Neuropsychological Assessment in the Distinction Between Biomarker Defined Frontal-Variant of Alzheimer’s Disease and Behavioral-Variant of Frontotemporal Dementia

Abstract

Background:

Frontal-variant of Alzheimer’s disease (fvAD) was purposed for patients with AD pathology that, despite the typical amnestic presentation, show early and progressive deterioration of behavior and executive functions, closely resembling the behavioral-variant of frontotemporal dementia (bvFTD). This leads to a challenging differential diagnosis where neuropsychological evaluation and in vivo pathological evidence are essential.

Objective:

To evaluate the contribution of a comprehensive neuropsychological assessment (NP) battery in distinguishing between fvAD-dementia and bvFTD supported by cerebrospinal fluid (CSF) biomarkers.

Methods:

We included 40 patients with a baseline NP profile with prominent early executive and/or behavioral dysfunction, who meet both diagnosis of bvFTD and fvAD-dementia, according to international criteria. All patients underwent comprehensive NP assessment and CSF-AD biomarker evaluation. Neuropsychological domains as well as clinical and sociodemographic features, and APOE genotype were compared between groups.

Results:

21 patients (52.5%) met the biological criteria for AD (decreased Aβ₄₂ together with increased T-tau or P-tau in CSF) and were therefore classified as fvAD (mean age was 64.57, with 47.6% female). There were no differences between groups regarding age/age-at-onset, gender, or educational level. Regarding neuropsychological profile, performances in language and memory functions were equivalent in both groups. Significant differences were found in visuo-constructional abilities (p = 0.004), Trail Making Test A (p < 0.001), and Raven’s Colored Progressive Matrices (p = 0.019), with fvAD patients showing worst performances.

Conclusion:

In patients with an early prominent frontal profile, a higher impairment in attention and visuo-spatial functions, signaling additional right hemisphere fronto-parietal dysfunction, point towards a diagnosis of fvAD-dementia and may be useful in clinical practice.

Keywords

ATN system behavioral-variant frontotemporal dementia cerebrospinal fluid biomarkers frontal-variant Alzheimer’s disease neuropsychological assessment

INTRODUCTION

Prominent frontal dysfunction is typical of the classic “frontal dementia” [1], now accepted as the behavioral-variant frontotemporal dementia (bvFTD) [2], which is the most common frontotemporal lobar degeneration (FTLD) syndrome. Within the same syndromic entity, cases of suspected or pathological confirmed Alzheimer’s disease (AD) have been recognized [3, 4], and this subgroup of AD-patients has been accepted by the American NIA-AA criteria [5] and formally purposed as the frontal-variant of AD (fvAD-dementia) by the International Working Group (IGW-2) [6]. These last criteria considered both typical and atypical AD, where fvAD-dementia is included, together with the logopenic and posterior cortical atrophy variants. fvAD-dementia was defined by two main criteria: 1) the presence of an early, predominant, and progressive behavioral change including association of primary apathy or behavioral disinhibition, or predominant executive dysfunction on cognitive testing; and 2) in vivo evidence of AD pathology: decreased Aβ₄₂, together with increased T-tau or P-tau in the cerebrospinal fluid (CSF); or increased tracer retention on amyloid PET; or Alzheimer’s disease autosomal dominant mutation present (in PSEN1, PSEN2, or APP) [6]. Since this original definition, patients presenting with either dysexecutive or behavioral-predominant syndromes have been described in case series and two distinct clinical phenotypes were assumed by the respective authors: the dysexecutive and behavioral variants of AD [7, 8]. No consensus international diagnostic criteria for these two entities have been established to date. Very recently, Ossenkkopelle et al. [9] purposed research criteria for the behavioral variant AD (bvAD), based on the core behavioral features of the diagnostic criteria of bvFTD: it is defined by cognitive impairment strictly followed by the personality/behavioral changes typical of bvFTD. As with all other atypical AD variants, the pattern of amyloid deposition in frontal variants is diffuse, so they purposed PET-tau as an additional and decisive in vivo biomarker for a possible diagnosis. Structural imaging can present with more prominent frontal atrophy and asymmetric shapes are not uncommon. Assessing FDG-PET results, frontal and parietal hypometabolism was observed in about half of cases [9]. Together with CSF, functional imaging studies appear to be crucial in the investigation of these overlapping clinical entities. Availability of using both PET-amyloid and PET-Tau already demonstrated in vivo correlations between neuropsychological patterns and regional neuropathology profiles in AD [10]. However, they are still very expensive to be used in clinical practice and currently are not widely available. Conversely, the behavioral and Neuropsychological assessment (NP) have an essential role in the initial comprehensive characterization, besides being non-invasive and affordable approaches. Specific scales based on the profile of behavioral symptoms have been suggested to improve the diagnostic accuracy in this group of patients [8]. Regarding NP, executive dysfunction and a relative sparing of episodic memory and visuospatial functions is described as a typical profile of bvFTD versus AD [2]. In a recent systematic review and meta-analysis with 591 bvAD patients [9], where the research diagnostic criteria for bvAD were purposed, authors found that compared to typical AD, this group showed more severe behavioral/neuropsychiatric symptoms; however, there were no significant differences in relation to bvFTD. Moreover, the results remained comparable when they separated core bvFTD criteria and neuropsychiatric features. Regarding cognition, worse executive performances were seen in bvAD-dementia when compared to typical AD-dementia, but not with bvFTD. Also, bvAD-dementia patients did not differ from bvFTD in memory tasks. The authors, however, recognized that there was a moderate to substantial heterogeneity in criteria and instruments with risk of bias across studies. Recent recommendations encourage a full NP evaluation instead of dementia screening tests to further investigate the role of NP profiles in the differential diagnosis of fvAD-dementia and bvFTD. We hypothesized that visuo-constructive abilities would be helpful in this distinction. Therefore, in order to test this hypothesis, we used a comprehensive NP battery to explore which tests and cognitive domains are capable of distinguish between milder forms of fvAD-dementia and bvFTD, in a cohort of patients with prominent frontal dysfunction overlapping both entities, with CSF-AD biomarker-based classification.

MATERIALS AND METHODS

Study population

We reviewed patients followed at the Memory Clinic of the Centro Hospitalar e Universitário de Coimbra (CHUC) between 2016 and 2020 who were investigated for a biological diagnosis of degenerative dementia with both neuroimaging and clinical features suggesting prominent frontal dysfunction. We selected: 1) patients who performed a baseline comprehensive NP assessment at mild disease stages; 2) that considering the cognitive and psychiatric phenotype, met the international criteria for both fvAD-dementia [6] and bvFTD [2]. Regarding frontal variants of AD, namely dysexecutive variant AD and bvAD, our patients met the very recently purposed research criteria for bvAD [9]; 3) with available CSF-AD biomarkers, allowing for in vivo evidence of AD pathology; 4) patients who presented with some degree of frontal atrophy on computerized tomography (CT) scan, and/or magnetic resonance imaging (MRI). The following exclusion criteria were considered: 1) sudden onset; unstable clinical syndrome, with significant comorbidities, such as major depression or other psychiatric diagnosis, cerebrovascular disease, toxic, inflammatory or metabolic disorders; 2) significant motor, visual, or auditory deficits, all of which may affect NP assessment. This study was approved by the local Ethics Committee (CE-029/2019) on June 24, 2019; and was conducted according to the Declaration of Helsinki and Good Clinical Practice guidelines. Informed consent was given by all study participants or their legal next of kin.

NP assessment

The baseline NP evaluation was performed at mild disease stages (Clinical Dementia Rating global score (CDR) ≤1 in all cases) and encompassed the following instruments: Mini-Mental State Examination (MMSE) [12], Montreal Cognitive Assessment (MoCA) [13], the Battery of Lisbon for the Assessment of Dementia [14], and the Trail Making Test (A and B) [15]. This battery includes some tests of the Wechsler Memory Scale (WMS) [16] and assesses the following cognitive abilities: attention (Cancellation Task); verbal initiative (Semantic Fluency), motor and graphomotor initiatives; verbal comprehension (Token Test); verbal and non-verbal reasoning (Interpretation of Proverbs and the Raven’s Colored Progressive Matrices – AB series); orientation (personal, spatial, and temporal orientation); visuo-constructional abilities (copy of a house and a flower); basic written and mental calculus; immediate memory (Digit Span Forward); semantic memory (WAIS Information test; 16), episodic visual memory (WMS Visual Reproduction Test); working memory (Digit Span Backward); learning and episodic verbal memory (WMS Verbal Paired-Associate Learning, Logical Memory and Word Recall). For the Logical Memory we also considered the Forgetting Index [17]. It is a more comprehensive measure of episodic verbal memory impairment which encompasses both immediate and delayed recall test results, being calculated by the following formula: Forgetting Index = [(LM delayed recall – LM immediate)/LM immediate)]*100. All tests were administered and scored according to standardized procedures. Individual test scores were converted into z-scores. The presence of impairment is considered when z-score< – 1. We assessed individual test scores and different patterns of deficits. It is well known that episodic memory and visuo-spatial abilities play an important role in the distinguishing between FTD and AD. As such, we classified patients according to their patterns of episodic verbal and visual memory and copy-drawing abilities. When assessing episodic memory, four patterns of impairment related to the underlying mechanisms of learning, encoding and retrieval were considered: 1) normal, 2) neocortical, with prominent learning/encoding deficits, without lack of material in delayed recall tasks, 3) hippocampal, where normal performances in immediate recall or learning tasks can be found, but consolidation/retrieval deficits are always the most salient feature supported by lower results on the Forgetting Index, and 4) mixed, where both neocortical and hippocampal dysfunction is present. Regarding visuo-constructional abilities, four patterns were observed: 1) normal, 2) frontal - with perseveration, lack of planning and inattention being the more frequent features, 3) parietal - a pattern of primary visuo-spatial deficits presenting with lack of elements and neglect, closing in and gestalt changes, or 4) mixed - a pattern that includes features of both types [18].

FTD mutation analysis

Prior to mutation analysis in FTD-related genes, progranulin (GRN) serum levels were determined in all FTD patients and cases with values below laboratory reference values underwent GRN mutation analysis [19]. All FTD patients were studied for the presence of C9orf72 hexanucleotide repeats and mutations in MAPT gene [20].

Cerebrospinal fluid biomarkers

CSF samples were collected as part of their routine clinical diagnosis investigation, in the absence of a contraindication for lumbar puncture. Pre-analytical and analytical procedures were done in accordance with the Alzheimer’s Association guidelines for CSF biomarker determination [21]. CSF Aβ₄₂, Aβ₄₀, t-Tau, and p-Tau181 were measured sequentially in a clinical routine setting by commercially available immunoassays. For samples collected between January 2016 and December 2018, these markers were determined separately, in duplicate, by commercially available sandwich ELISA kits (Innotest, Innogenetics/Fujirebio, Ghent, Belgium), as previously described [21]. Since January 2019, CSF biomarkers were determined in the fully automated chemiluminescence enzyme immunoassay platform LUMIPULSE G600II (Fujirebio, Ghent, Belgium) [22]. External quality control of the assays was performed under the scope of the Alzheimer’s Association Quality Control Program for CSF Biomarkers [23]. Patients were classified according to the most recent Amyloid/Tau/Neurodegeneration (A/T/N) system [24]. Individuals were rated for the presence of evidence of brain amyloid pathology – A (using the CSF Aβ42/Aβ₄₀ ratio), tauopathy - T (CSF p-Tau181), and neurodegeneration – N (CSF tTau), using previously determined reference values [21, 22]. Specifically, for samples analyzed by Innotest, Aβ₄₂/Aβ₄₀ ratio ≤0.068 was required for a positive classification (A+); p-Tau181 ≥38.0 pg/mL was classified as T+; and t-Tau ≥244 pg/mL was classified as N+. For samples analyzed by Lumipulse, Aβ₄₂/Aβ₄₀ ratio ≤0.068 was classified as A+; p-Tau181 ≥50.6 pg/mL was classified as T+; and t-Tau ≥335 pg/mL was classified as N+. Those that fell in the AD-continuum categories (A+T– N–; A+T+N–; A+T– N+; A+T+N+) were considered fvAD, while patients presenting normal (A– T– N–) or non-AD pathological changes (A– T– N+; A– T+N–; A– T+N+) categories were considered bvFTD.

Statistical analysis

Normal data distribution was assessed through Kolmogorov-Smirnov normality test. In cases without normal distribution (education, CSF biomarkers, naming, repetition, visual memory, and word recall) group comparisons were performed through Mann-Whitney test analysis. Other sociodemographic and neuropsychological tests were compared through Student’s T-test. Pearson’s chi-square test was used for group comparisons of nominal data. All tests were two-tailed and a p-value <0.05 was assumed to be statistically significant. The NP results were analyzed according to age and education based on the normative scores for the Portuguese population [13 –16] and z-scores were further calculated. All statistical analyses were performed using IBM SPSS Statistics 25 for Windows (IBM Corp, Armonk, NY, USA) package.

RESULTS

Sample description and overview

We selected 40 patients that met the inclusion/exclusion criteria defined, namely a cognitive and/or psychiatric profile compatible with both probable fvAD-dementia and probable bvFTD. Regarding the whole sample, all patients underwent a CT scan, and 23 (57.5%) performed an MRI. Based in CSF biomarker data, 21 (52.5%) patients had in vivo evidence of AD pathology, and were therefore classified as fvAD-dementia, while the remaining 19 (47.5%) were classified as bvFTD. Concerning genetic testing, one patient carried a GRN associated mutation (c.900_901dupGT p.Ser301Cysfs*61). General clinical and demographic characteristics of the study groups are presented in Table 1. Student’s T-test showed no differences regarding age at onset, age at baseline assessment, and gender. Mann-Whitney test analysis showed no differences regarding education. A significant higher percentage of APOE ɛ4 carriers was found in fvAD-dementia while bvFTD presented with a higher percentage of positive familial history of dementia.

Table 1

Demographic and clinical characteristics of fvAD-dementia and bvFTD patients

	fvAD-dementia (n = 21)	bvFTD (n = 19)	p
Age at onset (y)	61.95 (7.88)	61.37 (8.40)	0.957
Age at baseline (y)	64.57 (7.66)	63.79 (9.00)	1.000
Education (y)	7.43 (4.90)	7.89 (5.14)	0.649
Gender (M/F, n)	11/10	10/9	0.987
Familial history of dementia	5 (23.8)	8 (42.1)	<0.001^*
APOE (% E4)	13 (61.9)	4 (21.1)	0.009^*
Aβ₄₂ (pg/ml)	553 (179)	872 (267)	<0.001^*
Tau (pg/ml)	687 (488)	274 (174)	<0.001^*
p-tau (pg/ml)	98.9 (66.2)	45.9 (43.9)	<0.001^*
Aβ_42/40 (pg/ml)	0.045 (0.014)	0.113 (0.063)	<0.001^*

Data is presented as mean±standard deviation or total n + percentage (%). bvFTD, behavioral variant frontotemporal dementia; fvAD-dementia, frontal-variant of Alzheimer’s disease; y, years.

Neuropsychological comparison between fvAD-dementia and bvFTD

All patients were in mild disease stages: AD group (mean MMSE = 23.52; mean MoCA = 14.82; mean CDR total score = 1; mean CDR SB score = 4,5) and FTD group (mean MMSE = 24.21; mean MoCA = 15.10; mean CDR total score = 1; mean CDR SB score = 5 - data not shown), considering the normative data for the Portuguese population. As a first analysis, we found that there were no differences between groups regarding cognitive screening measures (MMSE: p = 0.377; and MoCA: p = 0.286; Table 2). Regarding the comprehensive NP assessment (Table 2), no differences were found in any language component, namely, verbal comprehension, naming, repetition, reading, and writing. In what concerns to memory, no differences were found in tests of immediate, semantic, or episodic (verbal or visual) memory. Significant differences were found in attention/processing speed, specifically in Trail Making Test (form A) (p < 0.001), and abstract visual reasoning – Raven Colored Progressive Matrices (RPCM) (AB series) (p = 0.019), with fvAD having worst performances than bvFTD patients. bvFTD patients also had significant better performances in visuo-constructional abilities (p = 0.004). We considered more extensively the domains of episodic memory and visuo-constructional abilities, according to their qualitative patterns of verbal memory and copy-drawing. There were no differences on the specific patterns of episodic verbal memory impairment: fvAD - normal (1 patient, 5%), hippocampal (3 patients, 15%), neocortical (7 patients, 35%), mixed (9 patients, 45%); bvFTD - normal (1 patient, 5.3%), hippocampal (7 patients, 36.8%), neocortical (4 patients, 21.1%), mixed (7 patients, 36.8%) (all p > 0.05, Fig. 1). Regarding visuo-constructional abilities, in fvAD we observed a predominant normal (8 patients, 38.1%) or parietal (9 patients, 42.9%) dysfunction, with a very slight percentage of patients showing a mixed pattern (1 patient, 4.8%) or isolated typical frontal features (3 patients, 14.3%). In bvFTD, however, there is a balance between normal (6 patients, 33.3%), frontal (7 patients, 38.9%), or mixed (fronto-parietal; 5 patients, 27.8%) performances in the absence of a parietal dysfunction alone (Fig. 2; p = 0.003).

Table 2

Standardized neuropsychological test scores for the two groups

fvAD-dementia (n = 21)	bvFTD (n = 19)	p
MMSE	– 5.59±3.90	– 4.44±3.60	0.377
MoCA	– 3.95±1.59	– 2.82±1.30	0.276
•Attention and executive functions
Cancellation task	– 0.89±1.06	– 0.78±0.98	0.698
Digit Span	– 0.92±1.35	– 0.20±2.03	0.092
Trail Making Test A	– 3.40±4.37	– 2.34±1.83	<0.001
Trail Making Test B	– 4.77±3.09	– 1.56±3.32	0.481
•Initiative
Semantic fluency	– 2.49±1.40	– 3.01±1.33	0.353
Motor initiative	– 3.42±3.49	– 2.58±3.36	0.507
Graphomotor initiative	– 0.82±1.83	– 0.72±1.41	0.231
•Reasoning
Proverbs	– 1.32±3.05	– 2.27±2.13	0.256
RCPM (AB series)	– 2.26±1.94	– 1.60±1.43	0.019
•Language
Naming	– 1.27±1.36	– 1.40±1.29	0.728
Repetition	– 0.11±0.14	– 0.01±0.02	0.076
Token Test	– 0.86±1.05	– 0.40±0.78	0.341
•Memory and learning
Word recall	– 3.01±1.53	– 2.15±1.49	0.232
Semantic memory	– 2.99±3.38	– 3.56±3.02	0.503
Verbal Paired-Associate Learning (IR)	– 2.49±1.20	– 2.35±1.38	0.478
Logical Memory (IR)	– 2.48±1.25	– 2.35±1.31	0.935
Visual Memory (IR)	– 0.42±1.57	– 0.44±1.15	0.696
Logical Memory (DR)	– 2.53±0.95	– 2.40±1.04	0.846
Forgetting Index ⁽¹⁾	– 2.23±0.57	– 2.68±1.59	0.858
•Calculation
Basic Written Calculus	– 1.21±1.64	– 0.96±1.53	0.620
•Visuo-constructional abilities
Copy task (flower + house)	– 1.11±1.48	– 0.78±1.10	0.004
•Orientation
Personal, temporal and spatial orientation	– 0.37±1.07	– 0.44±1.04	0.908

Data of variables is presented as mean±standard deviation. bvFTD, behavioral-variant frontotemporal dementia; fvAD, frontal-variant Alzheimer’s disease; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; RCPM, Raven’s Colored Progressive Matrices; IR, Immediate Recall; DR, Delayed Recall.⁽¹⁾ Forgetting Index = [(LM delayed recall – LM immediate)/LM immediate)]*100 Note: Statistically significant differences between the groups are presented in bold.

Fig. 1

Radar chart of episodic verbal memory patterns in fvAD and bvFTD patients. The dark lines represent the frequency of each profile (normal, neocortical, hippocampal, mixed) in the patients’ group (filled line – bvFTD; dotted line – fvAD). The grey lines represent the observed frequency from 1 (center line) to 9 (outer line).

Fig. 2

Radar chart of visuo-constructive abilities patterns in fvAD and bvFTD patients. The dark lines represent the frequency of each profile (normal, parietal, frontal, mixed) in the patients’ group (filled line – bvFTD; dotted line– fvAD). The grey lines represent the observed frequency from 1 (center line) to 9 (outer line).

DISCUSSION

The existence of fvAD-dementia as an independent variant has already been acknowledged in the international diagnostic criteria for AD dementia [5, 6]. We describe the NP profile of 40 patients with a baseline assessment with prominent early executive and/or behavioral dysfunction, overlapping between bvFTD and fvAD-dementia according to international criteria. During this year some authors purposed a further split of fvAD into a dysexecutive and a behavioral variant, but this distinction and research criteria are still in debate [7, 9]. The use of surrogate pathology biomarkers was applied to categorize this cohort, since in early stages of fvAD, paradoxically, the most prevalent atrophy or hypometabolism rates tend to primarily focus on typical AD regions, including the posterior cingulate, the precuneus, and the medial temporal lobe [9, 25]. The frontal involvement is variable, being in an intermediate state between bvFTD and typical amnestic AD [24, 25]. Based on CSF biomarker data, 21 (52.5%) patients had in vivo evidence of AD pathology, and were therefore classified as fvAD-dementia, while the remaining 19 (47.5%) were classified as bvFTD, which reveals a higher prevalence than the illustrated by the 10– 40% of patients clinically diagnosed with bvFTD who are found to have a positive amyloid-PET [26, 27]. This may suggest that CSF biomarkers likely add to accuracy in the detection of the pathology associated with this neurocognitive disorder. Regarding age at onset (61 years), gender and educational level, cohorts were equivalent, corroborating that fvAD shares the same demographic phenotype of bvFTD, presenting at a young age and with a higher prevalence in man. Considering genetic variables, we found more APOE ɛ4 carriers in fvAD-dementia while bvFTD presented with a higher percentage of positive familial history of dementia, both with statistically significant differences [28, 29]. Our main aim was to explore which tests and cognitive domains are capable of distinguish between milder forms of fvAD-dementia and bvFTD, using a comprehensive NP battery. Prior studies have already looked for potential cognitive distinctive features. Some of them are based in case reports [4 , 31] or casuistic studies, both with inconsistencies regarding asymmetrical involvement in cognitive domains. This may be explained by small sample sizes, different diagnostic criteria [9, 32] or may reflect a lack of cooperation of this particular population of patients with testing procedures [11]. We found measurable group differences between fvAD-dementia and bvFTD on standardized NP measures, corroborating the utility of a comprehensive NP evaluation on the identification of early potential distinctive features. Regarding executive functions, our results show a more severe pattern of frontal impairment in some specific tasks for fvAD-dementia patients, namely a higher impairment in TMT-A and RCPM AB series, both related to the right fronto-parietal cortex, when compared to bvFTD patients. Previous studies have already described the ability of TMT-A in assessing attention, visual scanning, and information processing [16], and associated the deficits in this particular task with functional activity in right superior parietal lobe, since it depends on visual functions [33]. Other studies also reported that in AD-dementia, the deterioration of specific brain regions is associated with dysfunction of visual perception and reasoning ability as assessed by RPCM AB series. They found a significant positive correlation between RCPM AB series and regional cerebral blood flow in right temporal, right parietal, and right frontal lobes in AD spectrum disorders [34]. Performances in motor, psychomotor, and flexibility tasks, as well as verbal working memory, verbal initiative, and verbal abstract reasoning were equivalent between groups. These results are in agreement with a previous study which described that executive performance was task-dependent: fvAD patients performed worse in Trails and Stroop and were similar to bvFTD patients in D-words and rule violations in design fluency task [25]. A recent meta-analysis shows that fvAD-dementia executive function was comparable to bvFTD and worse than typical amnestic-AD [9], as such, our results are reasonably consistent with this. Concerning visuospatial abilities, bvFTD patients had significant better results than fvAD-dementia, showing a balance between normal, frontal, or mixed (fronto-parietal) deficits in the absence of a parietal dysfunction alone. In contrast, in fvAD-dementia, we observed a predominant normal or parietal dysfunction, with a very slight percentage of patients showing a mixed pattern or isolated typical frontal features. A recent neuroimaging study supported the potential role of degeneration in more posterior cortical areas as an anatomical helpful sign to distinguish fvAD-dementia from bvFTD [35], which is consistent with our findings of greater visuo-constructional deficits in this variant. Another recent work described that fvAD-dementia is associated with parieto-frontal atrophy with relatively sparing of medial temporal regions when compared with typical AD phenotypes with FDG-PET scans showing frontal and parietal hypometabolism [3, 9]. The study of visuoconstructive patterns was also already conducted for some AD variants with neuropathological confirmation and correlation. The authors [36], intended to distinguish between AD-Corticobasal syndrome (CBS) versus CBS-nonAD patients using the Visual Object and Space Perception Battery (VOSP) to assess visuoconstructive patterns related to parietal lobes. The results showed a significant accuracy for all VOSP spatial subtests, with Cube Analysis achieving a sensitivity of 100% and specificity of 77%. The sensitivity, specificity, and odd ratios for the VOSP subtests exceeded those of other neuropsychological subtests including memory. Another study [37], with pathologically confirmed AD versus AD with Lewy body disease (LBD) indicated that of the three neuropsychological measures that were able to distinguish the two groups, the pentagon copy was the most sensitive to comorbid LBD pathology, correctly classifying 73% of this specific group. In 2018, other group [38], also investigated the relationship between visuospatial functions and lobar cortical thickness using Freesurfer analysis. The performance on constructional tests, especially in Block Design, was the best predictor of cortical thickness in the right parietal lobe.

When we looked for differences in memory, we found no differences, as expected, in immediate and semantic memory. Regarding episodic verbal and visual memory, there were also no differences in the patterns of impairment related to the underlying mechanisms of learning, encoding and retrieval, with low performances in both groups and high percentages of mixed deficits (both neocortical and hippocampal dysfunction). One possible explanation for the similarities between bvFTD and fvAD-dementia is the disruption of attentional and executive control processes leading to difficulties in encoding mechanisms [35]. Three past studies also found no differences between fvAD-dementia and bvFTD when assessing verbal episodic memory [25 , 39].

In terms of language, there was no distinctive pattern of dysfunction between groups. This was not unexpected since FTD-related aphasic variants as well as AD-logopenic variants were not included in our sample and is also consistent with a recent study where no differences were observed between fvAD-dementia and bvFTD or amnestic-AD [37]. Recently purposed research criteria for the fvAD-dementia also highlight that this clinical entity is characterized by an impairment in executive functions and/or episodic memory with relatively spared language abilities [9]. Temporal, spatial, and personal orientation were also assessed; however, no differences between groups were found. This may be due to patient’s disease stage at baseline assessment. As previously described, patients were assessed at the beginning/initial disease stages, where some issues with temporal orientation emerge in both groups, but fvAD-dementia patients are mostly still oriented in space. Studies comparing fvAD-dementia with bvFTD are typically targeted to memory, visuospatial, executive, and language domains so differences in orientation domain are not usually mentioned [31, 45]. Also, studies comparing bvFTD with typical AD patients showed contrasting results, and while some authors found a clear distinct pattern with AD patients presenting more impaired results [40], others found no differences between groups [41]. Our results are in accordance with previous findings suggesting that specific domains in NP evaluation can help to differentiate fvAD-dementia and bvFTD in their early stages but provide further support through a CSF biomarker-based diagnosis. However, our study has some limitations. First, our sample size is relatively small and from one single center, as the associations found need to be verified in a larger cohort. This is a challenge that previous studies have already faced, since only a small percentage of patients with a probable diagnosis of bvFTD ultimately have AD surrogates of pathology [42]. Second, social cognition measures were not performed in all study participants (including facial emotion recognition and theory of mind), so the results were not included in group comparisons. This is an important limitation. Third, the diagnoses were defined under clinical basis, without pathological confirmation, even though this limit is common to most of the studies in the field. Although these limitations may reduce generalizability, the highly homogeneous and extensive clinical characterization of the groups in early disease stages reduces the effect of confounding variables and allows the study of peculiar characteristics which help the distinguishing between groups. In addition, as the evaluation is standardized and done before the lumbar puncture procedure, both clinicians and neuropsychologist were blinded for allocation group, preventing possible interpretation biases. In patients with an early prominent frontal profile, a higher impairment in attention and visuo-spatial functions, signaling additional right hemisphere fronto-parietal dysfunction, point towards a diagnosis of fvAD-dementia. We are aware that there are still very large discrepancies between centers and countries regarding the access to both CSF biomarkers and Neuropsychological evaluation. Although in some reference centers CSF biomarkers are routinely used in dementia differential diagnosis, this is not the case for all European countries [43, 44]. Therefore, we believe that neuropsychological assessment is still useful in clinical practice as diagnostic support when biomarkers are not readily available.

Footnotes

ACKNOWLEDGMENTS

The author’s wish to thank all patients and their caregivers that participated in the study.

FUNDING

ML was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/144001/2019). The funding agency had no role in the study design, sample collection, data analysis or the writing of the manuscript.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

Englund

, Brun

, Gustafson

, Passant

, Mann

, Neary

, Snowden

(1994) Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57, 416–418.

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.

Ossenkoppele

, Pijnenburg

, Perry

, Cohn-Sheehy

, Scheltens

, Vogel

, Rabinovici

(2015) The behavioural/dysexecutive variant of Alzheimer’s disease: Clinical, neuroimaging and pathological features. Brain 138, 2732–2749.

Sawyer

, Rodriguez-Porcel

, Hagen

, Shatz

, Espay

(2017) Diagnosing the frontal variant of Alzheimer’s disease: A clinician’s yellow brick road. J Mov Disord 4, 1–9.

McKhann

, Knopman

, Chertkow

, Hyman

, Jack

Jr , Kawas

, 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.

Dubois

, Feldman

, Jacova

, Hampel

, Molinuevo

, Blennow

, Cummings

(2014) Advancing research diagnostic criteria for Alzheimer’s disease: The IWG-2 criteria. Lancet Neurol 13, 614–629.

Townley

, Graff-Radford

, Mantyh

, Botha

, Polsinelli

, Przybelski

, Machulda

, Makhlouf

, Senjem

, Murray

, Reichard

, Savica

, Boeve

, Drubach

, Josephs

, Knopman

, Lowe

, Jack

Jr , Petersen , Jones

(2020) Progressive dysexecutive syndrome due to Alzheimer’s disease: A description of 55 cases and comparison to other phenotypes. Brain Commun 2, fcaa068.

Polsinelli

, Apostolova

(2022) Atypical Alzheimer disease variants. Continuum (Minneap Minn) 28, 676–701.

Ossenkoppele

, Singleton

, Groot

, Dijkstra

, Eikelboom

, Seeley

, Pijnenburg

(2021) Research criteria for the behavioral variant of Alzheimer disease: A systematic review and meta-analysis. JAMA Neurol 79, 48–60.

10.

Brier

, Gordon

, Friedrichsen

, McCarthy

, Stern

, Christensen

, Owen

, Aldea

, Su

, Hassenstab

, Cairns

(2016) Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med 11, 338338ra66.

11.

Ranasinghe

, Rankin

, Lobach

, Kramer

, Sturm

, Bettcher

, Miller

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

12.

Freitas

, Simões

, Alves

, Santana

(2015) The relevance of sociodemographic and health variables on MMSE normative data. Appl Neuropsychol Adult 22, 311–319.

13.

Freitas

, Simões

, Alves

, Santana

(2011) Montreal Cognitive Assessment (MoCA): Normative study for the Portuguese population. J Clin Exp Neuropsychol 33, 989–996.

14.

Guerreiro

(1998) Contributo da neuropsicologia para o estudo das demências. Dissertação de doutoramento, Universidade de Lisboa, Faculdade de Medicina de Lisboa, Ciências Biomédicas. Unpublished doctoral thesis.

15.

Cavaco

, Gonçcalves

, Pinto

, Almeida

, Gomes

, Moreira

, Teixeira-Pinto

(2013) Trail Making Test: Regression-based norms for the Portuguese population. Arch Clin Neuropsychol 28, 189–198.

16.

Wechsler

(2008) WAIS-III: Manual da Escala de Inteligência de Wechsler para Adultos – 3^a Edição. Lisboa: CEGOC-TEA [Hogrefe].

17.

Silva

, Cardoso

, Guerreiro

, Maroco

, Mendes

, Alves

, Nogueira

, Baldeiras

, Santana

, de Mendonça

(2020) Neuropsychological contribution to predict conversion to dementia in patients with mild cognitive impairment due to Alzheimer’s disease. J Alzheimers Dis 74, 785–796.

18.

Lezak

, Howieson

, Loring

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

19.

Almeida

, Baldeiras

, Ribeiro

, Santiago

, Machado

, Massano

, Guimarães

, Resende Oliveira

, Santana

(2014) Progranulin peripheral levels as a screening tool for the identification of subjects with progranulin mutations in a Portuguese cohort. Neurodegener Dis 13, 214–223.

20.

Almeida

, Letra

, Pires

, Santos

, Rebelo

, Guerreiro

, Van der Zee

, Van Broeckhoven

, Santana

(2016) Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide (G₄C₂) repeat expansion in C9orf72 gene. Neurobiol Aging 40,191.e1–e191.

21.

Baldeiras

, Santana

, Leitão

, Gens

, Pascoal

, Tábuas-Pereira

, Beato-Coelho

, Duro

, Almeida

, Oliveira

(2018) Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment. Alzheimers Res Ther 10, 33.

22.

Leitão

, Silva-Spínola

, Santana

, Olmedo

, Nadal

, Le Bastard

, Baldeiras

(2019) Clinical validation of the Lumipulse G cerebrospinal fluid assays for routine diagnosis of Alzheimer’s disease. Alzheimers Res Therapy 11, 91.

23.

Mattsson

, Andreasson

, Persson

, Arai

, Batish

, Bernardini

, Bocchio-Chiavetto

, Blankenstein

, Carrillo

, Chalbot

, Coart

, Chiasserini

, Cutler

, Dahlfors

, Duller

, Fagan

, Forlenza

, Frisoni

, Galasko

, Galimberti

, Hampel

, Handberg

, Heneka

, Herskovits

, Herukka

, Holtzman

, Humpel

, Hyman

, Iqbal

, Jucker

, Kaeser

, Kaiser

, Kapaki

, Kidd

, Klivenyi

, Knudsen

, Kummer

, Lui

, LladÓ

, Lewczuk

, Li

, Martins

, Masters

, McAuliffe

, Mercken

, Moghekar

, Molinuevo

, Montine

, Nowatzke

, O’Brien

, Otto

, Paraskevas

, Parnetti

, Petersen

, Prvulovic

, de Reus

, Rissman

, Scarpini

, Stefani

, Soininen

, Schröder

, Shaw

, Skinningsrud

, Skrogstad

, Spreer

, Talib

, Teunissen

, Trojanowski

, Tumani

, Umek

, Van Broeck

, Vanderstichele

, Vecsei

, Verbeek

, Windisch

, Zhang

, Zetterberg

, Blennow

(2011) The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement 7, 386–395.

24.

Jack Jr CR , Bennett

, Blennow

, Carrillo

, Dunn

, Haeberlein

, Holtzman

, Jagust

, Jessen

, Karlawish

, Liu

, Molinuevo

, Montine

, Phelps

, Rankin

, Rowe

, Scheltens

, Siemers

, Snyder

, Sperling

(2018) NIA-AA research framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14, 535–562.

25.

Perry

, Brown

, Possin

, Datta

, Trujillo

, Radke

, Karydas

, Kornak

, Sias

, Rabinovici

, Gorno-Tempini

, Boxer

, De May

, Rankin

, Sturm

, Lee

, Matthews

, Kao

, Vossel

, Tartaglia

, Miller

, Seo

, Sidhu

, Gaus

, Nana

, Vargas

JNS

, Hwang

, Ossenkoppele

, Brown

, Huang

, Coppola

, Rosen

, Geschwind

, Trojanowski

, Grinberg

, Kramer

, Miller

, Seeley

(2017) Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain 140, 3329–3345.

26.

, Fan

, Chen

, Chiu

, Yen

, Lin

(2020) Frontal variant of Alzheimer’s disease with asymmetric presentation mimicking frontotemporal dementia: Case report and literature review. Brain Behav 10, e01548.

27.

Rabinovici

, Rosen

, Alkalay

, Kornak

, Furst

, Agarwal

, Mormino

, O’Neil

, Janabi

, Karydas

, Growdon

, Jang

, Huang

, De Armond

, Trojanowski

, Grinberg

, Gorno-Tempini

, Seeley

, Miller

, Jagust

(2011) Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology 77, 2034–2042.

28.

Mattsson

, Groot

, Jansen

, Landau

, Villemagne

, Engelborghs

, Mintun

, Lleo

, Molinuevo

, Jagust

, Frisoni

(2018) Prevalence of the apolipoprotein E ɛ4 allele in amyloid β positive subjects across the spectrum of Alzheimer’s disease. Alzheimers Dement 14, 913–924.

29.

Koriath

, Lashley

, Taylor

, Druyeh

, Dimitriadis

, Denning

, Koriatha

, Lashleyb

, Taylor

, Druyeh

, Dimitriadis

, Denning

, William

, Warren

, Fox

, Schott

, Rowe

, Collingea

, Rohrer

, Mead

(2019) ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid-β copathology. Alzheimers Dement (Amst) 11, 277–280.

30.

Wong

, Bertoux

, Savage

, Hodges

, Piguet

, Hornberger

(2016) Comparison of prefrontal atrophy and episodic memory performance in dysexecutive Alzheimer’s disease and behavioral-variant frontotemporal dementia. J Alzheimers Dis 51, 889–903.

31.

Bergeron

, Sellami

, Poulin

, Verret

, Bouchard

, Laforce

Jr (2020) The behavioral/dysexecutive variant of Alzheimer’s disease: A case series with clinical, neuropsychological, and FDG-PET characterization. Dement Geriatr Cogn Disord 49, 518–525.

32.

Giovagnoli

, Erbetta

, Reati

, Bugiani

(2008) Differential neuropsychological patterns of frontal variant frontotemporal dementia and Alzheimer’s disease in a study of diagnostic concordance. Neuropsychologia 46, 1495–1504.

33.

Shindo

, Terada

, Sato

, Ikeda

, Nagao

, Oshima

, Yokota

, Uchitomi

(2013) Trail making test part A and brain perfusion imaging in mild Alzheimer’s disease. Dement Geriatr Cogn Disord 3, 202–211.

34.

Yoshida

, Mori

, Shimizu

, Yoshino

, Sonobe

, Matsumoto

, Kikuchi

, Miyagawa

, Iga

, Mochizuki

, Ueno

(2017) Neural basis of visual perception and reasoning ability in Alzheimer’s disease: Correlation between Raven’s Colored Progressive Matrices test and 123I-IMP SPECT imaging results. Int J Geriatr Psychiatry 32, 407–413.

35.

Perez

, Phillips

, Norise

, Kinney

, Vaddi

, Halpin

, Rascovsky

, Irwin

, McMillan

, Xie

, Wisse

LEM

, Yushkevish

, Kallogjeri

, Grossman

, Cousins

(2022) Neuropsychological and neuroanatomical features of patients with behavioral/dysexecutive variant Alzheimer’s disease (AD): A comparison to behavioral variant frontotemporal dementia and amnestic AD groups. J Alzheimers Dis 89, 641–658.

36.

Boyd

, Tierney

, Wassermann

, Spina

, Oblak

, Ghetti

, Grafman

, Huey

(2014) Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome. Neurology 83, 510–519.

37.

Zink

, Miller

, Caldwell

, Bird

, Banks

(2018) The relationship between neuropsychological tests of visuospatial function and lobar cortical thickness. J Clin Exp Neuropsychol 40, 518–527.

38.

Azar

, Chapman

, Gu

, Leverenz

, Stern

, Cosentino

(2020) Cognitive tests aid in clinical differentiation of Alzheimer’s disease versus Alzheimer’s disease with Lewy body disease: Evidence from a pathological study. Alzheimers Dement 16, 1173–1181.

39.

Mendez

, Joshi

, Tassniyom

, Teng

, Shapira

(2013) Clinicopathologic differences among patients with behavioral variant frontotemporal dementia. Neurology 80, 561–568.

40.

Yew

, Alladi

, Shailaja

, Hodges

, Hornberger

(2013) Lost and forgotten? Orientation versus memory in Alzheimer’s disease and frontotemporal dementia. J Alzheimers Dis 33, 473–481.

41.

Ramanan

, Bertoux

, Flanagan

, Irish

, Piguet

, Hodges

, Hornberger

(2017) Longitudinal executive function and episodic memory profiles in behavioral-variant frontotemporal dementia and Alzheimer’s disease. J Int Neuropsychol Soc 23, 34–43.

42.

Blennerhassett

, Lillo

, Halliday

, Hodges

, Kril

(2014) Distribution of pathology in frontal variant Alzheimer’s disease. J Alzheimers Dis 39, 63–70.

43.

Bocchetta

, Galluzzi

, Kehoe

, Aguera

, Bernabei

, Bullock

, Ceccaldi

, Dartigues

, De Mendonça

, Didic M & Eriksdotter

(2015) The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey. Alzheimers Dement 11, 195–206.

44.

Frederiksen

, Nielsen

, Appollonio

, Andersen

, Riverol

, Boada

, Ceccaldi

, Dubois

, Engelborghs

, Frölich

, Hausner

(2021) Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer’s disease consortium survey. Int J Geriatr Psychiatry 36, 324–333.