INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Int J Geriatr Psychiatry 2002; 17: 641–648. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/gps.654
Do visuospatial and constructional disturbances differentiate frontal variant of frontotemporal dementia and Alzheimer’s disease? An experimental study of a clinical belief Dario Grossi1, Nina Antonetta Fragassi2, Laura Chiacchio2, Luigi Valoroso3, Rosaria Tuccillo3, Concetta Perrotta3, Paola Rapone3, Giovanna Conchiglia4 and Luigi Trojano5* 1
Department of Psychology, Second University of Naples, Italy Department of Neurological Sciences, Federico II University, Naples, Italy 3 Department of Neurosciences and Communication, Federico II University, Naples, Italy 4 Clinical Institute Alma Mater—Villa Camaldoli, Naples, Italy 5 Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese (BN), Italy 2
SUMMARY Background In recent years several attempts have been made to distinguish frontotemporal dementia (FTD) from Alzheimer’s disease (AD) on neuropsychological grounds; in particular, it has been suggested that FTD patients show spared spatial abilities with respect to AD patients. Objective We aimed at verifying whether patients with the frontal variant of frontotemporal dementia (fv-FTD) and AD patients perform differently on visuospatial and constructional tasks. Methods We assessed a wide range of visuospatial abilities and provided a qualitative analysis of constructional performances in 14 fv-FTD patients and 11 AD patients, matched for general cognitive abilities. Results The two groups of patients achieved similar scores on two copying tasks, presented similar drawing procedures in copying Rey complex figure and made a similar quantitative and qualitative pattern of errors in copying simple geometrical drawings. Moreover, no significant difference was found between fv-FTD and AD patients on a specific battery for visuospatial abilities. Conclusions Our data and a review of the literature suggest that basic visuospatial and constructional skills cannot be taken as a reliable diagnostic criterion for distinguishing fv-FTD and AD at a mild to moderate disease stage and that the clinical belief of spared spatial abilities in fv-FTD has to be referred to the lack of topographic disorientation in comparison to AD. Copyright # 2002 John Wiley & Sons, Ltd. key words — Frontal variant; frontotemporal dementia; Alzheimer’s disease; visuospatial skills; constructional skills
INTRODUCTION Frontotemporal dementia (FTD) is a degenerative disorder with early behavioral and language disturbances and with relative preservation of memory and visuospatial abilities (Cummings and Benson, 1983). Diagnostic criteria for FTD have been established via the
* Correspondence to: L. Trojano, Fondazione Maugeri, Istituto di Telese, IRCCS, Via Bagni Vecchi, 82037 Telese (BN), Italy. Tel: þ39 0824 909 111. Fax: þ39 0824 909 614. E-mail:
[email protected] Copyright # 2002 John Wiley & Sons, Ltd.
cooperative effort of Lund and Manchester research groups (1994), and subsequently refined (Neary et al., 1998). In recent years it has been suggested that two forms of FTD can be distinguished on the basis of behavioral and cognitive features, the temporal variant (tv-FTD) and the frontal variant (fv-FTD) (Hodges et al., 1999; Perry and Hodges, 2000). The former would be characterized by prominent language and semantic impairments (Hodges et al., 1992; Edwards-Lee et al., 1997), the latter by early psychiatric disorders and a defect in executive functions (Rahman et al., 1999; Gregory, 1999). Received 11 October 2001 Accepted 12 February 2002
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Table 1. Summary of papers comparing FTD and AD patients on visuospatial tasks First author (year)
No. of patients
Visuospatial tasks
FTD’s performances
Kumar (1990) Starkstein (1994) Mendez (1996) Frisoni (1996) Pachana (1996) Miller (1997) Hodges (1999)
Razani (2001)
11 right FTD, 11 left FTD, 16 AD
W.A.I.S. Copying drawing, block design Copying drawing Rey figure copy Rey figure copy Copying drawing Rey figure copy, Benton line orientation Rey figure copy, shape detection and position discrimination Rey figure copy, Visual Motor Integration
Similar to AD Similar to AD Better than AD Similar to mild AD Similar to AD Better than AD Similar to AD
Perry (2000)
3 FTD, AD 8 FTD, 8AD 39 FTD, 101 AD 14 FTD, 33 mild AD, 13 moderate AD 15 FTD, 16 AD 30 FTD, 30 AD 9 fv-FTD, 9 tv-FTD, 9 AD 10 fv-FTD, 5 tv-FTD, 10 AD
The effort at identifying more homogenous clinical forms of FTD has aimed to provide stringent diagnostic criteria to disentangle the different variants of nonAlzheimer degenerative dementias among each other and from AD itself. The relative preservation of visuospatial abilities is enlisted among cardinal features of FTD, and, together with relative sparing of memory, should allow to distinguish FTD from AD patients (Neary et al., 1998). However, no systematic in-depth study is available that explores visuospatial abilities in FTD. Moreover, the studies that have directly compared visuospatial performances in FTD and AD report contrasting data. Some of them found similar impairments in both patient groups, while others did not (see Table 1). While it is maintained that the relative sparing of visuospatial abilities should characterize both variants of FTD (Neary et al., 1998), the most recent studies on neuropsychological features of these patients failed in supporting this assumption. In particular, both Hodges et al. (1999) and Perry and Hodges (2000) did not find differences between fv-FTD and AD patients on several visuospatial tasks (Table 1). In the present paper we aimed at studying a wide range of visuospatial abilities and at providing a qualitative analysis of constructional performances in a sample of patients with the frontal variant of frontotemporal dementia. MATERIALS AND METHODS Subjects Frontal-variant FTD patients. We selected 22 patients with progressive dementia who matched the following inclusion criteria, extracted from previous papers characterizing fv-FTD (Hodges et al., 1999; Rahman et al., 1999; Perry and Hodges, 2000): Copyright # 2002 John Wiley & Sons, Ltd.
Similar to AD Left FTD better than AD on Rey figure
(a) History of progressive behavioral disturbances, lasting at least one year; (b) No topographical disorientation, acalculia, severe autobiographic amnesia or language disturbances, in particular of anomic type; (c) CT or MR evidence of selective or prominent frontal atrophy, supported when possible by SPECT findings of frontal hypoperfusion without accompanying signs of posterior hypoperfusion, that could be expected in patients with the socalled frontal variant of AD (Johnson et al., 1999). Moreover, to qualify for the present study, fv-FTD patients had to have attended at least five years of formal education, in order to obtain reliable scores on visuospatial tasks. Patients with a history of significant head trauma, stroke, alcoholism or movement disorders were excluded from this group. Eight fv-FTD who matched inclusion criteria did not complete the experimental assessment because they refused to participate to the second session (n ¼ 3; see below) or because they showed behavioral disturbances (e.g. restlessness, excessive distractibility or disinhibition) that did not ensure sufficient collaboration during the whole study (n ¼ 5). Therefore, our sample included 14 fv-FTD patients. AD patients. From a continuous series of outpatients with ‘probable’ AD with ‘typical’ clinical presentation (McKhann et al., 1984), we selected those with age, education and general intellectual impairment (as assessed by the Mini-Mental State Examination (MMSE); Folstein et al., 1975) matching those of the fv-FTD sample (MMSE score range: 18–27). Among these, eleven subjects accepted to participate to the second session (see below) on a voluntary basis. Int J Geriatr Psychiatry 2002; 17: 641–648.
visuospatial skills in fv-ftd and ad Control subjects. Sixty-four normal volunteers (mean age: 64.2 7.7; mean education: 9 4.4; mean MMSE score: 27.6 2), without history or signs of neurological or psychiatric diseases, participated in the experiment as the control group for our battery for visuospatial abilities. All subjects gave their informed consent to participate to the study. The experimental protocol was approved by local Ethics’ Committees. Materials and procedure All patients underwent a comprehensive assessment of cognitive abilities, including MMSE and tests that tap visuospatial and verbal immediate memory (span procedure), focused and sustained attention, verbal learning for paired words and for a brief story, spatial abstract reasoning abilities (Raven’s progressive matrices), and two tests known to be sensitive to frontal lobe lesions: Stroop colorword test, in a short version, and category verbal fluency. All tests were given according to Italian standard administration procedures (Caltagirone et al., 1979; Orsini et al., 1987; Spinnler and Tognoni, 1987; Venneri et al., 1993). Visuospatial constructional abilities were assessed by means of the copy of Rey-Osterreith complex figure, that also allows the analysis of copying procedures (Osterreith, 1944; Trojano et al., 1993) and by the copy of simple geometrical drawings (Set C of the Benton’s Visual Retention test; Benton et al., 1983), to perform a qualitative analysis of drawing errors. Three independent examiners, blind to patients’ clinical data, assigned quantitative scores and classified drawing procedures and errors; in case of discrepancies among examiners, the opinion of the senior investigator (DG) prevailed. In a second session, all selected patients completed the Battery for Visuospatial Abilities (BVA, known in Italy as TERADIC; Angelini and Grossi, 1993; Grossi and Trojano, 1999). The battery is composed by two sections. Perceptual abilities. This section comprises four tasks assessing visuospatial analysis abilities. These tasks have the format of four-choice recognition, with stimuli presented on the left and the four-choice display presented on the right. Items are presented one at a time and subjects have to point to the only item identical to the stimulus among the distractors, without time constraints. Each correct response is scored 1 point. (1) Line length judgement. This task includes 20 items; the patient has to identify in the fourCopyright # 2002 John Wiley & Sons, Ltd.
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choice display the line with the same length as the stimulus presented on the right side. Items are of increasing complexity as the linear differences among stimuli and distractors gradually decreases. Performance at this task is not affected by education (max score ¼ 20). (2) Line orientation judgement. It includes 10 items, in half of which the difference in orientation between stimulus and distractors is 30 , while in the remaining it is 15 . In the first seven items, distractors (of the same length as the stimulus) are presented in an ordered spatial arrangement, as in the Benton et al. test, while in the last three items distractors are randomly spread on the four-choice display. Performance at this task is strongly influenced by education (max score ¼ 10). (3) Angle width judgement. This task includes 10 items: the patient has to identify the stimulus (an angle) among four distractors differing for 15 to 90 from the stimulus. Scores are strongly affected by age and education (max score ¼ 10). (4) Point position identification. The stimuli (n ¼ 12) consist of squares containing 1 to 3 points; the four distractors have the same number of points of the stimulus but in different spatial arrangement. Also in this case scores are affected by education (range 0–12). Representational abilities. This section comprises four tasks which require subjects to mentally represent spatial relationships. The first three tasks of this section have the four-choice recognition format as the tasks of the previous section; each correct response is scored 1 point. The last one has a different arrangement. (1) Mental rotation. The 10 stimuli are shaped as the capital letter L (n ¼ 5) or as an italic capital S, with small white or black circles at the extremities. The patient has to identify the only distractor that matches the stimulus after mentally rotating it. Prior to the task, the patients receive two practice trials aided by the use of solid stimuli. Scores are affected by education (max score ¼ 10). (2) Complex figure identification (shape recognition). The ten stimuli consist in nonsense geometrical shapes of increasing complexity, not easily described verbally. Also in this case, two practice trials are given before the task (score range ¼ 0–10). (3) Hidden figure identification. The ten stimuli consist of nonsense geometrical patterns of increasing complexity. For each stimulus, the four-choice display includes more complex geometrical Int J Geriatr Psychiatry 2002; 17: 641–648.
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patterns, within one of which the stimulus is exactly embedded. Two practice trials are given; score range 0–10. (4) Mental construction. The ten stimuli for the mental construction task consist of squares randomly subdivided into four parts. The four components of each stimulus are randomly placed in the display; the patient is required to identify with which side two components named by the examiner are contiguous in the stimulus. Two questions are given for each trial; each correct response is scored 1 point (max score ¼ 20). Two practice trials with solid stimuli are given prior to the task. This task requires the patient to mentally assemble the stimuli to give correct answers, and, like all tasks of this section, is affected by educational level. Sixty-four normal subjects with age and education matching those of the patients were assessed on the BVA to obtain normal reference values for these tests. Statistical analysis Age, education and MMSE scores of the two groups of patients were compared by means of unpaired Student’s t-test. One-way multivariate analysis of variance has been used to detect group differences on continuous neuropsychological test scores, performing post-hoc comparisons by means of Fischer’s test (with significance level set at 0.05), when required. Chi-square was used to compare groups on discrete variables (copying procedures of the Rey figure, and analysis of drawing errors in copying geometrical figures of the Benton Visual Retention test). RESULTS Results of the neuropsychological assessment are presented in Table 2. The general analysis did not show differences between the two patient groups (Wilks’ lambda ¼ 0.38; p ¼ 0.19), but the analysis of specific effects in every task showed a difference on the semantic verbal fluency task, where fv-FTD achieved significantly lower scores ( p ¼ 0.033). The two groups presented similar drawing procedures in copying Rey complex figure (chi square ¼ 4, df ¼ 5, p ¼ 0.54): most patients of both groups (9/14 fv-FTD and 7/11 AD) adopted a piecewise copying procedure (Type IV). The two groups made a similar mean number of errors in copying simple geometrical drawings and did not show differential qualitative patterns of drawing errors (chi square ¼ 4, df ¼ 5, p ¼ 0.54): in particular, spatial Copyright # 2002 John Wiley & Sons, Ltd.
Table 2. Mean demographic data and neuropsychological scores in fv-FTD and AD patients AD
FTD
Mean
SD
67.2 8.7 2.1 21.6 5.1 3.8 3.8 33 6 7 16.6 52.1 10.5 12.2 5
Age, years Education, years Disease duration, years MMSE Verbal digit span Verbal word span Corsi’s visuospatial span Attentional matrices Logical memory Paired-associate learning Raven coloured PM Stroop test—time Stroop test—errors Category verbal fluency Copy of Benton’s Set C—score Copy of Benton’s Set C—number of errors Rey figure copy
Mean
SD
p
5.4 4.2 0.9 3.6 0.9 0.6 0.7 7 5 2 6.6 22 11 2.7 2.3
66.7 8.4 2.3 21.9 5.1 4 4 30.4 6.1 8.7 17.1 62.2 13.1 8.7 6.1
7.6 3.5 1.6 3.8 1.1 0.8 0.6 11 4.5 3.6 6.3 30 9.9 2.6 2.4
0.77* 0.89* 0.59* 0.95* 0.95 0.52 0.25 0.51 0.93 0.19 0.81 0.38 0.56 0.033 0.25
12.9
5.8
8.5
5.6
0.07
16.8
9.8
19.7
9.4
0.09
*p-values obtained by unpaired t-test (df ¼ 23); otherwise, p-values obtained by one-way multivariate analysis of variance (df ¼ 1.23). PM ¼ Progressive Matrices.
distortions were the most frequent type of error both in fv-FTD and AD patients (Table 3). Scores on BVA are presented in Table 4. Normal subjects performed significantly better (Wilks’ lambda ¼ 0.52; p < 0.001) than the two patient groups on all tests, but position discrimination ( p ¼ 0.127); post-hoc comparisons did not reveal differences between fv-FTD and AD patients. Multivariate analysis of variance repeated only on the two patient groups confirmed that fvFTD and AD groups did not differ on visuo-spatial tests (Wilks’ lambda ¼ 0.88; p ¼ 0.97).
Table 3. Type of errors in copying Set C of Benton’s visual retention test in fv-FTD and AD patients AD
Omissions Distortions Perseverations Rotations Wrong position Wrong dimension Total errors
FTD
Errors
Percent
Errors
Percent
17 87 5 5 21 7
12 61.3 3.5 3.5 14.8 4.9
11 71 3 4 14 16
9.2 59.7 2.5 3.4 11.8 13.4
142
100
119
100
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visuospatial skills in fv-ftd and ad Table 4. Means scores on the battery for visuospatial abilities in fv-FTD and AD patients AD
Line length Line orientation Angle width Point position Mental rotation Shape identification Hidden figures Mental construction
FTD
Controls
Mean
SD
Mean
SD
Mean
SD
p
13.6 4.7 3.5 9 3.2 6.3 3.1 9.1
2.9 1.2 1.9 2.1 2.2 2.3 2.3 7.5
14.3 4.7 4.2 9.1 3.7 6.3 2.9 7.9
3 1.9 2.2 2.1 3 2.4 1.9 7.4
15.6 6.5 5.3 9.7 6.6 7.8 6.1 16.5
2.1 2.3 2.2 2.2 2.4 1.9 2.7 3.2
0.016 0.003 0.030 0.45 0.0001 0.008 0.0001 0.0001
p-values obtained by one-way multivariate analysis of variance (df ¼ 2.86). No significant difference between AD and fv-FTD groups on Fischer’s test.
DISCUSSION The clinical belief that visuospatial and constructional abilities are relatively spared in both variants of FTD compared to AD, is based on the description of the first, prototypical clinical reports of frontal lobe dementia (Brun, 1987; Neary et al., 1988). These clinical observations tie in with the assumption that visuospatial functions are mainly correlated with parietal lobes, that are spared in fv-FTD but are involved in AD since its early stages (Cummings and Benson, 1983). In fact, disturbances of spatial short-term memory, constructional praxis and visuospatial abilities are among cardinal features of AD (Ajuriaguerra et al., 1960; Trojano et al., 1994). On this basis, there are sufficient grounds to claim that unimpaired visuospatial and constructional disturbances are useful in differentiating FTD from AD. Yet, no study has been specifically focused on the assessment of visuospatial performances in either variant of FTD. In the present paper we compared visuospatial and constructional abilities of a sample of fv-FTD patients with those of a sample of subjects with probable AD, matched for age, education and severity of dementia. Our experimental results did not reveal differences between the two patient groups and did not confirm the clinical belief of the relative sparing of visuospatial abilities in FTD. These null findings could be explained by a bias due to patient misclassification. However, we used the same selection criteria used in previous studies on fv-FTD patients, based upon the convergence of history, behavioral symptomatology and neuroradiological findings (Gregory, 1999; Gregory et al., 1999; Hodges et al., 1999; Bozeat et al., 2000; Perry and Hodges, 2000). Although the two patient groups of the present experiment did not Copyright # 2002 John Wiley & Sons, Ltd.
differ on several general neuropsychological measures, semantic word fluency was significantly lower in fv-FTD patients. This finding could suggest that our sample of patients with fv-FTD had a more severe impairment of frontal lobe functions with respect to the AD group. Accordingly, it has been claimed that impaired verbal fluency is among the most reliable neuropsychological tool to document the progression of frontotemporal dementia (Pasquier et al., 1999), although studies on fv-FTD patients suggest that letter fluency might be more sensitive than category fluency in discriminating between fv-FTD and AD patients (Hodges et al., 1999; Perry and Hodges, 2000). The lack of significant differences on the Stroop test between the two patient groups enrolled in the present study is not a novel finding and might suggest that this test is not specific to disentangle different forms of dementia (Hodges et al., 1999; Perry and Hodges, 2000). A second possible explanation of the present findings is that our selection criteria for AD patients (matching fv-FTD sample for age, education and MMSE score) are not adequate for identifying groups of patients at an equivalent stage of disease severity. Actually it has been suggested that MMSE is an insufficient measure of frontal lobe damage (Gregory and Hodges, 1996; Rahman et al., 1999; Bozeat et al., 2000). In other words, to match the two samples for MMSE score might provide two samples of equivalent general intellectual abilities but not homogeneous for disease severity: it could be argued that fv-FTD had a greater cognitive impairment with respect to AD patients, undetected by MMSE scores. However, the procedure of selecting fv-FTD and AD patients with comparable MMSE scores has already been adopted to ensure some kind of homogeneity Int J Geriatr Psychiatry 2002; 17: 641–648.
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between samples both in neuropsychological (Hodges et al., 1999; Perry and Hodges, 2000) and in neuropsychiatric (Bozeat et al., 2000) studies. Moreover, it must be noted that we took care in studying only fv-FTD patients that reliably coped with test instructions, excluding patients with gross behavioral disturbances. While we are aware of this possible selection bias, it is worth mentioning that the problem of missing values due to behavioral disturbances is part of the clinical picture in frontotemporal dementia (Smeding and de Koning, 2000). Last, according to the hypothesis that we selected fv-FTD patients with more severe impairment of frontal lobe functions, we should expect to find more prominent deficits in copying complex geometrical drawings (the copy of Rey figure is thought to rely on organization and planning abilities and therefore to be sensitive to frontal lobe damage; Hodges et al., 1999) or qualitative differences in constructional performances in comparison to AD patients. In fact, our data did not follow these predictions, since fv-FTD patients showed performances similar to AD group even in copying simple geometrical drawings. Therefore, the possible artefactual biases do not seem capable of explaining our experimental data. While the present findings seem to contradict a common clinical belief, they are in agreement with most data in literature, with the exception of the two studies by Mendez et al. (1996) and by Miller et al. (1997). However, the former provided only gross measures of visuoconstructional abilities (the copy of two pentagons scored on a pass or fail basis), and the latter did not select patients matched for disease severity (MMSE was significantly higher in FTD than in AD patients). It has been suggested that failure to find significant differences between FTD and AD patients may be due to heterogeneity of the FTD group (Razani et al., 2001). For this reason we focused upon a specific subset of FTD patients, identified by means of neuroimaging and behavioral features. Our findings are consistent with previous studies on the same subset of patients (Hodges et al., 1999; Perry and Hodges, 2000). However, adopting different classificatory criteria for FTD patients based on the asymmetry of hypoperfusion, Razani et al. (2001) have reported that FTD patients with prominent left hypoperfusion show better performances than AD patients on the copy of the Rey figure, while right FTD subjects do not differ from AD patients. In our patients no overt asymmetry of blood flow in frontal regions was observed, but further studies are necessary to verify whether subtle perfusion asymmetries may identify differential cognitive profiles within the fv-FTD Copyright # 2002 John Wiley & Sons, Ltd.
group (Razani et al., 2001). Future studies will also have to establish differential features to distinguish fv-FTD from the recently reported frontal variant of AD (Johnson et al., 1999). The unique contribution of the present paper is to have systematically investigated a wide range of visuospatial and constructional abilities and to have provided a qualitative analysis of drawing errors in fv-FTD patients. On the basis of our findings, the relative sparing of visuospatial and constructional abilities seems to be a clinical belief not supported by sufficient experimental evidence. This claim might not hold true during the whole course of the disease. Actually, at a very early stage of the disease fv-FTD patients have been shown to perform as well as normal subjects on several tasks assessing visuospatial abilities and spatial working memory (Rahman et al., 1999). At later stages of the disease, while AD massively deranges visuospatial and constructional skills until the appearance of the closing-in phenomenon (Grossi and Trojano, 2001), single fv-FTD patients can maintain some degree of visuospatial skills that allow the occasional clinical observation of correct copying of geometrical drawings. In non-selected patients at a mild to moderate disease stage, visuospatial and constructional tests do not seem capable of discriminating fv-FTD from AD reliably. These conclusions do not conflict with observations about the lack of spatial disorientation in FTD. None of our fv-FTD patients presented topographic disorientation, as foreseen by inclusion criteria and by virtually all diagnostic sets (e.g. The Lund and Manchester Groups, 1994; Pasquier and Petit, 1997; Neary et al., 1998; Neary, 1999) while 8/11 of our AD patients had experienced one or more episode of spatial disorientation in familiar surroundings. Correct spatial orientation imply the correct functioning of specific neural networks, among which medial temporal lobes and hippocampus that are early involved in AD and spared in FTD (Frisoni et al., 1996; Duara et al., 1999; Pfeffer et al., 1999; Laakso et al., 2000). The clinical belief of spared spatial abilities in fv-FTD has thus to be referred to the lack of topographic disorientation in comparison to AD.
KEY POINTS Frontal-variant frontotemporal dementia and Alzheimer’s disease are not reliably distinguished by visuospatial and constructional skills at a mild to moderate disease stage.
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