Abstract
Objective/Background: To determine whether difficulty in the early differentiation between frontotemporal dementia (FTD) and AD may arise from a failure to discriminate between the temporal and frontal variants of FTD.
Methods: Neuropsychological profiles of patients with early dementia of Alzheimer type (DAT; n = 10), the temporal variant of FTD (tv-FTD or semantic dementia; n = 5), and the frontal variant of FTD (fv-FTD; n = 10) were compared to each other and normal controls (n = 10). Structural MRI demonstrated temporal lobe atrophy in the tv-FTD patients and frontal lobe atrophy in the fv-FTD group.
Results: Subjects with tv-FTD showed severe deficits in semantic memory with preservation of attention and executive function. Subjects with fv-FTD showed the reverse pattern. Attention and executive function impairment separated the fv-FTD patients from the early DAT subjects, who were densely amnesic.
Conclusion: The double dissociation in performance on semantic memory and attention/executive function clearly separated the temporal and frontal variants of FTD and aids the early differentiation of FTD from AD. The characteristic cognitive profiles reflect the distribution of pathology within each syndrome and support the putative role of the inferolateral temporal neocortex in semantic memory, the medial temporal lobe structures of the hippocampal complex in episodic memory, and the frontal lobes in executive function.
The development of new symptomatic treatments for AD and the finding that serotonergic drugs can help behavioral symptoms in patients with frontotemporal dementia (FTD) highlight the importance of accurate diagnosis in the early stages of these conditions.1 The aim of this study was to differentiate the neuropsychological profiles of the frontal and temporal variants of FTD from each other and from that of early AD. The term FTD is now preferred to the older designation, Pick’s disease, and although having the benefit of avoiding specific pathologic connotations, it has the disadvantage of amalgamating patients with very different syndromes; namely, those associated with predominantly frontal or temporal lobe atrophy. Those with the frontal variant of FTD (fv-FTD), previously termed dementia of frontal type,2 frontal lobe degeneration,3 or frontal lobe degeneration of non-Alzheimer type,4 have marked changes in behavior and personality. By contrast, patients with the temporal lobe variant (tv-FTD) typically present with a progressive fluent aphasic syndrome that reflects breakdown in semantic knowledge, which has led to the designation semantic dementia.5,6
Previous attempts to differentiate FTD from AD on the basis of attention and executive dysfunction or memory have often shown inconclusive or even contradictory results,7-10 and much of this controversy may relate to the amalgamating of temporal and frontal cases in FTD, which is likely to blur important neuropsychological distinctions.8,10
In an earlier study10 we compared groups of patients with AD, fv-FTD, and tv-FTD on tests of episodic and semantic memory and demonstrated normal semantic memory in fv-FTD but severe impairments in tv-FTD. Our failure to include a comprehensive battery testing attention and executive function may have prevented us from demonstrating the reverse dissociation and a characteristic profile for fv-FTD.
We hypothesized that by selecting subjects with a purely frontal variant of FTD and by using a neuropsychological battery that includes tests specifically selected to be sensitive to frontal lobe pathology we would find a distinct cognitive profile for fv-FTD that is significantly different from that of AD and tv-FTD. Such a finding would clearly substantiate the splitting of FTD patients into frontal and temporal variants.
Methods.
Subjects.
Ten patients with dementia of the Alzheimer type (DAT), 10 with fv-FTD, 5 with tv-FTD, and 10 controls took part in the study. The DAT, tv-FTD, and fv-FTD subjects were chosen from patients undergoing longitudinal evaluation at the University of Cambridge Neurology unit. All patients were assessed by a neurologist, neuropsychologist, and psychiatrist and had [99Tc] hexylmethylpropylene amineoxine (HMPAO)–SPECT and MRI. Subjects were excluded if they had a history of known or suspected cerebral ischemic event, alcohol abuse, head injury, other major medical illness, or depressive illness.
The DAT patients presented with progressive cognitive deterioration with early and predominant memory loss and were selected from a larger cohort undergoing longitudinal assessment. They were diagnosed as having probable or possible AD according to the criteria developed by the National Institute of Neurologic and Communicative Disorders and Stroke–AD and Related Disorders Association (NINCDS-ADRDA), which consist of inclusion and exclusion criteria.11 The DAT subjects were selected on the basis of age and dementia severity, as measured by the Mini-Mental State Examination (MMSE),12 to match with the other groups.
The patients with fv-FTD were selected based on history, behavioral symptomatology, and neuroimaging results consistent with a progressive syndrome affecting the frontal lobes. They presented with a history of progressive change in personality and behavior with at least five of the following features: loss of insight, disinhibition, apathy, restlessness, emotional lability, distractibility, reduced empathy, lack of foresight, poor planning, impulsiveness, social withdrawal, poor self-care, reduced verbal output, verbal stereotypes or echolalia, perseveration, or features of the Kluver-Bucy syndrome.13 Progression was assessed clinically in terms of changes in functional abilities (e.g., job performance), the development of more of the behavioral features listed above, or the appearance of frontal lobe atrophy on MRI. All patients met the diagnostic research criteria for FTD set by the Lund-Manchester Group.14,15 Functional imaging with 99Tc HMPAO-SPECT showed hypoperfusion of the frontal lobes in all cases, with MRI being normal in one case and other cases showing predominantly frontal lobe atrophy.
The tv-FTD subjects all met previously reported criteria for semantic dementia.6 They presented with a progressive loss of memory for words and increasing difficulty recognizing familiar objects and people. Speech was characteristically empty with word-finding difficulties but was fluent with normal phonology and syntax. In contrast with the DAT patients, their memory for day-to-day events was relatively well preserved and visuospatial skills and nonverbal problem solving remained unaffected. All subjects showed focal atrophy of the inferolateral and polar temporal regions on structural MRI. Four cases had bilateral atrophy—two predominantly right sided, two predominantly left sided—and one case had markedly asymmetric left-sided temporal lobe atrophy.
Since completion of the study, two patients have died: one from the DAT group had pathologically confirmed AD and one fv-FTD patient had nonspecific histologic changes without intraneuronal inclusions.
Control subjects were selected from a larger control panel of volunteers from the Cambridge area. The controls were selected on the basis of age in an attempt to match for the relatively young age of the fv-FTD subjects. The local research ethics committee approved the study and written consent was obtained from all carers.
Neuropsychological assessment.
All patients and controls completed the test battery, which aimed to assess the cognitive domains of episodic memory (recall and recognition), semantic memory, attention and executive function, visuospatial function, and auditory–verbal short-term memory.
Episodic memory.
To test recall memory, subjects were given the Weschler Memory Scale–Revised (WMS-R) Logical Memory subtest,16 and recall of the Rey Complex Figure test after a 45-minute delay. Recognition memory was tested with the shortened version of the Warrington Recognition Memory Test for both words and faces.17
Semantic memory.
All subjects were given the Graded Naming Test,18 the three picture version of the Pyramids and Palm Trees Test,19 and the category fluency subtest of the Hodges and Patterson semantic battery,20 in which subjects have to produce as many examples as possible from each of the following categories: animals, birds, water creatures, household items, vehicles, and musical instruments. The Pyramids and Palm Trees Test is a nonverbal test of associative semantic knowledge in which subjects have to match conceptually related pictures. For example, a target picture of an Egyptian pyramid is shown above pictures of a palm tree and a pine tree, one of which has to be matched with the pyramid.
Attention and executive function.
Two subtests of the Test of Everyday Attention (TEA),21 the Stroop test,22 Wisconsin Card Sorting Test (WCST),23 and Della Sala et al.’s dual-task24 were given to assess attention and executive function. The Map Search test is a visual search task from the TEA in which subjects have to identify target symbols (e.g., a knife-and-fork sign representing eating facilities) from competing and irrelevant distractors on a map. The Elevator Counting with Distraction subtest from the TEA is an auditory task of selective attention in which subjects are required to count strings of low tones while ignoring higher pitched tones. The Della Sala et al. dual-task is a timed, pencil and paper task of divided attention designed to investigate the “central executive” component of working memory. It consists of two tasks, A and B, which are each performed on their own for 2 minutes before being performed simultaneously. Task A consists of repeating digit spans at the subject’s own span length and Task B of crossing out a trail of boxes on a sheet of paper. A dual-task, or mu, score is calculated as a percentage and represents the performance decrement on the dual-task relative to the performance on the two single tasks. No dual-task decrement is expressed as a score of 100. We employed the version of the classic Stroop paradigm designed by Trenerry et al.22 that measures the interference effect that a more automatic process, in this case reading words printed in different colored inks (e.g., the word red is printed in blue ink), has on a more complex process in which the subject has to name the color of the ink in which the word is printed (e.g., with the word “green” written in red ink, the subject should say red). The score is represented by the speed of naming on the interference condition. The WCST–Modified23 was included in our battery as a test of attentional set shifting in which the subject has to shift from concept to concept. The score taken was the number of categories correct out of a maximum of six.
Visuoperceptual and spatial abilities.
Two subtests—one perceptual (figure-ground screening test) and one spatial (position discrimination)—were taken from the Visual Object and Space Perception (VOSP) test.25 All subjects were also assessed on the copy of the Rey Complex Figure.
Auditory–verbal short-term memory (working memory).
The forward and backward digit span test from the Wechsler Adult Intelligence Scale26 was given to all subjects.
Statistical analysis was performed using Statview.27 One-way analysis of variance (ANOVA) was used to detect intergroup differences between control subjects and subjects with DAT, fv-FTD, and tv-FTD on individual neuropsychological tests. If a group effect was shown, pairwise differences were sought using a Student-Newman-Keuls test. To further analyze the data we calculated a domain score for each subject on each of the five cognitive domains tested (episodic memory, semantic memory, attention and executive function, visuospatial function, and auditory–verbal short-term [working] memory). A domain score for each subject was calculated by averaging the z-scores for each neuropsychological test within that particular domain.
Results.
Age and dementia severity.
The mean scores for age and dementia severity as measured by MMSE are shown in the table. One-way ANOVA revealed a group effect of MMSE (F = 8.94, p < 0.001) with post-hoc pairwise analysis showing that the patient groups did not differ significantly from each other but were all significantly different from the control group. There was no group effect of age (F = 1.83, p > 0.05).
Performance of control, dementia of Alzheimer’s type (DAT), frontal variant of frontotemporal dementia (fv-FTD), and temporal variant (tv-FTD) groups on the neuropsychological test battery
Episodic memory.
The performance of each subject group on each of the four measures of episodic memory is shown in the table. The most striking feature was the degree of impairment in recall memory shown by the DAT group (figure 1). One-way ANOVA showed significant overall group effects for all the tests of episodic memory. For the percent recall score of the logical memory (story recall) measure of the WMS-R (F[3,34] = 42.08, p < 0.0001), post-hoc pairwise analysis demonstrated that the DAT group was worse than all other groups (p < 0.0001), and that the fv-FTD group was worse than controls (p < 0.05), but the tv-FTD group did not differ from the fv-FTD or control group. For performance on the Rey figure recall test (F[3,34] = 16.29, p < 0.0001) only the DAT group was worse than the other groups (p < 0.0001); i.e., controls = fv-FTD = tv-FTD > DAT (see figure 1). On both word (F[3,34] = 16.79, p < 0.0001) and face (F[3,34] = 8.07, p < 0.001) recognition memory all patient groups performed worse than the control group, with the DAT group being more impaired on the words than the tv-FTD and fv-FTD groups (i.e., controls > fv-FTD = tv-FTD > DAT). There was no significant difference between the performance of the three patient groups on facial recognition (controls > fv-FTD = tv-FTD = DAT).
Figure 1. Performance of patient groups on individual tests of episodic memory (A [Wechsler Memory Scale–Revised, logical memory] and B [Rey figure recall]), attention and executive function (C [Test of Everyday Attention Map Search] and D [Wisconsin Card Sorting Test]), and semantic memory (E [Graded Naming Test] and F [Pyramids and Palm Trees]). DAT = dementia of the Alzheimer type; FTD = frontotemporal dementia; fv = frontal variant; tv = temporal variant.
By averaging each subject’s z scores for the two visual tests and for the two verbal tests we were able to look for different patterns of impairment in visual or verbal episodic memory. Although there was a group effect for both (F[3,34] = 25.4, p < 0.0001 for verbal episodic memory and F[3,34] = 12.1, p < 0.0001 for the visual tests), post-hoc analysis for pairwise differences revealed that the patient groups showed the same pattern of impairment for both visual and verbal episodic memory (i.e., controls > fv-FTD = tv-FTD > DAT).
To examine episodic memory performance as a whole, an episodic memory score was calculated for each subject by averaging the subject’s z-scores on each of the four measures of episodic memory. A group effect was shown (F[3,34] = 24.8, p < 0.0001) and further pairwise analysis showed that relative to controls all patient groups were significantly impaired in the domain of episodic memory. The DAT patients had worse performance than both the tv-FTD (p < 0.005) and the fv-FTD group (p < 0.0001) (controls > fv-FTD = tv-FTD > DAT). The episodic memory performance of each of the dementia groups, illustrating the severe deficit in episodic memory that is known to characterize the cognitive profile of early DAT, is illustrated in figures 1 and 2⇓. Figure 2 shows the proportion of the overall cognitive deficit accounted for by each cognitive domain. It can be seen that 68.5% of the measured cognitive deficit in DAT was accounted for by episodic memory loss as compared to 41.1% in fv-FTD and 26.4% in tv-FTD. It is also interesting to note that despite having symptomatic histories of relatively preserved day-to-day memory, both the tv-FTD and fv-FTD groups showed significant episodic memory deficits on formal neuropsychological testing.
Figure 2. Cognitive profiles of dementia of the Alzheimer type (A) and frontal variant (B) and temporal variant (C) frontotemporal dementia show relative contributions of each cognitive domain as percentage of overall cognitive deficit measured by all neuropsychological tests. Calculated from z-scores by averaging the z-scores from each subject in each dementia group for each cognitive domain.
Semantic memory.
The performance of the subject groups on each of the three measures of semantic memory is shown in the table. Again, one-way ANOVA revealed significant overall group effects for all tests. Subsequent pairwise analysis of the Pyramids and Palm Trees test (F[3,34] = 13.9, p < 0.0001) showed equivalent performance of the control, DAT, and fv-FTD subjects but highly significant impairment in the performance of the tv-FTD patients relative to all other groups (i.e., control = fv-FTD = DAT > tv-FTD) (see figure 1). Category fluency performance (F[3,34] = 4.6, p < 0.01) demonstrated a different pattern of intergroup differences: although all the dementia groups were significantly worse than controls, this test failed to differentiate among the three patient groups (controls > DAT = fv-FTD = tv-FTD). With the third test of semantic memory, the Graded Naming Test (F[3,34] = 45.7, p < 0.0001), post hoc pairwise analysis showed that the tv-FTD patients were significantly worse than all other subject groups (see figure 1). Whereas the fv-FTD group had equivalent performance to the controls, the DAT patients also demonstrated significant naming deficits (controls = fv-FTD > DAT). Of note is the fact that two of the semantic tasks (the Graded Naming and Pyramids and Palm Trees Tests) were able to separate the groups, with all five tv-FTD patients falling below the range of the other two patient groups.
As with episodic memory, we were able to compare the semantic abilities of each patient group more clearly by calculating an overall semantic memory score, formed by averaging the z scores on each of the three tests of semantic memory. An ANOVA again showed an overall group effect (F[3,34] = 20.0, p < 0.0001). Post hoc analysis demonstrated that although there was no significant difference among the fv-FTD, DAT, and control groups, the tv-FTD patients had significantly greater impairment on semantic memory than any other group (controls = fv-FTD = DAT > tv-FTD). Figure 2 illustrates how the cognitive profile of tv-FTD was dominated by semantic memory loss, which accounted for 64.4% of the overall cognitive deficit. By comparison, semantic memory loss accounted for only 9.9% of the deficit in early DAT. For fv-FTD, the contribution of semantic deficit (13.8%) was less than the contribution of both episodic memory and attention and executive dysfunction.
Attention and executive function.
Significant overall group effects were seen by one-way ANOVA for all the tests of attention and executive function, except the Della Sala et al. dual-task. Although there was a tendency for the fv-FTD patients to show a greater dual-task decrement than the other subject groups (see the table), the overall group effect failed to reach significance. For three of the tests of attention and executive function—the TEA Map Search (F[3,34] = 6.7, p < 0.005), the WCST (F[3,34] = 7.3, p < 0.001), and the TEA Elevator Counting with Distraction (F[3,34] = 3.4, p < 0.05)—the fv-FTD subjects were worse than the DAT, tv-FTD, and control groups, with no difference between the latter (i.e., control = tv-FTD = DAT > fv-FTD) (see figure 1). The Stroop test (F[3,34] = 7.5, p < 0.001) was able to differentiate controls from all patient groups but no significant differences among the dementia groups were found (controls > tv-FTD = DAT = fv-FTD).
For comparisons of group performance on attention and executive function as a domain, z scores were averaged as previously described. Group effects were seen (F[3,34] = 10.7, p < 0.0001) and subsequent analysis demonstrated that although the DAT patients were impaired relative to controls (p < 0.01), the fv-FTD subjects had poorer performance than the DAT (p < 0.05), tv-FTD (p < 0.001), and control (p < 0.0001) groups. Figure 2 illustrates that attention and executive function impairment accounted for a substantial proportion (30%) of the overall cognitive deficit in fv-FTD compared to 11% of the measured cognitive deficit in DAT and 1% in tv-FTD.
Visuospatial function.
One-way ANOVA revealed no significant overall group effects for the VOSP Shape Detection, VOSP Position Discrimination, or Rey Figure copy. The table and figure 2 show that visuospatial function was well preserved and visuospatial dysfunction accounted for less than 10% of the overall measured cognitive deficit in all three dementia types.
Discussion.
The three patient groups, matched for dementia severity, showed clear differences from each other and from normal controls. Distinct neuropsychological profiles emerged for fv-FTD, tv-FTD (semantic dementia), and DAT that reflect the predominant distribution of pathology in the three dementias. These neuropsychological profiles, having been validated in these groups of subjects who were differentiated by neuroimaging characteristics, may provide supportive diagnostic evidence in early cases of FTD or DAT where neuroimaging may be normal.28
The cognitive profile shown by the DAT group was dominated by a profound impairment in episodic memory that accounted for 69% of the overall cognitive deficit. On all four tests of episodic memory there were highly significant deficits in comparison to normal controls. The DAT subjects could be differentiated from the fv-FTD and tv-FTD patients on all episodic memory tasks, except facial recognition. The predominant episodic memory loss accords with previous studies29,30 and reflects the known sites of pathology in early DAT, which affects the transentorhinal region in the medial temporal lobe, effectively deafferenting the hippocampal complex and preventing the formation of new episodic memories.31 Apart from the universal and severe amnesia, this group of early DAT subjects was also significantly impaired in the domains of attention and executive function and semantic memory, but visuospatial function and auditory–verbal short-term memory were spared. Significant impairment in attention and executive function was seen in the early DAT group when performance on all five tasks in the domain was averaged. More detailed analysis of individual tests revealed that only the Stroop test differentiated DAT subjects from controls. The Stroop is a complex task that draws upon multiple aspects of attention, including target selection, response inhibition, and mental speed. This probably explains its sensitivity to brain pathology as well as the lack of specificity to different types of dementia.
The variable semantic memory deficits previously demonstrated in early DAT, reflecting patchy involvement of the temporal neocortex,20 were seen in the current study as demonstrated by mild deficits in naming and category fluency. In this study, the DAT group showed no impairment in visuospatial function, whether analyzed by individual tests or by overall cognitive domain. This pattern of amnesia, with incipient impairment of attention and executive functions and semantic memory but preservation in visuospatial function, is consistent with the findings of previous studies in early DAT32 and questions the usefulness of visuospatial measures in differentiating DAT from fv-FTD at a stage in the disease where accurate diagnosis is most warranted.
As in previous studies,6 the tv-FTD (semantic dementia) subjects showed a highly distinctive neuropsychological profile characterized by a striking impairment in semantic memory, which accounted for 65% of the overall cognitive deficit. The degree of semantic impairment was significantly greater than in the other dementia groups. Functional imaging studies using semantic activation paradigms have pointed to a widespread network of areas in the left hemisphere, including inferior frontal, temporal, and temporoparietal lobes.33 The semantic impairments of the tv-FTD patients, who had predominantly temporal lobe atrophy on MRI, together with the normal semantic memory performance of the fv-FTD subjects, supports previous evidence that it is the temporal, rather than the frontal lobes, that are a critical neural substrate for semantic memory.34 That the temporal lobes have little part to play in the chosen tasks of attention and executive function can be inferred from the normal performance of the tv-FTD patients on all but one of these tests. One of the diagnostic features of semantic dementia is the preservation of day-to-day (episodic) memory,15 and although patients usually remain well oriented until late in the course of the disease, formal neuropsychological tests of episodic memory, especially involving verbal material, often reveal deficits.35 It has been postulated that these deficits reflect a breakdown in semantic representations underlying language comprehension rather than pathologic involvement of the hippocampal complex, which is typically less involved. In the current study, the tv-FTD patients showed normal recall of the Rey figure and stories but mild impairment on the recognition memory tests.
In terms of the differentiation of the tv-FTD and DAT patients, the most significant finding was the normal performance of the tv-FTD group on tasks of attention and executive function. Of more importance was our hypothesis that by selecting appropriate measures we could differentiate the patients with the fv-FTD from those with early DAT and tv-FTD, not just by a lack of impairment, but by the demonstration of specific deficits.
The fv-FTD patients could be clearly differentiated from the other dementia groups on the basis of their performance on the domains of episodic memory, semantic memory, and attention and executive function. Although episodic memory was impaired relative to the normal controls, the fv-FTD group performed significantly better than the DAT group on three out of four of the individual tests. These findings confirm our earlier study by showing sparing of episodic memory, relative to DAT, and of semantic memory, relative to DAT and tv-FTD, in the frontal variant.10 The lack of impairment is, however, rather weak evidence for a distinction and might be explained on the basis of test sensitivity. It is, therefore, the finding of significantly greater involvement of attention and executive function in fv-FTD that constitutes the best evidence for the differentiation of this group. Deficits in attention and executive function have been linked to frontal lobe damage through a mass of lesion and neuroimaging studies (see Perry and Hodges36 for review). We selected tests of attention and executive function that would theoretically be sensitive to frontal lobe pathology. Predominant frontal activation has been seen in neuroimaging studies using the cognitive paradigms similar to those underlying the Stroop test, WCST, and Della Sala et al.’s dual-task,37-39 and two tests from the TEA.40,41 The fv-FTD group was impaired relative to controls on all of the individual tasks. When compared to the DAT group, they showed significant deficits on both the WCST and TEA Map Search and the overall domain score. In comparison with the tv-FTD group, the fv-FTD patients showed clear differences in performance in four out of the five tests.
One difficulty of neuropsychological studies of frontal lobe function is that different regions of the frontal lobe are likely to have different cognitive and behavioral significance.42,43 There is increasing evidence that the dorsolateral prefrontal cortex is involved in the complex cognitive operations of planning, divided attention, and manipulation of information (see Owen44 for review). Given this, it is perhaps surprising that the backward digit span task and the divided attention task failed to differentiate between the fv-FTD group and the DAT group. Task difficulty may explain this finding in part but another possibility is that the initial frontal locus of pathology in fv-FTD is the orbitofrontal and ventromedial rather than the dorsolateral prefrontal cortex. Patients with nondegenerative lesions in these areas can perform normally on standard tests of frontal function despite gross abnormalities in behavior and decision-making in everyday situations.45 It is interesting to note that two of our fv-FTD patients, despite having progressive behavioral syndromes that meet the diagnostic criteria for FTD,15 performed normally in all cognitive domains. Our data support the previous proposal, based on the pattern of behavioral symptomatology in FTD,28 that the orbitofrontal and ventromedial portion of the frontal lobes is usually the initial site of pathology.28,43 Thus, although we have shown that tasks of selective attention and concept shifting can differentiate between groups of patients with DAT and fv-FTD, future research may show that specifically developed tasks based upon decision making or social/emotional judgments, sensitive to orbital/ventromedial frontal damage, may reveal deficits in early cases where performance on conventional “frontal lobe tasks” is still normal.
The pattern of normal semantic memory with impaired attention and executive function was, therefore, the converse of that found in the tv-FTD group. This finding supports and advances the previous claims that the temporal and frontal presentations of the frontotemporal degenerations are clearly separable.
Acknowledgments
Supported by a MRC project grant to J.R.H. R.J.P. was supported by Novartis.
- Received September 20, 1999.
- Accepted in final form March 17, 2000.
References
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