Neuropsychological Profile in the C9ORF72 Associated Behavioral Variant Frontotemporal Dementia

Abstract

While the C9ORF72 expansion is a major cause of behavioral variant frontotemporal dementia (bvFTD), little is known of the resultant cognitive profile. Our aim was to characterize the neuropsychological profile of the C9ORF72 associated bvFTD. We contrasted structured neuropsychological assessments of the C9ORF72 expansion carrier bvFTD patients (n = 26) with non-carrier bvFTD patients (n = 47) and those with Alzheimer’s disease (AD) (n = 47). As compared to the non-carrier bvFTD patients, the C9ORF72 expansion carriers performed at a higher level in an immediate verbal memory test while showing poorer phonemic verbal fluency. Additionally, the expansion carriers committed more errors in the Stroop test and the Alternating S task relative to the non-carriers. Finally, while the AD patients outperformed both bvFTD patient groups in working memory, their performance was more impaired in episodic memory tasks relative to the bvFTD groups. We conclude that bvFTD patients carrying the C9ORF72 expansion may display more pronounced executive deficits together with less severe verbal memory impairment as compared to their non-carrier bvFTD counterparts. Knowledge of the specific neuropsychological features associated with the C9ORF72 related bvFTD may aid in the early diagnosis of the disease as well as in targeting genetic testing.

Keywords

Alzheimer’s disease frontotemporal dementia frontotemporal lobar degeneration genetics neuropsychological tests progressive aphasia semantic dementia

INTRODUCTION

Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia after Alzheimer’s disease (AD) in patients under the age of 65 years [1]. It encompasses a clinically, genetically, and pathologically heterogeneous group of progressive diseases that are divided into three main clinical subtypes. While behavioral variant frontotemporal dementia (bvFTD) is the most frequent phenotype and is usually characterized by personality change, social dysfunction and executive deficits [2], semantic variant primary progressive aphasia (svPPA) and nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) are both characterized by progressive language deficits [3]. The spectrum of FTLD also shows a notable overlap with motor neuron disease (MND), especially amyotrophic lateral sclerosis (ALS) [4].

A positive family history of dementia is present in about 40–50% of patients with FTLD [5]. The hexanucleotide expansion in chromosome 9 open reading frame 72 (C9ORF72) has been isolated as the major genetic cause of FTLD and ALS especially in Finland, where the C9ORF72 expansion is present in nearly 50% of the familial FTLD cases [6 –8]. While mutations in microtubule-associated protein tau (MAPT) and progranulin (PGRN) are also associated with a familial FTLD, they have rarely been found in Finnish patients [9, 10]. The most frequent clinical phenotype associated with the C9ORF72 expansion is bvFTD, but language variants have also been reported [11]. The core features of the C9ORF72 expansion related bvFTD include executive dysfunction, behavioral, and psychiatric symptoms including late onset psychosis [11 –14]; additionally, some studies have also reported memory impairment as a distinct feature compared to the classic bvFTD profile [13]. Some degree of parkinsonism has been commonly reported as well [15].

In the absence of definite diagnostic biomarkers, the diagnosis of bvFTD relies purely on clinical diagnostic criteria [2]. Because of the clinical heterogeneity of the disease, an early diagnosis remains a challenge: bvFTD patients are often misdiagnosed with AD [16] due to the clinical criteria potentially lacking in sensitivity in differentiating these two dementia syndromes [17]. Examining the pattern of cognitive deficits in neuropsychological assessment can aid in differential diagnosis [18, 19]. However, knowledge of the typical cognitive profile associated with the C9ORF72 expansion is still very limited. The results from these preliminary studies focusing on the cognitive performance in the C9ORF72 expansion carriers have been controversial and their sample sizes relatively small [13]. To this end, our aim was to compare the neuropsychological performance of bvFTD patients carrying the C9ORF72 expansion with that of non-carrier bvFTD patients, and AD patients in fine detail.

MATERIALS AND METHODS

Patients

The study population consisted of C9ORF72 expansion carrier FTLD patients (N = 29; 26 bvFTD, 1 svPPA, 2 nfvPPA), non-carrier FTLD patients (N = 60; 47 bvFTD, 4 svPPA, 9 nfvPPA), and AD patients (N = 47) diagnosed per current diagnostic guidelines [2 , 20] in two memory outpatient clinics in Finland (Kuopio University and Oulu University Hospitals). Of the C9ORF72 expansion carrier bvFTD patients, 17.2% (N = 5) showed also symptoms of MND. By contrast, of the non-carriers, only one patient with nfvPPA had features of MND.

All patients were clinically examined by a neurologist specialized in memory disorders, and neurological status was documented. Neuropsychological assessment was available for all patients. For diagnostic purposes, data from structural brain imaging by magnetic resonance imaging (MRI) and/or computed tomography (CT) were available for all cases and cerebrospinal fluid analyses of the biomarkers Aβ₄₂, tau, and phosphotau in the majority of the cases (65% in FTLD and 68% in AD). Demographic features, medical history, family history, age at onset, initial symptoms, time of first referral, and time of diagnosis were recorded. The FTLD patients were diagnosed based on the Frontotemporal Dementia Consortium (FTDC) criteria for bvFTD [2] and the Gorno-Tempini criteria for language variants [3]. The AD patients were diagnosed according to the McKhann criteria [20]. The C9ORF72 expansion (>40 repeats) was detected from genomic DNA using Repeat-Primed PCR (RP-PCR) [8]. RP-PCR method was verified using amplicon length analysis [21].

The study was approved by the ethics committees of the University of Eastern Finland/Kuopio University Hospital and the Oulu University Hospital. Participants and their caregivers received oral and written information on the study and provided written informed consent in accordance with the Declaration of Helsinki.

Neuropsychological assessment

All patients had undergone a structured neuropsychological assessment including tests of general cognitive functioning (the Mini-Mental State Examination (MMSE) [22]), language skills (semantic (animals) and phonemic (letter S) verbal fluency tests [23], 15-item version of the Boston Naming Test (BNT) [24], Similarities and Comprehension subtests from the Wechsler Adult Intelligence Scale-III (WAIS-III) [25]), working memory (Digit Span subtest from the WAIS-III), verbal memory (Word List Learning, Recall and Recognition subtests from the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery (CERAD-NB) [24], Logical Memory (story A) and Word List subtests from the Wechsler Memory Scale-III (WMS-III) [26]), visual memory (Benton Visual Retention Test version C (Benton-C) [27] and recall trial of the Rey-Osterrieth Complex Figure Test (CFT) [23]), executive functioning and processing speed (the Trail-Making Test parts A and B (TMT-A and TMT-B) [28], the Stroop Test [29], the Alternating S task [30], Clock Drawing subtest from the CERAD-NB, and Digit Symbol subtest from the WAIS-III), visuospatial skills (copy trial of the CFT, Picture Completion and Block Design subtests from the WAIS-III), and psychomotor speed (finger tapping test [23]). The neuropsychological assessments were conducted primarily for clinical purposes and thus not all tests were available for all patients. For reporting the percentages of clinically impaired patients, Finnish norms adjusted for age, gender, and schooling were used when available. Z-scores below –1.5 or scores below the 10th percentile were considered as impaired.

Statistical analysis

The IBM SPSS Statistics software for Windows, Version 23.0 (IBM Corp., Armonk, USA) was used for statistical analysis. For continuous variables, we calculated means and standard deviations (SD). For categorical variables, percentages were used. Non-parametric tests (Kruskal-Wallis test or Mann-Whitney U-test in pairwise comparison) were used for continuous variables when comparing study groups. Categorical variables were analyzed using Chi-Square tests or Fisher’s exact test, as appropriate. Two-tailed p-values are reported and a p-value <0.05 was considered statistically significant.

RESULTS

Demographic and clinical characteristics

Patient demographics and clinical characteristics are summarized in Table 1. The C9ORF72 expansion carrier FTLD patients, non-carrier FTLD patients, and AD patients did not differ in gender (p = 0.558), educational level (p = 0.535), or the MMSE scores (p = 0.728). However, the C9ORF72 expansion carriers were younger both at onset and evaluation (mean age 55.8 and 58.4 years, respectively) as compared to the non-carriers (mean age 61.6 and 63.4 years) and the AD patients (mean age 60.5 and 62.3 years). Excluding the svPPA and nfvPPA patients from the analyses did not influence the results.

Table 1

Demographic and clinical characteristics

	C9ORF72 carrier FTLD (N = 29)			Non-carrier FTLD (N = 60)			AD (N = 47)
	bvFTD	svPPA	nfvPPA	bvFTD	svPPA	nfvPPA		p-value^*
	(N = 26)	(N = 1)	(N = 2)	(N = 47)	(N = 4)	(N = 9)
Age at onset, mean (SD)	55.2 (8.0)	51.0	65.0 (7.1)	61.7 (6.4)	60.5 (7.9)	62.0 (8.0)	60.5 (4.5)	0.003
Age at evaluation, mean (SD)	57.7 (7.5)	61.0	67.0 (5.7)	63.3 (6.5)	62.5 (7.9)	64.3 (8.2)	62.3 (4.7)	0.010
Gender								0.558
Women, N (%)	13 (50)	0 (0)	2 (100)	20 (42.6)	2 (50)	4 (44.4)	25 (53.2)
Men, N (%)	13 (50)	1 (100)	0 (0)	27 (57.4)	2 (50)	5 (55.6)	22 (46.8)
Education years								0.535
<8, N (%)	9 (34.6)	1 (100)	1 (50)	11 (23.4)	2 (50)	2 (22.2)	10 (21.3)
8–12, N (%)	9 (34.6)	0 (0)	1 (50)	27 (57.4)	1 (25)	3 (33.3)	23 (48.9)
>12, N (%)	8 (30.8)	0 (0)	0 (0)	9 (19.1)	1 (25)	4 (44.4)	14 (29.8)
MMSE, mean (SD)	23.3 (5.9)	23.0	15.5 (10.6)	23.7 (3.7)	18.8 (5.7)	23.7 (3.8)	24.2 (3.3)	0.728

FTLD, frontotemporal lobar degeneration; AD, Alzheimer’s disease; bvFTD, behavioral variant frontotemporal dementia; svPPA, semantic variant primary progressive aphasia; nfvPPA, nonfluent/agrammatic variant primary progressive aphasia; SD, standard deviation; MMSE, Mini-Mental State Examination. ^*Statistical analyses were conducted between C9ORF72 expansion carrier FTLD, non-carrier FTLD, and AD groups.

Initial symptoms at onset of dementing disorder were identified from the patient records and are reported in Table 2. In some cases, as it was not possible to identify one single first symptom, multiple initial symptoms were recorded for such patients. For both the expansion carrier and non-carrier bvFTD patients, behavioral symptoms and memory deficits comprised the most frequent first symptom classes. Psychosis as initial symptom was present in six (23.1%) of the expansion carriers and six (12.8%) of the non-carrier bvFTD patients. Language deficits were present at onset in some of the bvFTD cases (11.5% of the carriers and 8.5% of the non-carriers). Depression was reported in two (7.7%) expansion carrier bvFTD patients. As expected, language deficits comprised the most common first symptoms in the language variants of FTLD, both in the expansion carriers and non-carriers. However, memory deficits represented a relatively common initial symptom type for these patients as well. Interestingly, in one expansion carrier nfvPPA patient, psychosis was present at onset. In the AD group, almost all patients (95.7%) exhibited a memory deficit as the initial symptom. However, in some AD cases, behavioral symptoms (8.5%) and language deficits (4.3%) were present at onset as well.

Table 2

Initial symptoms of the dementing disorder in the C9ORF72 expansion carrier FTLD, non-carrier FTLD, and AD patients

	C9ORF72 carrier FTLD (N = 29)			Non-carrier FTLD (N = 60)			AD (N = 47)
	bvFTD	svPPA	nfvPPA	bvFTD	svPPA	nfvPPA
	(N = 26)	(N = 1)	(N = 2)	(N = 47)	(N = 4)	(N = 9)
Memory deficit, N (%)	13 (50)	1 (100)	1 (50)	29 (61.7)	2 (50)	4 (44.4)	45 (95.7)
Psychosis, N (%)	6 (23.1)	0 (0)	1 (50)	6 (12.8)	0 (0)	0 (0)	0 (0)
Depression, N (%)	2 (7.7)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Other behavioral symptom, N (%)	15 (57.7)	0 (0)	0 (0)	29 (61.7)	0 (0)	1 (11.1)	4 (8.5)
Language deficit, N (%)	3 (11.5)	1 (100)	1 (50)	4 (8.5)	4 (100)	8 (88.9)	2 (4.3)

In some cases, it was not possible to identify only one initial symptom, thus multiple symptoms were recorded. FTLD, frontotemporal lobar degeneration; AD, Alzheimer’s disease; bvFTD, behavioral variant frontotemporal dementia; svPPA, semantic variant primary progressive aphasia; nfvPPA, nonfluent/agrammatic variant primary progressive aphasia.

Results in neuropsychological assessment

SvPPA and nfvPPA patients were excluded from the analyses of cognitive data due to a small number of cases in these groups. The results from the neuropsychological assessments for the C9ORF72 expansion carrier bvFTD, non-carrier bvFTD, and AD patients and p-values for the between-group comparisons are reported in Table 3. In addition, the percentage of clinically impaired patients in each group is reported in Table 3 for the tests for which normative data were available.

Table 3

Results from the neuropsychological assessments in the C9ORF72 expansion carrier bvFTD, non-carrier bvFTD, and AD patients

	C9ORF72 carrier bvFTD			Non-carrier bvFTD			Carriers	AD (N = 47)			Carriers	Non-
							versus non-				versus	carriers
							carriers				AD	versus AD
	N	Mean (SD)	Impaired^*	N	Mean (SD)	Impaired^*	p-value	N	Mean (SD)	Impaired^*	p-value	p-value
Language skills
Phonemic fluency (letter S)	16	5.5 (3.6)	63%	44	9.2 (3.8)	46%	0.002	46	10.9 (4.8)	48%	< 0.001	0.122
Semantic fluency (animals)	24	12.3 (6.1)	71%	43	13.0 (4.5)	56%	0.651	46	14.8 (5.0)	41%	0.098	0.050
15-item BNT	17	10.7 (2.8)	71%	36	11.7 (2.6)	50%	0.181	44	12.0 (2.4)	34%	0.071	0.558
WAIS-III Similarities	14	7.6 (3.1)	29%	36	7.5 (2.7)	19%	0.710	46	8.6 (2.8)	15%	0.358	0.065
WAIS-III Comprehension	13	4.8 (2.9)	62%	25	4.4 (2.9)	68%	0.585	40	7.0 (3.6)	38%	0.061	0.004
Working memory
WAIS-III Digit Span	25	7.2 (3.8)	28%	40	7.2 (2.5)	25%	0.954	46	8.7 (2.5)	9%	0.047	0.008
Digit span forwards	25	5.0 (1.3)		41	4.9 (0.8)		0.759	46	5.5 (0.9)		0.060	0.001
Digit span backwards	25	3.2 (1.5)		41	3.2 (1.1)		0.792	46	3.5 (1.1)		0.360	0.140
Verbal memory
CERAD Word List Learning	14	13.4 (4.3)	71%	27	14.2 (5.3)	70%	0.962	32	14.4 (4.2)	66%	0.495	0.446
CERAD Word List Recall (%)	14	49.5 (34.5)	57%	28	53.2 (35.7)	54%	0.725	31	41.0 (30.0)	71%	0.355	0.259
CERAD Word List Recognition (%)	11	80.9 (18.9)	55%	26	83.1 (12.4)	58%	0.954	32	81.4 (12.7)	66%	0.683	0.710
WMS-III Logical Memory immediate	20	10.6 (5.2)	20%	41	7.7 (3.5)	37%	0.021	43	5.7 (3.6)	58%	< 0.001	0.011
WMS-III Logical Memory delayed	20	7.9 (5.0)	35%	41	5.3 (4.0)	51%	0.065	43	2.2 (2.9)	84%	< 0.001	< 0.001
WMS-III Word List learning	10	19.4 (8.0)	70%	16	19.8 (6.8)	69%	0.887	19	21.4 (5.0)	58%	0.323	0.397
WMS-III Word List delayed recall (%)	10	43.0 (33.1)	60%	14	36.9 (32.3)	64%	0.649	18	9.8 (16.2)	100%	0.010	0.019
Visual memory
Benton-C	14	4.0 (1.8)	50%	24	3.6 (1.9)	50%	0.524	32	3.7 (1.8)	41%	0.723	0.708
CFT recall	7	12.5 (4.5)		12	9.8 (7.3)		0.160	27	6.3 (4.9)		0.004	0.109
Executive functioning and processing speed
TMT-A (s)	21	80.7 (40.3)	43%	44	76.5 (35.9)	55%	0.953	46	73.2 (37.6)	39%	0.311	0.429
TMT-B (s)	20	218.6 (78.9)	55%	42	239.5 (82.7)	69%	0.320	46	239.0 (75.6)	67%	0.264	0.775
Stroop color naming (s)	13	111.8 (32.0)	92%	28	118.3 (42.5)	89%	0.928	40	105.1 (39.4)	78%	0.257	0.109
Stroop color naming (errors)	12	3.9 (6.4)		28	1.8 (2.9)		0.079	40	1.6 (3.0)		0.010	0.381
Stroop interference (s)	11	212.0 (62.4)	100%	28	233.8 (88.1)	82%	0.617	36	200.4 (83.2)	81%	0.254	0.093
Stroop interference (inhibition errors)	10	11.2 (12.3)	80%	26	4.3 (8.2)	42%	0.034	36	3.8 (5.4)	53%	0.035	0.419
Stroop interference (other errors)	10	1.7 (4.7)		26	0.3 (1.0)		0.448	36	0.4 (1.5)		0.409	0.902
Alternating S (correct responses)	10	47.4 (24.6)		22	52.0 (34.7)		0.865	32	60.4 (31.7)		0.263	0.235
Alternating S (errors)	10	6.1 (3.3)		22	3.0 (3.0)		0.023	32	2.6 (3.2)		0.004	0.436
Clock Drawing	23	3.9 (1.9)	44%	35	4.0 (1.7)	43%	0.988	45	3.9 (1.8)	44%	0.930	0.896
WAIS-III Digit Symbol	25	5.6 (2.3)	48%	41	5.6 (3.1)	63%	0.413	46	6.2 (2.6)	39%	0.335	0.139
Visuospatial skills
CFT copy	17	27.7 (8.2)		24	29.6 (5.3)		0.679	39	26.4 (11.0)		0.807	0.770
WAIS-III Block Design	17	5.1 (3.2)	59%	42	5.1 (3.3)	50%	0.990	47	5.2 (3.3)	49%	0.864	0.803
Psychomotor speed
Finger tapping right (/10 s)	16	40.2 (10.2)		27	41.5 (7.5)		0.779	41	44.4 (8.9)		0.395	0.265
Finger tapping left (/10 s)	16	39.7 (10.5)		27	37.6 (8.6)		0.400	41	40.3 (8.1)		0.420	0.460

All test data are represented as raw scores, except for WAIS-III subtests for which standard scores are used. bvFTD, behavioral variant frontotemporal dementia; AD, Alzheimer’s disease; SD, standard deviation; BNT, Boston Naming Test; WAIS-III, Wechsler Adult Intelligence Scale-III; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery; WMS-III, Wechsler Memory Scale-III; Benton-C, Benton Visual Retention Test version C; CFT, Complex Figure Test; TMT, Trail-Making Test; ^*Percentage of clinically impaired (z-score < –1.5 or <10th percentile) patients according to norms adjusted for age, gender, and schooling. Blank cells indicate that normative data were not available. Bold indicates are p < 0.5.

C9ORF72 expansion carriers versus non-carriers

The C9ORF72 expansion carriers performed at a lower level in phonemic fluency as compared to the non-carriers. They also made a greater number of uncorrected inhibition errors on the interference part of the Stroop test as well as perseveration errors in the Alternating S task as compared to the non-carriers. In contrast, the C9ORF72 expansion carriers showed less impaired performance on the immediate recall of the Logical Memory as compared to the non-carriers. The expansion carriers tended to perform at a higher level than the non-carriers also on the delayed recall of the Logical Memory test, but this result failed to reach statistical significance.

C9ORF72 expansion carrier bvFTD versus AD

The C9ORF72 expansion carrier bvFTD patients performed at a poorer level as compared to the AD patients on the phonemic fluency and Digit Span tests. They also made a greater number of errors on the color naming and interference parts of the Stroop test as well as on the Alternating S task as compared to those with AD. The AD patients had lower scores as compared to the C9ORF72 expansion carriers on the immediate and delayed recall of the Logical Memory, delayed recall of the WMS-III Word List, and recall trial of the CFT.

Non-carrier bvFTD versus AD

The non-carrier bvFTD patients showed poorer performance as compared to the AD patients on the Digit Span and Comprehension subtests of the WAIS-III. The AD patients performed at a lower level on the immediate and delayed recall of the Logical Memory, and delayed recall of the WMS-III Word List as compared to the non-carrier bvFTD patients.

BvFTD versus AD

We also compared all bvFTD patients regardless of their genetic status to those with AD. The bvFTD general group performed at a poorer level on both semantic and phonemic fluency, as well as in the Digit Span and Comprehension subtests of the WAIS-III, as compared to the AD group. However, the AD group achieved lower scores in both the immediate and delayed recall of the Logical Memory, delayed recall of the WMS-III Word List, and recall trial of the CFT, as compared to the bvFTD general group.

DISCUSSION

To our knowledge, this is the first study aimed at comparing the neuropsychological performance of the C9ORF72 expansion carrier bvFTD patients against that of non-carrier bvFTD and AD patients. We found that the C9ORF72 expansion carriers showed poorer performance in phonemic fluency, and made more errors on the Stroop test and the Alternating S task, as compared to the non-carriers. Interestingly, all of these tests tap into executive functioning. Secondly, the C9ORF72 expansion carriers showed superior performance on the immediate recall of the Logical Memory test as compared to the non-carriers. Only a handful of previous studies have compared the C9ORF72 carriers and non-carriers on a range of neuropsychological tests, and the sample sizes of these studies have been smaller as compared to those in the present study. For example, Sha and colleagues reported a difference between the C9ORF72 carrier and non-carrier bvFTD patients only on working memory, with the expansion carriers showing more impaired performance [31]. In two additional studies, the expansion carriers were reported to display more pronounced visuospatial dysfunction [32, 33] and show more impaired naming of nouns [33]. This is in contrast with our study, in which working memory, visuospatial, and naming tasks failed to differentiate between the expansion carriers and non-carriers. Thus, the present study failed to replicate these previous results that were obtained from a limited number of the C9ORF72 cases.

The current data pinpointed both similarities and differences in the neuropsychological profiles that on one hand distinguished the C9ORF72 expansion carrier bvFTD and AD patients, and on the other, the non-carrier bvFTD and AD patients. As expected, both of the bvFTD groups performed at a higher level as compared to the AD group on episodic memory tests, namely the immediate and delayed recall of the Logical Memory, as well as the delayed recall of the WMS-III Word List. However, both bvFTD groups showed poorer performance on working memory (the Digit Span test) as compared to the AD group. Interestingly, however, additional results highlighted a significant difference between solely the C9ORF72 expansion carrier bvFTD and the AD patients on phonemic fluency and the number of errors made on the Stroop test and the Alternating S task; these are the same measures of executive functioning that differentiated also the expansion carrier and non-carrier bvFTD patients. It thus appears that these very measures show particular utility in discriminating the C9ORF72 expansion carrier bvFTD patients from both the non-carrier bvFTD patients and those with AD.

Verbal fluency tasks are widely employed neuropsychological tests both in clinical practice and in studies on FTLD. In addition to measuring language abilities, both semantic and phonemic fluency tests have also been found to have a significant executive functioning component that is especially apparent in bvFTD patients [34]. Phonemic fluency has been previously found to differentiate between FTLD and AD [35, 36], as well as between bvFTD and AD [37]. One previous study has compared the C9ORF72 expansion carrier FTLD and non-carrier FTLD patients on phonemic fluency [38], and found no between-group difference on this measure at baseline; however, the expansion carriers showed greater annualized decline on this measure than the non-carriers. In our study, the C9ORF72 expansion carrier bvFTD patients performed at a lower level on phonemic fluency already at the initial assessment as compared to the non-carrier bvFTD patients. In addition, both semantic and phonemic fluency tests differentiated the bvFTD and AD groups in our study. Thus, the present findings provide further support to the diagnostic value of verbal fluency tests in bvFTD.

Our results also underscore the importance of taking into consideration both the frequency and types of errors committed in neuropsychological tests, in addition to the performance times. Specifically, we found that the C9ORF72 expansion carrier bvFTD patients were more prone to errors in inhibiting wrong reactions on the interference part of the Stroop test as well as to perseverative errors on the Alternating S task, as compared to both the non-carrier bvFTD patients and the AD patients. By contrast, there were no between-group differences in performance speed on these tests. It has been noted before that considering both the qualitative performance characteristics and error types made by patients can enhance the accuracy of differentiation between bvFTD and AD [39]. Specifically, Thompson and colleagues found that perseveration on naming and drawing tests was a predictive feature of bvFTD. However, in our study, only the expansion carrier bvFTD patients were more vulnerable to perseveration errors on the Alternating S task as compared to the AD patients. On this test, the patient is required to alternate between habituated and novel activity by writing the letter S and then reversing it [30]. A meta-analytic review by Hutchinson and Mathias failed to find the Stroop test as useful in differentiating bvFTD and AD patients [40]. However, only three studies had explored the number of errors made by patients on the incongruent trial of the Stroop test. Again in our study, only the expansion carrier bvFTD patients differed from the AD patients on the Stroop test. Thus, this suggests that the subtle differences in cognitive performance between bvFTD patients with or without the C9ORF72 expansion may be lost or diluted in studies in which the patients are grouped together; subsequently, this hampers the differentiation between bvFTD and AD.

Our major finding was that the C9ORF72 expansion carrier bvFTD patients showed more pronounced executive deficits as compared to the non-carriers. This is in line with previous studies reporting profound executive dysfunction in the C9ORF72 expansion carriers [11 , 41–43] although these studies failed to compare the expansion carriers and non-carriers directly. Some previous studies have also reported notable episodic memory impairments in the C9ORF72 expansion carriers [42, 44]. However, our results failed to provide support to these latter-mentioned findings; on the contrary, we found more preserved verbal memory in the expansion carriers as compared to the non-carriers.

A major strength of our study includes the fact that the neuropsychologists conducting the assessments were blinded to the results of genetic testing. Furthermore, a wide range of neuropsychological tests were included in order to enable the identification of the most sensitive measures for discriminating the C9ORF72 expansion carrier bvFTD patients from the non-carrier bvFTD patients and those with AD. It is noteworthy that the current study also has some limitations. First, as mentioned before, the neuropsychological assessments used in this study were conducted mainly for clinical purposes, and thus not all cognitive tests were available for all patients. However, for a majority of the tests used in this study, the sample sizes are still larger than in previous studies with C9ORF72 patients. Second, the expansion carrier patients were significantly younger than the non-carriers and AD patients, which may have influenced the neuropsychological scores obtained. It nevertheless seems highly unlikely that the lower age characterizing the expansion carriers would explain their poorer performance on the executive tests.

In conclusion, our results suggest that bvFTD patients carrying the C9ORF72 expansion may be characterized by more pronounced executive deficits in the face of less severe verbal memory impairment as compared to their non-carrier bvFTD counterparts. Specifically, the C9ORF72 expansion carriers exhibited greater impairments on phonemic verbal fluency and increased tendency toward inhibition and perseverative errors on the executive tasks, together with more preserved ability on the logical memory test, as compared to the non-carriers. In this vein, we hope that future studies with sizeable samples of C9ORF72 expansion carriers would be directed into this clinically and diagnostically significant field. To achieve this goal, however, international collaboration and uniformity in the neuropsychological test battery used in the different centers would be critical to ensure more sizeable samples and the comparability of results across studies. Enhancing our knowledge of the specific neuropsychological features associated with the C9ORF72 related bvFTD promises to aid in the early diagnosis of the disease as well as in targeting genetic testing.

Footnotes

ACKNOWLEDGMENTS

We would like to thank Maria Raatikainen, Risto Siivola, Satu Winqvist, and Marja Äikiä for participating in conducting neuropsychological assessments for this study. We also extend our thanks to Anna Järvinen for proofreading the manuscript.

This study was supported by grants from the Finnish Brain Foundation sr and the Finnish Cultural Foundation.

Authors’ disclosures available online ().

References

Ratnavalli

, Brayne

, Dawson

, Hodges

(2002) The prevalence of frontotemporal dementia. Neurology 58, 1615–1621.

Rascovsky

, Hodges

, Knopman

, Mendez

, Kramer

, Neuhaus

, van Swieten

, Seelaar

, Dopper

, Onyike

, Hillis

, Josephs

, Boeve

, Kertesz

, Seeley

, Rankin

, Johnson

, Gorno-Tempini

, Rosen

, Prioleau-Latham

, Lee

, Kipps

, Lillo

, Piguet

, Rohrer

, Rossor

, Warren

, Fox

, Galasko

, Salmon

, Black

, Mesulam

, Weintraub

, Dickerson

, Diehl-Schmid

, Pasquier

, Deramecourt

, Lebert

, Pijnenburg

, Chow

, Manes

, Grafman

, Cappa

, Freedman

, Grossman

, Miller

(2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477.

Gorno-Tempini

, Hillis

, Weintraub

, Kertesz

, Mendez

, Cappa

, Ogar

, Rohrer

, Black

, Boeve

, Manes

, Dronkers

, Vandenberghe

, Rascovsky

, Patterson

, Miller

, Knopman

, Hodges

, Mesulam

, Grossman

(2011) Classification of primary progressive aphasia and its variants. Neurology 76, 1006–1014.

Lillo

, Hodges

(2009) Frontotemporal dementia and motor neurone disease: Overlapping clinic-pathological disorders. J Clin Neurosci 16, 1131–1135.

Rohrer

, Guerreiro

, Vandrovcova

, Uphill

, Reiman

, Beck

, Isaacs

, Authier

, Ferrari

, Fox

, Mackenzie

, Warren

, de Silva

, Holton

, Revesz

, Hardy

, Mead

, Rossor

(2009) The heritability and genetics of frontotemporal lobar degeneration. Neurology 73, 1451–1456.

DeJesus-Hernandez

, Mackenzie

, Boeve

, Boxer

, Baker

, Rutherford

, Nicholson

, Finch

, Flynn

, Adamson

, Kouri

, Wojtas

, Sengdy

, Hsiung

, Karydas

, Seeley

, Josephs

, Coppola

, Geschwind

, Wszolek

, Feldman

, Knopman

, Petersen

, Miller

, Dickson

, Boylan

, Graff-Radford

, Rademakers

(2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256.

Majounie

, Renton

, Mok

, Dopper

, Waite

, Rollinson

, Chio

, Restagno

, Nicolaou

, Simon-Sanchez

, van Swieten

, Abramzon

, Johnson

, Sendtner

, Pamphlett

, Orrell

, Mead

, Sidle

, Houlden

, Rohrer

, Morrison

, Pall

, Talbot

, Ansorge

, Chromosome 9-ALS/FTD Consortium, French research network on FTLD/FTLD/ALS, ITALSGEN Consortium, Hernandez

, Arepalli

, Sabatelli

, Mora

, Corbo

, Giannini

, Calvo

, Englund

, Borghero

, Floris

, Remes

, Laaksovirta

, McCluskey

, Trojanowski

, Van Deerlin

, Schellenberg

, Nalls

, Drory

, Lu

, Yeh

, Ishiura

, Takahashi

, Tsuji

, Le Ber

, Brice

, Drepper

, Williams

, Kirby

, Shaw

, Hardy

, Tienari

, Heutink

, Morris

, Pickering-Brown

, Traynor

(2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study. Lancet Neurol 11, 323–330.

Renton

, Majounie

, Waite

, Simon-Sanchez

, Rollinson

, Gibbs

, Schymick

, Laaksovirta

, van Swieten

, Myllykangas

, Kalimo

, Paetau

, Abramzon

, Remes

, Kaganovich

, Scholz

, Duckworth

, Ding

, Harmer

, Hernandez

, Johnson

, Mok

, Ryten

, Trabzuni

, Guerreiro

, Orrell

, Neal

, Murray

, Pearson

, Jansen

, Sondervan

, Seelaar

, Blake

, Young

, Halliwell

, Callister

, Toulson

, Richardson

, Gerhard

, Snowden

, Mann

, Neary

, Nalls

, Peuralinna

, Jansson

, Isoviita

, Kaivorinne

, Holtta-Vuori

, Ikonen

, Sulkava

, Benatar

, Wuu

, Chio

, Restagno

, Borghero

, Sabatelli

, ITALSGEN Consortium, Heckerman

, Rogaeva

, Zinman

, Rothstein

, Sendtner

, Drepper

, Eichler

, Alkan

, Abdullaev

, Pack

, Dutra

, Pak

, Hardy

, Singleton

, Williams

, Heutink

, Pickering-Brown

, Morris

, Tienari

, Traynor

(2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268.

Kaivorinne

, Kruger

, Kuivaniemi

, Tuominen

, Moilanen

, Majamaa

, Remes

(2008) Role of MAPT mutations and haplotype in frontotemporal lobar degeneration in Northern Finland. BMC Neurol 8, 48–2377–8–48.

10.

Kruger

, Kaivorinne

, Udd

, Majamaa

, Remes

(2009) Low prevalence of progranulin mutations in Finnish patients with frontotemporal lobar degeneration. Eur J Neurol 16, 27–30.

11.

Snowden

, Rollinson

, Thompson

, Harris

, Stopford

, Richardson

AMT

, Jones

, Gerhard

, Davidson

, Robinson

, Gibbons

, Hu

, DuPlessis

, Neary

, Mann

DMA

, Pickering-Brown

(2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135, 693–708.

12.

Boeve

, Graff-Radford

(2012) Cognitive and behavioral features of c9FTD/ALS. Alzheimers Res Ther 4, 29.

13.

Patel

, Sampson

(2015) Cognitive profile of C9orf72 in frontotemporal dementia and amyotrophic lateral sclerosis. Curr Neurol Neurosci Rep 15, 59–015–0582–9.

14.

Solje

, Aaltokallio

, Koivumaa-Honkanen

, Suhonen

, Moilanen

, Kiviharju

, Traynor

, Tienari

, Hartikainen

, Remes

(2015) The phenotype of the C9ORF72 expansion carriers accordingto revised criteria for bvFTD. PLoS One 10, e0131817.

15.

Boeve

, Boylan

, Graff-Radford

, DeJesus-Hernandez

, Knopman

, Pedraza

, Vemuri

, Jones

, Lowe

, Murray

, Dickson

, Josephs

, Rush

, Machulda

, Fields

, Ferman

, Baker

, Rutherford

, Adamson

, Wszolek

, Adeli

, Savica

, Boot

, Kuntz

, Gavrilova

, Reeves

, Whitwell

, Kantarci

, Jack

CRJ

, Parisi

, Lucas

, Petersen

, Rademakers

(2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135, 765–783.

16.

Mendez

, Shapira

, McMurtray

, Licht

, Miller

(2007) Accuracy of the clinical evaluation for frontotemporal dementia. Arch Neurol 64, 830–835.

17.

Harris

, Thompson

, Gall

, Richardson

, Neary

, du Plessis

, Pal

, Mann

, Snowden

, Jones

(2015) Do NIA-AA criteria distinguish Alzheimer’s disease from frontotemporal dementia? Alzheimers Dement 11, 207–215.

18.

Rascovsky

, Grossman

(2013) Clinical diagnostic criteria and classification controversies in frontotemporal lobar degeneration. Int Rev Psychiatry 25, 145–158.

19.

Riedl

, Mackenzie

, Forstl

, Kurz

, Diehl-Schmid

(2014) Frontotemporal lobar degeneration: Current perspectives. Neuropsychiatr Dis Treat 10, 297–310.

20.

McKhann

, Knopman

, Chertkow

, Hyman

, Jack

Jr , Kawas

, Klunk

, Koroshetz

, Manly

, Mayeux

, Mohs

, Morris

, Rossor

, Scheltens

, Carrillo

, Thies

, Weintraub

, Phelps

(2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263–269.

21.

van der Zee

, Gijselinck

, Dillen

, Van Langenhove

, Theuns

, Engelborghs

, Philtjens

, Vandenbulcke

, Sleegers

, Sieben

, Baumer

, Maes

, Corsmit

, Borroni

, Padovani

, Archetti

, Perneczky

, Diehl-Schmid

, de Mendonca

, Miltenberger-Miltenyi

, Pereira

, Pimentel

, Nacmias

, Bagnoli

, Sorbi

, Graff

, Chiang

, Westerlund

, Sanchez-Valle

, Llado

, Gelpi

, Santana

, Almeida

, Santiago

, Frisoni

, Zanetti

, Bonvicini

, Synofzik

, Maetzler

, Vom Hagen

, Schols

, Heneka

, Jessen

, Matej

, Parobkova

, Kovacs

, Strobel

, Sarafov

, Tournev

, Jordanova

, Danek

, Arzberger

, Fabrizi

, Testi

, Salmon

, Santens

, Martin

, Cras

, Vandenberghe

, De Deyn

, Cruts

, Van Broeckhoven

, van der Zee

, Gijselinck

, Dillen

, Van Langenhove

, Theuns

, Philtjens

, Sleegers

, Baumer

, Maes

, Corsmit

, Cruts

, Van Broeckhoven

, van der Zee

, Gijselinck

, Dillen

, Van Langenhove

, Philtjens

, Theuns

, Sleegers

, Baumer

, Maes

, Cruts

, Van Broeckhoven

, Engelborghs

, De Deyn

, Cras

, Engelborghs

, De Deyn

, Vandenbulcke

, Borroni

, Padovani

, Archetti

, Perneczky

, Diehl-Schmid

, Synofzik

, Maetzler

, Muller Vom Hagen

, Schols

, Synofzik

, Maetzler

, Muller Vom Hagen

, Schols

, Heneka

, Jessen

, Ramirez

, Kurzwelly

, Sachtleben

, Mairer

, de Mendonca

, Miltenberger-Miltenyi

, Pereira

, Firmo

, Pimentel

, Sanchez-Valle

, Llado

, Antonell

, Molinuevo

, Gelpi

, Graff

, Chiang

, Westerlund

, Graff

, Kinhult Stahlbom

, Thonberg

, Nennesmo

, Borjesson-Hanson

, Nacmias

, Bagnoli

, Sorbi

, Bessi

, Piaceri

, Santana

, Santiago

, Santana

, Helena Ribeiro

, Rosario Almeida

, Oliveira

, Massano

, Garret

, Pires

, Frisoni

, Zanetti

, Bonvicini

, Sarafov

, Tournev

, Jordanova

, Tournev

, Kovacs

, Strobel

, Heneka

, Jessen

, Ramirez

, Kurzwelly

, Sachtleben

, Mairer

, Jessen

, Matej

, Parobkova

, Danel

, Arzberger

, Maria Fabrizi

, Testi

, Ferrari

, Cavallaro

, Salmon

, Santens

, Cras

, European Early-Onset Dementia Consortium (2013) A pan-European study of the C9orf72 repeat associated with FTLD: Geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat 34, 363–373.

22.

Folstein

, Folstein

, McHugh

(1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12, 189–198.

23.

Lezak

, Howieson

, Bigler

, Tranel

(2012) Neuropsychological Assessment (5th ed.), Oxford University Press, New York.

24.

Morris

, Heyman

, Mohs

, Hughes

, van Belle

, Fillenbaum

, Mellits

, Clark

(1989) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 39, 1159–1165.

25.

Wechsler

(2005) Wechsler Adult Intelligence Scale - Third Edition: Finnish Manual, Psykologien kustannus Oy, Helsinki.

26.

Wechsler

(2007) Wechsler Memory Scale - Third Edition: Finnish Manual, Psykologien kustannus Oy, Helsinki.

27.

Sivan

(1992) Benton Visual Retention Test (5th ed.), The Psychological Corporation, San Antonio, TX.

28.

Reitan

(1958) Validity of the Trail Making Test as an indication of organic brain damage. Perceptual Mot Skills 8, 271–276.

29.

Golden

(1978) Stroop Color and Word Test, Stoelting Company, Chicago.

30.

Allison

(1966) Perseveration as a sign of diffuse and focal brain damage. I. Br Med J 2, 1027–1032 contd.

31.

Sha

, Takada

, Rankin

, Yokoyama

, Rutherford

, Fong

, Khan

, Karydas

, Baker

, DeJesus-Hernandez

, Pribadi

, Coppola

, Geschwind

, Rademakers

, Lee

, Seeley

, Miller

, Boxer

(2012) Frontotemporal dementia due to C9ORF72 mutations: Clinical and imaging features. Neurology 79, 1002–1011.

32.

Devenney

, Hornberger

, Irish

, Mioshi

, Burrell

, Tan

, Kiernan

, Hodges

(2014) Frontotemporal dementia associated with the C9ORF72 mutation: A unique clinical profile. JAMA Neurol 71, 331–339.

33.

Floris

, Borghero

, Cannas

, Di Stefano

, Ruiu

, Murru

, Corongiu

, Cuccu

, Tranquilli

, Sardu

, Marrosu

, Chio

, Marrosu

(2015) Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: Broadening the clinical and neuropsychological phenotype. Amyotroph Lateral Scler Frontotemporal Degener 16, 8–15.

34.

Laisney

, Matuszewski

, Mezenge

, Belliard

, de la Sayette

, Eustache

, Desgranges

(2009) The underlying mechanisms of verbal fluency deficit in frontotemporal dementia and semantic dementia. J Neurol 256, 1083–1094.

35.

Haanpaa

, Suhonen

, Hartikainen

, Koivisto

, Moilanen

, Herukka

, Hanninen

, Remes

(2015) The CERAD Neuropsychological Battery in Patients with Frontotemporal Lobar Degeneration. Dement Geriatr Cogn Dis Extra 5, 147–154.

36.

Yoshizawa

, Vonsattel

JPG

, Honig

(2013) Presenting neuropsychological testing profile of autopsy-confirmed frontotemporal lobar degeneration. Dement Geriatr Cogn Disord 36, 279–289.

37.

Ranasinghe

, Rankin

, Lobach

, Kramer

, Sturm

, Bettcher

, Possin

, Christine You

, Lamarre

, Shany-Ur

, Stephens

, Perry

, Lee

, Miller

, Gorno-Tempini

, Rosen

, Boxer

, Seeley

, Rabinovici

, Vossel

, Miller

(2016) Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage. Neurology 86, 600–610.

38.

Irwin

, McMillan

, Brettschneider

, Libon

, Powers

, Rascovsky

, Toledo

, Boller

, Bekisz

, Chandrasekaran

, Wood

, Shaw

, Woo

, Cook

, Wolk

, Arnold

, Van Deerlin

, McCluskey

, Elman

, Lee

, Trojanowski

, Grossman

(2013) Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 84, 163–169.

39.

Thompson

, Stopford

, Snowden

, Neary

(2005) Qualitative neuropsychological performance characteristics in frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76, 920–927.

40.

Hutchinson

, Mathias

(2007) Neuropsychological deficits in frontotemporal dementia and Alzheimer’s disease: A meta-analytic review. J Neurol Neurosurg Psychiatry 78, 917–928.

41.

Hsiung

, DeJesus-Hernandez

, Feldman

, Sengdy

, Bouchard-Kerr

, Dwosh

, Butler

, Leung

, Fok

, Rutherford

, Baker

, Rademakers

, Mackenzie

IRA

(2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135, 709–722.

42.

Mahoney

, Beck

, Rohrer

, Lashley

, Mok

, Shakespeare

, Yeatman

, Warrington

, Schott

, Fox

, Rossor

, Hardy

, Collinge

, Revesz

, Mead

, Warren

(2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: Clinical, neuroanatomical and neuropathological features. Brain 135, 736–750.

43.

Simon-Sanchez

, Dopper

EGP

, Cohn-Hokke

, Hukema

, Nicolaou

, Seelaar

, de Graaf

JRA

, de Koning

, van Schoor

, Deeg

DJH

, Smits

, Raaphorst

, van den Berg

, Schelhaas

, De Die-Smulders

CEM

, Majoor-Krakauer

, Rozemuller

AJM

, Willemsen

, Pijnenburg

YAL

, Heutink

, van Swieten

(2012) The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135, 723–735.

44.

Galimberti, D, Fenoglio, C, Serpente, M, Villa, C, Bonsi, R, Arighi, A, Fumagalli, GG, Del Bo, R, Bruni, AC, Anfossi, M, Clodomiro, A, Cupidi, C, Nacmias, B, Sorbi, S, Piaceri, I, Bagnoli, S, Bessi, V, Marcone, A, Cerami, C, Cappa, SF, Filippi, M, Agosta, F, Magnani, G, Comi, G, Franceschi, M, Rainero, I, Giordana, MT, Rubino, E, Ferrero, P, Rogaeva, E, Xi, Z, Confaloni, A, Piscopo, P, Bruno, G, Talarico, G, Cagnin, A, Clerici, F, Dell’Osso, B, Comi, GP, Altamura, AC, Mariani, C, Scarpini, E (2013) Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: Late-onset psychotic clinical presentation. Biol Psychiatry 74, 384–391.