CURRENT CLINICAL NEUROLOGY - PART 9 docx

282 Libon et al. This nosology, constructed without the aid of imaging technology we now take for granted, is still relevant today (5). Despite Durand-Fardel’s insightful work, historical accounts of VaD often begin with the small series of cases described by Binswanger in 1884 (6,7). Binswanger suggested that WMA were caused by vascular insufficiency that could impair mental functioning. He coined the term encephalitis subcorticalis chronica progressiva to describe this syndrome (6,7). Microscopic information regard- ing these patients was never published; nonetheless, in 1902, Alzheimer (8) made observations that substantiated Binswanger’s findings. Case descriptions provided by Olszewski (9) and Caplan and Schoene (10) have supported the clinical and neuropathological observations of both Binswanger and Alzheimer. Throughout most of the 20th century, dementia associated with arteriosclerosis was believed to cause widespread cortical atrophy secondary to an attenuation of brain perfusion. Hachinski and colleagues (11,12) proved that this was not true and introduced the term of multiinfarct dementia (MID). However, after Hachinski’s seminal work, the term MID was used to denote almost all pre- sentations of VaD. Indeed, until the introduction of the diagnostic criteria from the Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) (13) and National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neuro- sciences (NINDS-AIREN) criteria (14), Hachinski’s Ischemic Scale (11,12) was the convention by which MID or VaD was typically defined. Until recently, Binswanger’s disease or dementia associated with subcortical WMAs was viewed as a rather obscure illness or even marginalized as an epiphenomenon. Newer research is changing this perception, but many questions remain. Our current interest in VaD in general, and subcortical WMA in particular, owes a substantial debt to French neurological science. Many of these original observations have withstood the test of time. Perhaps it is time to recall another bit of French wis- dom, plus ça change, plus c’est le même (the more things change, the more things stay the same). 2. OVERLAP BETWEEN VASCULAR DEMENTIA AND ALZHEIMER’S DISEASE A traditional perspective regarding the diagnosis of dementia suggests that specific pathological changes in the brain should result in a specific clinical presentation. However, there is research indicat- ing that among patients suffering from dementia, the relationship between pathology and clinical presentation may not be linear or direct. Indeed, some of the most interesting research to emerge during the last several years addresses mixed diagnoses and suggests that vascular disease may alter the devel- opment and distribution of the senile plaques and neurofibrillary tangles (NFT) associated with AD. For example, Nagy and colleagues (15) found that patients who met pathological criteria for AD and displayed evidence of cardiovascular disease (CVD) had lower numbers of senile plaques and NFT when compared to patients with AD who presented with minimal or no cerebrovascular pathol- ogy. Nagy and colleagues (15) described several cerebrovascular alterations, including single infarcts, small macroscopic infarcts, multiple microinfarcts, and cribriform alterations, tissue rarefaction, and white matter myelin pallor. They speculated that neuropathologic evidence of vascular lesions could have a significant impact regarding the clinical expression of these patients’ dementia, because these patients had less AD pathology. Similarly, Snowdon and colleagues (16) reported that patients with AD with evidence of CVD, primarily involving subcortical infarcts, presented with fewer NFT throughout the cortex. Other studies have shown that the incidence of so-called pure AD may be much lower than previ- ously reported. For example, Victoroff and colleagues (17) indicated that 86% of their patients diag- nosed with AD in life also displayed evidence of other possible dementing disorders, including CVD. Bowler and colleagues (18) found that on autopsy, only 44% of their cases had pure AD without any other coexisting causes of dementia. More recently, Crystal and colleagues (19) reported that of their Alzheimer’s Disease and Vascular Dementia 283 patients diagnosed in life with AD, only half of these patients actually met neuropathological criteria for AD. However, of the patients who met pathological criteria for AD, many also presented with a variety of cerebrovascular lesions that could have contributed to the dementia. Such research has even led some to speculate that AD might even be a type of vascular disorder (20). Clearly, more research is necessary to resolve this issue. 3. NEUROPSYCHOLOGY OF SUBCORTICAL VASCULAR DEMENTIA Throughout the past decade, there have been many studies examining the neuropsychological profile associated with subcortical vascular lesions. Overall, there is a relationship between increased subcortical periventricular and deep WMA and subcortical lacunar infarctions and greater impair- ment on tests of executive control, with some relative sparing on tests of memory and language (21–24). Yet there has been little effort to interpret or integrate these findings within any larger context. Some authors have invoked the construct of working memory (25) to describe the mechanism that underlies executive control deficits associated with subcortical pathology. However, we believe deficits in establishing and maintaining a mental set is a more parsimonious construct that helps explain execu- tive control impairment and, perhaps, elements of the declarative memory disorder associated with subcortical VaD (26,27). We characterize the ability to establish and maintain a mental set as the ability of patients to appreciate and understand the nature of a task and to respond within the context of that task until the task is completed. Described in Sections 3.1.–3.3. are several recent studies from our laboratory that attempt to elucidate the parameters regarding the difficulty patients with subcortical VaD exhibit on tests of executive control, memory, and language. 3.1. Executive Control Lamar and colleagues (28) studied deficits in establishing and maintaining mental set by looking at the perseverative behavior produced by patients with AD and subcortical VaD primarily associ- ated with WMA. Two interesting findings emerged from this study. First, and perhaps not surpris- ingly, the overall number of perseverations was greater in patients with moderate to severe subcortical vascular lesions as compared to patients with AD. Second, and more interesting, the type of perseverations made by patients with moderate to severe subcortical WMA was distinctive. For example, patients with subcortical VaD often produced hyperkinetic/interminable perseverations (i.e., persisting in the production of responses even when there was no command to do so). The perseverations generated by patients with AD were different. For example, when asked to write the sentence “three squares and two circles,” these patients might produce an activity perseveration, whereby they would draw three squares and two circles; or an element perseveration, such as draw- ing a circle when asked to produce a square. The mechanisms that underlie these difficulties in maintaining mental set were different. Among patients with subcortical VaD, hyperkinetic/interminable perseverations were correlated with poor performance on tests of motor functions. This suggests that impaired regulation of motor behavior may be the mechanism responsible for their difficulty. In the AD group activity/element perseverations were correlated with poorer performance on the Boston Naming Test and reduced output on the animal word list generation task. This suggests that problems in the response selection of lexical/semantic information may underlie their difficulty. In another study Giovannetti and colleagues (29) examined problems in establishing and maintaining mental set with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Similarities subtest, a test of verbal concept formation. Zero-point responses were recoded into two broad categories, in-set vs out-of-set errors. An in-set error was coded when a response was vague but retained some superordinate relationship (i.e., dog-lion—they’re alive). By contrast, an out-of-set error was coded when no superordinate relationship was conveyed (i.e., dog-lion—one barks and 284 Libon et al. the other growls). Overall, it was found that patients with subcortical VaD made more out-of-set errors, whereas patients with AD made more in-set errors. When these two types of errors were included in a factor analysis with other neuropsychological tests, out-of-set errors loaded with variables consistent with gross deficits in establishing and maintaining mental set, such as perseverations made on the Graphical Sequence Test (28) or errors made on clock drawing (30). Similar to Lamar and colleagues (28), in-set errors loaded with variables related to problems in the selection of lexical/semantic information. More recently, Lamar and colleagues (31) investigated the capacity of patients with dementia to establish and maintain a complex mental set using the Boston Revision of the Wechsler Memory Scale Mental Control subtest. This test consists of tasks such as asking patients to identify letters that rhyme with the word key and to identify printed letters that contain a curved line. In this study, tasks were divided into three equal sections and all errors and correct responses were summed separately for each of the three sections on each task. However, in the AD group, performance declined from the first to the middle sections of these tasks but remained stable when the middle portion of the test was compared to the latter portion of the test. In the VaD group, errors accumu- lated and performance declined throughout all three sections of the task. In a second experiment, the number of responses generated over time on tests of letter fluency tasks (FAS) was examined. Each 1-min letter trial was divided into four 15-s intervals, and the number of responses generated for each interval was compared. Interestingly, when performance was controlled for total output, the percentage of correct responses generated by patients with AD within each quadrant was no different from normal control participants. By contrast, patients with VaD tended to generate their maximum output during the first 15-s epoch. We believe that when viewed as a whole, executive control deficits associated with subcortical VaD tend to be pandemic, capable of compromising virtually all areas of cognitive functioning. By contrast, the executive control deficits associated with AD are more restricted and context specific, that is related to lexical/semantic operations. These findings are consistent with the theoretical con- structs put forth by Luria (32) and recent research suggesting that subcortical gray matter structures, such as the caudate, help to modulate or gate frontal lobe activity (26,27). In this context, it is intrigu- ing to speculate whether subcortical WMA are capable of acting as a surrogate or in an analogous fashion as subcortical gray matter structures regarding the etiology of executive control deficits asso- ciated with VaD. This is another area for future research. 3.2. Memory and Learning Recent research also shows that patients with subcortical WMA retain some capacity to learn new information, a profile different from AD (33–37). On the nine-word dementia version of the Califor- nia Verbal Learning Test (CVLT) (34,38) patients with AD display poor retention, rapid forgetting, little to no benefit from cued recall or recognition test conditions, and many intrusion errors. How- ever, patients with subcortical VaD produce a different profile. They obtain higher scores on mea- sures of delayed free and cued recall memory and produce improvement on the recognition discriminability index. The profile produced by patients with VaD is similar to the profile produced by patients with Parkinson’s disease and Huntington’s disease (39–41). Davis and colleagues (42) have investigated the mechanisms that underlie the types of errors produced on the immediate free recall portion of the nine-word CVLT. They define initial intrusions as denoting the first time an intrusion error is produced. A trans-trial perseveration is coded when intrusions reoccurred in later free recall learning trials. Finally, within-trial perseverations are scored when patients repeated a response that was produced earlier in any single free recall learning trial. Similar to our previous work regarding executive control deficits in dementia (28,29,31), Davis and colleagues (42) speculated that deficits in the response selection of lexical/semantic information might be the mechanism that underlies the production of initial and trans-trial errors; whereas poor self- monitoring might be responsible for the production of within-trial perseverations. Partial support was Alzheimer’s Disease and Vascular Dementia 285 found for this prediction is that initial intrusion errors were correlated with poor scores on the animal word list generation Association Index (see Carew et al. [43]), a measure of the lexical-semantic organization. Davis and colleagues (42) also examined the distribution of false positive responses produced by patients with AD and subcortical VaD on the CVLT-9 word delayed recognition task. Within- group analyses indicated that as a percentage of the total number of foils endorsed, patients with subcortical VaD endorse more interference (list B) foils than semantic or unrelated foils. By con- trast, patients with AD endorsed more semantic and unrelated foils. Also, there was a significant correlation between the production of interference (list B) foils and the production of perseverations, as measured with the Graphical Sequence Test (28). Similar to the research of Lamar and colleagues (28,31) and Giovannetti and colleagues (29), Davis and colleagues (42) concluded that on serial list learning tests deficits in executive control and lexical/semantic knowl- edge underlie many of the errors produced by VaD and AD, respectively. 3.3. Language/Semantic Knowledge Deficits of language and semantic knowledge in patients with subcortical VaD have not been extensively studied. Carew and colleagues (43) designed a paradigm to measure the lexical/seman- tic organization on the animal word list generation task, a popular test that is often part of the neuropsychological work-up for dementia. On this task, patients are given 60 s to generate animal names (animal categories are not supplied). Carew and colleagues (43) coded all responses on the following six categories: size (big or small), geographic location (foreign or North America), diet (herbivore, carnivore, or omnivore), zoological class (insect, mammal, bird, etc.), habitat (farm, Africa/jungle, widespread, etc.), and biological order/related groupings (feline, canine, bovine, etc.). An Association Index was calculated by totaling the number of shared attributes between successive responses and then dividing by the number of total responses. The authors believe that the Association Index provides a measure of the lexical/semantic organization between successive responses independent of the number of words produced. Carew and colleagues (43) found that the total number of responses made by patients with AD and subcortical VaD did not differ. Regarding the Association Index, normal control participants and patients with subcortical VaD did not dif- fer. However, both groups obtained higher scores on this measure as compared to patients with AD. Carew and colleagues (43) interpreted their data as consistent with the idea that lexical/se- mantic knowledge is relatively intact in subcortical VaD as compared to AD. In conclusion, the studies reviewed suggest that dementia associated with moderate to severe MRI- WMA can be differentiated from dementia associated with little or mild MRI-WMA. The neuropsy- chological profile associated with subcortical WMA revolves around poor performance on tests of executive control but relatively better performance on delayed-recognition tasks. Semantic knowl- edge can be relatively intact among patients with substantial subcortical WMA. Several preliminary conclusions might be drawn from these data. First, from an anatomic perspective, the pattern of performance produced by patients with moderate to severe MRI-WMA could be caused by a disrup- tion of the frontal-basal ganglia-thalamic pathways (44,45). Second, from a clinical perspective, these data suggest that to identify or diagnose subcortical VaD, dissociation between tests of executive control vs tests of memory/ language should be obtained. However, exactly how severe or what volume of MRI-WMA is necessary to produce this profile? 4. THE RESEARCH CRITERIA FOR SUBCORTICAL VASCULAR DEMENTIA Erkinjuntti and colleagues (46) have proposed some modification to the existing diagnostic crite- ria for VaD. These changes focus on subcortical VaD associated with radiological evidence of periventricular and deep WMAs and/or lacunar stroke. Clinically, to diagnose subcortical VaD as proposed by Erkinjuntti and colleagues (46), two broad criteria must be satisfied—radiological evi- 286 Libon et al. dence of subcortical CVD, sufficient to be associated with dementia, and a profile on neuropsycho- logical tests showing greater impairment on tests of executive control and less impairment on tests of delayed-recognition memory. However, as stated in Section 3.3., it is unclear exactly how much WMA is necessary to produce this kind of profile on neuropsychological tests. We now present data that will attempt to address this issue. The authors’ goal is to provide some concrete operational guidelines for a putative diagnosis of subcortical VaD, as suggested by Erkinjuntti and colleagues (46). In the data presented in Section 6., MRI-WMA were measured using the 40-point leukoaraiosis scale of Junque (47,48). Measures of executive control, memory, and language were drawn from the studies discussed in Section 3. If dementia seen in conjunction with subcortical WMA is associated with a relative dissociation on tests of executive control vs memory as suggested by Erkinjuntti and colleagues (46), then it is reasonable to expect that patients with minimal to mild MRI-WMA will present with greater impairment on tests of delayed-recognition memory and, perhaps language as compared to tests of executive control. Conversely, patients with severe MRI-WMA should yield the opposite profile (i.e., greater impairment on tests of executive control as compared to tests of delayed recognition memory/language). In the data presented in Section 6., patients with dementia are divided into mild, moderate, and severe white matter groups on the basis of the severity of their MRI WMAs as measured with the leukoaraiosis scale of Junque (47,48). The prediction to be tested is that there should be a statisti- cally significant interaction between the severity of MRI-WMA and performance on neuropsycho- logical tests of executive control and memory/language. 5. METHODS 5.1. Patients A total of 105 patients were studied. All patients were clinically diagnosed with either AD or VaD and were enrolled from the Crozer-Chester Medical Center Alexander Silberman Geriatric Assessment Program, an outpatient dementia evaluation program. All patients were examined by a neurologist, neuropsychologist, psychiatrist, geriatrician, and social worker. An MRI study of the brain and appropriate diagnostic laboratory studies were obtained to evaluate for reversible causes of dementia. A clinical diagnosis was determined at an interdisciplinary team conference. On the basis of team diagnosis, 55 patients with National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) probable AD (49), and 50 patients with probable/possible ischemic VaD) using ADDTC criteria (13) were studied. Patients with AD and IVD with cortical cerebrovascular accidents (CVAs) on MRI scans were excluded. Patients were excluded if there was any history of head injury, sub- stance abuse, major psychiatric disorders (including major depression), epilepsy, or B 12 , folate, or thyroid deficiency. This information was gathered from a knowledgeable family member. 5.2. MRI Protocol All MRI scans were conducted on a Siemens 1.5 Tesla machine. Both T1- (TR - 500 ms, TE - 15 ms) and T2- (TR - 4000 ms, TE - 90 ms) weighted studies were obtained. The severity of WMA was quantified using the 40-point leukoaraiosis scale described by Junque and colleagues (47,48). This scale divides each hemisphere into five areas: the frontal centrum semiovale, the parietal centrum semiovale, the white matter around the frontal horns, the white matter around the body of the lateral ventricles, and the white matter around the atrium and occipital horns. The severity of WMA was then graded from 0 to 4 and summed across all 10 areas. Leukoaraiosis scores were calculated by two board-certified neuroradiologists who were blind to all clinical information (inter-rater reliability, r = 0.98, p < 0.001) (35). Patient’s leukoaraiosis scores ranged from 1 to 28. Alzheimer’s Disease and Vascular Dementia 287 5.3. Patient Groups To test the direct association between white matter severity and neuropsychological functioning, patients who were diagnosed with either AD or VaD were recategorized into three groups based on their leukoaraiosis scale (47,48), i.e., a mild WMA group (Junque scores, 0–8, n = 54), a moderate WMA group (Junque scores, 8–17, n = 36), and a severe WMA group (Junque scores, 18–28, n = 15). There were no between-group differences among these three groups with respect to age, education, level of dementia as assessed with the Mini-Mental State Examination (MMSE) (50), and depression as assessed with the Geriatric Depression Scale (GDS) (51) (see Table 1). 5.4. Neuropsychological Assessment 5.4.1. Executive Systems Functioning (WMS-Accuracy) Executive systems functioning (WMS-Accuracy) was assessed with the Boston Revision of the Wechsler Memory Scale-Mental Control subtest (WMS-MC) (31). In addition to the three tasks that comprise the standard WMS-MC subtest (52) (i.e., counting from 20 to 1, reciting the alphabet, and adding serial 3’s), the Boston Revision of the WMS-MC (31) subtest includes four additional tasks: reciting the months of the year forward and backward, an alphabet rhyming task that requires patients to identify letters that rhyme with the word “key,” and an alphabet visualization task that requires patients to visualize and identify all block printed letters that contain curved lines. Patients were allowed to work as long as necessary on these tasks provided they were working meaningfully. The dependent variable derived from this test was an accuracy index (AcI) derived only from the three non- automatized tasks (i.e., months backward, alphabet rhyming, and alphabet visualization). These accuracy indices were based on the following algorithm: AcI = [1 – (false positives + misses/no. possible correct)] × 100. This algorithm yielded a percentage score ranging from 0–100, such that patients obtaining a score of 100% correct identified all targets and made no false positive responses or misses. A composite score was calculated by averaging the WMS-Mental Control AcI’s for all three tasks for each patient. 5.4.2. Visuoconstructional Functioning (Clock Errors) Visuoconstructional functioning (clock errors) was assessed by asking patients to draw the face of a clock with the hands set for “ten after eleven” to command and copy (53). Following procedures described by Libon and colleagues (30), errors related to graphomotor impairment, errors in hand/ number placement, and errors related to executive control impairment were scored as either 1 (i.e., present) or 0 (i.e., absent). The dependent variable derived from this test was the total number of errors summed across the command and copy test conditions. 5.4.3. Language/Semantic Functioning (Animal Association Index) Language/semantic functioning (animal association index) was assessed with the animal word list generation task (43,54). On this task, patients were given 1 min to generate animal names. The Table 1 Demographic Information and Junque Leukoaraiosis Scores Age Education MMSE GDS Junque LA score Mild MRI-WMA 76.56 (5.43) 12.15 (2.54) 21.80 (3.62) 5.44 (3.80) 3.76 (2.75) Moderate WMA 78.83 (5.44) 11.64 (2.68) 21.36 (3.74) 7.00 (4.06) 12.83 (2.30) Severe MRI-WMA 77.00 (6.73) 11.20 (3.43) 20.20 (4.81) 5.80 (2.51) 22.07 (3.03) Abbr: MMSE, Mini-Mental State Examination; GDS, geriatric depression scale; LA, Junque leukoaraiosis scale; MRI-WMA, periventricular and deep white matter alterations. 288 Libon et al. dependent variable derived from the animal fluency task was the total association index (animal-AI). The animal-AI is a special scoring technique that measures the semantic organization between suc- cessive responses. A high score on this measure is believed to reflect generally intact semantic memory stores. Complete details regarding how the animal-AI index is calculated can be found in Carew and colleagues (43). 5.4.4. Declarative Memory (CVLT-Recognition Discrimination) Declarative memory was assessed with the nine-word dementia version of the CVLT (34,38). The dependent variable used in the present research was the delayed recognition discriminability index (CVLT-discrim). 5.5. Statistical Analysis Using z-scores based on the performance of a normal control group (n = 18), two indices were created from the four neuropsychological dependent variables described (see Table 2). An execu- tive control index was created by averaging the z-scores from the WMS-Mental Control Accuracy Index and total clock drawing errors. A memory/language index was created by averaging the z-scores from the CVLT-discrim index and the animal Association Index. The authors’ prediction regarding the dissociation between tests of executive control vs memory/language among patients with mild, moderate, and severe MRI-WMA was tested with a 3 (white matter groups) × 2 (execu- tive control and memory/ language indices) repeated measures analysis of variance (ANOVA). Simple correlations between the Junque leukoaraiosis scale and all neuropsychological measures were also conducted. 6. RESULTS 6.1. Correlation Analyses Pearson Product Moment correlations between the Junque leukoaraiosis scale indicated little association between the MMSE and the Junque scale (r = –0.220, ns). By contrast, all four neuro- Table 2 Neuropsychological Data: Test Scores and z-Scores MRI-WMA Mild Moderate Severe WMS Accuracy Index Test score 69.6 (16.2) 57.7 (21.9) 33.7 (20.8) z-score –2.0 (1.5) –3.1 (2.0) –5.4 (1.9) Clock Drawing Errors Test score 3.4 (1.6) 5.4 (2.5) 7.1 (2.8) z-score 1.2 (1.0) 2.5 (1.6) 3.6 (1.8) WLG-AI Test score 2.7 (.87) 3.3 (.70) 3.7 (.73) z-score –1.6 (1.7) –.41 (1.4) .45 (1.5) CVLT-discrim Test score 67.3 (12.4) 75.7 (14.9) 80.2 (7.8) z-score –5.8 (2.5) –4.1 (3.1) –3.1 (1.6) Abbr: MRI-WMA, periventricular and deep white matter alterations; WMS Accuracy Index, WMS Mental Control non-automatized accuracy index (AcI); The clock drawing scale is based on errors. A positive z-score signals impaired performance; WLG-AI, animal word list generation association index (AI); CVLT-discrim, CVLT recognition discriminability index. Alzheimer’s Disease and Vascular Dementia 289 psychological variables were significantly related to the severity of MRI-WMA. Thus, as the leukoaraiosis scale increased, patients obtained low scores on the WMS Mental Control Accuracy Index (r = – 0.554, p < 0.001) and made more errors on their clock drawings (r = 0.531, p < 0.001). Increasing amounts of MRI-WMA also resulted in relatively better scores on the animal fluency Association Index (r = 0.455, p < 0.001) and on the CVLT-discrim index (r = 0.348, p < 0.001). Our prediction regarding the dissociation between executive control vs memory/language test performance across groups of patients with mild, moderate, and severe MRI-WMA was tested with a 3 × 2 repeated measures ANOVA. This analysis yielded a significant two-way interaction (F[4,116] = 22.73, p < 0.001). Neither main effect was significant. 6.2. Between-Group Comparisons Between-group follow-up analyses were first conducted with two separate univariate ANOVAs (see Table 3). Both of these analyses were highly significant (executive control - F[2, 62] = 27.13, p < 0.001; memory/language - F[2, 62] = 19.24, p < 0.001). Between-group pairwise comparisons were conducted with Tukey tests (significance – p < 0.01). For the executive control index, the mild MRI-WMA group obtained a better score than either the moderate MRI-WMA (p < 0.006) or severe MRI-WMA group (p < 0.001). Also, the moderate MRI-WMA group obtained a better score than the severe MRI-WMA group (p < 0.001). On the memory/language index, the mild MRI-WMA displayed greater impairment than both the moderate MRI-WMA group (p < 0.001) and the severe MRI-WMA group (p < 0.001). There was no difference on this index between the moderate and severe MRI-WMA groups. 6.3. Within-Group Comparisons Within-group comparisons were conducted with paired t-tests (significance set for p < 0.01). Participants in the mild MRI-WMA group obtained a significantly lower score, i.e., demonstrating worse test performance on the memory/language index compared to the executive control index (t[30] = 8.29, p < 0.001). The opposite profile was observed in the severe MRI-WMA group such that these participants obtained a lower score on the executive control index as compared to the memory/ language index (t[15] = 6.97, p < 0.001). There was no within-group difference between the execu- tive control and memory/language indices in the moderate MRI-WMA group (see Table 4). 7. SUMMARY AND CONCLUSIONS Several conclusions can be drawn from these data. First, increased levels of subcortical MRI- WMA as measured with the Junque leukoaraiosis scale resulted in significant impairment on tests of executive control, whereas performance on tests of memory and language were relatively spared. An Table 3 Between-Group Performance on the Executive Control vs Memory/Language Indices: z-Scores (Means and Standard Deviations) MRI-WMA Mild Moderate Severe Significance p Executive Control Index (z-scores) –1.4 (.90) –2.7 (1.6) –4.5 (1.5) Mild < moderate < 0.006 Mild < severe < 0.001 Moderate < severe < 0.001 Memory/Language Index (z-scores) –3.9 (1.6) –1.7 (1.5) –1.4 (.88) Mild > moderate < 0.001 Mild > severe < 0.001 Moderate = severe ns Abbr: MRI-WMA, periventricular and deep white matter alterations. 290 Libon et al. association between subcortical WMA and poor performance on tests of executive control has been described by other researchers (24). The mechanism that underlies the executive control defi- cits associated with MRI-WMA revolves around problems in establishing and maintaining mental set as operationalized by an increased number of perseverations (28) and an increased number of omission and commission errors. These errors occur as participants with dementia attempt to main- tain mental set for the task at hand (31). The correlations between MRI-WMA and performance on the animal AI and CVLT-discrim mea- sures suggest relatively better performance on these tests as MRI-WMA increases. This may appear to be counterintuitive. Deficits in memory/semantic organization are, of course, usually associated with AD. One possible explanation for the positive correlations between MRI-WMA and perfor- mance on tests of memory/language is that this reflects either the absence or some altered distribution of senile plaques and NFT (15,16). Such a suggestion is controversial and requires greater research. Second, can these data be used to provide some operational guidelines regarding Erkinjuntti’s criteria for the diagnosis of subcortical VaD? From a statistical viewpoint, some interesting relation- ships between subcortical white matter alterations as measured with the Junque leukoaraiosis scale and neuropsychological tests emerged from the data described above. Between-group, as well as within-group, comparisons regarding the mild MRI-WMA group revealed that performance on the memory/language index was approximately twice as impaired as compared to the executive control index. Similar comparisons regarding the severe MRI-WMA group revealed the opposite profile, i.e., their score on the executive index was approximately twice as impaired as compared to the memory/ language index. The profile of neuropsychological test performance observed in the moderate MRI- WMA is revealing for two reasons. First, there was no difference in the severity of impairment on tests of executive versus memory/language. Second, as demonstrated by the between-group analyses, executive control test performance becomes more impaired in relation to increasing MRI-WMA, whereas performance on tests of memory/language improves. These data offer further evidence that vascular pathology might be influencing the presence and/or distribution of senile plaques and NFT. Does this dissociation regarding performance on tests of executive control and memory/language in relation to MRI-WMA provide the basis of an operational definition of subcortical VaD as sug- gested by Erkinjuntti and colleagues (46)? Using the methodology described above, the authors iden- tified 15 patients from their sample of 105 patients who exhibited striking impairment on tests of executive control as compared to memory and language. However, this represents only approxi- mately 15% of the sample. Also, the mean leukoaraiosis score of this group was high (i.e., a mean of 22.07) and represents slightly more than 50% of the total subcortical white matter as measured by the Junque LA scale (47,48). Although it certainly appears that white matter does matter for this group of patients, it may be overly conservative to limit the diagnosis of subcortical VaD to these guidelines. Alternatively, Roman and colleagues (14) have suggested that perhaps only 25% of white matter needs to be involved to be judged clinically significant. In terms of the Junque leukoaraiosis scale this would be defined as a score of 10. This guideline is consistent with a mean and standard devia- Table 4 Within-Group Performance on the Executive Control vs Memory/Language Indices: z-Scores (Means and Standard Deviations) Memory/language index Executive control index Significance Mild MRI-WMA Group –3.9 (1.6) –1.4 (.90) p < 0.001 Moderate MRI-WMA Group –1.7 (1.5) –2.7 (1.6) ns Severe MRI WMA Group –1.4 (.88) –4.5 (1.5) p < 0.001 Abbr: MRI-WMA, periventricular and deep white matter alterations. Alzheimer’s Disease and Vascular Dementia 291 tion of the Junque leukoaraiosis scale of the moderate MRI-WMA group (i.e., M = 12.8; SD = 2.3, respectively). As noted above, this group produced equal impairment on tests of executive control vs memory/language. This profile does not necessarily satisfy some of the requirements to diagnose subcortical VaD as suggested by Erkinjuntti and colleagues (46). Nonetheless, a profile of equal impairment on tests of executive control vs memory/language is not what is expected in AD for which a dense anterograde amnesia is the hallmark neuropsychological feature of the disease. There- fore, the authors maintain that a moderate degree of MRI-WMA (i.e., a Junque leukoaraiosis score between 10 and 15 is likely sufficient to alter the neuropsychological presentation of patients with putative AD vs subcortical VaD). They also maintain that this characterization regarding the relation- ships between neuropsychological test performance and MRI-WMA may be consistent with the find- ings reported by Nagy and colleagues (15) and Snowdon and colleagues (16) who have shown that subcortical CVD influences the expression of senile plaques and NFT. One solution to the problem of diagnosing subcortical VaD might be to diagnose probable subcor- tical VaD when MRI scans indicate severe white matter loss and a striking dissociation on neuropsy- chological tests of executive control vs memory/language and to diagnose possible subcortical VaD when scans show only moderate white matter loss and relatively equal impairment on executive control and memory/language test. However, the authors believe that to set such boundaries is artifi- cial and likely does not represent clinical reality as it exists in nature. Also, trying to graft NINCDS- ADRDA terminology onto the diagnosis of the VaDs has likely created more problems than it has solved. Another solution to the problem of diagnosing subcortical VaD is to use some combination of neuroradiological and neuropsychological data as a grouping or independent variable without neces- sarily assigning any diagnostic labels. In their research, the authors used the leukoaraiosis scale of Junque as the means to operationally define subcortical white matter disease. However, they make no claim that this is best or even the optimal method to measure MRI-WMA. Other scales have been proposed (55–57). Indeed, the newly proposed rating scale of Wahlund and colleagues (57) has some distinct advantages over other rating scales, including the Junque scale (47,48). Dementia continues to be a worldwide public health problem. The data presented above sug- gests that dementia associated with moderate to severe periventricular and deep WMA is associ- ated with a pattern of performance on neuropsychological tests that is distinctly different than AD. The authors’ proposal to use neuroradiological criteria as a grouping variable is made to achieve greater diagnostic specificity. Medications for many of the dementias are now available. 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