and the FBI [10, 15] were cross-sectionally recruited from the Memory Disorders Clinic of the Samsung Medical Center between 2011 and 2013. Specifically, 281 SCD and 513 aMCI subjects above the age of 50 years participated in the present investigation. Their clinical diagnosis was established at a multi-disciplinary conference applying the standard research criteria for SCD [16] and MCI [7, 8]. Among the people with MCI, those with subcortical vascular MCI (i.e., focal neurological symptoms and significant ischemia on MRI [17]) were excluded. In addition, criteria published by the SCD-Initiative Working Group were applied to define SCD as either the subjective change in any cognitive domain with a particular concern, or the appraisal of an inferior cognitive capacity, compared with the same age group [16].

Standard protocol approval, registration, and patient consent

The Institutional Review Boards of the Samsung Medical Center approved this study and written informed consent was obtained from all participants prior to the start of the investigation.

Frontal behavioral impairment (FrBI)

The FBI provides a measure of the severity of behavioral deficits using a 3-point scale [10]. It consists of 24 items assessing the following: apathy, aspontaneity, indifference/flat affect, inflexibility, concreteness, personal neglect, disorganization, inattention, loss of insight, perseveration, logopenia, verbal apraxia, irritability, excessive jocularity, poor judgment, inappropriateness, impulsivity, restlessness, aggression, hyperorality, hypersexuality, utilization behavior, incontinence, and alien hand syndrome. However, the logopenia, verbal apraxia, and alien hand items were excluded from our FBI given that such symptoms would indicate language, speech or motor abnormalities rather than frontal behavioral abnormalities, even though they are commonly observed in frontotemporal dementia syndrome, including non-fluent variant primary progressive aphasia, corticobasal degeneration syndrome (CBS), and progressive supranuclear palsy syndrome (PSPS) [18, 19].

While the negative items (i.e., deficit behaviors) included apathy, aspontaneity, emotional indifference, inflexibility, concreteness, disorganization, inattention, and loss of insight, the positive items of disinhibition included perseveration, irritability, jocularity, poor judgment, inappropriateness, impulsivity, restlessness, aggression, hyperorality, hypersexuality, utilization behavior, and incontinence [10].

In addition to the FBI, subjects underwent clinical interviews and neurological examinations conducted by a qualified neurologist and were grouped into people with FrBI, and without FrBI (non-FrBI). Specifically, FrBI was defined as a minimum FBI score of 1, considering that we focused on either the presence or absence of behavioral symptoms. Finally, people with FrBI were additionally subdivided into three groups based on the original FBI study: negative symptoms only, positive symptoms only, and a third group with both negative and positive symptoms [10].

Cortical thickness analyses

We acquired 3-dimensional T1-weighted images from 794 participants using an Achieva 3.0-Tesla MRI scanner (Philips, Best, the Netherlands) at the Samsung Medical Center between 2011 and 2013. Briefly, the imaging parameters included the following: 1.0 mm-thick sagittal slices with 50% overlap; no gap; a repetition time of 9.9 ms; an echo time of 4.6 ms; a flip angle of 8°; and a matrix size of 240×240 pixels reconstructed to 480×480 over a field of view of 240 mm. To measure cortical thickness, the T1-weighted images were processed using the standard Montreal Neurological Institute image processing software, as previously described [20, 21]. While the native MRI images were registered into a standardized stereotaxic space through a linear transformation [22], the N3 algorithm was used to correct the images for intensity-based non-uniformities [23] caused by non-homogeneities in the magnetic field. Successively, the registered and corrected images were classified into white matter, gray matter, cerebrospinal fluid, and background, using a 3D stereotaxic brain mask and the Intensity-Normalized Stereotaxic Environment for the Classification of Tissues algorithm [24]. Furthermore, the surfaces of the inner and outer cortex were automatically extracted with the Constrained Laplacian-Based Automated Segmentation with Proximities algorithm [25]. Additionally, cortical thickness values were calculated in the native space, rather than the Talairach space, given the existing limitations in the linear stereotaxic normalization. Considering that the MR volumes in the native space were transformed into the stereotaxic space with a linear transformation matrix, the inverse transformation matrix was applied to the cortical thickness models for their reconstruction in the native space [26]. Specifically, the cortical thickness was defined as the Euclidean distance between the linked vertices of the inner and outer surfaces [25]. Subsequently, the thickness value was spatially normalized using surface-based two-dimensional registration with a sphere-to-sphere warping algorithm, meaning that the vertices of each subject were non-linearly registered to a standard surface template [27, 28]. Thereafter, the individual cortical surface of each subject was registered to the pre-categorized template and divided into frontal, temporal, parietal, and occipital lobes via automated processing. Finally, the averaged thickness values at all vertices across each hemisphere and lobar region were used for global analysis.

Neuropsychological tests

All subjects were assessed using a standardized neuropsychological assessment, i.e., the Seoul Neuropsychological Screening Battery, which consists of several tests assessing the following five domains: attention, language and related functions, visuospatial functions, memory, and executive functions [29]. Specifically, such tests included the digit span forward and backward task for attention; the Korean version of the Boston Naming Test (K-BNT) [30] for language and related functions; the Rey-Osterrieth Complex Figure Test (RCFT; copy) for visuospatial functions; the immediate and a 20-minute delayed recall, as well as the recognition trial, of the RCFT and the Seoul Verbal Learning Test (SVLT; three learning/free recall trials of 12 words, a 20-minute delayed recall trial for these 12 items, and a recognition test) for memory; and the phonemic and semantic trials of the Controlled Oral Word Association Test (COWAT), as well as a Stroop Test (word and color reading of 112 items during a 2-minute period), for executive functions. Finally, the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB) were also administered to all individuals through an interview conducted by a qualified neurologist.

Clinical follow-up

Furthermore, the follow-up neuropsychological data from 368 of the 794 people who completed at least two follow-up neuropsychological tests were retrospectively collected. The clinical follow-up for progression to dementia was performed until 2016. Although the follow-up times and durations varied among participants, the mean duration was 24 months and the follow-up tests were conducted 3 times on average. The diagnosis of dementia was based on the criteria from the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) and required the evidence of impaired social or occupational functioning, supplied by the Seoul-Instrumental Activities of Daily Living scale [31]. Different types of converted dementia were determined using the diagnostic criteria of AD, including hippocampal atrophy on visual interpretation [32], bvFTD including frontal and anterior temporal atrophy on visual interpretation [33], CBS including perirolandic atrophy [19], PSPS including midbrain atrophy [19], and dementia with Lewy bodies (DLB) [34].

Statistical analyses

To compare the demographic variables between people with and without FrBI, the Student’s t-test and the chi-squared test were performed for continuous and categorical variables, respectively. Additionally, to assess the difference in cortical thickness between people with and without FrBI, a multiple linear regression analysis was conducted after controlling for age, sex, intracranial volume, and MMSE score. Similarly, to analyze the localized differences and the statistical map of cortical thickness on the surface model, a linear regression was performed vertex-by-vertex after controlling for age, sex and MMSE score. Thereafter, the resulting statistical maps were thresholded using a false discovery rate (FDR) [35] with a q value of 0.05, after pooling the p-values from the linear regression analysis.

To analyze the differences in cognitive outcome measures at baseline between people with and without FrBI, a multiple linear regression analysis was employed after controlling for age, sex, and education. Moreover, to assess the conversion to dementia in people with and without FrBI, a Cox regression was performed after controlling for age, sex, and education.

Finally, the longitudinal neuropsychological test data of 368 individuals were analyzed using a linear mixed effects model, with the individual as the random effect component, and age, sex, education, group, time, and the interaction between group and time (group by time) as the fixed effects components. We also corrected multiple comparisons using FDR. All the analyses were conducted using SPSS 22.0 (SPSS Inc., Chicago, IL, USA).

Results

Participant demographics

The participants’ baseline characteristics are shown in Table 1 and Supplementary Table 1. Briefly, the sample included 245 men (30.9%) and 549 women (69.1%), with a mean age of 69.1 (SD = 9.0) years.

Table 1

Demographic characteristics of the study participants at baseline

	Non-FrBI (N = 198)	FrBI (N = 596)	p ^*
Baseline age, y	67.3±9.2	69.7±8.9	0.001
Female, N (%)	143 (72.2)	406 (68.1)	0.288
Education, y	10.0±5.2	9.89±5.2	0.662
MMSE, points	27.5±2.6	26.1±3.5	<0.001
MCI, N (%)	104 (52.5)	409 (68.6)	<0.001

Values are presented as means (standard deviation) or number (%) ^*p value using Student’s t-test for continuous variables and chi-squared test for categorical variables. FrBI, frontal behavioral impairment; N, number; MMSE, Mini-Mental Status Examination; MCI, mild cognitive impairment.

Of a total of 794 individuals, 198 (24.9%) were classified as people without FrBI and 596 (75.1%) as people with FrBI. People with FrBI were older (p < 0.001), had lower MMSE scores (p < 0.001) and were more frequently diagnosed with MCI than were people without FrBI.

Furthermore, people with FrBI showed varied neuropsychiatric symptoms (NPS), of which irritability (12.2%), followed by inflexibility (11.8%) and apathy (10.4%), were the most frequently observed (Supplementary Table 2). Of the people with FrBI, 382 presented both positive and negative symptoms, whereas 148 showed only negative symptoms, and 66 presented with only positive symptoms.

Cortical thickness in people with non-FrBI and FrBI

The multiple linear regression analysis indicated that people with FrBI had reduced cortical thickness in the frontal, temporal, and parietal lobes than did people without FrBI (B = –0.037∼–0.024, p < 0.05; Supplementary Table 3). Moreover, the statistical map of the cortical thickness differences reported that compared to people without FrBI, people with FrBI have significantly reduced cortical thickness in the bilateral superior and middle frontal areas, right orbital prefrontal cortex, bilateral middle and inferior temporal, left cingulate, bilateral medial temporal areas, bilateral supra-marginal gyri and superior parietal lobules, and left lateral occipital cortex (Fig. 1A).

Fig.1

Three-dimensional significance maps of reduced cortical thickness of (A) people with FrBI compared to people with non-FrBI, (B) people with FrBI with only negative symptoms compared to people with non-FrBI, (C) people with FrBI with only positive symptoms compared to people with non-FrBI, and (D) people with FrBI with both positive and negative symptoms compared to people with non-FrBI. Statistically significant cortical thickness reductions were colored in red-yellow (false discovery rate [FDR] corrected p < 0.05). The covariates included age, sex, and MMSE score. NC, normal control; MBI, mild behavioral impairment; FrBI, frontal behavioral impairment; MMSE, Mini-Mental State Examination.

Similarly, compared to people without FrBI, people with FrBI with only negative symptoms showed reduced cortical thickness in the bilateral frontal areas, temporo-parietal junction and precuneus, whereas those with only positive symptoms displayed reduced cortical thickness in the bilateral superior frontal gyrus, supramarginal gyrus and precuneus. Furthermore, compared to people without FrBI, people with FrBI with both negative and positive symptoms showed reduced cortical thickness across widespread bilateral regions, excluding the right corpus callosum and the occipitotemporal gyrus (Fig. 1B-D).

Baseline cognitive function in people with non-FrBI and FrBI

The multiple linear analysis showed that people with FrBI perform poorly on the MMSE and CDR-SB, and exhibit impairments in multiple cognitive domains (e.g., language, memory, and executive functions) as opposed to people without FrBI (B = –0.517∼3.939, p < 0.05; Supplementary Table 3). In addition, while people with FrBI with only negative symptoms performed poorly on the CDR-SB and exhibited impairments in language, verbal memory, visual memory and executive function (B = –4.261∼0.439, p < 0.05), those with sole positive symptoms performed poorly on the MMSE and demonstrated impairments in language, verbal and visual memory (B = –3.668∼–1.308, p < 0.05). Finally, people with FrBI with both negative and positive symptoms performed poorly on the MMSE and CDR-SB, and had impairments in language, verbal memory, visual memory, and executive function (B = –1.320∼8.964, p < 0.05; Supplementary Table 4). After multiple comparisons, the above associations remained the same.

Conversion to dementia in people with non-FrBI and FrBI

While 122 of the 287 people with FrBI developed dementia (114 AD [36], 2 bvFTD [33], 1 CBS [19], 1 PSPS [19], 4 DLB [34]), 11 of the 77 people without FrBI also developed dementia, suggesting that people with FrBI were more likely to develop dementia than people without FrBI (hazard ratio = 3.48, 95% confidence interval 1.88–6.47). Specifically, most people with FrBI developed AD (93.4%) rather than either bvFTD (1.6%) or other neurodegenerative conditions (Fig. 2).

Fig.2

Follow-up diagnosis of people with FrBI. A) In a longitudinal study of non-FrBI and FrBI, people with FrBI were more likely to develop dementia than people with non-FrBI. B) The people with FrBI who developed dementia mainly developed AD (93.4%) rather than bvFTD (1.6%). FrBI, frontal behavioral impairment; AD, Alzheimer’s disease; bvFTD, behavioral variant frontotemporal dementia; CBS, corticobasal syndrome; PSPS, progressive supranuclear palsy syndrome; DLB, dementia with Lewy bodies.

Longitudinal cognitive change in people with non-FrBI and FrBI

Supplementary Table 1 summarized the characteristics of the subjects included in the longitudinal study. A linear mixed effects model analysis identified a steeper slope for people with FrBI on the MMSE, CDR-SB, K-BNT, RCFT (immediate recall, delayed recall, and recognition), SVLT (immediate recall, delayed recall, and recognition), COWAT (semantic trial), and Stroop test (color condition) than for people without FrBI (B = –0.152∼–0.018, p < 0.001; Table 2, Fig. 3).

Table 2

Comparison of longitudinal neuropsychological changes between people with non-frontal behavioral impairment and frontal behavioral impairment

Neuropsychological tests	Non-FrBI	FrBI
		^*Total		Negative		Positive		Both
		Average difference (SE)	p	Average difference (SE)	p	Average difference (SE)	p	Average difference (SE)	p
MMSE	Reference	–0.020 (0.006)	0.001^†	–0.020 (0.008)	0.019^†	–0.006 (0.009)	0.510	–0.023 (0.006)	<0.001^†
CDR-SB	Reference	0.018 (0.004)	<0.001^†	0.016 (0.004)	<0.001^†	0.009 (0.005)	0.080	0.020 (0.004)	<0.001^†
Attention
Digit span forward	Reference	–0.001 (0.003)	0.624	0.002 (0.003)	0.582	–0.001 (0.004)	0.850	–0.003 (0.003)	0.313
Digit span backward	Reference	–0.001 (0.002)	0.610	–0.001 (0.003)	0.783	0.002 (0.004)	0.685	–0.002 (0.002)	0.452
Language and related functions
K-BNT	Reference	–0.031 (0.012)	0.009^†	–0.038 (0.016)	0.021^†	–0.001 (0.017)	0.605	–0.033 (0.012)	0.005^†
Visuospatial function
RCFT copy	Reference	0.006 (0.012)	0.624	–0.006 (0.015)	0.687	0.045 (0.016)	0.004^†	0.002 (0.012)	0.895
Memory
SVLT (immediate recall)	Reference	–0.056 (0.011)	<0.001^†	–0.073 (0.018)	<0.001^†	–0.050 (0.018)	0.005^†	–0.051 (0.010)	<0.001^†
SVLT (delayed recall)	Reference	–0.025 (0.005)	<0.001^†	–0.028 (0.007)	<0.001^†	–0.016 (0.008)	0.049^†	–0.025 (0.005)	<0.001^†
SVLT (recognition)	Reference	–0.010 (0.005)	0.047	–0.023 (0.006)	<0.001^†	0.004 (0.007)	0.595	–0.008 (0.005)	0.135
RCFT (immediate recall)	Reference	–0.024 (0.010)	0.022^†	–0.037 (0.014)	0.008^†	–0.024 (0.018)	0.187	–0.020 (0.011)	0.086
RCFT (delayed recall)	Reference	–0.026 (0.010)	0.014^†	–0.037 (0.014)	0.008^†	–0.022 (0.018)	0.227	–0.023 (0.011)	0.040
RCFT (recognition)	Reference	–0.012 (0.005)	0.017^†	–0.007 (0.007)	0.308	–0.006 (0.008)	0.429	–0.015 (0.005)	0.003^†
Executive function
COWAT (semantic fluency)	Reference	–0.053 (0.022)	0.014^†	–0.055 (0.030)	0.068	0.015 (0.038)	0.698	–0.062 (0.023)	0.007^†
COWAT (phonemic fluency)	Reference	–0.045 (0.025)	0.079	–0.072 (0.034)	0.036	0.020 (0.044)	0.641	–0.046 (0.026)	0.081
Stroop test (color reading)	Reference	–0.152 (0.042)	<0.001^†	–0.167 (0.054)	0.002^†	–0.074 (0.068)	0.273	–0.154 (0.046)	0.001^†

p < 0.05 between people with non-FrBI and either all people with FrBI, those with only negative symptoms, with only positive symptoms, or with both negative and positive symptoms; linear mixed effects models were performed after adjusting for age, sex, and education. ^†p < 0.05 corrected multiple comparisons using false discovery rate. ^*The total FrBI comprised people with FrBI with only negative symptoms, only positive symptoms, and both negative and positive symptoms. FrBI, frontal behavioral impairment; MMSE, Mini-Mental Status Examination; CDR-SB, Clinical Dementia Rating-Sum of Boxes; COWAT, Controlled Oral Word Association Test; K-BNT, Korean version of Boston Naming Test; RCFT, Rey-Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test; SE, standard error.

Fig.3

Cognitive changes in the follow-up duration between people with non-FrBI and FrBI. People with FrBI showed a steeper decline on MMSE, CDR-SB, and K-BNT scores; delayed recall on the SVLT and RCFT, semantic fluency on the COWAT, and color reading on the Stroop test. FrBI, frontal behavioral impairment; MMSE, Mini-Mental State Examination; CDR-SB, Clinical Dementia Rating Sum of Boxes; K-BNT, Korean version of the Boston Naming Test; RCFT, Rey-Osterrieth complex figure test; SVLT, Seoul Verbal Learning Test; COWAT, Controlled Oral Word Association Test.

Furthermore, a linear mixed effects model analysis was performed on the people with FrBI with only negative, only positive, and both negative and positive symptoms. While people with FrBI with only negative symptoms exhibited a decline on MMSE and CDR-SB scores, as well as deficits in language, visual memory, verbal memory, and executive function (B = –0.073∼0.016, p < 0.05), those with only positive symptoms presented a decline in the visuospatial domain and verbal memory (B = –0.050∼0.045, p < 0.05). In contrast, people with FrBI with both negative and positive symptoms displayed a decline on MMSE and CDR-SB scores, as well as language, visual memory, verbal memory, and executive function (B = –0.154∼0.020, p < 0.05; Table 2). After multiple comparisons, the above associations remained the same except for people with FrBI with both negative and positive symptoms, who showed a decline on MMSE and CDR-SB scores, as well as language, verbal memory, and executive function.

Discussion

New data regarding the clinical effects of FrBI, including decreased cortical thickness and cognitive decline, on a relatively large-sized aMCI and SCD cohort were reported. Our major findings were the following: compared with people without FrBI, people with FrBI showed reduced cortical thickness in both the temporo-parietal and frontal regions. Additionally, they were more likely to develop dementia, mainly AD rather than bvFTD. Moreover, they demonstrated a steeper decline in multiple cognitive domains, including language, memory, and executive functions. Overall, our findings provided new evidence of the role of FrBI in the prediction of worse clinical outcomes that were not necessarily specific to frontal dysfunction.

In total, 75.1% of the participants showed FrBI symptoms (74.4% SCD, 79.3% aMCI), which was consistent with previous studies reporting that behavioral symptoms were commonly observed in 50–85% of people with MCI [11 , 37–39] and around 70% of people with SCD [40, 41]. In the present investigation, irritability was the most frequent symptom, followed by inflexibility and apathy. Several hospital-based studies have documented people with MCI to generally exhibit depression, anxiety, irritability, agitation and apathy [37 , 43]. Other research has also described people with SCD to commonly report depression, irritability, anxiety, agitation, and apathy [40, 44].

Our conclusion (i.e., the role of FrBI in the prediction of worse clinical outcomes) is supported by the following observations: 1) relative to people without FrBI, people with FrBI had reduced cortical thickness, suggesting that they might represent a more advanced stage of degenerative disease, in both the temporo-parietal and frontal regions; 2) compared to people without FrBI, people with FrBI were more likely to develop dementia and displayed a decline in multiple cognitive domains, including language, memory and executive functions; 3) AD was the most commonly observed dementia in people with FrBI. Therefore, our findings suggest that the worse clinical outcomes of FrBI might be related to accelerated brain changes, rather than the predictive course of the disease.

A previous study revealed that mild behavioral impairment (MBI) affected clinical outcomes [45, 46] and suggested that people with MBI could develop all types of dementia, such as AD, vascular dementia, bvFTD, and Lewy body dementia [46]. While the MBI items consist of perception/thought content as well as frontal dysfunction, only the frontal behavioral symptoms were included in the present investigation. Although such behavioral symptoms were common in bvFTD, they were recognized to represent an early manifestation of AD [46 –49]. Specifically, irritability (42–76%), apathy (40–72%), agitation (45–60%), and depression (50–60%) were frequent symptoms of AD [13 , 51]. Furthermore, atypical subtypes of AD exist, suggesting that prominent personality and behavioral changes in the early stage of AD mimic bvFTD [52]. Therefore, our findings suggested that people with FrBI might represent a prodromal stage of AD rather than bvFTD. Indeed, while 114 of the 122 people who developed dementia in the present study developed AD, only two people developed bvFTD.

Although the pathological mechanism by which worse clinical outcomes extend to multiple cognitive functions (not limited to frontal dysfunction) remains to be elucidated, the default mode network (DMN), which includes the prefrontal cortex, precuneus, posterior cingulate cortex, and temporo-parietal cortex, may be involved. In fact, such DMN regions generally overlap with the topography of cortical thickness reductions associated with FrBI. Moreover, previous studies have suggested the behavioral symptoms to be related to the deterioration of connectivity in the DMN [53, 54]. Furthermore, reduced connectivity of the DMN results in declines in visuospatial, language, and executive function as well as memory [55, 56]. Therefore, deterioration of connectivity between DMN regions may be related to worse clinical outcomes, as described in a recent study using the frontal dysfunction of people with aMCI to predict the conversion to dementia of the Alzheimer-type [57].

In the present investigation, people with only negative symptoms exhibited worse clinical outcomes, including reduced cortical thickness and greater cognitive decline, when compared to people with only positive symptoms. Similarly, people with both negative and positive symptoms presented worse clinical outcomes than did people with either negative or positive symptoms alone. It is possible that people with only negative symptoms, or both negative and positive symptoms, might be in the more advanced stage of neurodegeneration than those with only positive symptoms. Therefore, detecting people with FrBI, especially those with negative symptoms, is important to predict their prognosis and establish a preventive strategy.

While the strengths of the current study include its prospective setting, standardized MRI imaging protocol and relatively large sample size, limitations were also present. First, molecular imaging and pathological examinations were not performed for people with conversion to AD; hence, it is possible that people with FrBI will have developed other types of dementia. However, this argument is mitigated to some degree by the topography of the cortical thickness reductions or the involved domains of cognitive decline. Further studies are needed to investigate the pathobiology of the clinical effects of FrBI using molecular imaging, such as amyloid and tau positron emission tomography. Second, only 46.4% of the subjects completed the follow-up neuropsychological testing. However, differences in the demographics between people who did and did not conduct follow-up testing were not observed.

In conclusion, FrBI predict worse clinical outcomes including reduced cortical thickness and cognitive decline, which are not necessarily specific to frontal dysfunction.

Footnotes

ACKNOWLEDGMENTS

We thank the study participants and their families. We would also like to thank our colleagues for the helpful discussions.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. NRF-2017R1A2B2005081), a research fund (2018-ER6203-00) from the Korea Center for Disease Control and Prevention, and the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2016M3C7A1913844).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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