ORIGINAL ARTICLE
Episodic Memory in Alzheimer Disease, Frontotemporal Dementia, and Dementia With Lewy Bodies/Parkinson Disease Dementia Disentangling Retrieval From Consolidation Alexandra Economou, PhD,* Christopher Routsis, MA,* and Sokratis G. Papageorgiou, MD, PhDw
Introduction: Differences in episodic memory performance in patients with Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB)/Parkinson disease with dementia (PDD) are inconsistent and task dependent. The inconsistencies may be attributed to the different tasks drawing on different memory processes. Few studies have examined episodic memory impairment in the above groups using memory tests that facilitate encoding, to distinguish memory deficits due to impairment of specific processes. Methods: We examined the memory performance of 106 AD patients, 51 FTD patients, 26 DLB/PDD patients, and 37 controls using the Five-Words Test, a 5-item memory test that facilitates encoding. Results: The patient groups did not differ in modified Mini Mental State Examination scores. AD patients scored lowest on the FiveWords Test overall, and showed the greatest reduction from immediate total recall to delayed free recall relative to the other 2 groups, consistent with a predominantly consolidation deficit. DLB/PDD patients showed the largest improvement from delayed free to delayed total recall relative to the other 2 groups, consistent with a predominantly retrieval deficit. Discussion: Deficits in both consolidation and retrieval underlie the memory impairment of the patients, to different extents, and contribute to the theoretical understanding of the nature of the memory impairment of the patient groups. Key Words: memory, Alzheimer disease, dementia with Lewy bodies, Parkinson disease with dementia, frontotemporal dementia
(Alzheimer Dis Assoc Disord 2016;30:47–52)
Received for publication September 8, 2014; accepted January 16, 2015. From the *Department of Psychology, School of Philosophy; and wCognitive Neurology-Extrapyramidal Disorders Unit, 1st University Department of Neurology, Eginition Hospital, Medical School, University of Athens, Athens, Greece. Present address: Sokratis G. Papageorgiou, MD, PhD, Behavioral Neurology Unit, 2nd University Department of Neurology, ATTIKON University General Hospital at Haidari, University of Athens, Athens, Greece. A preliminary version of this study was presented at the 21st Meeting of the European Neurological Society. The authors declare no conflicts of interest. Reprints: Alexandra Economou, PhD, Department of Psychology, School of Philosophy, The University of Athens, Panepistimiopolis, Ilissia, Athens 157 84, Greece (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
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pisodic memory impairment is a hallmark of the early stages of Alzheimer disease (AD), characterized by an accelerated forgetting rate. Its neural substrate includes the mesial temporal lobes, the diencephalon, and the basal forebrain.1 Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), however, are also characterized by episodic memory impairment, albeit to a somewhat lesser extent; and severity of memory impairment is similar in AD and progressive behavioral variant FTD (bvFTD) of similar disease severity.2,3 The patterns of memory impairment in the different degenerative disorders are associated with the brain structures most affected by the disorders. Patients with AD show lower delayed recall relative to patients with PDD and DLB, attributed to AD pathology affecting medial temporal lobe structures to a greater extent than Lewy body pathology.3,4 Patients with FTD show better learning and memory scores relative to patients with AD in some studies, attributed to the greater difficulty of the patients in generating and implementing organized strategies for the encoding and retrieval of information from memory. This difficulty affects free recall performance regardless of the delay interval. However, as it affects consolidation to a lesser extent, cued recall is less impaired than in AD patients.5 Nevertheless, 10% to 15% of patients with pathologically confirmed frontotemporal lobar degeneration (FTLD) present with severe amnesia, and episodic memory impairment is more common than previously thought.6,7 Recall of verbal information likely depends on the integration between hippocampal structures and prefrontal cortices and the differential contribution of the 2 to episodic memory needs to be clarified.2 Task-dependent differences in the performance of AD, DLB, and PDD patients are consistent with a retrieval deficit in the latter 2 groups, attributed to executive dysfunction.8,9 Degenerative disorders that primarily affect subcorticalfrontal structures manifest in deficits in encoding and retrieval strategies. Although the episodic memory performance of DLB and PDD patients using word-list learning tasks is not consistently superior to that of AD patients across studies, it is consistently better when logically constructed story passages are used, attributed to the contextual support offered by the stories.5 PDD patients benefit from cueing, indicating a predominantly retrieval deficit.10 DLB patients’ poor memory might result from impaired encoding rather than from defective consolidation, because of their better savings scores relative to AD patients in story recall and list
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learning.2,4 However, the overlap of the neuropsychological profiles of DLB and PDD outweighs their differences when the groups are matched for demographic factors and severity of dementia.11,12 Patterns of anterograde memory performance across the FTD subtypes are not always distinctive.5 Patients with bvFTD do not normally show the accelerated forgetting of patients with AD and benefit from retrieval cues. They manifest pathologic heterogeneity in medial temporal lobe involvement, although significant hippocampal atrophy has been reported at postmortem early in the course of the disease.6 The correlations of memory performance with magnetic resonance imaging ratings of regional brain atrophy and findings of prefrontal cortex atrophy in bvFTD provides support for the hypothesis that the memory deficits of the bvFTD is mediated primarily by damage to prefrontal regions, so it is important to employ tests that can differentiate between prefrontal and medial temporal lobe atrophy.6,13 The provision of cues in recall contributes to the disentangling of memory deficits attributed to poor consolidation of information versus those that are primarily due to inefficient encoding and retrieval strategies. The relative superiority of cued versus free recall of FTD patients indicates an inefficient search strategy of information stored in memory, rather than a rapid decay of information.14 However, episodic memory performance has not been examined using memory tasks specifically targeting prefrontal cortex (responsible for encoding and retrieval), versus medial temporal lobe-dependent memory processes (responsible for consolidation), so it is unclear whether poor response to cues is due to inefficient encoding or impaired consolidation of information. Behavior-executive and language FTD patients showed consistently higher recall and steeper rate of learning across multiple presentations of a supraspan list than AD patients, but did not differ from AD patients in delayed recognition memory, and showed equivalent enhancement of memory performance when cued recall was compared with free recall.15 The authors propose that the poor memory of FTD patients is not attributed to a selective retrieval deficit, but to impaired encoding; however, the study did not employ a test that controls for encoding. The only study of FTD and AD patients that employed such a test, to the best of our knowledge, showed that patients with frontal-variant FTD and AD of the same dementia severity did not differ in shortterm memory and in free (immediate and delayed) recall.16 The improvement observed in FTD relative to AD when a cue was provided, together with lower forgetting, suggested predominantly retrieval difficulties, although performance did not reach normal values. Facilitation of encoding of information improves consolidation and retrieval, making it easier to distinguish memory deficits due to impairment of specific memory processes from
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apparent memory deficits due to use of inefficient strategies.17,18 Tests that use the same category cues at acquisition and retrieval optimize encoding specificity, show high sensitivity and specificity to dementia, and superior performance to conventional verbal memory tests.18,19 The Five-Words Test (5WT) is a simple, rapid verbal episodic memory test that controls for encoding, thus allowing the qualitative analysis of type of memory impairment (encoding, consolidation, or retrieval).20 The test performed comparably to the conceptually similar Free and Cued Selective Reminding Test, a supraspan task, and was useful in discriminating mild-moderate dementia from isolated subjective memory complaints.21,22 The qualitative analysis of encoding, consolidation, and retrieval strategies is helpful for the differential diagnosis of dementia, and optimizing encoding can distinguish patients with dementia, especially AD, from persons with subjective memory complaints,22 presumably because it can distinguish between deficits in consolidation from deficits in the encoding/retrieval of information due to optimized encoding. The purpose of this study was to compare memory performance in AD, FTLD, and DLB/PDD patients using a Greek version of the 5WT. A retrieval deficit would manifest in greater cued versus free recall in both immediate and delayed memory, whereas a consolidation deficit would manifest in lower delayed recall, and little benefit from cueing. Assuming a predominantly retrieval deficit in DLB/ PDD and FTLD patients, we predicted that they would benefit more from cueing than AD patients.
METHODS Research Participants A group of 183 neurological patients (106 women), 106 AD patients, 51 FTLD patients, and 26 DLB/PDD patients (8 DLB, 18 PDD patients), comprised the patient sample (see Table 1 for demographic characteristics of the sample). Patients were recruited from the department of neurology of Eginition hospital. They underwent a structured interview, neurological examination, detailed neuropsychological assessment, and laboratory investigations explained elsewhere.23 Diagnoses were specified by the same behavioral neurologist (S.G.P.) according to the existing criteria. AD patients met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, American Psychiatric Association) and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorder Association (NINCDS/ADRDA) diagnostic criteria for probable AD.24,25 FTD patients were diagnosed based on the consensus on FTLD.26 Of the 51 FTD patients, 33 received the diagnosis of bvFTD, 13 of semantic dementia, and 5 of progressive nonfluent aphasia. DLB and PDD patients were diagnosed based on the guidelines by McKeith et al.27
TABLE 1. Demographic Characteristics and Performance of the Participant Groups
Groups AD FTLD PDD/DLB Control
n
Age (y) ± SD
Education ± SD
mMMSE ± SD
106 51 26 37
73.01 ± 8.74 65.35 ± 10.16 73.27 ± 5.65 63.40 ± 8.80
10.21 ± 4.64 11.63 ± 4.32 8.42 ± 5.78 10.73 ± 3.91
33.42 ± 10.84 33.29 ± 11.60 31.81 ± 9.21 51.43 ± 2.97
AD indicates Alzheimer disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; mMMSE, modified Mini Mental State Examination; PDD, Parkinson disease with dementia.
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A group of 37 healthy controls was assessed (22 women) for comparison (Table 1). The study was approved by the IRB of the University of Athens Medical School.
Test Materials and Procedure The 5WT is a 5-item immediate and delayed free and cued recall memory test, which employs the same semantic cues to facilitate encoding of the words, and to elicit retrieval if free recall is incomplete.20 A Greek adaptation of the test was administered. Patients were given a sheet of A4 size paper with 5 semantically unrelated words printed centered, in 36-point upper case letters. They were instructed to read them aloud and to remember them, because they would be asked to recall them later on. The words were: museum, grasshopper, lemonade, truck, and strainer. After reading the words aloud, patients were asked to point out and name the word corresponding to the semantic cue given by the examiner in the following order: refreshment, kitchen utensil, vehicle, building, and insect. The sheet was then removed and patients were asked to recall the words in any order (immediate free recall). The examiner provided the semantic cues to elicit retrieval (immediate total recall) for those words that were not recalled. For any words still not recalled, the examiner showed the sheet again and pointed out the missing words, saying the name of the semantic cue corresponding to the word. The sheet was then removed and patients were provided the semantic cues of the words they had missed. This step was repeated as many times as necessary, to ensure encoding of all the words. After a period of about 5 minutes, during which other tests were administered, the patients were asked to produce the 5 words (delayed free recall). For the words not recalled, the examiner provided the semantic cue to elicit retrieval (delayed total recall). Four scores were derived from the test: immediate free recall (0 to 5 points); immediate total recall, which is the sum of the words recalled with cues and those recalled without cues (0 to 5 points); delayed free recall (0 to 5 points); and delayed total recall, which is the sum of the words recalled with cues and those recalled without cues (0 to 5 points). Patients also received a battery of tests that included a Greek adaptation of the modified Mini Mental State Examination (mMMSE, maximum score: 57), the Clock Drawing Test, and the Frontal Assessment Battery.28–30
Episodic Memory in AD, FTD, and DLB/PDD
RESULTS One-way analyses of variance showed a significant effect of age (F3,220 = 15.82, P < 0.0001) and education (F3,219 = 2.93, P < 0.05) (missing education data for 1 control participant). Bonferroni comparisons showed that the control group was younger than the AD and the DLB/ PDD groups (P < 0.0001), and the FTD group was younger than the AD (P < 0.0001) and the DLB/PDD groups (P = 0.01), as expected. Moreover, the FTD group was more educated than the DLB/PDD group (P < 0.05). The 3 patient groups did not differ in mMMSE score, however (F2,182 = 0.24, P > 0.05) (see Table 1 information for mean group scores). Pearson correlation coefficients between age, education, mMMSE, and the 5WT for the patient groups showed that the mMMSE correlated slightly with age, with education, and with all 4 measures of the 5WT. The 5WT delayed recall score correlated slightly with age, and 3 of the 4 measures of the test correlated with education (Table 2). Repeated-measures analyses with Measure as withinsubject factor, Group as between-subject factor, and age (y) and education (y) as covariates, showed no significant main effect for Measure (F3,642 = 0.72, P > 0.05), a significant main effect for Group (F3,214 = 43.53, P < 0.0001, Z2p = 0.38), and a significant Group by Measure interaction (F9,642 = 12.07, P < 0.0001, Z2p = 0.15). Compared with the control group, all patient groups showed lower memory performance (all Ps < 0.0001), as expected. Moreover, AD patients had lower memory performance than FTD patients (P < 0.01) and DLB/PDD patients (P = 0.0001), but DLB/ PDD patients did not differ significantly from FTD patients (P > 0.05). An examination of the Group by Measure interaction showed that the reduction in memory performance from immediate total recall to delayed free recall differed among the groups (F3,214 = 19.86, P < 0.0001, Z2p = 0.22). As expected, the reduction was lowest in the control group and highest in the AD group; FTD and DLB/PDD patients did not differ from each other. Moreover, the improvement from delayed free recall to delayed total recall differed among the groups (F3,214 = 4.38, P < 0.01, Z2p = 0.06). Improvement was smaller in the control group, reflecting the group’s nearceiling performance; it was larger in the DLB/PDD group relative to the other 2 groups (Fig. 1). The nonfluent patients (n = 5) were excluded from the FTLD group and repeated-measures analyses with Measure as within-subject factor, Group as between-subject factor,
TABLE 2. Correlation Coefficients of Demographic Variables and mMMSE (Patient Groups, Only)
Variables 1. 2. 3. 4. 5. 6. 7.
1
Age Education mMMSE Five-words Five-words Five-words Five-words
2 0.05
3 0.17* 0.28***
IFR ITR DFR DTR
4 0.01 0.13 0.36***
5
6
0.00 0.22** 0.53*** 0.73***
0.18* 0.22** 0.22** 0.49*** 0.40***
7 0.07 0.21** 0.36*** 0.49*** 0.60*** 0.69***
*P < 0.05. **P < 0.01. ***P < 0.001. DFR indicates delayed free recall; DTR, delayed total recall (delayed free + cued recall); IFR, immediate free recall; ITR, immediate total recall (immediate free + cued recall); mMMSE, modified Mini Mental State Examination.
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FIGURE 1. Five-Word Test performance by group and measure. AD indicates Alzheimer disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; PDD, Parkinson disease with dementia.
and age (y) and education (y) as covariates, showed no significant main effect for Measure (F3,633 = 0.82, P > 0.05), a significant main effect for Group (F3,211 = 42.07, P < 0.0001, Z2p = 0.37), and a significant Group by Measure interaction (F9,633 = 11.53, P < 0.0001, Z2p = 0.14). Compared with the control group, all patient groups showed lower memory performance (all Ps < 0.0001), as expected. Moreover, AD patients had lower memory performance than FTD patients and DLB/PDD patients (P < 0.01), but DLB/PDD patients did not differ significantly from FTD patients (P > 0.05). An examination of the Group by Measure interaction showed that the reduction in memory performance from immediate total recall to delayed free recall differed among the groups (F3,211 = 19.11, P < 0.0001, Z2p = 0.21). As expected, the reduction was lowest in the control group and highest in the AD group; FTD and DLB/PDD patients did not differ from each other. Moreover, the improvement from delayed free recall to delayed total recall differed among the groups (F3,211 = 3.73, P < 0.05, Z2p = 0.05). Improvement was smaller in the control group, reflecting the group’s nearceiling performance; it was larger in the DLB/PDD group relative to the other 2 groups (Fig. 2). The above analyses were repeated excluding the control group, with the bvFTD group (n = 33), to examine memory differences using a subgroup of FTD patients with a more homogeneous neuropsychological profile. Repeated-measures analyses with Measure as within-subject factor, Group as between-subject factor, and age (y) and education (y) as covariates, showed a significant main effect for Group (F2,160 = 11.25, P < 0.0001, Z2p = 0.12), no significant main effect for Measure (F3,480 = 0.30, P > 0.05), and a significant
Group by Measure interaction (F6,480 = 4.17, P < 0.0001, Z2p = 0.05). Similar to the previous analyses, AD patients had lower memory performance than bvFTD patients and DLB/ PDD patients (all Ps < 0.0001), but DLB/PDD and bvFTD patients did not differ significantly from each other. An examination of the Group by Measure interaction showed a marginal interaction from delayed free recall to delayed total recall among the groups (F2,160 = 2.90, P = 0.058, Z2p = 0.04). Improvement was larger in the DLB/PDD group relative to the other 2 groups (see Supplementary Digital Content for mean values, http://links.lww.com/WAD/A110). The possibility that performance of the DLB/PDD group reflected 2 heterogeneous groups was explored in an additional repeated-measures analysis. There was no significant main effect for Measure (F3,66 = 0.06, P > 0.05), no significant main effect for Group (F1,22 = 2.51, P > 0.05), and no significant Group by Measure interaction (F3,66 = 0.39, P > 0.05).
DISCUSSION The 3 patient groups did not differ in mMMSE score, which covers a broader number of areas than the MMSE. AD patients had lower overall memory performance than both FTD and DLB/PDD patients, consistent with most studies,6,12 with no differences between the latter 2 groups. Because the 5WT is within the normal word span, immediate free recall is expected to benefit both from shortterm memory strategies and from the facilitation of encoding during learning. No differences were found in immediate free recall among the patient groups, possibly because of reliance on short-term memory; however, their
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Episodic Memory in AD, FTD, and DLB/PDD
FIGURE 2. Five-Word Test performance by group and measure (excluding the 5 nonfluent frontotemporal lobar degeneration patients). AD indicates Alzheimer disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; PDD, Parkinson disease with dementia.
lower performance relative to the control group indicates encoding difficulties even with 5 items. Memory loss was larger from immediate total recall to delayed free recall in the AD group, suggesting a consolidation deficit consistent with AD pathology.1 Of greater interest are the differences between delayed free and total recall observed among the patient groups. Because the 5WT facilitates encoding, a retrieval deficit would manifest in greater improvement with cues, whereas a consolidation deficit would manifest in lower delayed recall and smaller differences between free and total recall. Improvement was greater in the DLB/PDD group relative to the other groups, indicating that the patients benefited more from the provision of cues. The results were replicated with the bvFTD patients, only. Differences in delayed total recall between FTD and DLB/PDD patients are especially notable because of their similar delayed free recall. However, the total recall of DLB/PDD patients remained significantly below that of the control group, indicating that retrieval is not the only deficient process observed in the patients. To the best of our knowledge, no studies have compared the memory performance of the 3 groups of patients. Very few studies have employed memory tests that facilitate encoding to explore the specific memory processes that are impaired.18,19,31,32 The present study indicates that deficits in both consolidation and retrieval contribute to the memory impairment of the patients, albeit to different extents. Because the deficits were observed even in a brief, within-span memory test and were evident even in immediate free recall, they are all the more salient. Patients with DLB/ PDD benefit the most from cues, consistent with a predominantly retrieval deficit. The findings contribute to the clarification of inconsistencies in the memory performance of Copyright
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DLB/PDD and FTD patients, and indicate a predominantly retrieval deficit in PDD.5,6,10 The results are partly consistent with the 1 study that compared patients with FTD and AD using a test that controls for encoding, which showed that the patients did not differ in free recall, but differed in the extent of their improvement when cues were provided, indicating mainly retrieval difficulties, although performance did not reach normal values.16 The greater benefit from cues of the DLB/PDD patients relative to the other 2 patient groups needs to be explored further with a larger number of patients with DLB/PDD, bvFTD, and semantic dementia. The study contributes to the theoretical understanding of the nature of the memory impairment in AD, PDD/DLB, and FTD.
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7. Piguet O, Hornberger M, Mioshi E, et al. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol. 2011;10:162–172. 8. Litvan I, Mohr E, Williams J, et al. Differential memory and executive functions in demented patients with Parkinson’s and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1991;54: 25–29. 9. Aretouli E, Brandt J. Episodic memory in dementia: characteristics of new learning that differentiate Alzheimer’s, Huntington’s, and Parkinson’s diseases. Arch Clin Neuropsychol. 2010; 25:396–409. 10. Robottom BJ, Weiner WJ. Dementia in Parkinson’s disease. Int Rev Neurobiol. 2009;84:229–244. 11. Lippa CF, Duda JE, Grossman M, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. 2007;68:812–819. 12. Tro¨ster A. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson’s disease with dementia: differentiation, early detection, and implications for “mild cognitive impairment” and biomarkers. Neuropsychol Rev. 2008;18:103–119. 13. Pennington C, Hodges JR, Hornberger M. Neural correlates of episodic memory in behavioral variant frontotemporal dementia. J Alzheimers Dis. 2011;24:261–268. 14. Collette F, van der Linden M, Salmon E. Dissociation between controlled and automatic processes in the behavioral variant of fronto-temporal dementia. J Alzheimers Dis. 2010;22:897–907. 15. Glosser G, Gallo JL, Clark CM, et al. Memory encoding and retrieval in frontotemporal dementia and Alzheimer’s disease. Neuropsychology. 2002;16:190–196. 16. Pasquier F, Grymonprez L, Lebert F, et al. Memory impairment differs in frontotemporal dementia and Alzheimer’s disease. Neurocase. 2001;7:161–171. 17. Brodaty H, Low LF, Gibson L, et al. What is the best screening instrument for general practitioners to use? Am J Geriatr Psychiatry. 2006;14:391–400. 18. Buschke H, Kuslansky G, Katz M, et al. Screening for dementia with the memory impairment screen (MIS). Neurology. 1999;52:231–237. 19. Kuslansky G, Buschke H, Katz M, et al. Screening for Alzheimer’s disease: the Memory Impairment Screen versus the conventional Three-Word Memory Test. JAGS. 2002;50:1086–1091.
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20. Dubois B, Touchon J, Portet F, et al. “The 5 words”: a simple and sensitive test for the diagnosis of Alzheimer’s disease. Presse Med. 2002;31:1696–1699. 21. Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol. 1987;3:13–36. 22. Mormont E, Jamart J, Robaye L. Validity of the five-word test for the evaluation of verbal episodic memory and dementia in a memory clinic setting. J Geriatr Psych Neur. 2012;25: 78–84. 23. Papageorgiou SC, Kontaxis T, Bonakis A, et al. Frequency and causes of early-onset dementia in a tertiary referral center in Athens. Alzheimer Dis Assoc Disord. 2009;23:347–351. 24. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. Author. 25. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer’s disease. Neurology. 1984;34:939–944. 26. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546–1554. 27. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47:1113–1124. 28. Stern Y, Sano M, Paulson J, et al. Modified Mini-Mental State Examination: validity and reliability. Neurology. 1987;37(suppl 1): 179. 29. Royall DR, Cordes JA, Polk M. CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry. 1998;64: 588–594. 30. Dubois B, Slachevsky A, Litvan I, et al. The FAB: a frontal assessment battery at bedside. Neurology. 2000;55:1621–1622. 31. Pillon B, Blin J, Vidailhet M, et al. The neuropsychological pattern of corticobasal degeneration: comparison with progressive supranuclear palsy and Alzheimer’s disease. Neurology. 1995;45:1477–1483. 32. Tounsi H, Deweer B, Ergis AM, et al. Sensitivity to semantic cuing: an index of episodic memory dysfunction in early Alzheimer disease. Alzheimer Dis Assoc Disord. 1999;13:38–46.
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Episodic Memory in Alzheimer Disease, Frontotemporal Dementia, and Dementia With Lewy Bodies/Parkinson Disease Dementia Disentangling Retrieval From Consolidation Alexandra Economou, PhD,* Christopher Routsis, MA,* and Sokratis G. Papageorgiou, MD, PhDw
Introduction: Differences in episodic memory performance in patients with Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB)/Parkinson disease with dementia (PDD) are inconsistent and task dependent. The inconsistencies may be attributed to the different tasks drawing on different memory processes. Few studies have examined episodic memory impairment in the above groups using memory tests that facilitate encoding, to distinguish memory deficits due to impairment of specific processes. Methods: We examined the memory performance of 106 AD patients, 51 FTD patients, 26 DLB/PDD patients, and 37 controls using the Five-Words Test, a 5-item memory test that facilitates encoding. Results: The patient groups did not differ in modified Mini Mental State Examination scores. AD patients scored lowest on the FiveWords Test overall, and showed the greatest reduction from immediate total recall to delayed free recall relative to the other 2 groups, consistent with a predominantly consolidation deficit. DLB/PDD patients showed the largest improvement from delayed free to delayed total recall relative to the other 2 groups, consistent with a predominantly retrieval deficit. Discussion: Deficits in both consolidation and retrieval underlie the memory impairment of the patients, to different extents, and contribute to the theoretical understanding of the nature of the memory impairment of the patient groups. Key Words: memory, Alzheimer disease, dementia with Lewy bodies, Parkinson disease with dementia, frontotemporal dementia
(Alzheimer Dis Assoc Disord 2016;30:47–52)
Received for publication September 8, 2014; accepted January 16, 2015. From the *Department of Psychology, School of Philosophy; and wCognitive Neurology-Extrapyramidal Disorders Unit, 1st University Department of Neurology, Eginition Hospital, Medical School, University of Athens, Athens, Greece. Present address: Sokratis G. Papageorgiou, MD, PhD, Behavioral Neurology Unit, 2nd University Department of Neurology, ATTIKON University General Hospital at Haidari, University of Athens, Athens, Greece. A preliminary version of this study was presented at the 21st Meeting of the European Neurological Society. The authors declare no conflicts of interest. Reprints: Alexandra Economou, PhD, Department of Psychology, School of Philosophy, The University of Athens, Panepistimiopolis, Ilissia, Athens 157 84, Greece (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
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pisodic memory impairment is a hallmark of the early stages of Alzheimer disease (AD), characterized by an accelerated forgetting rate. Its neural substrate includes the mesial temporal lobes, the diencephalon, and the basal forebrain.1 Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), however, are also characterized by episodic memory impairment, albeit to a somewhat lesser extent; and severity of memory impairment is similar in AD and progressive behavioral variant FTD (bvFTD) of similar disease severity.2,3 The patterns of memory impairment in the different degenerative disorders are associated with the brain structures most affected by the disorders. Patients with AD show lower delayed recall relative to patients with PDD and DLB, attributed to AD pathology affecting medial temporal lobe structures to a greater extent than Lewy body pathology.3,4 Patients with FTD show better learning and memory scores relative to patients with AD in some studies, attributed to the greater difficulty of the patients in generating and implementing organized strategies for the encoding and retrieval of information from memory. This difficulty affects free recall performance regardless of the delay interval. However, as it affects consolidation to a lesser extent, cued recall is less impaired than in AD patients.5 Nevertheless, 10% to 15% of patients with pathologically confirmed frontotemporal lobar degeneration (FTLD) present with severe amnesia, and episodic memory impairment is more common than previously thought.6,7 Recall of verbal information likely depends on the integration between hippocampal structures and prefrontal cortices and the differential contribution of the 2 to episodic memory needs to be clarified.2 Task-dependent differences in the performance of AD, DLB, and PDD patients are consistent with a retrieval deficit in the latter 2 groups, attributed to executive dysfunction.8,9 Degenerative disorders that primarily affect subcorticalfrontal structures manifest in deficits in encoding and retrieval strategies. Although the episodic memory performance of DLB and PDD patients using word-list learning tasks is not consistently superior to that of AD patients across studies, it is consistently better when logically constructed story passages are used, attributed to the contextual support offered by the stories.5 PDD patients benefit from cueing, indicating a predominantly retrieval deficit.10 DLB patients’ poor memory might result from impaired encoding rather than from defective consolidation, because of their better savings scores relative to AD patients in story recall and list
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learning.2,4 However, the overlap of the neuropsychological profiles of DLB and PDD outweighs their differences when the groups are matched for demographic factors and severity of dementia.11,12 Patterns of anterograde memory performance across the FTD subtypes are not always distinctive.5 Patients with bvFTD do not normally show the accelerated forgetting of patients with AD and benefit from retrieval cues. They manifest pathologic heterogeneity in medial temporal lobe involvement, although significant hippocampal atrophy has been reported at postmortem early in the course of the disease.6 The correlations of memory performance with magnetic resonance imaging ratings of regional brain atrophy and findings of prefrontal cortex atrophy in bvFTD provides support for the hypothesis that the memory deficits of the bvFTD is mediated primarily by damage to prefrontal regions, so it is important to employ tests that can differentiate between prefrontal and medial temporal lobe atrophy.6,13 The provision of cues in recall contributes to the disentangling of memory deficits attributed to poor consolidation of information versus those that are primarily due to inefficient encoding and retrieval strategies. The relative superiority of cued versus free recall of FTD patients indicates an inefficient search strategy of information stored in memory, rather than a rapid decay of information.14 However, episodic memory performance has not been examined using memory tasks specifically targeting prefrontal cortex (responsible for encoding and retrieval), versus medial temporal lobe-dependent memory processes (responsible for consolidation), so it is unclear whether poor response to cues is due to inefficient encoding or impaired consolidation of information. Behavior-executive and language FTD patients showed consistently higher recall and steeper rate of learning across multiple presentations of a supraspan list than AD patients, but did not differ from AD patients in delayed recognition memory, and showed equivalent enhancement of memory performance when cued recall was compared with free recall.15 The authors propose that the poor memory of FTD patients is not attributed to a selective retrieval deficit, but to impaired encoding; however, the study did not employ a test that controls for encoding. The only study of FTD and AD patients that employed such a test, to the best of our knowledge, showed that patients with frontal-variant FTD and AD of the same dementia severity did not differ in shortterm memory and in free (immediate and delayed) recall.16 The improvement observed in FTD relative to AD when a cue was provided, together with lower forgetting, suggested predominantly retrieval difficulties, although performance did not reach normal values. Facilitation of encoding of information improves consolidation and retrieval, making it easier to distinguish memory deficits due to impairment of specific memory processes from
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apparent memory deficits due to use of inefficient strategies.17,18 Tests that use the same category cues at acquisition and retrieval optimize encoding specificity, show high sensitivity and specificity to dementia, and superior performance to conventional verbal memory tests.18,19 The Five-Words Test (5WT) is a simple, rapid verbal episodic memory test that controls for encoding, thus allowing the qualitative analysis of type of memory impairment (encoding, consolidation, or retrieval).20 The test performed comparably to the conceptually similar Free and Cued Selective Reminding Test, a supraspan task, and was useful in discriminating mild-moderate dementia from isolated subjective memory complaints.21,22 The qualitative analysis of encoding, consolidation, and retrieval strategies is helpful for the differential diagnosis of dementia, and optimizing encoding can distinguish patients with dementia, especially AD, from persons with subjective memory complaints,22 presumably because it can distinguish between deficits in consolidation from deficits in the encoding/retrieval of information due to optimized encoding. The purpose of this study was to compare memory performance in AD, FTLD, and DLB/PDD patients using a Greek version of the 5WT. A retrieval deficit would manifest in greater cued versus free recall in both immediate and delayed memory, whereas a consolidation deficit would manifest in lower delayed recall, and little benefit from cueing. Assuming a predominantly retrieval deficit in DLB/ PDD and FTLD patients, we predicted that they would benefit more from cueing than AD patients.
METHODS Research Participants A group of 183 neurological patients (106 women), 106 AD patients, 51 FTLD patients, and 26 DLB/PDD patients (8 DLB, 18 PDD patients), comprised the patient sample (see Table 1 for demographic characteristics of the sample). Patients were recruited from the department of neurology of Eginition hospital. They underwent a structured interview, neurological examination, detailed neuropsychological assessment, and laboratory investigations explained elsewhere.23 Diagnoses were specified by the same behavioral neurologist (S.G.P.) according to the existing criteria. AD patients met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, American Psychiatric Association) and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorder Association (NINCDS/ADRDA) diagnostic criteria for probable AD.24,25 FTD patients were diagnosed based on the consensus on FTLD.26 Of the 51 FTD patients, 33 received the diagnosis of bvFTD, 13 of semantic dementia, and 5 of progressive nonfluent aphasia. DLB and PDD patients were diagnosed based on the guidelines by McKeith et al.27
TABLE 1. Demographic Characteristics and Performance of the Participant Groups
Groups AD FTLD PDD/DLB Control
n
Age (y) ± SD
Education ± SD
mMMSE ± SD
106 51 26 37
73.01 ± 8.74 65.35 ± 10.16 73.27 ± 5.65 63.40 ± 8.80
10.21 ± 4.64 11.63 ± 4.32 8.42 ± 5.78 10.73 ± 3.91
33.42 ± 10.84 33.29 ± 11.60 31.81 ± 9.21 51.43 ± 2.97
AD indicates Alzheimer disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; mMMSE, modified Mini Mental State Examination; PDD, Parkinson disease with dementia.
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A group of 37 healthy controls was assessed (22 women) for comparison (Table 1). The study was approved by the IRB of the University of Athens Medical School.
Test Materials and Procedure The 5WT is a 5-item immediate and delayed free and cued recall memory test, which employs the same semantic cues to facilitate encoding of the words, and to elicit retrieval if free recall is incomplete.20 A Greek adaptation of the test was administered. Patients were given a sheet of A4 size paper with 5 semantically unrelated words printed centered, in 36-point upper case letters. They were instructed to read them aloud and to remember them, because they would be asked to recall them later on. The words were: museum, grasshopper, lemonade, truck, and strainer. After reading the words aloud, patients were asked to point out and name the word corresponding to the semantic cue given by the examiner in the following order: refreshment, kitchen utensil, vehicle, building, and insect. The sheet was then removed and patients were asked to recall the words in any order (immediate free recall). The examiner provided the semantic cues to elicit retrieval (immediate total recall) for those words that were not recalled. For any words still not recalled, the examiner showed the sheet again and pointed out the missing words, saying the name of the semantic cue corresponding to the word. The sheet was then removed and patients were provided the semantic cues of the words they had missed. This step was repeated as many times as necessary, to ensure encoding of all the words. After a period of about 5 minutes, during which other tests were administered, the patients were asked to produce the 5 words (delayed free recall). For the words not recalled, the examiner provided the semantic cue to elicit retrieval (delayed total recall). Four scores were derived from the test: immediate free recall (0 to 5 points); immediate total recall, which is the sum of the words recalled with cues and those recalled without cues (0 to 5 points); delayed free recall (0 to 5 points); and delayed total recall, which is the sum of the words recalled with cues and those recalled without cues (0 to 5 points). Patients also received a battery of tests that included a Greek adaptation of the modified Mini Mental State Examination (mMMSE, maximum score: 57), the Clock Drawing Test, and the Frontal Assessment Battery.28–30
Episodic Memory in AD, FTD, and DLB/PDD
RESULTS One-way analyses of variance showed a significant effect of age (F3,220 = 15.82, P < 0.0001) and education (F3,219 = 2.93, P < 0.05) (missing education data for 1 control participant). Bonferroni comparisons showed that the control group was younger than the AD and the DLB/ PDD groups (P < 0.0001), and the FTD group was younger than the AD (P < 0.0001) and the DLB/PDD groups (P = 0.01), as expected. Moreover, the FTD group was more educated than the DLB/PDD group (P < 0.05). The 3 patient groups did not differ in mMMSE score, however (F2,182 = 0.24, P > 0.05) (see Table 1 information for mean group scores). Pearson correlation coefficients between age, education, mMMSE, and the 5WT for the patient groups showed that the mMMSE correlated slightly with age, with education, and with all 4 measures of the 5WT. The 5WT delayed recall score correlated slightly with age, and 3 of the 4 measures of the test correlated with education (Table 2). Repeated-measures analyses with Measure as withinsubject factor, Group as between-subject factor, and age (y) and education (y) as covariates, showed no significant main effect for Measure (F3,642 = 0.72, P > 0.05), a significant main effect for Group (F3,214 = 43.53, P < 0.0001, Z2p = 0.38), and a significant Group by Measure interaction (F9,642 = 12.07, P < 0.0001, Z2p = 0.15). Compared with the control group, all patient groups showed lower memory performance (all Ps < 0.0001), as expected. Moreover, AD patients had lower memory performance than FTD patients (P < 0.01) and DLB/PDD patients (P = 0.0001), but DLB/ PDD patients did not differ significantly from FTD patients (P > 0.05). An examination of the Group by Measure interaction showed that the reduction in memory performance from immediate total recall to delayed free recall differed among the groups (F3,214 = 19.86, P < 0.0001, Z2p = 0.22). As expected, the reduction was lowest in the control group and highest in the AD group; FTD and DLB/PDD patients did not differ from each other. Moreover, the improvement from delayed free recall to delayed total recall differed among the groups (F3,214 = 4.38, P < 0.01, Z2p = 0.06). Improvement was smaller in the control group, reflecting the group’s nearceiling performance; it was larger in the DLB/PDD group relative to the other 2 groups (Fig. 1). The nonfluent patients (n = 5) were excluded from the FTLD group and repeated-measures analyses with Measure as within-subject factor, Group as between-subject factor,
TABLE 2. Correlation Coefficients of Demographic Variables and mMMSE (Patient Groups, Only)
Variables 1. 2. 3. 4. 5. 6. 7.
1
Age Education mMMSE Five-words Five-words Five-words Five-words
2 0.05
3 0.17* 0.28***
IFR ITR DFR DTR
4 0.01 0.13 0.36***
5
6
0.00 0.22** 0.53*** 0.73***
0.18* 0.22** 0.22** 0.49*** 0.40***
7 0.07 0.21** 0.36*** 0.49*** 0.60*** 0.69***
*P < 0.05. **P < 0.01. ***P < 0.001. DFR indicates delayed free recall; DTR, delayed total recall (delayed free + cued recall); IFR, immediate free recall; ITR, immediate total recall (immediate free + cued recall); mMMSE, modified Mini Mental State Examination.
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FIGURE 1. Five-Word Test performance by group and measure. AD indicates Alzheimer disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; PDD, Parkinson disease with dementia.
and age (y) and education (y) as covariates, showed no significant main effect for Measure (F3,633 = 0.82, P > 0.05), a significant main effect for Group (F3,211 = 42.07, P < 0.0001, Z2p = 0.37), and a significant Group by Measure interaction (F9,633 = 11.53, P < 0.0001, Z2p = 0.14). Compared with the control group, all patient groups showed lower memory performance (all Ps < 0.0001), as expected. Moreover, AD patients had lower memory performance than FTD patients and DLB/PDD patients (P < 0.01), but DLB/PDD patients did not differ significantly from FTD patients (P > 0.05). An examination of the Group by Measure interaction showed that the reduction in memory performance from immediate total recall to delayed free recall differed among the groups (F3,211 = 19.11, P < 0.0001, Z2p = 0.21). As expected, the reduction was lowest in the control group and highest in the AD group; FTD and DLB/PDD patients did not differ from each other. Moreover, the improvement from delayed free recall to delayed total recall differed among the groups (F3,211 = 3.73, P < 0.05, Z2p = 0.05). Improvement was smaller in the control group, reflecting the group’s nearceiling performance; it was larger in the DLB/PDD group relative to the other 2 groups (Fig. 2). The above analyses were repeated excluding the control group, with the bvFTD group (n = 33), to examine memory differences using a subgroup of FTD patients with a more homogeneous neuropsychological profile. Repeated-measures analyses with Measure as within-subject factor, Group as between-subject factor, and age (y) and education (y) as covariates, showed a significant main effect for Group (F2,160 = 11.25, P < 0.0001, Z2p = 0.12), no significant main effect for Measure (F3,480 = 0.30, P > 0.05), and a significant
Group by Measure interaction (F6,480 = 4.17, P < 0.0001, Z2p = 0.05). Similar to the previous analyses, AD patients had lower memory performance than bvFTD patients and DLB/ PDD patients (all Ps < 0.0001), but DLB/PDD and bvFTD patients did not differ significantly from each other. An examination of the Group by Measure interaction showed a marginal interaction from delayed free recall to delayed total recall among the groups (F2,160 = 2.90, P = 0.058, Z2p = 0.04). Improvement was larger in the DLB/PDD group relative to the other 2 groups (see Supplementary Digital Content for mean values, http://links.lww.com/WAD/A110). The possibility that performance of the DLB/PDD group reflected 2 heterogeneous groups was explored in an additional repeated-measures analysis. There was no significant main effect for Measure (F3,66 = 0.06, P > 0.05), no significant main effect for Group (F1,22 = 2.51, P > 0.05), and no significant Group by Measure interaction (F3,66 = 0.39, P > 0.05).
DISCUSSION The 3 patient groups did not differ in mMMSE score, which covers a broader number of areas than the MMSE. AD patients had lower overall memory performance than both FTD and DLB/PDD patients, consistent with most studies,6,12 with no differences between the latter 2 groups. Because the 5WT is within the normal word span, immediate free recall is expected to benefit both from shortterm memory strategies and from the facilitation of encoding during learning. No differences were found in immediate free recall among the patient groups, possibly because of reliance on short-term memory; however, their
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Episodic Memory in AD, FTD, and DLB/PDD
FIGURE 2. Five-Word Test performance by group and measure (excluding the 5 nonfluent frontotemporal lobar degeneration patients). AD indicates Alzheimer disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; PDD, Parkinson disease with dementia.
lower performance relative to the control group indicates encoding difficulties even with 5 items. Memory loss was larger from immediate total recall to delayed free recall in the AD group, suggesting a consolidation deficit consistent with AD pathology.1 Of greater interest are the differences between delayed free and total recall observed among the patient groups. Because the 5WT facilitates encoding, a retrieval deficit would manifest in greater improvement with cues, whereas a consolidation deficit would manifest in lower delayed recall and smaller differences between free and total recall. Improvement was greater in the DLB/PDD group relative to the other groups, indicating that the patients benefited more from the provision of cues. The results were replicated with the bvFTD patients, only. Differences in delayed total recall between FTD and DLB/PDD patients are especially notable because of their similar delayed free recall. However, the total recall of DLB/PDD patients remained significantly below that of the control group, indicating that retrieval is not the only deficient process observed in the patients. To the best of our knowledge, no studies have compared the memory performance of the 3 groups of patients. Very few studies have employed memory tests that facilitate encoding to explore the specific memory processes that are impaired.18,19,31,32 The present study indicates that deficits in both consolidation and retrieval contribute to the memory impairment of the patients, albeit to different extents. Because the deficits were observed even in a brief, within-span memory test and were evident even in immediate free recall, they are all the more salient. Patients with DLB/ PDD benefit the most from cues, consistent with a predominantly retrieval deficit. The findings contribute to the clarification of inconsistencies in the memory performance of Copyright
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DLB/PDD and FTD patients, and indicate a predominantly retrieval deficit in PDD.5,6,10 The results are partly consistent with the 1 study that compared patients with FTD and AD using a test that controls for encoding, which showed that the patients did not differ in free recall, but differed in the extent of their improvement when cues were provided, indicating mainly retrieval difficulties, although performance did not reach normal values.16 The greater benefit from cues of the DLB/PDD patients relative to the other 2 patient groups needs to be explored further with a larger number of patients with DLB/PDD, bvFTD, and semantic dementia. The study contributes to the theoretical understanding of the nature of the memory impairment in AD, PDD/DLB, and FTD.
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7. Piguet O, Hornberger M, Mioshi E, et al. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol. 2011;10:162–172. 8. Litvan I, Mohr E, Williams J, et al. Differential memory and executive functions in demented patients with Parkinson’s and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1991;54: 25–29. 9. Aretouli E, Brandt J. Episodic memory in dementia: characteristics of new learning that differentiate Alzheimer’s, Huntington’s, and Parkinson’s diseases. Arch Clin Neuropsychol. 2010; 25:396–409. 10. Robottom BJ, Weiner WJ. Dementia in Parkinson’s disease. Int Rev Neurobiol. 2009;84:229–244. 11. Lippa CF, Duda JE, Grossman M, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. 2007;68:812–819. 12. Tro¨ster A. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson’s disease with dementia: differentiation, early detection, and implications for “mild cognitive impairment” and biomarkers. Neuropsychol Rev. 2008;18:103–119. 13. Pennington C, Hodges JR, Hornberger M. Neural correlates of episodic memory in behavioral variant frontotemporal dementia. J Alzheimers Dis. 2011;24:261–268. 14. Collette F, van der Linden M, Salmon E. Dissociation between controlled and automatic processes in the behavioral variant of fronto-temporal dementia. J Alzheimers Dis. 2010;22:897–907. 15. Glosser G, Gallo JL, Clark CM, et al. Memory encoding and retrieval in frontotemporal dementia and Alzheimer’s disease. Neuropsychology. 2002;16:190–196. 16. Pasquier F, Grymonprez L, Lebert F, et al. Memory impairment differs in frontotemporal dementia and Alzheimer’s disease. Neurocase. 2001;7:161–171. 17. Brodaty H, Low LF, Gibson L, et al. What is the best screening instrument for general practitioners to use? Am J Geriatr Psychiatry. 2006;14:391–400. 18. Buschke H, Kuslansky G, Katz M, et al. Screening for dementia with the memory impairment screen (MIS). Neurology. 1999;52:231–237. 19. Kuslansky G, Buschke H, Katz M, et al. Screening for Alzheimer’s disease: the Memory Impairment Screen versus the conventional Three-Word Memory Test. JAGS. 2002;50:1086–1091.
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20. Dubois B, Touchon J, Portet F, et al. “The 5 words”: a simple and sensitive test for the diagnosis of Alzheimer’s disease. Presse Med. 2002;31:1696–1699. 21. Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol. 1987;3:13–36. 22. Mormont E, Jamart J, Robaye L. Validity of the five-word test for the evaluation of verbal episodic memory and dementia in a memory clinic setting. J Geriatr Psych Neur. 2012;25: 78–84. 23. Papageorgiou SC, Kontaxis T, Bonakis A, et al. Frequency and causes of early-onset dementia in a tertiary referral center in Athens. Alzheimer Dis Assoc Disord. 2009;23:347–351. 24. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. Author. 25. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer’s disease. Neurology. 1984;34:939–944. 26. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546–1554. 27. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47:1113–1124. 28. Stern Y, Sano M, Paulson J, et al. Modified Mini-Mental State Examination: validity and reliability. Neurology. 1987;37(suppl 1): 179. 29. Royall DR, Cordes JA, Polk M. CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry. 1998;64: 588–594. 30. Dubois B, Slachevsky A, Litvan I, et al. The FAB: a frontal assessment battery at bedside. Neurology. 2000;55:1621–1622. 31. Pillon B, Blin J, Vidailhet M, et al. The neuropsychological pattern of corticobasal degeneration: comparison with progressive supranuclear palsy and Alzheimer’s disease. Neurology. 1995;45:1477–1483. 32. Tounsi H, Deweer B, Ergis AM, et al. Sensitivity to semantic cuing: an index of episodic memory dysfunction in early Alzheimer disease. Alzheimer Dis Assoc Disord. 1999;13:38–46.
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