Age and Ageing 1996:25:443-448 The Effect of White Matter Low Attenuation on Cognitive Performance in Dementia of the Alzheimer Type K. AMAR, R. S. BUCKS, T. LEWIS, M. SCOTT, G. K. WILCOCK Summary The effect of leukoaraiosis or white matter low attenuation (WMLA) on cognitive function is not fully understood. We compared the neuropsychological performance of 37 Alzheimer's disease patients with WMLA on CT brain scans with a similar group of 31 Alzheimer's disease patients with no evidence of white matter lesions. Patients with WMLA performed significantly worse on tests of visuospatial function (Cube Analysis test, p = 0.004), and cognitive speed (Kenrick Digit Copying test, p = 0.05) compared to those with no visible white matter lesions. Patients with widespread WMLA performed generally worse in tests of cognitive function than those with frontal or a mixture of frontal and occipital WMLA. This was most significant in the areas of attention (forward digit span, p = 0.003), visual recognition (p = 0.004), and cognitive speed (p = 0.03). There is an association between impaired cognitive performance and the presence of WMLA in Alzheimer's disease patients, with WMLA probably contributing to the cognitive impairment. This is most evident in patients with widespread white matter lesions. Keywords: Leuko-araiosis, White matter low attenuation, Dementia. Introduction Areas of white matter low attenuation (WMLA) (leukoaraiosis) are commonly observed on brain CT scans of demented patients, particularly those with vascular dementia. They have also been reported to be present in some 'normal' elderly people (Figure) [1 4]. Although numerous reports have linked WMLA to vascular risk factors, particularly hypertension and heart disease, their exact significance, particularly their effect on cognitive function, is not fully understood [5-8]. While some studies have failed to show any difference in cognitive performance between normal subjects and demented patients with and without white matter changes [9, 10], others have revealed subtle deficits, especially in subcortical functions, in those with WMLA [11 14]. The presence of white matter lesions in patients with dementia could therefore have an effect on the pattern of cognitive impairment in these patients. This is especially important in vascular dementia patients, where white matter lesions are very common [15, 16]. The aim of this study was to discover: (1) if a significant difference exists in neuropsychological performance between Alzheimer's disease patients with WMLA, and a similar Alzheimer's disease group without WMLA; (2) if the neuropsychological performance depends on the site or extent of white matter lesions. Methods Only patients with Alzheimer's disease were included in this study. Those with a history of alcoholism or significant head trauma were excluded. All patients were referred to our Memory Disorders Clinic because of possible dementia. Assessment included a full history from the patient and a close carer, physical examination including full cardiovascular and neurological examination, as well as a laboratory dementia screen and CT brain scan. In selected patients full psychiatric assessment by a psychiatrist, EEG, MRI or SPECT scan was also performed. The diagnosis of each patient is made in a case conference which involves two physicians, a psychiatrist and at least two psychologists who are experienced in this field. All patients fulfilled the DSMIIIR criteria for dementia and the NINCDS criteria for probable Alzheimer's disease according to McKhann et al. [17, 18]. All patients were assessed with a neuropsychological test battery (Table II), testing memory, language, abstract thinking, cognitive sp>eed, and visuospatial skills [19-24]. In all patients the psychologists were blind to the findings on the brain CT scan. CT scans were assessed by an experienced neuroradiologist (T.L.) who was blind to the patient's clinical information. The presence of WMLA was recorded, as well as its site and severity. The severity of white matter lesions was calculated using a modified formula devised by Blennow et al. derived by
444. K. AMAR ET AL. Figure. CT scan of brain showing mainly frontal white matter low attenuation. adding the scores of WMLA extent and intensity [6]. WMLA means of more than two subsets while multiple comparisons extent was graded on a four-point scale where 0 = no visible were controlled for by the Bonferroni method. white matter lesions, 1 = WMLA localized to the frontal and/ or occipital periventricular regions of the lateral ventricles, 2 = as in 1 but WMLA extending towards the centrum Results semiovale, and 3 = extensive WMLA coalescing with the Seventy-six Alzheimer's disease patients who fulfilled centrum semiovale. Intensity of WMLA was graded on a the inclusion criteria were referred to our centre four-point scale (0 3), where 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. Patients were also classified between January 1991 and December 1992, eight of according to the distribution of white matter lesions into whom were excluded from the study because of three groups; mainly frontal WMLA, a mixture of frontal and insufficient clinical information or missing brain CT occipital, and uniform or extensive WMLA. Although it scans. Fifty-four per cent (37 patients) were discovered would have been better to have two different neuroradioloto have WMLA on their brain CT (Table I). The mean gists assessing the CT scans, we were unable to do so in this age for the patients with WMLA was 75.2 years study for practical reasons. (SD = 6.8), compared with 71.6 years (SD = 7.7) in Statistical analysis was performed using the Statistical patients without WMLA (p = 0.04). There was no Package of Social Sciences (SPSS). Chi square was used to significant difference between patients with and withevaluate significant differences between frequency distribuout WMLA with regards to sex, years of education, or tions, while differences of means between two groups were duration of illness. assessed by Student's t test. One-way analysis of variance followed by Scheffe's pott hoc analyses were used to compare Comparing neuropsychological performance in
WHITE MATTER LOW ATTENUATION AND COGNITIVE PERFORMANCE 445 Table I. Demographic characteristics of patients with and without WMLA All patients With WMLA No WMLA Number Mean age (SD) Men: Women Years of education (SD) Duration of symptoms in months (SD) Vascular risk factors Smoking History of hypertension Heart disease Diabetes Cholesterol >6.5mmol Mean Mini-mental state examination (SD) Median MMSE 68 73.5 (7.4) 17/51 10.2(3.0) 39.3 (37.8) 11 10 16 3 32 17.1 (6.5) 19 p = 0.04 (Student's t test); fp = 0.01 (Pearson's chi square). patients with and without WMLA revealed that patients with WMLA performed worse on most tests compared with those without white matter lesions (Table II). This was significant in tests of cube analysis (visuospatial function, p = 0.004), and Kenrick's digit copying (speed, p = 0.05). Both remained significant after allowing for the confounding effects of age (with age being a covariate in an analysis of variance model). As can be seen from Table III, patients with extensive WMLA, i.e. leucency score greater than four, which included all those with uniform or extensive WMLA, performed consistently worse on all tests compared with those with no visible white matter lesions. This was again significant in the cube analysis test (p = 0.01), and remained so after allowing for age. Differences on the digit copying test and 37 75.2 (6.8) 7/30 9.8 (2.9) 37.7 (26.2) 7 9 11 1 20 16.4(6.1) 18 31 71.6(7.7)* 10/21 10.9(3.0) 41.2(48.5) 4 It 5 2 12 20 forward digit span (attention) were just outside the 5% level of statistical significance (p = 0.06). The distribution of white matter lesions (Table IV) shows that patients with mainly frontal white matter lesions performed generally worse that those with a mixture of frontal and occipital WMLA while those with extensive WMLA performed significantly worse than the former two groups in the areas of attention (digits forward, p = 0.003), immediate visual recall (p = 0.004), and cognitive speed (digit copying, p = 0.03). Discussion Table II. Difference in cognitive performance between patients with and without WMLA Function Attention/concentration Language Memory Abstract thinking Speed Visuospatial General cognitive Test administered Digit span forward Digit span backward Verbal fluency Frenchay aphasia screening test$ Story recall Visual recall immediate Visual recall delayed Visual recognition Concept formation/ Logical relationships Digit copying Cube analysis Mean MMSE Median score The clinical significance of WMLA is the subject of intense debate. Its exact effect on cognitive function, in Mean (SD) score* 7.1 (0.9) 5.4(1.3) 56.5 (12.9) 14.6(0.5) 16.1 (4.4) 11.9(5.0) 15.7(6.0) 1.1 (3.6) 0.4 (0.6) 127.1 (14.2) 1.3(1.0) No WMLA 6.0(1.8) 3.4(1.7) 29.3 (11.6) 10.8 (3.9) 2.0(1.8) 30.7 (4.5) 34.9 (2.4) 14.5(13.3) 5.7 (4.2) 89.1 (31.1) 6.6 (4.1) 20 With WMLA 5.9(1.9) 3.0(1.5) 24.0(13.4) 9.3 (4.4) 2.9 (3.3) 31.4(3.8) 35.5 (1.6) 11.6(11.9) 6.7 (4.9) 76.2 (23.0) 9.7 (3.9) 16.4(6.1) 18 p valuef 0.90 0.29 0.14 0.16 0.21 0.49 0.23 0.42 0.40 0.05 0.004 0.29 Based on 40 normal adults aged 61-87 years. f p value after Bonferroni correction. X Composite score of reading, reception and expression. An error score (higher score = worse performance).
446 K. AMAR ET AL. Table III. Cognitive performance according to the extent of white matter lesions Test No WMLA (n = 31) WMLA score 2-4 (n = 26) WMLA score 4-6 p valuef Digits forward Digits backward Story recall Verbal fluency Language Visual recall-immediate Visual recall delayed Recognition Abstract thinking Digit copying Cube analysis MMSE 6.0 (1.8) 3.4 (1.7) 2.05 (1.8) 29.3 (11.6) 10.8 (3.9) 30.7 (4.5) 34.9 (2.4) 14.5 (13.3) 5.7 (4.2) 89.1 (31.1) 6.6 (4.1) 6.4(1.4) 3.0(1.5) 3.3 (3.7) 25.7 (14.7) 9.8 (4.5) 30.9 (3.9) 35.6(1.2) 9.5 (10.8) 6.7 (4.9) 80.4 (23.3) 9.4 (4.10) 16.7(5.6) 4.8(2.5) 2.9(1.6) 1.9(1.6) 20.1 (8.7) 8.1 (4.2) 32.5(3.5) 35.2 (2.4) 18.0(14.0) 6.8 (5.2) 66.7 (20.2) 10.2(3.5) 15.6(7.3) Overlaps with nine patients with uniform WMLA (in Table IV). f Using one-way analysis of variance with post hoc Scheffe comparisons comparing no WMLA, WMLA score 2-4 and WMLA score 4 6. particular, is far from defined. Initial reports by Steingart et al. and Gupta et al. claiming that normal subjects and demented patients with WMLA suffer cognitively, particularly in subcortical functions, have been later challenged by others who failed to show a significant deficit in cognitive performance in normal subjects with white matter lesions [9 12]. These negative studies have been criticized for the small number of their subjects and more recent studies appear to confirm earlier reports of a role for WMLA in causing cognitive impairment [13, 14, 25, 26]. If so, then it is important to establish if such an effect is dependent on the extent or distribution of white matter lesions. In a similar study to ours, Lopez et al. compared the neuropsychological performance of 22 Alzheimer's disease patients with WMLA, to a similar group of patients without WMLA, but discovered no significant Table IV. Cognitive performance according to the distribution of the white matter lesions Test Digits forward Digits backward Story recall Verbal fluency Language Visual recall immediate Visual recall delayed Recognition Abstract thinking Digit copying Cube analysis MMSE Without WMLA (n = 31) 6.0(1.8) 3.4(1.7) 2.0(1.8) 29.3 (11.6) 10.8 (3.9) 30.7 (4.5) 34.9 (2.4) 14.5(13.3) 5.7 (4.2) 89.1 (31.1) 6.6 (4.1) Frontal WMLA (n = 18) 6.2(1.2) 3.0(1.4) 2.8 (3.6) 24.5 (14.8) 9.4 (4.5) 32.0 (3.8) 35.5(1.4) 10.5 (12.9) 7.4 (4.8) 76.6 (22.0) 9.9 (4.3) 16.1 (5.2) 0.06 0.56 0.19 0.13 0.20 0.44 0.44 0.27 0.71 0.06 0.01 0.52 difference betwen these two groups (although patients with WMLA were at higher risk of suffering cerebrovascular accidents on 1-year follow-up) [27]. In our study, patients with WMLA performed significantly worse on tests of speed and visuospatial function and although there was no documented incidence of cerebrovascular accidents on follow-up, hypertension was significantly more common in the patients with WMLA (Table I). The negative result of the Lopez et al. study could be due to the small number of patients they investigated, which made it difficult to detect a significant difference between the two groups, especially in view of the fact that the WMLA group performed worse on most tests. Although patients with white matter lesions were significantly older than patients without WMLA, the correlation between WMLA and impaired cognitive function remained significant after allowing for age. Fronto-occipital WMLA (n = 10) 7.0 (1.6) 3.3 (1.7) 4.05 (3.5) 26.6 (13.9) 10.8 (4.1) 28.4 (3.5) 35.0 (2.5) 12.4 (12.2) 5.2 (4.4) 88.7 (23.8) 8.6 (3.4) 18.9 (6.1) Uniform WMLA (n = 9) 4.2 (2.4) 2.7(1.6) 1.6(1.5) 19.8(9.8) 7.5 (4.5) 33.7(2.1) 36.0 13.0(11.4) 7.1 (5.7) 61.6(16.6) 10.5 (3.7) 14.2 (7.4) p value* 0.003 0.77 0.32 0.57 0.30 0.004 0.43 0.91 0.56 0.03 0.61 0.52 Using analysis of variance followed by post hoc Scheffe, comparing frontal, fronto-occipital and uniform WMLA.
WHITE MATTER LOW ATTENUATION AND COGNITIVE PERFORMANCE 447 Also, the fact that patients with white matter lesions had a similar duration of symptoms to those without WMLA means that the difference in cognitive performance could not be attributed to a longer duration of illness in those with poorer performance. It might be argued that our findings could be due to multiple testing of hypotheses which could result in a positive finding simply by chance, especially at the 5% confidence level. Although this possibility cannot be excluded, we believe that it is unlikely because the correlation between WMLA and visuospatial function was highly significant (p = 0.004) and is unlikely to occur by chance, while the impairment in digit copying is substantiated by similar recent findings on tests of speed by Ylikoski et al., Schmidt et al. and Breteler et al. [14, 13, 26]. Also, the fact that only Alzheimer's disease patients were included in this study, unlike some of the earlier studies (Gupta et al., Steingart et al., Kertesz et al.), eliminates a potential source of bias through dealing with different disease processes and thus makes these findings more robust [11, 12, 28]. There is evidence that the extent and pattern of white matter lesions are important in influencing cognitive performance. Boone et al. suggested a threshold effect for white matter lesions that have to be reached before a perceptible change could be detected on neuropsychological tests in normal subjects [29]. It is clear from Table IV that there is a trend for neuropsychological performance to deteriorate with increasing severity of white matter lesions and that this is most significant in tests of visuospatial function although tests of cognitive speed and attention were just outside statistical significance. Our finding of an impairment in visuospatial function in demented patients with white matter lesions has also been reported by Almkvist et al. [25], and interestingly by Rao et al. [9] in their study of normal subjects with white matter lesions, though they thought that this was probably a chance finding [9, 25]. Few studies have examined the distribution of white matter lesions and its effect on cognitive function. Damian et al. emphasized the significance of lesion pattern as well as lesion extent in causing cognitive impairment. They found that subcortical rather than periventricular white matter lesions correlated with cognitive deficit [30]. Almkvist et al. reported that cognitive deficit was mainly associated with posterior white matter lesions [25]. In this study patients with WMLA were also classified into three main groups according to the distribution of white matter lesions (Table IV). This revealed that patients with frontal WMLA performed generally worse than those with frontal and occipital WMLA, while those with uniform or extensive WMLA had the worst performance. This difference in performance was significant for attention, visual memory and cognitive speed. As reported in similar studies, there was no significant relationship between the presence of WMLA, its extent or site and tests of global cognitive function (the MMSE or Kew tests). Pathological studies show that areas of WMLA visible on CT scan correspond to white matter ischaemia with demyelination, axonal loss, arteriolar hyaline degeneration, and in some studies variable degrees of cerebral amyloid angiopathy [31 33]. This and the higher incidence of vascular risk factors, especially hypertension, in the Alzheimer's disease patients with WMLA raise the possibility of a vascular component to their dementia. This means that approximately a third of all Alzheimer's disease patients could be suffering from a mixture of Alzheimer's disease and vascular dementia. Although this vascular component will vary in different patients, probably depending on the extent of white matter disease, it is likely to be small in most cases. It may be possible to slow down the progression of dementia in those Alzheimer's disease patients with a significant vascular component by correcting vascular risk factors such as hypertension and heart disease. Finally, the association between a worse performance in Alzheimer's disease patients on some of the neuropsychological tests detected in this study does not necessarily mean that this is due to a direct effect of the white matter lesions on cognitive function. It is possible that some other factors or mechanisms, such as concurrent medications, could have played a significant role in the neuropsychological performance of our patients. 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