Dissociation of Vascular Dementia and Alzheimer s Disease using a Sequential. Working Memory and Recognition Task. A Dissertation

Transcription

1 Dissociation of Vascular Dementia and Alzheimer s Disease using a Sequential Working Memory and Recognition Task A Dissertation Submitted to the Faculty of Drexel University by Benjamin M. Hampstead in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2006

2 Copyright 2006 Benjamin M. Hampstead. All Rights Reserved

3 ii DEDICATIONS To my wife Sara for all her love and support and to my family, especially my parents, who have shown so much strength and courage.

4 iii ACKNOWLEDGEMENTS I wish to thank my committee for their helpful comments on this project and for their individual guidance throughout graduate school. I also wish to thank Dr. Anthony Y. Stringer for his help with data analyses and interpretation of the results. I would especially like to thank Dr. David J. Libon for his mentorship during this study as well as Dr. Douglas L. Chute for all of his guidance and Dougisms over the past five years.

5 iv TABLE OF CONTENTS ABSTRACT... ix CHAPTER 1. INTRODUCTION Alzheimer's Disease Neuropsychological Profile and Neuropathology of AD Vascular Dementia Diagnostic Criteria for VaD Pathological Processes in Vascular Dementia Neuropsychological Profile of VaD Comparisons between Alzheimer's Disease and Vascular Dementia Neuropsychological Comparisons Functional Neuroimaging Alzheimer's Disease Vascular Dementia Alzheimer's Disease versus Vascular Dementia Conclusions of the Differences between Alzheimer's Disease and Vascular Dementia Memory for Temporal Order and Executive Functioning Lesion Studies Functional Neuroimaging Temporal Order Memory and Dementia Summary... 27

6 v 1.5 Hypotheses, and Predictions for the Sequencing Task Methods to Increase the Likelihood of Errors Predictions for Foil Selection Design and Predictions for the Recognition Phase Summary of Hypotheses and Predictions CHAPTER 2. METHODS Subjects Materials The Sequencing Test to Evaluate Alternative Dementias (STEAD) Sequence Creation Test Design Scoring System for the STEAD Statistical Analysis CHAPTER 3. RESULTS Demographic Variables STEAD Results Raw Error Analyses During the Sequencing Test Error Score Analyses During the Sequencing Test Serial Position Effect Foil Selection Recognition Task Results Correlational Analyses CHAPTER 4. DISCUSSION... 52

7 vi 4.1 Executive Functioning Sequencing Task Findings Foil Selection Summary of Executive Functioning in Relation to the STEAD Encoding Abilities Limitations Implications CHAPTER 5. CONCLUSIONS CHAPTER 6. WORKS CITED Appendix A. STEAD Instructions Appendix B. STEAD Test Form... 80

8 vii LIST OF TABLES Table 1 Total Error Points Table 2 Demographic Data Table 3 Effect Sizes Table 4 Correlational Analyses... 51

9 viii LIST OF FIGURES Figure 1: Total Raw Errors Figure 2: Raw Errors by Span Length Figure 3: Total Error Score Figure 4: Error Score by Span Length Figure 5: Serial Position Effect Figure 6: Foil Selection Figure 7: Recognition Performance Figure 8: Sequence Incorrect - Recognition Correct Trials... 49

10 ix ABSTRACT Dissociation of Vascular Dementia and Alzheimer s Disease using a Sequential Working Memory and Recognition Task Benjamin M. Hampstead Douglas L. Chute, Ph.D. Previous research suggests that it is possible to differentiate between patients with dementia due to subcortical ischemic white matter disease (i.e. vascular dementia VaD) from those with Alzheimer s disease (AD), as the former generally demonstrate executive dysfunction within the context of preserved recognition memory (i.e. encoding ability) whereas the opposite pattern is present in patients with AD. Executive abilities, specifically working memory, are important in utilizing the temporal aspects of memory (e.g. the sequence in which events occurred). Thus, a novel test was developed wherein participants were asked to sequence and then recognize a series of letters from among distracters with the expectation that the VaD patients would perform more poorly on the sequencing task whereas those with AD would do worse on the recognition component. Participants with mild AD (n=14), mild VaD (n=13), and healthy controls (n=10) were administered the experimental task and traditional neuropsychological tests of working memory and recognition memory. The patients were diagnosed with either AD or VaD and were required to have either low or high white matter damage, respectively, as evidenced by MRI scans. The VaD group performed worse during the sequencing task and also demonstrated difficulty utilizing the temporal aspects of memory. There was some evidence that encoding was relatively preserved in the VaD group compared to the AD patients following even the short delays used in this study (i.e. 15 seconds). Thus, the

11 x results support the relationship between executive abilities and the temporal aspects of memory and suggest that white matter damage can result in deficits analogous to those observed with cortical lesions. Additionally, the methods used in the experimental task may hold promise for examining such abilities within these and other populations.

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13 CHAPTER 1. INTRODUCTION According to recent census data, there are 36 million Americans aged 65 or older, who account for over 12 percent of the current population ( An additional 68 million individuals will turn 65 within the next 20 years. With this influx of elderly comes the increased probability of dementia. Alzheimer s disease (AD) is widely accepted as the most common form of dementia in Western countries (Yanagihara, 2002). Current prevalence rates of AD range from approximately 1 million to 4 million cases in the United States alone (e.g. Brookmeyer, Gray, & Kawas, 1998). One recent study followed over 7,000 adults, aged 55 or older, for an average of almost six years and found an AD incidence rate of 7.2 per 1000 (Ruitenberg, Ott, van Swienten, Hofman, & Breteler, 2001). Vascular dementia (VaD) was the second most common form of dementia in this study with an incidence rate of 1.5 per A similar rate of VaD (2.52 per 1000) was found in another large study over a five year period (Hebert, Lindsay, Verreault, Rockwood, Hill, & Dubois, 2000). However, the true incidence of VaD is difficult to determine due to variability in diagnostic criteria (see section 1.2.1). Additionally, there is evidence that VaD and AD frequently co-exist (e.g. Roman, Erkinjuntti, Wallin, Pantoni, & Chui, 2002; Desmond, Moroney, Paik, Sano, Mohr, Aboumatar, Tseng, Chan, Williams, Remien, Hauser, & Stern, 2000; Heyman, Fillenbaum, Welsh-Bohmer, Gearing, Mirra, Mohs, Peterson, & Pieper, 1998) making the true prevalence of each condition difficult to determine. Statistical models have predicted there will be eight to ten million cases of Alzheimer s disease by the year 2050, approximately three times the current number

14 (Brookmeyer et al., 1998; Sloane, Zimmerman, Suchindran, Reed, Wang, Boustani, & Sudha, 2002). Such increases could result in over one million new cases of dementia diagnosed annually (Brookmeyer et al., 1998), with associated costs ranging from $12,000 to over $56,000 per patient per year (see Moore, Zhu, & Clipp, 2001 for a brief review). Family members typically provide the majority of care, especially during the mild to moderate stages of dementia, and these informal costs have been estimated at over $18,000 per patient per year (Moore et al., 2001). The early diagnosis and treatment of dementia could markedly improve the quality of life for both patients and their families. Several new treatments have been developed and employed in those with both VaD and AD, with the intention of slowing or, if possible, halting disease progression (see Desmond, 2004 or Roman et al., 2002 for reviews). Brookmeyer et al. (1998) estimated annual savings of $10 billion if the onset of Alzheimer s disease was postponed for one year, $4.7 billion if delayed for six months. In order for these benefits to be realized the cognitive profiles associated with the respective dementing disorder need to be as sophisticated as possible. 1.1 Alzheimer s Disease Neuropsychological Profile and Neuropathology of Alzheimer s Disease A great deal of research has been performed on the cognitive and memory deficits associated with Alzheimer s disease and these deficits are best understood within the context of the cerebral pathology. Braak and Braak (1991, 1997) performed histological examination on over 2,600 brains in order to chart the progression of neurofibrillary tangles (NFT), neuropil threads (NT), neuritic plaques, and amyloid protein deposits (AP)

15 during AD. The neuritic plaques develop in a patchy, ill defined manner later in the course of the disease and, for this reason, will not be further considered. Although individual differences are observed, these other pathological changes first develop within the inferior temporal lobe, especially the entorhinal cortex (NFT/NT stages I II; Braak & Braak, 1991). It has been estimated that up to 50 percent of the neurons within the entorhinal cortex are lost during the very early stages of the disease (i.e. Clinical Dementia Rating = 0.5) while over 90 percent are lost in the severe stages (see Morrison & Hof, 2002 for a more thorough review). Additionally, APs are often encountered in the basal frontal, temporal, and occipital cortices during the early stages of the disease (AP stage A; Braak & Braak, 1991). Pathology then spreads into the subiculum and CA1 field of the hippocampus, damaging the perforant pathway and thereby isolating the hippocampus from the rest of the cortex (tangles: stages III IV; APs stage A; Braak & Braak, 1997). Such changes are evident in volumetric reductions in the hippocampus and temporal horn (Morrison & Hof, 2002). The importance of the medial temporal lobes (i.e. parahippocampal, perirhinal, and entorhinal cortices and the hippocampus) for the formation of new memories is well established (e.g. Squire & Zola-Morgan, 1991); thus, it is not surprising that progressively worsening memory difficulty is often the first symptom of AD (Knopman & Selnes, 2003). During the later stages, the NFTs / NTs (stage V VI) and APs (stage B C) spread and affect all cortical associational areas (Braak & Braak, 1991). Morrison and Hof (2002) reported significant cell loss in area 9 of the prefrontal cortex in those with a Clinical Dementia Rating Scale (CDR) of 2 (i.e. moderate AD) as compared to those with CDR scores of 0.5 (very mild) or 1 (mild AD). Continued cell loss was observed in those

16 with a CDR of 3 (severe AD). Similarly, total cortical atrophy was percent greater in those with moderate to severe AD compared to healthy controls (Mouton, Martin, Calhoun, Dalforno, & Price, 1998). Such findings are related to increased difficulty with language (e.g. word finding, fluency, and naming), executive functioning (e.g. working memory, planning, self-monitoring and inhibition, mental flexibility), visuospatial abilities, and processing speed, although mild deficits in these domains may be observed during the early stages of the illness. Similarly, functional independence becomes progressively worse with disease progression (Morrison & Hof, 2002). Primary motor and sensory areas are left relatively intact until the very late stages of the disease (i.e. NFT/NT stage VI and AP stage C; Braak & Braak 1991). Cognitive decline in those with AD generally begins with memory difficulty that is initially restricted to the learning and retention of new information (i.e. encoding deficits), but also encompasses remote knowledge as the disease progresses. Language deficits involving impaired lexical access and frank loss of semantic knowledge are also evident early in the disease and additional deficits in the areas of executive functioning and visuospatial abilities follow (Knopman & Selnes, 2003). Primary motor and sensory cortices remain relatively intact until late in the disease process. The primary diagnostic criteria for the disease have been in place for over 20 years (NINCDS-ADRDA) and have proven useful for both clinical and research purposes (McKhann et al., 1984). Briefly, these criteria require significant cognitive deficits in two or more cognitive domains, including memory, that have demonstrated a progressive decline in the absence of any systemic disorders or other brain diseases.

17 1.2 Vascular Dementia Diagnostic Criteria for Vascular Dementia Several different classification systems have been developed in an attempt to diagnose vascular dementia; unfortunately, the heterogeneity of the disorder has limited the sensitivity and specificity of these systems. A thorough discussion of the diagnostic criteria for VaD is beyond the scope of the present review; however, the guidelines recommended by Roman and colleagues are most relevant to the current study because they relate to subcortical ischaemic vascular dementia (SIVD; Roman, Erkinjuntti, Wallin, Pantoni, & Chui, 2002). The cognitive criteria for SIVD include the presence of a dysexecutive syndrome, memory impairment (impaired recall with relatively intact recognition), and evidence of deterioration from a higher level of functioning. A history of cerebrovascular disease must also be present with signs evident via neuroimaging. Specific neuroimaging criteria were set forth and include the presence of periventricular and deep white matter lesions / hyperintensities or lacunes in the deep grey matter and at least moderate white matter lesions and no evidence of hemorrhages or non-lacunar infarcts (among other requirements) (Roman et al., 2002). The results of two recent studies are consistent with these diagnostic criteria and will serve as the basis for patient selection in the current study. Cosentino and colleagues compared the frequency of diagnosis and clinical characteristics of patients previously diagnosed with AD or VaD using four of the most common classification systems (i.e. ADDTC criteria for Ischaemic Vascular Dementia, NINDS-AIREN criteria for Vascular Dementia (van Straaten et al., 2003), ICD-10 criteria for Vascular Dementia, Bennett s criteria for Binswanger s disease; (Cosentino et

18 al., 2004). This study additionally sought to identify other factors, such as the presence/extent of white matter abnormalities and the neuropsychological profile, associated with those diagnosed within each system. Across all schemes, neuroimaging accurately classified 100% of patients regardless of the criteria used, while clinical history (46%) and neurologic deficit (28%) were less useful in this process. When cerebral white matter hyperintensities were examined using the leukoaraiosis scale (LA) developed by Junque and colleagues (Junque et al., 1990), the VaD group received ratings approximately three times as high as the AD group regardless of the diagnostic scheme used (Cosentino et al., 2004). The cognitive profile of those diagnosed with VaD was consistent with the SIVD criteria (i.e. greater executive dysfunction with relatively preserved encoding) and is discussed in more detail below. Another recent study classified patients based solely on the extent of white matter damage, as measured by the LA score, into low (0 20 percent), medium (22 42 percent), and severe (45-70 percent) pathology (Price, Jefferson, Merino, Heilman, & Libon, 2005). Whereas the low group demonstrated impaired memory and language with relatively preserved executive and visuoconstructional functions, the severe group showed the opposite pattern. The moderate group also demonstrated milder executive and visuoconstructional dysfunction within the context of preserved memory and language skills. The results of these studies are generally consistent with the diagnostic criteria for subcortical ischaemic vascular dementia (SIVD) set forth by Roman and colleagues (Roman et al., 2002). The reason(s) for the observed pattern of cognitive deficits is best

19 understood within the context of the pathological mechanisms, which are discussed below Pathological processes in Vascular Dementia Whereas the pathological mechanisms and clinical course of Alzheimer s disease are relatively predictable the cause(s) and course of dementia resulting from cerebrovascular disease is more variable and less understood. Libon and colleagues discussed common extra- and intra-cranial causes of vascular dementia (VaD; Libon, Price, Davis-Garrett, & Giovannetti, 2004). Atherosclerosis, emboli, and thrombi were all sources of extra-cranial pathology that commonly affect both large and small cerebral vessels. Atherosclerosis, caused by gradual buildup of fibroblasts, limits the plasticity of the vessel, thereby increasing the likelihood of blockage. This process has been associated with increased risk of lacunar infarcts and microinfarcts (Vinters et al., 2000). Emboli (typically a blood clot) are often formed elsewhere in the body (e.g. heart, lungs) and, upon entering the bloodstream, block a cerebral vessel causing sudden symptom onset. The effects of a thrombotic infarct occur more gradually due to relatively slow buildup of blood cells in cerebral vessels (Blumenfeld, 2002). Given the nature of the patients used in the current study, review of subsequent literature will primarily focus on those with ischemic white matter disease. Evidence of white matter disease, termed leukoaraiosis (LA), is demonstrated on structural neuroimaging where abnormalities appear as hyperintense signal on T2 weighted MRI and hypodense areas on CT. Risk factors for LA include increased age, diabetes mellitus, and hypertension (Pantoni and Garcia, 1997). Periventricular and subcortical white matter

20 are the most common areas for LA, presumably because these areas are perfused by small penetrating arteries that lengthen and become more torturous with age (Pantoni and Garcia, 1997). Given their small size, these arteries are especially susceptible to arteriolosclerosis, which results in chronic hypoperfusion to the surrounding white matter. Contributing to this hypoperfusion is the impaired autoregulation of blood pressure in the small vessels of those with LA (Pantoni and Garcia, 1997). Such difficulty manifests as alterations in circadian rhythm where blood pressure varies greatly during the day and does not demonstrate the typical nocturnal drop that is found in healthy individuals. This inability to regulate cerebral blood flow increases the likelihood of ischemic injury both in general and especially with a sudden drop in blood pressure (e.g. with orthostatic hypotension). From a pathological standpoint, rarefaction of the white matter is evident by loss and/or separation of the myelin from the axon, enlarged extracellular space, loss of oligodendrocytes, and astrogliosis (Pantoni and Garcia, 1997; Udaka, Sawada, & Kameyama, 2002). Additionally, breakdown of the blood brain barrier may allow cerebral proteins into the brain parenchyma, resulting in a toxic effect. Evidence of this process comes from both animal and human literature. For example, immunostaining of the brain of surgically-induced hypertensive monkeys revealed evidence of microinfarcts and extensive gliosis within the cerebral white matter as well as leaks in the blood brain barrier, abnormalities that were most common within the prefrontal cortex (Kemper, Blatt, Killiany, & Moss, 2001). Additionally, patients with cerebral small vessel disease demonstrated significant differences in endothelial function, as measured by the presence of various blood proteins, compared to healthy controls (Hassan et al.,

21 2003). Importantly, different patterns of abnormalities were evident in those with lacunar infarcts (i.e. acute occurrences of hypoperfusion) and patients with leukoaraiosis (i.e., chronic hypoperfusion). Similarly, increased levels of C-reactive protein, a systemic marker of inflammation, were highly associated with white matter lesions in nondemented elderly patients (van Dijk et al., 2005). Whereas immediate cognitive deficits are seen with hemorrhagic strokes or infarctions within major arteries, a more insidious onset has been reported in those with leukoaraiosis (e.g. Desmond, 2004; Libon et al., 2004), which is consistent with the notion of a chronic process. In this regard, Wardlaw (2005) posited that a critically toxic point is reached where axons cease to transmit signals and, presumably, cognitive dysfunction arises as a result. There is a growing body of research that has examined the neurocognitive profile of those with vascular dementia and a rather consistent profile of cognitive deficits is emerging from this work Neuropsychological Profile of Vascular Dementia The cognitive criteria set forth for SIVD (i.e. executive dysfunction with relatively preserved memory) appear to comprise the core deficits associated with patients with significant white matter disruptions and is supported by numerous findings. In one of the largest studies to date, patients diagnosed with VaD or vascular cognitive impairment (VCI) as the result of ischaemic stroke were compared with healthy controls and other stroke patients who were cognitively intact (Sachdev et al., 2004). All subjects received a thorough neuropsychological assessment and an MRI that was rated for atrophy, infarctions, and periventricular and deep white matter hyperintensities. Total

22 stroke volume was significantly greater in those with VaD when compared to the VCI group; however, both of these groups showed significantly more white matter abnormalities than the cognitively intact stroke patients, who demonstrated more hyperintensities than the healthy controls. Cognitively, the most severe deficits in both the VaD and VCI groups were in the domains of executive functioning (i.e. working memory, abstraction and reasoning, mental flexibility, and fluency), visuoconstructional abilities, processing speed, and visual, but not verbal, learning and retention (Sachdev et al., 2004). Neuropsychological dysfunction in these patients was significantly correlated with the extent of white matter pathology, especially within the frontal white matter and internal capsule. These results are consistent with a meta-analysis that found an inverse relationship white matter hyperintensities, as measured by MRI and CT, and cognitive functioning in non-demented patients (Gunning-Dixon and Raz, 2000). Specifically, performance on measures of immediate and delayed memory, processing speed, executive functioning, and global cognitive functioning (e.g. MMSE) worsened as the severity of the hyperintensities increased. White matter hyperintensities were observed in one third of a large group (N=3301) of elderly subjects and were correlated with factors such as age, silent stroke, and hypertension. These lesions were related to cognitive dysfunction, as measured by the MMSE and the digit-symbol substitution test (Longstreth et al., 1996). Similar results have been found using diffusion tensor imaging, which allows for quantitative analysis of white matter integrity in the visible hyperintensities as well as in normal appearing white matter (e.g. Moseley, Bammer, & Illes, 2002). This method has

23 been used to assess white matter in a variety of populations (e.g. healthy aging, multiple sclerosis, and dementia). O Sullivan and colleagues applied this technique to patients with leukoaraiosis evident on MRI, all of whom had a history of lacunar stroke (O Sullivan, Morris, Huckstep, Jones, Williams, & Markus, 2004). These patients demonstrated increased diffusivity within both the hyperintensities and the normal appearing white matter (i.e. indicative of rarefied white matter) when compared to controls. While there was no relationship between lesion load, as measured on traditional MRI, and cognitive performance, a significant correlation was found between the diffusivity of the normal appearing white matter and Full Scale IQ (WAIS-R) and tests of executive functioning (WCST). Sachdev et al. (2004) suggest the executive deficits in VaD are caused by disconnection of frontal lobes from striatum, thalamus, and medial temporal lobes. Were this to be true, patients with vascular dementia should perform similarly to those with traditional subcortical dementia (i.e. Parkinson s disease) on neuropsychological measures. In fact, the neuropsychological performances of those with vascular dementia were indistinguishable from patients with Parkinson s disease (PD) using both a battery of tests (Libon et al., 2001) and by examining performance during an individual task (Experiment 2; Lamar, Price, Davis, Kaplan, & Libon, 2002). Based on these results, Libon et al. (2001) suggest that vascular dementia is best classified as a subcortical form of dementia. This claim was recently supported when VaD and PD patients showed similar patterns of executive dysfunction (Lamar, Swenson, Kaplan, & Libon, 2004; see section for more details).

24 1.3 Comparisons between Alzheimer s disease and Vascular Dementia Neuropsychological Comparisons A review of the literature published before 1998 comparing VaD and AD found that patients diagnosed with VaD were more impaired on measures of executive functioning but had relatively preserved verbal memory compared to those with AD (Looi & Sachdev, 1999). Patients with vascular dementia (and high LA) demonstrated almost twice the level of executive and visuoconstructional dysfunction when compared to those with AD (Cosentino et al., 2004). Conversely, the AD patients were almost twice as impaired on measures of language/semantic functioning and memory. Importantly, this double dissociation was evident regardless of the vascular dementia classification system used. This same profile was evident when patients were classified solely based on the extent of white matter pathology as patients with low LA scores showed relatively intact executive and visuoconstructional skills but impaired memory and language abilities whereas those with severe LA scores (i.e percent of white matter) demonstrated the opposite pattern (Price et al., 2005). Similarly, patients demonstrating only white matter abnormalities on neuroimaging demonstrated significantly worse working memory and were more perseverative than pure AD subjects (i.e. those without evidence of vascular disease; Traykov, Baudic, Thibaudet, Rigaud, Smagghe, & Boller, 2002). These vascular patients performed as well as controls on measures of recognition memory whereas those with AD were significantly impaired. This same pattern of results has been reported when comparing patients with probable small vessel ischaemic dementia (Cannata, Alberoni, Franceschi, & Mariani, 2002) and

25 extensive white matter pathology (Graham, Emery, and Hodges, 2004; Libon et al., 2001) with AD groups. These results strongly suggest that patients with vascular dementia primarily involving the cerebral white matter have greater difficulty with executive abilities than do those with AD. Additional information about the nature of this executive deficit was obtained through analysis of patient performance using the Boston Revision of the WMS Mental Control (MC) subtest (Experiment 1; Lamar et al., 2002). Compared to those with AD, the vascular patients were less accurate and made more errors of commission (i.e. intrusions, false positives, and perseverations) while performing the non-automatized aspects of MC (reciting months backward, providing letters of the alphabet that rhyme with key, naming letters that have curves in them). These tasks place greater demands on working memory and require the subject to maintain mental set more than the overlearned (i.e. automatic) components of the scale (counting 20-1, serial 3s, and months forward). In a second experiment, patients with vascular dementia and Parkinson s disease produced significantly fewer words overall during the Controlled Oral Word Association Test (i.e. FAS) compared to those with AD and normal controls (Experiment 2; Lamar et al., 2002). When the pattern of responding was examined, the vascular group produced a significantly greater proportion of words during the first 15 seconds of the task whereas the AD group s output was consistent over time, suggesting the subcortical group had greater difficulty maintaining mental set. The nature of this executive dysfunction was further examined in patients with cortical (AD) and subcortical (VaD and PD) dementia through use of a principal component analysis (Lamar, Swenson, Kaplan, & Libon, 2004). These patients

26 completed a range of tasks assessing various aspects of executive functioning and a four component model was found to account for 62 percent of the variance in performance. While no significant differences were observed between vascular and Parkinson s patients on any of the components, the vascular patients were significantly more impaired on the factors assessing working memory, irrelevant interference (e.g. perseverations, inability to inhibit unrelated responses), and establishing preparatory mental set. AD patients had greater difficulty inhibiting responses that were plausible, but incorrect. In summary, research has shown a double dissociation between those with vascular dementia and Alzheimer s disease, such that the former experience greater executive dysfunction, especially for tasks requiring working memory, inhibition, and maintenance of mental set, but has relatively preserved memory encoding ability. The opposite pattern is exhibited by patients with mild Alzheimer s disease. The consistency of these findings is impressive especially considering the wide variety of tasks used to assess these domains. Functional neuroimaging techniques, such as fmri, PET, and SPECT, have allowed for in-vivo examination of cognitive functioning. As such, these methods may provide additional evidence of medial temporal and frontal lobe dysfunction in patients with mild Alzheimer s disease and vascular dementia, respectively Functional Neuroimaging The following studies support the notion of relatively preserved executive functioning but deficient medial temporal lobe processes in mild AD and the opposite pattern in those with vascular dementia.

27 Alzheimer s Disease Patients with mild AD were compared with healthy, age-matched controls on a two-choice facial recognition task after delays of 1, 6, 11, and 16 seconds (Grady, Furey, Pietrini, Horwitz, & Rapoport, 2001). Although remaining above chance levels, accuracy of those with AD declined as the delay increased, while performance of the control group remained stable. Patients with Alzheimer s disease demonstrated significantly greater frontal lobe activity but less medial temporal lobe activation when compared to the controls. Working memory was preserved in patients with mild AD as they were able to continuously rehearse word lists of 5 or 10 words as well as healthy age-matched controls throughout a 2 minute presentation period (Woodard, Grafton, Votaw, Green, Dobraski, & Hoffman, 1998). Both groups demonstrated activity, as measured by PET, within the dorsolateral prefrontal cortex that increased with greater memory load (i.e. 10-word list). The AD group was impaired relative to controls on measures of recall and recognition for the 10, but not the 5, word list. Although no imaging data were reported for the recall and recognition tasks, this pattern suggests encoding deficits within the context of preserved working memory. Patients with probable AD, like control subjects, showed greater prefrontal activation as memory load increased during a verbal working memory task (Becker, Mintun, Aleva, Wiseman, Nichols, & DeKosky, 1996). Compared to controls, AD patients did not show hippocampal activity during these tasks and, not surprisingly, their performance was impaired during a free recall period. Likewise, normal prefrontal activity, but no hippocampal activation, was observed in a group with mild AD during a

28 cued word-stem completion task (Backman, Andersson, Nyberg, Winblad, Nordberg, & Almkvist, 1999). Consistent with previous reports, Backman et al. (1999) reported a 17% reduction in metabolism within the temporoparietal regions bilaterally within these AD patients. These findings continue to suggest that working memory is relatively preserved during the early stages of Alzheimer s disease and working memory abilities are related to prefrontal activity. Interestingly, frontal activation in these patients often exceeded that of age-matched controls (e.g. Grady et al., 2001; Woodard et al., 1998; Becker et al., 1996; Backman et al., 1999) and, in combination with reduced medial temporal functioning led Grady et al. (2001) to conclude this additional activity may serve as a compensatory strategy to alleviate deficits caused by medial temporal dysfunction Vascular Dementia As with the neuropsychological literature, most of the studies identified have compared functioning between groups (i.e. VaD versus AD) rather than examining vascular dementia in isolation. One study identified two different patterns of hypoperfusion when patients with small vessel vascular dementia underwent SPECT as five of the 17 patients showed reduced blood flow only within the frontal lobes, while diffuse reduction was observed in the other 12 (Yoshikawa et al., 2003a). Similar results have been attributed to possible inclusion of patients with a mixed dementia, as the posterior activation deficits were indistinguishable from patients with AD (Hanyu, Shimuzu, Tanaka, Takasaki, Koizumi, & Abe, 2004). Frontal lobe hypometabolism was also observed in patients with Binswanger s disease and those with multiple infarct

29 dementia (Tanaka, Okamoto, & Hirai, 2002). Capizzano and colleagues (2000) observed a negative correlation between the volume of white matter hyperintensities and N-acetyl aspartate (NAA), a marker of neuronal integrity, within the frontal lobes (Capizzano, Schuff, Amend, Tanabe, Norman, Maudsley, Jagust, Chui, Fein, Segal, & Weiner, 2000). Significant reductions in another marker of neuronal integrity ([ 11 C] flumazenil) were found within the frontal lobes of demented patients with severe leukoaraiosis (Ihara et al., 2004). These studies indicate some, albeit limited, evidence of frontal lobe dysfunction in those with VaD relative to healthy controls. As with the cognitive data, a distinctive pattern of impairment is found within each group upon direct comparison Alzheimer s Disease versus Vascular Dementia One comprehensive study examined the pattern of psychiatric, neuropsychological, and cerebral blood flow in patients diagnosed with vascular dementia or AD (Starkstein, Sabe, Vazquez, Teson, Petracca, Chemerinski, Di Lorenzo, Leiguarda, 1996). Vascular patients exhibited a profile consistent with frontal lobe dysfunction as they were found to have greater levels of mood instability and executive deficits (i.e. verbal fluency, shifting mental set). Additionally, the vascular patients demonstrated reduced cerebral blood flow, as measured by SPECT, within the frontal lobes and basal ganglia compared to the AD group. Similarly, significant hypoperfusion within the frontal lobes and anterior cingulate was also observed in patients diagnosed with Binswanger s disease when compared to those with AD, who had greater reduction in the temporoparietal areas and posterior cingulate (Hanyu et al., 2004). Reduced blood

30 flow has also been observed in the anterior portions of the cortex in patients with VaD, while the AD group demonstrated a pattern of posterior hypoperfusion (Yoshikawa et al., 2003b). Decreased NAA/Cr ratios were found within the hippocampus of patients with Alzheimer s disease but no lacunae compared with healthy controls whereas hippocampal functioning was intact in those with subcortical ischemic vascular dementia (Capizzano et al., 2000). Reduced NAA within the frontal white matter was found only in patients with vascular dementia and these patients also demonstrated reductions within the frontal cortex (i.e. grey matter) that corresponded to the presence of white matter hyperintensities. Although both VaD and AD patients were impaired during performance of a continuous verbal recognition test, a double dissociation was found in the pattern of cortical activity associated with these deficits (Reed, Eberling, Mungas, Weiner, & Jagust, 2000). Hypometabolism in the prefrontal cortex was significantly correlated with memory deficits in the vascular group while reduction within the medial temporal gyrus and hippocampus accounted for this deficit in AD patients. The VaD patients were also significantly more impaired than those with AD when target words were repeated immediately or with only one intervening word. These findings again suggest that vascular patients experience greater working memory deficits and are more prone to interference effects than are patients with Alzheimer s disease.

31 1.3.3 Conclusions of the Differences between Alzheimer s disease and Vascular Dementia Taken as a whole, the previously reviewed literature suggests it is possible to dissociate patients with vascular dementia from those with mild Alzheimer s disease using neuropsychological data and structural and functional neuroimaging techniques. The neuropsychological literature consistently reveals that vascular patients experience a pattern of executive dysfunction, especially in regards to working memory and establishing and maintaining mental set, relative to patients with Alzheimer s disease. Conversely, the AD patients are markedly more impaired at encoding new memories. These conclusions are supported by patterns of reduced frontal and medial temporal activation in VaD and AD patients, respectively. With these deficits in mind, it should be possible to develop a test that would differentiate these groups based on the core deficits they experience Memory for Temporal Order and Executive Functioning Knowledge of when events occurred is an essential aspect of episodic memory. Evidence from several patient populations, using a variety of techniques, suggests that executive functioning, especially working memory, is imperative for the ability to accurately perceive the passage of time (Mangels, Ivry, & Shimizu, 1998), recall such information, and make judgments based on this attribute. Several different methodologies are discussed below, all of which require the patient to remember and compare the time at which a given stimulus (or stimuli) was encountered and make a decision based on this information.

32 Lesion studies Milner (1971) first reported impaired ability to make recency judgments in patients who had undergone frontal lobectomy for the treatment of epilepsy. These subjects were impaired when required to determine which of two previously seen items was presented most recently; however, they demonstrated normal item recognition memory. The opposite pattern was seen in patients with temporal lobe lesions as recency judgments were accurate, but recognition was impaired. These results were replicated in a later study (Milner, McAndrews, & Leonard, 1990). Patients with frontal lobe lesions have also demonstrated impairment during order reconstruction tasks. During this method, patients are presented with a list of stimuli and, following a delay and subsequent recognition task, are instructed to place the items in the order of presentation. Mangles (1997) found order reconstruction impairment when subjects had to employ structure during the encoding phase. She notes that this process requires earlier items to be actively held in mind and that the list be updated with each newly presented stimulus, a task heavily reliant on working memory. Daum and Mayes (2000) used a facial list discrimination task wherein they presented two separate lists of faces separated by a 30 minute delay. Patients then performed a recognition memory task and, if they identified the face as previously seen, were instructed to identify whether it was presented in the first or second list. Patients with frontal lobe lesions were significantly less accurate in making these judgments than control subjects. Not surprisingly, these patients also demonstrated significant executive dysfunction.

33 The role of the frontal cortex in temporal order judgments has also been investigated and supported in animal studies. Monkeys with selective lesions to the middorsolateral frontal cortex (BA 46 & 9) were impaired at making recency judgments for items that occurred in the middle sequential positions when compared with monkeys with posterior dorsolateral prefrontal lesions (BA 8 & 6) and non-operated control animals (Petrides, 1991). Importantly, the animals with mid-prefrontal lesions performed as well as the other two groups when the task involved either the first or last stimuli presented (i.e. primacy or recency effect). Thus, lesions to the mid-dorsolateral frontal cortex appear to disrupt the animal s ability to monitor the serial order of stimuli. Similar findings were recently observed using transitory lesions via lidocaine infusion to the rat medial PFC (mpfc) or perirhinal cortex (Hannesson, Howland, & Phillips, 2004). Lesions to the mpfc produced impairment in recency discrimination but had no effect on object recognition, while infusions to the perirhinal cortex impaired both object recognition and recency discrimination, presumably due to encoding deficits. Lidocaine induced lesions to the mpfc again impaired temporal order judgments but had no effect on spatial recognition memory when these forms of memory were assessed using the radial arm maze (Hannesson, Vacca, Howland, Phillips, 2004). In sum, these findings support the notion that functions mediated by the frontal lobes, such as working memory, are intricately involved in the ability to associate and compare the temporal aspects of a given memory trace. However, it is possible the lesions described in these studies had more diffuse effects that disrupted other skills necessary for successful temporal order judgments; therefore, it is worthwhile to consider

34 evidence from other techniques, especially those involving in-vivo assessment of these abilities Functional Neuroimaging Results from both human and animal literature support the role of the frontal lobes, and presumably working memory, in temporal order memory. Animal Literature: Selective activation of cells within the lateral prefrontal cortex of monkeys during short delay periods was associated with the sequence in which visual objects were presented (Ninokura, Mushiake, & Tanji, 2003). Additional study of this process revealed that more extensive lateral prefrontal activity was associated with the integration of the physical and temporal properties of these objects (i.e., recreating the order of item presentation; Ninokura, Mushiake, & Tanji, 2004). The location and nature of this activity is consistent with the involvement of working memory. Human Literature: A different pattern of activity, as measured by EEG, was found during tasks of item recognition and recency judgments in healthy young adults (Tendolkar & Rugg, 1998). Following presentation of two separate lists, participants performed either a recency judgment (experiment 1) or an item recognition task (experiment 2) wherein three types of word pairs were presented: two novel words, a previously seen (i.e. old) and a novel word, or two old words. Pairs that could be solved via item recognition alone (i.e., old-new pairs in experiment 1, all pairs in experiment 2) resulted in a pattern of left temporal-parietal activation whereas those requiring recency judgments (old pair in experiment 1) demonstrated additional bilateral prefrontal activity. Thus, the recency judgment condition required participants to not only recognize

35 previously encountered stimuli, but to also retrieve and actively compare the temporal properties of the stimuli, a process dependent on working memory. Functional neuroimaging has also provided evidence of the involvement of the frontal lobes during tasks that require judgments based on time. Sustained activity, as measured by fmri, was found within the dorsolateral prefrontal cortex throughout a 10 second delay while participants performed an n-back test (Cohen, Perlstein, Braver, Nystrom, Noll, Jonides, & Smith, 1997). This task requires subjects to not only hold information in mind but to also attend to the order in which these items were presented. The extent of this activity increased with load (i.e. more information), which suggests this area is involved in the temporary maintenance of sequential information. However, this involvement does not appear to be limited to the temporary storage of information (i.e. on the order of seconds) as increased activity, measured through PET, was observed within the prefrontal cortex of young adults as they performed a recency discrimination task following delays of two to three minutes (Cabeza, Mangels, Nyberg, Habib, Houle, McIntosh, & Tulving, 1997). Item recognition was associated with temporal lobe activity in these participants, suggesting dissociable contributions of the temporal and frontal lobes to item and temporal judgments, respectively. Similarly, frontal lobe activation was observed as participants determined in which of two lists a given word had been presented, after a delay of about 3 hours (Suzuki et al., 2002). Healthy control participants were presented with a list of words and then asked to make either easy temporal-order judgments, which consisted of either the first or last word in the list (i.e. primacy or recency) and a word from the middle of the list, or difficult judgments that only involved words from the middle of the list (Konishi,

36 Uchida, Okuaki, Machida, Shirouzu, & Miyashita, 2002). Although accurate in both conditions (i.e. >85 percent correct), the participants performed significantly better and had shorter response latencies on the easy trials. Significantly more frontal lobe activation was observed during the difficult trials as compared to the easier trials. Specifically, this increased activity was most pronounced in the middle (BA 9) and inferior lateral prefrontal cortex (BA 45), areas that closely correspond to other fmri and lesion-based studies. Additionally, activity was observed in the anterior prefrontal cortex (BA 46) and medial temporal lobes during the more difficult trials, suggesting a widespread network is involved in the retrieval and comparison of these memory traces. Research involving age-related changes in temporally based judgments also supports the relationship of such abilities to frontal lobe functioning. For example, Cabeza and colleagues found older adults were impaired at temporal-order, but not itembased, judgments relative to healthy young controls (Cabeza, Anderson, Houle, Mangles, Nyberg, 2000). Older adults also demonstrated less activity in the right prefrontal lobe, as measured by PET, during the temporal-order trials whereas ventromedial temporal lobe activity during the item memory trials was unaffected by age. Similarly, young women outperformed older women during both an item and source recognition test; however, the effect size was nearly twice as large during the source task, indicating the older women had significantly greater difficulty with this task (Wegesin, Friedman, Narughese, & Stern, 2002). Additionally, EEG revealed a different pattern of activity between these groups; most significant was the lack of right frontal activity in the older group. This lack of activity appears analogous to the hypometabolism, evident on PET, in Cabeza et al. s study (2000).

37 In combination with the lesion literature, these studies suggest that the functions mediated by the frontal lobes (e.g. working memory) are involved in the initial maintenance and integration of temporal properties as well as later judgments involving this attribute Temporal Order Memory and Dementia There has been relatively little research on temporal order memory abilities in patients with dementia and, to our knowledge, no studies have examined such abilities in patients with vascular dementia. However, the performance of patients with Parkinson s disease (PD) may be informative in this regard given the similarity in neuropsychological profiles (Libon et al., 2001; Lamar et al., 2004). Deficits in the use of strategic memory (i.e. self-ordered pointing, temporal ordering, and free, categorical, and cued recall) were significantly correlated with working memory in a group of unmedicated patients with PD (Gabrieli, Singh, Stebbins, & Goetz, 1996). Patients with Parkinson s disease were also impaired in the verbal recreation of sequentially presented letters during an inspection time loop task (Shipley, Deary, Tan, Christie, & Starr, 2002). However, performance improved when these patients were given additional time to perform the task, suggesting slowed processing speed may have contributed to these deficits. Similarly, performance of those with multiple sclerosis may also be relevant to VaD performance due to the white matter pathology associated with each condition. In fact, patients with multiple sclerosis were less accurate at recreating the order of previously seen word lists but demonstrated intact recognition memory for these words (Arnett et al., 1997). These patients also demonstrated greater difficulty performing the