Cognitive and Behavioral Profiles of Left and Right Semantic Dementia: Differential Diagnosis with Behavioral Variant Frontotemporal Dementia and Alzheimer’s Disease

Abstract

Background:

Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by semantic memory loss and preserved abilities of other cognitive functions. The clinical manifestations of SD require a differential diagnosis with Alzheimer’s disease (AD), especially those with early onset, and behavioral variant FTD (bvFTD).

Objective:

The present study aimed to compare cognitive performances and neuropsychiatric symptoms in a population of AD, bvFTD, and left and right SD defined with the support of molecular imaging (amyloid and 2-[¹⁸F] fluoro-2-deoxy-D-glucose positron emission tomography) and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases.

Methods:

Eighty-seven participants (32 AD, 20 bvFTD, and 35 SD (17 Left-SD and 18 Right-SD) completed a comprehensive neuropsychological battery that included memory, language, attention and executive functions, visuospatial function, visuoconstructional skills, and tasks designed specifically to evaluate prosopagnosia and facial emotions recognition. The Neuropsychiatric Inventory was administered to assess neuropsychiatric symptoms.

Results:

An episodic memory test that included semantic cues, a visuospatial test (both impaired in AD), a naming test and a prosopagnosia task (both impaired in SD) were the four most valuable cognitive metrics for the differential diagnosis between groups. Several behavioral abnormalities were differentially present, of which aggression, self-care (both more frequent in bvFTD), and eating habits, specifically overeating and altered dietary preference (more frequent in SD), were the most valuable in group discrimination.

Conclusion:

Our study highlights the value of a comprehensive neuropsychological and neuropsychiatric evaluation for the differential diagnosis between FTD syndromes and AD.

Keywords

Alzheimer’s disease behavior behavioral variant frontotemporal dementia cognition semantic dementia

INTRODUCTION

Neuropsychology has played a critical role in characterizing the cognitive changes associated with dementing disorders. This has improved our ability to accurately diagnose dementia subtypes, to identify subtle cognitive changes that occur in the prodromal phase of the disease, and to track clinical progression [1]. In patients with suspected dementia, a comprehensive neuropsychological and neuropsychiatric evaluation is an indispensable diagnostic element.

Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) commonly associated to TDP-43 protein deposits, and to a lesser extent to tau protein [2, 3]. Clinically, SD is a primary progressive aphasia syndrome which is characterized by specific semantic memory loss and preserved abilities of other cognitive functions [4, 5]. The initial cognitive profile shows a loss of semantic knowledge [6, 7], with relatively preserved episodic memory, in particular, visual memory, visuospatial capacity, and executive functions. Tests of visual confrontation naming, single-word comprehension, category fluency, and word-picture matching are useful to confirm the loss of semantic knowledge in this group of patients [8, 9]. It has been reported that SD patients also perform poorly on tests of verbal episodic memory, such as list learning and story recall, and recognition memory for visual materials [10]. Patients with early Alzheimer’s disease (AD) generally show preserved semantic knowledge for ordinary objects/animals. On tests of autobiographical memory, SD patients recall recent life events significantly better than their memory for early life periods, whereas AD patients exhibit an inverse pattern [11].

Although SD typically presents with a left predominant anterior temporal atrophy, up to 30% of cases exhibit right predominant involvement at onset [12]. In each case, the contralateral anterior temporal lobe becomes affected as the disease progresses [13]. Thus, SD can be divided into two clinical presentations: Left-sided SD (L-SD) and right-sided SD (R-SD). L-SD patients show more naming and comprehension difficulties [14], whereas R-SD patients typically exhibit behavioral changes and prosopagnosia [6 , 16]. Behavioral changes most commonly referred include disinhibition, apathy, aggression, lack of interpersonal engagement, loss of empathy, compulsive and rigid behaviors, restricted food preference in favor of sweet food and hyper-religiosity [17, 18].

The prominence of behavioral symptoms described in R-SD patients requires differential diagnosis with the behavioral variant frontotemporal dementia (bvFTD). bvFTD is characterized by progressive and insidious behavioral alterations associated with a pattern of cognitive performance defined by the relative preservation of episodic memory and visuospatial functions with executive dysfunction [7]. Thus, differential diagnosis may be particularly challenging, especially in the early disease phase of bvFTD [19] when the neuropsychological performance can be normal. However, there are conflicting reports concerning the extent to which episodic memory is preserved [20]. A growing number of studies have shown that bvFTD may have a moderate episodic memory disorder comparable to the one seen in AD [20, 21] which cannot be entirely explained by executive dysfunction but reflects some degree of disruption to memory storage and its consolidation processes [22, 23]. Two discrete behavioral syndromes have been described among patients with bvFTD: 1) the apathetic type, distinguished by declined volition and motivation, loss of socio-emotional awareness, isolating behaviors and increased latency to pain response; and 2) the disinhibited type which is characterized by hyper-orality, preference for sweet foods, perseverative behaviors, and motor stereotypies [24]. Increased disinhibition and impulsivity can lead to inappropriate comments (e.g., sexually explicit), inadequate social behavior, overspending, pathological gambling, and more rarely, hyper-religiosity [25 –27]. R-SD share symptoms with bvFTD, such as lack of empathy, disinhibition, changes in diet preferences, and a decline in personal care [28]. However, while patients with R-SD typically show prosopagnosia, obsessions, rigid behavior, personality changes, and disorientation, bvFTD patients show higher degrees of apathy and executive dysfunction [16, 28].

The other principal differential diagnosis of SD is AD. Clinically, typical AD is characterized by progressive cognitive decline, particularly involving episodic memory. This episodic memory impairment is usually the earliest and most salient aspect of the AD dementia syndrome. It has been shown that the memory deficit reflects an inability to encode and store new information effectively. Additionally, some studies are reporting that semantic memory is early impaired in AD patients, affecting verbal fluency and naming. The semantic memory loss in AD may occur several years before diagnosis [29]. Additionally, some AD patients, typically exhibiting younger onset ages, present a disproportionately greater executive dysfunction than memory impairment [30, 31]. Furthermore, distinct studies have also evidenced that typical AD patients show mild to severe executive impairment across a variety of neuropsychological tests such as attention, verbal fluency, and working memory, concluding that AD subjects might perform similarly to bvFTD patients [32 –34]. However, AD manifestations are not limited to cognitive symptoms; but they can also include a wide range of neuropsychiatric symptoms like depression, apathy, sleep disorder, agitation, and psychosis [35].

Thus, AD, especially young-onset AD, bvFTD, and SD present an overlap of cognitive and neuropsychiatric symptoms, which make it necessary to carry out a comprehensive differential diagnosis. Previous studies have already tried to address this issue; however, they had some limitations. First of all, SD is a rare disease, and most publications include relatively small samples from single centers. (Table 1 shows a review of the main published series which included at least more than 15 patients with SD). Secondly, the right temporal atrophy onset is commonly underdiagnosed being usually underrepresented in SD series, since, apart from structural magnetic resonance imaging (MRI), most published studies did not use disease biomarkers to precisely categorize patients.

Table 1

Review of the main series of SD (more than 15 patients)

Authors [Ref]	SD total (n)	L-SD (%)	R-SD (%)	NPS-A	NPCH-A	Neuroimaging	Biomarkers (FDG-PET)

Galton et al., 2001 [78]	18	n.s.	n.s.	√	x	√	x
Thompson et al., 2003 [7]	47	76.59	23.40	√	√	√	x
Brambati et al., 2009 [15]	19	68.42	31.57	√	√	√	x
Chan et al., 2009 [12]	30	33.33	66.66	√	√	√	x
Josephs et al., 2009 [16]	28	28.57	71.42	√	√	√	X
Duval et al., 2012 [79]	15	n.s	n.s.	√	√	√	√ (n = 9)
Irish et al., 2013 [80]	22	54.54	45.45	√	√	√	x
Libon et al., 2013 [81]	15	n.s.	n.s.	√	x	√	x
Ding et al., 2016 [82]	19	n.s.	n.s.	√	x	√	x
Binney et al., 2016 [83]	33	63.63	36.36	√	x	√	x
Kumfor et al., 2016 [66]	31	70.96	29.03	√	√	√	x
Sakai et al., 2017 [84]	18	61.11	38.88	√	x	√	x
Bejanin et al., 2016 [85]	21	76.19	23.80	√	x	√	x
Snowden et al. 2017 [14]	41	75.60	24.39	√	x	√	X
Josephs et al., 2008 [86]	27	n.s.	n.s.	√	√	√	x
Bejanin et al., 2018 [77]	16	n.s.	n.s	√	x	√	√ (n = 16)
Chen et al., 2018 [87]	35	48.57	51.42	√	x	√	x
Hurley et al., 2018 [88]	19	n.s.	n.s.	√	x	√	x

SD, semantic dementia; L-SD, left semantic dementia; R-SD, right semantic dementia; NPS-A, Neuropsychological assessment; NPCH-A, Neuropsychiatric assessment; n.s., non specified in the article.

One of the breakthroughs in the field has been the incorporation of molecular imaging to dementia diagnosis. Positron emission tomography (PET) techniques have provided significant advances, promoting novel approaches to support an earlier and more accurate differential dementia diagnosis. These diagnostic tools have robustly shown its utility in the differential diagnosis of AD versus FTD syndromes [36 –38].

We propose a study systematically assessing cognitive performances and neuropsychiatric symptoms in one of the largest cohorts of SD to date, with substantial representation of R-SD, compared to a population of young AD and bvFTD defined by the support of molecular imaging (amyloid PET (Pittsburgh Compound-B (PiB)) and 2-[¹⁸F] fluoro-2-deoxy-D-glucose (FDG) PET). We aimed to describe SD profile and to evaluate the accuracy of various neuropsychological parameters to distinguish these neurodegenerative syndromes from young AD and bvFTD. In addition, we aimed to compare the neuropsychiatric and neuropsychological assessment between L-SD, R-SD, and bvFTD.

We hypothesize that the AD group will obtain worse scores in episodic verbal memory and visuospatial capacity; the bvFTD group will score significantly worse in tasks that measure executive functions and emotion recognition and will show marked behavioral disorders; finally, SD patients will obtain worse performance in tasks that measure semantic memory, a test of visual confrontation naming, categorical fluency, as well as in tasks that evaluate prosopagnosia. We hypothesized that of all neuropsychological assessment, a detailed evaluation of language, episodic memory, and prosopagnosia will help us with the differential diagnosis.

METHODS

Participants

Our patients have been consecutively recruited during the last five years from the University Hospital Marqu $\overset{´}{e}$ s de Valdecilla Memory Unit. Our center is essentially a secondary referral unit where patients are referred by their general practitioners. Patients were seen on a first visit by one of the unit’s neurologists and then a neuropsychologist performed the neuropsychological assessment. In a few weeks, the patients returned to the neurologist who, considering the neuropsychological study and MRI images results, decided to order the PIB and FDG PET. Finally, with all the tests, the members of the Memory Unit by consensus decided the diagnosis. Patients meeting the revised criteria of AD, bvFTD, and SD [39 –42] who also had PIB and FDG-PET available were selected. We recruited eighty-seven participants, including 32 AD, 20 bvFTD, and 35 SD (17 L-SD and 18 R-SD patients). PiB and FDG-PET images were acquired in 71.4% of patients (in 25 out of the 35 SD and in all AD and bvFTD). Patients older than 50 years with a classic amnesic clinical presentation of AD and positive PiB-PET scan were recruited, excluding atypical cases (i.e., frontal variant, logopenic progressive aphasia, posterior cortical atrophy, corticobasal syndrome). bvFTD patients with no evidence of brain atrophy and disease progression were also excluded to avoid potential non-progressive “phenocopy” cases [43]. All cases with SD presented with anterior temporal lobe atrophy on structural MRI. Patients with a pattern of MRI changes typical of SD but with markedly greater left >right anterior temporal lobe atrophy in coronal sections on a 3T MRI were classified as L-SD. Patients with a pattern of MRI changes typical of SD but with markedly greater right >left anterior temporal lobe atrophy in coronal sections on a 3T MRI were classified as R-SD. When in doubt, the FDG-PET hypometabolism pattern was used. Diagnoses were established by a clinical committee formed by three neurologists (PSJ, ERR, and CL) and one neuropsychologist (AP). All patients were assessed by a multidisciplinary team to exclude other neurological or psychiatric etiologies. The study was approved by the ethical committee of UHMV, and written informed consent was obtained from all the patients.

Neuropsychological assessment

All participants underwent a comprehensive neuropsychological battery by a trained neuropsychologist (AP) that included the main cognitive domains (episodic and semantic memory, language, attention and executive functions, visuospatial function, visuoconstructional skills) and some tasks specifically designed to evaluate prosopagnosia and emotions recognition. Neuropsychological test scores were adjusted for age and educational level. Normative neuropsychological data were previously collected from a sample of healthy elders from Spain (NEURONORMA PROJECT, [44]. Scaled scores of each test were calculated by correcting raw scores for age and education. Following the NEURONORMA authors’ recommendations, a scaled score ≤6 (percentile ≤10) was considered deficient.

The Mini-Mental State Examination test (MMSE) [45, 46] and the Memory Alteration Test (MAT) [47] were used as global tests of cognition. Episodic verbal memory was assessed by the Spanish version of the Free and Cued Selective Reminding Test (FCSRT) [48]. The visual episodic recall was measured using the 30 minutes delayed recall condition of the Rey Complex Figure (RCF) [48, 49]. The Boston Diagnostic Aphasia Examination Battery Spanish version was used to explore verbal repetition of low-probability sentences and verbal comprehension of commands [50]. The Boston Naming Test (BNT) [51] was applied to evaluate visual confrontation naming. The visuoconstruction skills was assessed using the RCF test [48, 49] or the CERAD battery [52]. The “Number Location” subtest from the Visual Object and Space Perception Battery (VOSP) was used to evaluate elementary visuospatial functions [53]. Attention and executive functions were assessed by phometic fluency (“P-words”) [54], Trail Making Test – parts A and B (TMT-A, TMT-B) [55], the Digit Span and Digit Symbol from the WAIS III battery [55], and the Stroop test [56]. Semantic memory was measured by BNT, semantic category fluency (“animals”) [54] and by the description of objects with questions such as “What is a nail clipper?” or “How is an elephant?”. The task consisted of the description of 7 elements of different frequency and familiarity belonging to two categories: “living things” and “man-made objects”. The answers “I do not know”, “I have never heard that word”, and “it sounds familiar to me, but I do not know what it is” were scored as zero. Information that had nothing to do with the correct answer was also scored as zero. After answers like “I do not know”, the patient was urged to try to express some characteristic that might be associated with the item presented. The total score was the number of correct descriptions.

Moreover, patients were assessed with a prosopagnosia task that included 27 items designed and developed by our group. Famous faces of both sexes from the Spanish and international scene (actors, politicians, athletes, singers, TV presenters) were shown to the patients. None of the images exhibited decorative elements such as hats, sunglasses, or handkerchiefs and all of them had the same size and were in color. Through a slide presentation on a PC, participants were asked to provide the first name and surname for each famous person where possible. If they could not come up with the name, participants were encouraged to describe the individual and to be as specific as possible (e.g., “Why they were famous?” or “What was the occupation or nationality?”). Any case where they could not name the person but detailed semantic information was given counted as correct recognition. As an example: Responses such as “he is a sportsman” were considered too vague to constitute correct recognition for “Rafa Nadal“, whereas an answer such as “he is a tennis player from Mallorca, he wins everything” was counted as sufficiently detailed to constitute a correct answer. Those items in which the name could not be recalled and only a vague sense of familiarity without clear semantic information was evidenced were counted as incorrect. The maximum score of the task was 27 points.

Neuropsychiatric assessment

The severity of general neuropsychiatric symptoms was evaluated by the Neuropsychiatric Inventory (NPI, ranging from 0 to 120, where a higher score reflects a more severe neuropsychiatric condition) [57]. In addition, a reference relative was interviewed to obtain clinical and neuropsychiatric information about the presence of the following 15 symptoms: apathy, disinhibition, obsessional behavior, behavior rigidity, loss of insight, loss of empathy, aggression, hyper-religiosity, decline in personal care, depression, somatization disorder, overeating, altered food preference, hallucinations, and delusions.

Finally, we evaluated emotions recognition with a task that consisted of recognizing six basic emotions (happiness, sadness, surprise, fear, disgust, and anger [58]) in black-and-white photos. Each correctly recognized emotion was given 1 point, with a maximum total score of 6 points.

Statistical analyses

Differences among groups on demographic variables and neuropsychological measurements were analyzed with one-way analysis of variance (ANOVA) and Tukey’s post-hoc contrasts. χ² was used to assess group differences in the case of dichotomous variables. To identify the items which best differentiated between the dementia groups, we built binary logistic regression models and used a forward stepwise selection method. Based on the univariate analysis, all neuropsychological variables that were statistically significant were entered into the models adjusting by age at onset and sex. The same analysis was performed for neuropsychiatric variables. IBM SPSS Statistics V.20.0 (International Business Machine Corporation, Armonk, NY, USA) was used for all tests.

RESULTS

Demographics

Demographic data are summarized in Table 2. Patients with AD were significantly younger than patients with bvFTD and SD. The proportion of male patients was significantly higher in the bvFTD group compared with the two other groups. There were no significant between-group differences in disease duration, education, and MMSE score. All patients with AD had a positive amyloid PET, while the amyloid PET was negative in all bvFTD and 24 out of 25 SD patients. The SD patient with a positive amyloid PET was a 78-year-old woman with a clinical picture compatible with an SD diagnosis. Four years earlier, she started with increasing word-finding difficulties and behavioral abnormalities. Episodic memory was relatively preserved. Her family referred that she had developed a fixed daily routine and a preference for sweet food, as well as aggressivity, loss of empathy, and a decline in personal care. The MRI scan showed right temporal lobe atrophy, supporting the diagnosis of SD. FDG-PET revealed predominantly anterior hypometabolism with bilateral frontoparietal involvement, more accentuated in the right hemisphere. Unexpectedly, the PiB-PET showed widespread retention of the radiotracer.

Table 2

Demographics in AD, bvFTD, SD, L-SD, and R-SD

	AD (n = 32)	bvFTD (n = 20)	SD (n = 35)	L-SD (n = 17)	R-SD (n = 18)	p
Sex (fem %)	71.87	25.00	48.57	44.4%	52.9%	0.003
Mean Age (y)±SD	66.44 (5.92)	72.7 (7.28)	71.34 (8.36)	71.1(8.41)	71.50 (8.56)	0.005
Mean Disease duration (mo)±SD	44.06 (23.04)	43.74 (24.85)	45.00 (31.27)	40.12 (20.51)	49.33 (38.53)	0.985
Mean Education (y)±SD	10.50 (3.33)	10.60 (3.50)	9.60 (3.09)	8.94 (2.65)	10.22 (3.42)	0.426
Mean MMSE±SD	21.52 (5.00)	23.44 (3.70)	22.50 (4.76)	22.60 (3.91)	22.40 (5.98)	0. 453

AD, Alzheimer’s disease; bvFTD, behavior variant frontotemporal dementia; SD, semantic dementia; L-SD, left semantic dementia; R-SD, right semantic dementia; MMSE, Mini-Mental State Examination. In bold, p < 0.05.

Comparative neuropsychological performance between AD, bvFTD, and SD

Neuropsychological test scores for AD, bvFTD, and SD groups are shown in Table 3. All neuropsychological variables were adjusted for age and gender. There were statistically significant differences across the three diagnostic groups on total free recall (p = 0.049), total recall (p = 0.001), and delayed total recall (p = 0.009). Patients with AD and SD were significantly more impaired compared to those with bvFTD on verbal memory. While AD and SD patients exhibited an overall impairment in episodic memory tasks, bvFTD subjects appeared to benefit more from the controlled learning through category cues. Likewise, in the test evaluating semantic memory through the description of objects, SD group described different objects very poorly, without providing distinctive details and with many “I don’t know” answers. There were highly significant differences in this simple task between SD (Mean = 2.30±1.8) versus AD (Mean = 5.78±1.40) (p = 5.25×10–8) and SD versus bvFTD (Mean = 5.05±1.57) (p = 0.000002).

Table 3

Performance of neuropsychological assessment

	AD (n = 32)	bvFTD (n = 20)	Total SD (n = 32)	L-SD (n = 15)	R-SD (n = 17)	Group Effect	AD versus bvFTD	AD versus SD	SD versus bvFTD	L-SD versus R-SD
	Mean (SD)	Mean (SD)	Mean (SD)	Mean (SD)	Mean (SD)	p	p	p	p	p
Memory
FCSRT Total free recall (0–48)	5.44 (4.69)	10.15 (6.90)	6.52 (8.38)	7,58 (11.09)	5.67 (5.67)	0.049	0.042	0.811	0.165	0.565
FCSRT Total Recall (0–48)	14.19 (4.69)	24.85 (12.19)	12.85 (11.49)	14.17 (13.96)	11.80 (5.67)	0.001	0.004	0.891	0.001	0.605
FCSRT Delayed free recall (0–16)	0.75 (1.72)	2.30 (2.83)	1.52 (2.96)	1.75 (2.70)	1.33 (3.24)	0.096	0.081	0.469	0.541	0.724
FCSRT delayed total recall (0–16)	3.91 (3.85)	7.50 (4.75)	3.81 (4.81)	4.83 (5.50)	3.00 (4.19)	0.009	0.016	0.997	0.017	0.335
Rey Figure Memory (0–36)	3.52 (3.82)	5.32 (4.72)	3.95 (4.71)	3.62 (5.05)	4.29 (4.55)	0.437	0.415	0.935	0.608	0.737
CERAD Figure Recall (0–11)	2.00 (2.82)	0.40 (0.89)	1.50 (2.81)	1,00 (1.41)	1.75 (3.50)	0.548	0.522	0.929	0.745	0.795
Semantic memory
Animal fluency	10.52 (5.35)	8.05 (4.17)	7.34 (4.24)	6.33 (4.90)	8.24 (3.47)	0.025	0.164	0.023	0.857	0.211
Description of objects (0–7)	5.78 (1.40)	5.05 (1.57)	2.30 (1.80)	2.00 (1.73)	2.55 (1.91)	<0001	0.239	<0001	<0001	0.517
Boston naming test (0–60)	43.78 (9.29)	39.75 (8.69)	32.14 (10.71)	28.44 (12.61)	34.69 (8.79)	0.0001	0.309	0.0001	0.032	0.185
Language
Comprehension (0–15)	10.81 (1.61)	10.60 (1.78)	10.19 (2.13)	9.73 (2.93)	10.63 (0.80)	0.417	0.916	0.390	0.729	0.252
Repetition (0–8)	7.53 (0.87)	7.40 (0.75)	6.90 (1.49)	6.13 (1.76)	7.63 (0.61)	0.078	0.912	0.075	0.279	0.004
Attention and Executive functions
Phonemic fluency	10. 94 (5.75)	7.75 (3.97)	8.29 (4.32)	6.93 (3.86)	9.56 (4.45)	0.035	0.610	0.084	0.920	0.091
Digits span forward (0–9)	5.12 (1.07)	4.80 (1.05)	5.23 (1.08)	5.00 (0.96)	5.41 (1.17)	0.374	0.540	0.926	0.354	0.302
Digits span backward (0–8)	3.09 (1.05)	2.80 (1.10)	3.57 (1.22)	3.54 (0.96)	3.59 (1.41)	0.058	0.636	0.234	0.055	0.914
Trail making test-A (Time)	113.34 (63.13)	146.11 (83.55)	109.32 (74.25)	100.90(67.42)	114.93 (80.28)	0.200	0.267	0.976	0.223	0.653
Trail making test-B (Time)	140.14 (71.12)	192.00 (77.97)	121.13 (48.99)	104.00 (22.77)	138.25 (65.57)	0.223	0.419	0.835	0.198	0.362
Stroop Interference	13.48 (10.96)	16.00 (9.48)	16.25 (11.05)	14.82 (8.78)	17.46 (12.90)	0.578	0.716	0.609	0.997	0.571
Digit Symbol (0–133)	20.81 (13.52)	17.61 (9.48)	26.29 (15.40)	25.36 (16.98)	27.08 (14.60)	0.105	0.696	0.288	0.100	0.793
Visuospatial function
VOSP number location (0–10)	5.31 (3.03)	6.63 (3.28)	7.67 (2.88)	7.45 (2.80)	7.85 (3.05)	0.020	0.301	0.015	0.514	0.748
Visuoconstruction skills
Rey Complex Figure (0–36)	24.86 (10.49)	22.19 (11.59)	29.48 (5.58)	28.25 (6.18)	30.71 (4.87)	0.048	0.645	0.200	0.047	0.291
CERAD Figures Copy (0–11)	6.75 (2.37)	6.00 (3.24)	5.29 (2.13)	5.50 (2.12)	5.20 (2.38)	0.547	0.863	0.517	0.881	0.884
Prosopagnosia
Face Recognition (0–27)	20.75 (6.26)	19. 00 (6.74)	7.61 (9.32)	9.90 (11.68)	5.85 (7.02)	<0001	0.698	<0001	0.0001	0.312

Patients with SD performed worse than the other two groups in all language tasks. The BNT was severely impaired in the SD group compared to the AD (p = 0.0001) and the bvFTD (p = 0.032) groups. Statistically significant differences were seen across the three diagnostic groups in Animal Fluency (p = 0.025), where patients with SD performed worse than the other two groups, but only reached significant differences in comparison with the AD group (p = 0.023). bvFTD patients performed worse on all tasks that evaluate attention and executive functions; however, there were only statistically significant differences among groups in regard to phonemic fluency (p = 0.035), where bvFTD tended to say fewer words that start with “P” in a minute. Moreover, there was a borderline significant trend (p = 0.058) for the backward digits span (working memory).

Differences between the three groups were evident in visuospatial function and visuoconstruction skills. AD patients obtained lower scores in the visuospatial test (VOSP); statistically significant differences were found with patients with SD (p = 0.015) but no with bvFTD. bvFTD performed significantly worse than SD (p = 0.047) in the RCF copy.

In the prosopagnosia task patients with SD (Mean = 7.61±9.32) were significantly more impaired than AD (Mean = 20.75±6.2) (p =4.10×10–7) and bvFTD (Mean = 19.00±6.74) (p = 0.0001), with the latter two groups performing similarly.

Comparative neuropsychological performance between L-SD, R-SD, and bvFTD

L-SD patients differed significantly from bvFTD patients in memory (total recall (p = 0.026)), language (BNT (p = 0.032), verbal repetition (p = 0.008), description of objects (p = 0.00004), and the prosopagnosia task (p = 0.013). BvFTD group showed better scores in all these domains.

In a similar manner, there were statistically significant differences on total recall (p = 0.005) and delayed total recall (p = 0.018), description of objects (p = 0.0004) as well as the task that measured prosopagnosia (p = 0.00003) between R-SD and bvFTD. In contrast, R-SD and bvFTD scored similarly in the BNT and the verbal repetition.

L-SD and R-SD only differed significantly in verbal repetition task (p = 0.004).

Comparative neuropsychiatric assessment between AD, bvFTD, and SD

All included individuals, except for one SD patient, completed the semi-structured neuropsychiatric interview. There were statistically significant differences across the three diagnostic groups on the NPI score (p = 0.005) and in the emotion recognition task (p = 0.000004) (Table 4). Patients with bvFTD tended to show more neuropsychiatric symptoms than the AD and the SD patients. Post-hoc tests showed that differences between AD and bvFTD (p = 0.003) were statistically significant.

Table 4

NPI and emotion recognition performance according to diagnostic group

	AD	bvFTD	SD	L-SD	R-SD	Group effect	AD versus bvFTD	AD versus SD	bvFTD versus SD	L-SD versus R-SD
	Mean (SD)	Mean (SD)	Mean (SD)	Mean (SD)	Mean (SD)	p	p	p	p	p
NPI total	11.83 (10.71)	23.58 (14.48)	16.12 (10.39)	13.00 (9.36)	18.79 (10.82)	0.005	0.003	0.139	0.05	0.161
Emotion recognition	4.45 (0.88)	4.84 (1.25)	2.55 (2.11)	1.75 (1.48)	3.08 (2.35)	<0001	0.205	<0001	<0001	0.173

AD, Alzheimer’s disease; bvFTD, behavior variant frontotemporal dementia; SD, semantic dementia; NPI, Neuropsychiatric Inventory. In bold, p < 0.05.

Patients with SD were significantly more impaired on the emotion recognition task than AD (p = 0.00005) and bvFTD (p = 0.00001). Interestingly, no significant differences were noted when comparing the latter ones.

The prevalence of various neuropsychiatric symptoms in AD, bvFTD, and SD is summarized in Table 5. Apathy (56.3%) and depression (56.3%) were the most frequent symptoms in AD followed by loss of empathy (28.1%) and aggression (28.1%). The most common in bvFTD were apathy (70%) and loss of empathy (70%), followed by the decline in personal care, present in 65%. Apathy (51.4%) and a decline in personal care (51.4%) were the most frequently observed behavioral symptoms in SD. Behavioral rigidity (48.6%) was also a prominent feature in the SD group.

Table 5

Neuropsychiatric symptoms in the AD, bvFTD, SD, L-SD and R-SD

	AD (n = 32)	bvFTD (n = 20)	Total SD (n = 34)	L-SD (n = 17)	R-SD (n = 17)	Group Effect	AD versus bvFTD	AD versus SD	SD versus bvFTD	L-SD versus R-SD
	n(%)	n(%)	n(%)	n(%)	n(%)	p	p	p	p	p
Apathy	18 (56)	14 (70)	18 (51.4)	8 (47)	10 (55.6)	0.467	0.389	0.678	0.218	0.492
Disinhibition	5(15)	9 (45)	13 (37.1)	5 (29.4)	8 (47.1)	0.056	0.024	0.047	0.625	0.290
Behavioral rigidity	7 (21.9)	4 (20)	11 (31.4)	6 (35.3)	5 (29.4)	0.528	0.827	0.379	0.328	0.714
Obsessional behavioral	8 (25)	6 (30)	17 (48.6)	6 (35.3)	11 (64.7)	0.102	0.743	0.045	0.151	0.086
Loss of empathy	9 (28.1)	14 (70)	15 (42.9)	8 (47.1)	7 (41.2)	0.016	0.004	0.208	0.065	0.730
Loss of insight	5 (15.6)	7 (35)	10 (28.6)	4 (23.5)	6 (35.3)	0.269	0.121	0.204	0.669	0.452
Aggression	9 (28.1)	8 (40)	5 (14.3)	2 (11.8)	3 (17.6)	0.108	0.417	0.161	0.036	0.628
Hyper-religiosity	1 (3.1)	2 (10)	6 (17.1)	1 (5.9)	5 (29.4)	0.180	0.331	0.067	0.445	0.072
Decline in personal care	7 (21.9)	13 (65)	18 (51.4)	9 (52.9)	9 (52.9)	0.006	0.002	0.012	0.387	1.00
Depression	18 (56.3)	6 (30)	15 (42.9)	8 (47.1)	7 (41.2)	0.140	0.050	0.261	0.304	0.730
Somatization disorder	5 (15.6)	5 (25)	8 (22.9)	3 (17.6)	5 (29.4)	0.683	0.436	0.456	0.903	0.419
Over-eating	2 (6.3)	3 (15)	12 (34.3)	6 (35.3)	6 (35.3)	0.012	0.316	0.005	0.108	1.00
Altered food preference	4 (12.5)	10 (50)	16 (45.7)	7 (41.2)	9 (52.9)	0.005	0.004	0.003	0.835	0.492
Hallucinations	1 (3.1)	1 (5)	2 (5.7)	1 (5.9)	1 (5.9)	0.404	0.209	0.170	0.891	1.00
Delusions	1 (3.1)	1 (5)	5 (14.3)	1 (5.9)	4 (23.5)	0.203	0.750	0.110	0.273	0.146

AD, Alzheimer’s disease; bvFTD, behavior variant frontotemporal dementia; SD, semantic dementia; L-SD, left semantic dementia; R-SD, right semantic dementia. In bold, p < 0.05.

Group differences on neuropsychiatric symptoms are shown in Table 5. There were statistically significant differences across the three groups on the following neuropsychiatric symptoms: loss of empathy (p = 0.016), a decline in personal care (p = 0.006), eating habits (over-eating (p = 0.012), and altered food preference (p = 0.005)). Patients with AD and bvFTD differed significantly in disinhibition (p = 0.024), loss of empathy (p = 0.004), a decline in personal care (p = 0.002), and change in food preference (p = 0.004), usually in favor of sweet foods. These four symptoms were most frequent in the bvFTD group. There were five features significantly more frequent in SD than in AD: disinhibition (p = 0.047), obsessional behavioral (p = 0.045), neglect in self-care (p = 0.012), alteration of eating habits like the increase in intake (p = 0.005), and altered food preference (p = 0.003). bvFTD and SD showed similar neuropsychiatric symptoms, with only aggression (p = 0.036) being significantly more common within the bvFTD group.

Comparative neuropsychiatric assessment between L-SD, R-SD, and bvFTD

There were no statistically significant differences in the total NPI score after comparing between L-SD versus bvFTD, R-SD versus bvFTD, and L-SD versus R-SD. Patients with bvFTD performed significantly better than both SD groups in the emotion recognition test (p = 0.00001 and p = 0.006; L-SD and R-SD respectively). L-SD and R-SD scored similarly in these tasks.

Regarding the different subitems, obsessional behavior (p = 0.035) was the one neuropsychiatric feature that differed significantly between L-SD and bvFTD, while aggression (p = 0.020) was the only symptom that significantly varied between R-SD and bvFTD. There were no statistically significant differences between L-SD and R-SD in neuropsychiatric symptoms.

Toward a more parsimonious assessment of neuropsychological and neuropsychiatric symptoms

A forward stepwise selection method was used to evaluate how the neuropsychological assessment differentiated between the groups, and to identify which of those variables had the greatest discriminant value. Figure 1 shows in a schematic way the results obtained in the logistic regression.

Fig.1

Cognitive and neuropsychiatric variables that best predict diagnoses AD versus bvFTD, SD versus bvFTD, and AD versus SD. Note: Neuropsychiatric symptoms are in red font and neuropsychological symptoms are in black font.

AD versus bvFTD

The total recall (p = 0.014) was the primary predictor to discriminate between these two groups. The AD group obtained lower scores in total recall.

Regarding neuropsychiatric symptoms, the only significant predictor of group membership was the decline in personal care (p = 0.045); this symptom was more present in the bvFTD group.

AD versus SD

Lower performance in the VOSP test (p = 0.025) among the AD and impaired Description of objects in the SD group (p = 0.041) were the most effective cognitive tasks.

Changes in eating habits, like over-eating (p = 0.039) and altered food preference (p = 0.059) were the two neuropsychiatric symptoms that were superior predictors to differentiate between AD and SD diagnosis; these neuropsychiatric symptoms were more frequent in the SD group.

SD versus bvFTD

The BNT (p = 0.020) and the prosopagnosia task (p = 0.045) were the two cognitive variables that were statistically significant predictors of group membership. The SD group performed worse on both tasks.

In our multivariate analysis, aggression, more common in bvFTD (p = 0.023), was the only significant neuropsychiatric discriminator, and more overeating in SD was borderline significant (p = 0.058).

L-SD versus R-SD

The verbal repetition task (p = 0.025) was the only predictor that significantly discriminated between these two groups; L-SD performed worse in this task. No neuropsychiatric symptoms were able to differentiate between L-SD and R-SD.

DISCUSSION

This study aimed to describe the main neuropsychological and neuropsychiatric features of a relatively large SD population diagnosed with the support of FDG and PiB-PET; trying to distinguish those items that allow to discriminate them from young-onset AD and bvFTD patients.

We decided to recruit patients with young AD (over 50 years old) with a positive PiB-PET because we believe that this population, especially at early disease stages, comprise the most challenging differential diagnosis with bvFTD and SD.

Our results revealed an overlap of many of the cognitive and neuropsychiatric symptoms. However, a prosopagnosia task, an episodic memory test that included semantic cues, a visuospatial, and a naming test were the four most helpful cognitive tests for the differential diagnosis. Besides, we described several behavioral abnormalities with discriminative power. Among them, aggression, personal care, and eating habits, specifically over-eating and altered food preference, were the most powerful items for group categorization.

In our study, we found differences across the distinct groups in all the neuropsychological domains explored with the only exception of attention and executives function tests which appeared as the tasks with less discriminative power between the groups. Even though a dysexecutive pattern is a part of the bvFTD diagnostic criteria [7] when compared with SD and early AD cases, we found that differences were not statistically significant.

As expected, AD group showed verbal and visual memory impairment, and they did not benefit from the controlled learning afforded by category cues. FCSRT enables the identification of memory storage failure defining the amnesic syndrome of the hippocampal type [59], primarily characterized by insensitivity to cueing and by a low total recall. Similar to other authors, we found that patients with AD were more impaired in episodic memory tests than bvFTD patients, with total recall the most helpful test to distinguish between these two diseases. Conversely, AD and SD performed similarly in episodic memory tests. Both the AD and SD groups were significantly impaired on verbal memory when compared to the bvFTD, while only patients with AD were impaired on visual memory. These results are consistent with previous studies that have demonstrated that SD scored below the normative values in episodic memory tasks [60]. We believe that the involvement of verbal language in the episodic memory task can explain these results. The bvFTD group was characterized by a memory profile that improved with category cues, unlike the memory profile found in AD and SD. Another expected finding was the AD patients’ lower performance in the visuospatial subtests from the VOSP. This test was especially helpful in the discrimination of AD versus SD.

Another result was that globally, patients with bvFTD showed worse performance on the copy condition of the RCF relative to the other clinical groups. However, differences were only significant when compared to SD. This result goes against the trend found in previous studies that presented patients with bvFTD with relative preservation of visuoconstruction skills [41, 61]. Interestingly, in simpler tasks, such as the CERAD Figures Copy, our bvFTD patients did not perform worse than AD or SD, which is strongly suggestive of a primary deficit in the planning and organization skills necessary for the correct execution of the RCF test rather than visuospatial or visuoconstruction disturbances per se.

SD group showed a pronounced impairment in the BNT and scored lower in animal fluency. In the description of objects task, that evaluates semantic memory, patients with SD performed worse than AD and bvFTD, with a higher number of “don’t know” and “I recognize it but ... ” “never heard it” responses and over-inclusively categories like “animal” to describe a camel or “vegetable” to describe an eggplant, ignoring the distinctive characteristics of each of them. The observed pattern of neuropsychological findings was generally consistent with previous reports [4, 62].

In the literature, about 30% of SD patients present with a predominant right temporal lobe atrophy. Frequently, it is difficult to differentiate R-SD from a bvFTD, the nosology of R-SD remaining uncertain [16 , 63]. We compared neuropsychological performance between L-SD and R-SD and each of them with bvFTD. Surprisingly, we found significant differences in verbal repetition; being it relatively poorer in L-SD patients. L-SD group repeats worse than the R-SD, however, both groups continue to score within normal limits. More studies exploring the quality of the errors elicited on verbal repetition of low probability sentences, rather than a total achievement score, may shed light on this finding.

A remarkable result was the absence of statistically significant differences in the BNT when comparing R-SD with bvFTD. This finding is broadly in line with studies that argue that a predominant right anterior temporal lobe atrophy is associated with behavioral changes and prosopagnosia while naming and comprehension are disproportionately impaired in patients with more severe left atrophy [14]. The prosopagnosia task allowed differentiating patients with L-SD versus bvFTD and R-SD versus bvFTD, both SD group (especially R-SD) presenting a manifested difficulty for the famous face recognition when compared with bvFTD.

Neuropsychiatric symptoms were present across the three diagnostic groups. Patients with bvFTD showed more neuropsychiatric symptoms, followed by SD and finally AD, the differences being of statistical significance between bvFTD and AD. Our results are in line with Gainotti’s 2015 review which concludes that right temporal atrophy subsumes non-verbal representations and the left temporal atrophy lexical-semantic representations [64].

In our study, apathy was prevalent in patients with AD, bvFTD, and SD. Consistently with Chow et al. [65], it was particularly frequent in bvFTD, although no significant differences between groups were noted. We found that aggression, loss of empathy, the decline in personal care and eating habits, like over-eating and altered food preference, were the main neuropsychiatric features that permitted differentiation between AD and the FTD diseases.

Patients with bvFTD and SD share many behavioral symptoms, such as lack of empathy, disinhibition, changes in diet, and decline in personal care [28]. We confirmed these results, adding apathy as one of the most frequent non-cognitive symptoms in both groups. Aggression, most frequent among bvFTD patients, was the most discriminative neuropsychiatric symptom between bvFTD and SD, specifically with R-SD.

In line with the existing literature [6 , 29], we found that R-SD presented more neuropsychiatric features than L-SD; however, those differences were not statistically significant in our population. Kumfor et al. in 2016 [66] obtained similar results to us, concluding that L-SD and R-SD evolve into a similar clinical profile, with social cognition affected in both phenotypes. Differences between studies might be related to several factors like the proportion of R-SD included, the assessment time point during the disease course, sample size or patient’s selection methods (Table 1). We think that the systematic use of molecular imaging and the relatively large percentage of R-SD ascertained are two strong points in our study.

bvFTD patients typically show deficits in facial emotion recognition [67 –69]. A recently published meta-analysis described severe deficits in total emotion recognition compared to AD [70]. However, in our study, these differences did not reach statistical significance. At odds with previous studies, we found that the SD group was significantly associated with more severe deficits than AD and bvFTD in face emotion recognition. These results differ with several studies that indicate that patients with bvFTD show impairments on tests of face emotion processing [69, 71] and other studies that demonstrate that AD patients show similar deficits on tests of face emotion processing to those seen in bvFTD [72, 73]. A putative explanation for this phenomenon is the fact that prosopagnosia might contribute, to a certain degree, to face emotion recognition impairment in SD patients. The fact that after adjustment for prosopagnosia, the facial emotion recognition was no longer significantly discriminative supports this hypothesis. Additionally, language deficits present in SD patients can also contribute to explain this finding. Perry et al., 2001 [74] reported that emotion recognition might be particularly compromised in R-SD, supporting a differential contribution of left and right anterior temporal lobe regions to face processing [75]. Nevertheless, we found that both L-SD and R-SD showed equally impaired ability to recognize emotions and that there were no significant differences between these two groups; predominant language deficits in L-SD and prosopagnosia in R-SD might again complicate interpretation of these findings.

Although we do not replicate fully the results obtained by other studies regarding prosopagnosia and recognition of emotions, our work has found similar trends. A likely explanation is that the neuropsychological tools to evaluate these areas have not been sensitive enough to detect these differences, this being an important limitation to consider. Another limitation of the present study was the loss of statistical power in our multivariate analysis because of missing values, mainly in neuropsychological variables. The missing values for neuropsychological variables was 39.1%, with the majority corresponding to the group of SD patients (62.8% available). Multivariate analysis could, however, be performed with 78.1% AD and 75% bvFTD. For behavioral symptoms and NPI, there was no significant missing values and the multivariate analysis could be performed with 97.7% of the total sample (96.8% AD, 100% bvFTD, and 97.1% SD).

Few studies have compared cognitive and neuropsychiatric performance in young AD, bvFTD, and SD. Previous reports have studied the neuropsychological patterns in FTD and AD [41, 76] but did not include the assessment of the main neuropsychiatric symptoms, as well as tasks to evaluate prosopagnosia and emotions recognition, which, as shown by our data, are key elements for the differential diagnosis. Our study evaluated all these aspects in a relatively large and well-characterized cohort of patients. Specifically, the SD population included in this article is one of the largest and more comprehensively-studied samples of this disease described so far (see Table 1), with a very high representation of R-SD cases. Another important advantage of the current study is that most clinical diagnosis (all patients with young AD and bvFTD, and in 24 out of 35 patients with SD) were supported by typical patterns of hypometabolism on FDG-PET and PiB-PET results. Thus, minimizing patient’s misclassification, a capital factor increasing the validity of our observations. Very few SD series have studied patients using FDG and PiB-PET and of the existing ones, the largest is composed of only 16 patients studied with FDG-PET [77].

SD is a clinical diagnosis with a high predictive value of TDP-43 pathology. Thus, an accurate diagnostic categorization is of particular interest, as this phenotype could potentially be used in patient’s selection for clinical trials targeting TDP43 pathology. In the present study, we were able to demonstrate the utility of an adequate neuropsychological evaluation for the differential diagnosis between SD, bvFTD, and young AD. In addition to neuropsychological tests, the information offered by families about non-cognitive symptoms was particularly important, altogether offering clinical clues to differentiate between the three clinical syndromes. Despite the latest advances in biomarkers and neuroimaging techniques, this paper demonstrates the significant contribution of a detailed and theoretically motivated neuropsychological evaluation in the differential diagnosis between SD, bvFTD and young AD.

Footnotes

ACKNOWLEDGMENTS

We would like to thank all the patients and relatives for their generous collaboration.

Pascual Sanchez Juan was supported by grants from IDIVAL, Instituto de Salud Carlos III (Fondo de Investigación Sanitario, PI08/0139, PI12/02288, PI16/01652, JPND (DEMTEST PI11/03028) and the CIBERNED program and Siemens Healthineers (Valdecilla Cohort for Memory and Brain Aging).

Authors’ disclosures available online ().

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