Cognition and White Matter Changes on Magnetic Resonance Imaging in Dementia Andrew Kertesz, MD,

FRCPC; Marsha Polk, MA; Tom Carr, MD, FRCPC

\s=b\ In a prospective magnetic resonance imaging and cognitive study of 38 demented patients and 15 control subjects, 11 of 27 patients with Alzheimer's disease and 8 of 11 patients with vascular dementia had significant periventricular hyperintensities. Memory and language testing in the early investigation of dementia is useful to distinguish patients with or without periventricular hyperintensities on magnetic resonance imaging. Patients without periventricular hyperintensities are worse on memory and conceptualization tests than patients with periventricular hyperintensities, who tend to be worse on comprehension and attention tests. These differences in cognitive pattern are present between patients with different pathogen-

esis who are otherwise matched for dementia severity. Language and some nonverbal cognitive deficits correlate with the extent of cortical and ventricular atrophy in Alzheimer's disease. (Arch Neurol. 1990;47:387-391)

tomographic Computed magnetic resonance

(CT) and imaging

(MRI) appearance of white matter changes, other than infarcts, have

been described in 7% to 30% of the "normal" aging population,15 in 28% to 80% of stroke patients,3"7 and impli¬ cated in dementia2-812 even though the clinical and pathological relationships remain controversial. Alzheimer's dis¬ ease (AD) is characterized by cerebral atrophy with cortical and subcortical gray matter changes, but white matter changes in dementia are believed to be more characteristic of vascular dis¬ ease, and they are often attributed to Binswanger's disease (BD).1-8-10" Vascular dementia has been differ¬ entiated from AD pathologically and clinically, although their relationship Accepted for publication September 13, 1989. From the Departments of Neurology (Drs Kertesz and Carr) and Nuclear Medicine (Ms Polk), St Joseph's Health Centre, University of Western Ontario, London, Canada. Reprints not available.

is complex and the two may coexist.1318 Multi-infarct dementia (MID) is a clin¬ ical concept characterized by stepwise evolution and/or focal signs.19 Binswanger20 described white matter changes with slowly progressive de¬ mentia and arteriosclerosis, and Alz¬ heimer21 provided further pathological definition of what he called BD. Olszewski22 rekindled interest in the entity, collected some pathologically examined cases, and called it subcortical arteriosclerotic encephalopathy. The pathological and clinical features of BD were reviewed recently by Babikian and Ropper.23 Periventricular white matter hypodensities on CT and hyperintensities on MRI (periventricular hyperintensi¬ ties [PH]) were considered a manifes¬ tation of BD by several investiga¬ tors.811·24·26 Recently, Hachinski et al27 applied the term leuko-araiosis to this appearance on CT, expressing cau¬ tion about any relationship to the cause. The higher sensitivity of MRI for these white matter abnormalities has been reported by several inves¬

tigators.13-5-8-22·23 Magnetic imaging not only shows

resonance more PH

but also different patterns of change that may represent different pathol¬

ogies.2·512 Magnetic resonance imaging

differentiation of AD from vascular dementia due to multiple infarcts, la¬ cunes, and/or BD has been attempted with small groups of patients.2·8·12·23 Most MRI studies of PH and dementia were retrospective, with limited clini¬ cal data and few patients. Some in¬ cluded stroke patients, or were se¬ lected from a stroke population.7·2830 Few of the studies of PH on MRI or CT correlated it with dementia severity or cognitive deficit,9-12·29-30 while some studies concluded there was no signif¬ icant relationship.717 The clinical and particularly the neuropsychological findings of BD are not well defined. We attempted to differentiate between those primary dementia patients with a significant amount of white matter

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hypertensities on MRI and those with¬

out, in a prospective study with exten¬ sive cognitive examination.

SUBJECTS AND METHODS

Subjects

selected from 88 patients referred for initial dementia diagnosis and underwent detailed clinical neurological and neuropsychological exam¬ inations and neuroimaging. In addition, 15 clinically normal control subjects were re¬ cruited from spouses of patients or outpa¬ tients seen for a nondementing condition. The criteria for exclusions were perceptual problems such as blindness or deafness, advanced stages of dementia precluding who

were

were

testing, pseudodementia (such as signifi¬ depression according to clinical crite¬ ria and the Beck Depression Inventory), se¬ vere anxiety disrupting testing procedures, schizophrenia, language barrier, stroke (see criteria below), Parkinson's disease, progressive supranuclear palsy, Creutz¬ feldt-Jakob disease, communicating hydrocephalus, and claustrophobic response dur¬ ing the MRI procedure. All remaining pa¬ tients fulfilled the Diagnostic and Statistical Manual ofMental Disorders, Re¬ vised, Third Edition3' criteria of dementia. Computed tomographic scans were used to cant

exclude brain tumor and confirm the extent of ventricular and cortical atrophy. All MRI studies were performed with a 0.15-T resis¬ tive magnet (Technicare). Images were ob¬ tained using a multispin echo pulse se¬ quence with a 2-second repetition time of 30 to 90 and 120 milliseconds. Time to echo, a 1-cm-slice thickness in a 256 X 256 matrix. Even though we excluded patients with a definite history of stroke, those with an is¬ chemie score32 of 7 or more were a priori classified as vascular dementia (Table 1). All the remaining nonvascular patients satisfied the Diagnostic and Statistical Manual of Mental Disorders, Revised, Third Edition31 and the National Institute of Neurological Disorders and StrokeAlzheimer's Disease and Related Disorders Association33 criteria of AD and were fur¬ ther divided independently and "blindly" based on the clinical diagnosis according to MRI criteria (below) into those with signif¬ icant PH and those with no PH (NPH). Al¬ together, 53 subjects, 38 demented and 15 control subjects, were included. Magnetic resonance imaging and CT evaluation was performed by two of us (T.C.

This 75-year-old man had a single transient ischemie attack and memory loss. The stars are adjacent to the unidentified bright objects, the arrows point to the rim, and the arrowheads point to the caps. Unidentified bright object counts were 10 and 12, caps were rated as 2, and 3 rims as 2 and 2, and ventricular atrophy as 2 and 2 by two raters.

. ., respectively) according to the following scale for rated variables: 0, no abnormality; 1, mild; 2, moderate; 3, severe; and 4, very severe. Ventricular and sulcal atrophy and the periventricular "rim" and "caps" around the poles of the ventricles were rated. An example of the rating is il¬ lustrated in the Figure. This patient who was clinically in the vascular group because and

of a transient ischemie attack was classi¬ fied in the PH group on the basis of the MRI. Unidentified bright objects, which are small hyperintensities in the periventricu¬ lar white matter, subcortical or cortical areas, not related to focal clinical signs and not present on CT,5 were counted. The rat¬ ers diagnosed PH if more than 1 unidenti¬ fied bright object and/or moderate or se¬ vere caps and rims were present. Mild, thin rimming or capping was not considered abnormal.25 Patients with ventricular and sulcal atrophy (score of 2 or above) are sep¬ arated from control subjects on the "blind¬ ed" radiological classification. This way a few of the NPH demented patients were rated as normal and vice versa (Table 1). Interrater disagreement regarding MRI di¬ agnostic groups was arbitrated by a third rater; all other quantitative scores were averaged. The ratings were used subse¬ quently for grouping of patients, and to correlate the severity of dementia with the severity of the hyperintensities. Neuropsychological testing included sev¬ eral standardized measures of cognitive

functions. We chose the Mattis Dementia Rating Scale (MDRS)34 for a cognitive screen. The subscales are sufficiently com¬

prehensive to examine attention, memory, conceptualization, constructional ability, and word fluency. The scoring was modifed slightly to combine motor commands and repetitive design to obtain a motor persis¬ tence score. Control subjects had only the MDRS. These subjects had to achieve the cut-off score of 127/144 or higher to be con¬

sidered normal. For the clinical correla¬ tions all patients below the cut-off point of 127 on the MDRS were included. This cut¬ off point is a rather conservative or strict measure of normal function, used by one study of 85 normal subjects35 and repre¬ sents 2 SDs below the mean of the control group of another study.36 For the assess¬ ment of language, the Western Aphasia Battery3' was used. For other cognitive measures, the Wechsler Adult Intelligence Scale-Revised,38 the Wechsler Memory Scale,39 or the Wechsler Memory ScaleRevised" were administered. RESULTS

The three MRI groups defined by blinded to the clinical diagnosis and symptoms were as follows: NPH, 19; PH, 19; and negative, 10. The rela¬ tionship of the MRI rating to the clin¬ ical diagnosis is expressed in Table 1. The most interesting result is that 11 raters

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(41%) of 27 patients who had AD clin¬ ically had a sufficient amount of PH to be placed in the PH group. Most (73%) of the clinically diagnosed vascular dementias (designated as MID in Ta¬ ble 1) were placed in the PH group on neuroimaging, although the three ex¬ ceptions (false-negatives) are interest¬ ing. Three of 15 nondemented control subjects were considered to have larger than normal ventricles and two others were considered to have signif¬ icant periventricular changes, raising the rate of false-positives to 5 (33%) of

15 (these cases remained in the control group as their MDRS scores were

above 127). The

radiologically defined subjects did not differ significantly from each other in

groups and the control age or education toms (Table 2).

or

duration of symp¬

Separate stepwise discriminant function analyses of Wilk41 were per¬ formed on correlated sets of variables of the MDRS, Western Aphasia Battery, Wechsler Adult Intelligence Scale-Revised, and Wechsler Memory Scale. Prior probability of member¬ ship was set at .05. Student's t and Mann-Whitney U tests were also used to determine the differences between the groups on each subtest with a con-

MRI

Clinical

No. of

Diagnosis

Subjects

—

PH

=

Age, y Education, y llness, mo

tive *

NPH indicates

ble. *

MRI indicates

no

=

=

magnetic resonance imaging; NPH,

periventricular hyperintensities: PH, periventricular hyperintensities; AD, Alzheimer's disease; and MID, no

multi-infarct dementia. tTwo of the central subjects having NPH.

were

diagnosed

as

servative level of significance of .01. The results of the MDRS are sum¬ marized in Table 3. The two patient groups are well matched for severity of dementia, represented by the total MDRS score. However, atten¬ tion (P .005) and conceptualization (P .05) were significant discrimina¬ tors on discriminant function analysis. Patients with PH do poorly on atten¬ tion, while patients with NPH have more difficulty with conceptualization. Eighty-one percent of the patients were correctly classified on the basis of all MDRS variables. Word fluency is lower in patients with PH, indicating more language deficit, but memory is poorer in patients with NPH (none of these differences were significant for individual subtests on t tests or MannWhitney U tests). Language subtest performance on the Western Aphasia Battery revealed lower mean scores for the PH com¬ pared with the NPH group (Table 4). Comparison of the overall aphasia quotient shows nearly equivalent to¬ tals for each group. Three of 10 lan¬ guage subtests on the Western Apha¬ sia Battery showed trends of being significant discriminators: spontane¬ =

=

speech content (P .09), repeti¬ (P .07), and comprehension of yes/no questions (P .09), in addition to calculation (P .04). Patients with NPH were slightly more impaired on content and repetition subtests and patients with PH were more impaired on comprehension and calculation items (Table 4). These individual subtests did not differ, however, on t test and Mann-Whitney U compari¬ ous

tion

Control Subjects, PH, 19, 15, (SD) (SD) 74.05 (6.27) 71.40(6.86) 10.64(3.30) 10.20(2.34) NA -24.71(22.97) periventricular hyperintensities; PH, periventricular hyperintensities; and NA, not applica¬

NPH, 19, (SD) 72.11(10.47) 10.11(3.50) 18.71(12.79)

Diagnosis Nega¬

NPH

Magnetic Resonance Imaging Subject Groups*

Table 2.

Table 1.—The Relationship of Clinical and MRI Diagnoses*

=

=

=

=

sons.

The memory subtests of the Wechsler Memory Scale yielded five significant discriminators: delayed re¬ call performance of paired word as¬ sociates (P .007); delayed recall of memory passages (P .01); immedi¬ ate recall of paired associates (P .01); immediate recall of memory pas¬ sages (P .008); and delayed visual reproduction (P .01). On these =

=

=

=

=

Table 3.—Modified Mattis Dementia Test*

NPH, PH, Control Subjects, 19, 19, N_= 15, N_= Variable " (SD) S (SD) Score x(SD) Attention t 37 34.40 (2.08) 33.37 (3.41) 36.00 (1.25) 18.60 (2.16) Word fluency 11.22 (3.99) 10.54 (5.22) Motor persistence 4.46 (1.79) 5.21 (1.60) 6.53 (0.83) Construction 6.00 (0.00) 4.60 (1.56) 5.17 (1.49) 35.73 (3.20) 26.52 (5.75) 27.98 (6.98) Conceptualization t 15.37 (6.05) 24.27 (.80) 14.37 (3.71) Memory Total 104.20 (14.01) 105.25 (20.08) 137.60 (5.19) 144 *NPH indicates no periventricular hyperintensities; PH, periventricular hyperintensities. tDiscriminating variable. tThe scoring was modified slightly to combine motor commands and repetitive design to obtain a motor per¬ Maximum

sistence

=

score.

subtests, patients with NPH recall fewer word pairs, story ideas, and visual items in both immediate and delayed conditions than patients with PH (Table 5). The Wechsler Adult Intelligence Scale-Revised showed no significant discriminators on any subtest, indicat¬ ing that the groups were well matched for most other areas of cognitive func¬ tion other than language and memory

(Table 6). Cognitive deficits correlated best with cortical atrophy and ventricular size in the patients with NPH. Aphasia quotient (.45), speech content (.34), word fluency (.35), word comprehen¬ sion (.15), and naming (.15) showed significant correlations (Spearman), with cortical atrophy in patients with AD. Block design (.63) correlated with

ventricular size. Correlations of the cognitive deficit with PH were not found to be significant in the PH group. Combining the two demented groups did not show significant correlations between any of the cognitive deficits and the ratings of the neuroimaging abnormalities. COMMENT

The clinical significance of the white matter changes in dementia needs clarification in view of the apparent overlap between normal aging, cere¬ brovascular disease, and nonvascular dementia. The presence of white mat¬ ter changes does not necessarily mean dementia, as 2 of 15 nondemented con¬ trol subjects had enough PH to be classified in the PH group radiologically. This is only 13%, less than other

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populations,14 but similar to our pre¬ vious group of control subjects,5 and some other studies where the PH was graded and strokes were excluded.1·4·8·17 Moderate to severe extent of PH* seems to be associated with dementia in a clinically relevant fashion, even though there are exceptions to this. The majority of the patients with clin¬ ically diagnosed vascular dementias had PH, but also a substantial number (41%) of the patients clinically diag¬ nosed as having AD showed signifi¬ cant PH indicating an overall inci¬ dence of 50% in the total demented population vs the 13% incidence in control subjects. Even though the inci¬ dence figures support the relationship of PH to dementia in this study, the cor¬ relations of the actual deficits with the severity rating of the PH were not sig¬ nificant either in the group selected for having significant PH or in the overall demented population. Nondemented subjects with PH need to be followed up to see if dementia develops later to determine if this radiological feature is an early predictor of dementia. Alzheimer's dementia is not consid¬ ered obviously different from vascular dementia in its clinical manifestation, except in the history of abrupt onset risk factors or stepwise deteri¬ oration.12 Multiple infarcts often pro¬ duce cognitive changes, such as speech and articulatory abnormalities, par¬ ticularly if focal infarctions of the cor¬ tical and subcortical structures are in¬ cluded in the series.42 Sometimes these changes are included under the um¬ brella of MID. Neither the original de¬ scription of MID19 nor the diagnostic

Table 4.—Language Differences* Maximum Score

NPH, 19, PH, 19, S (SD) x(SD) 85.33 (13.01) Aphasia quotient 84.76(11.21) Contentt 7.84 (1.98) 8.13 (1.49) 10 Fluency 8.68 (1.34) 8.63 (1.15) Yes/no questionst 56.29 (3.51) 58.16(3.02) 60 Word comprehension 58.05 (4.20) 56.97 (4.94) 80 69.16 (15.41) 67.69 (11.56) Sequential commands 100 86.37 (15.80) 88.15 (14.21) Repetitiont Object naming 55.58 (7.39) 52.45 (10.19) Word fluency 9.32 (5.41) 8.19 (4.37) 10 9.42 (1.12) Sentence completion 9.38 (1.10) 10 9.58 (0.90) Responsive speech 9.63 (0.74) 24 Calculationt 20.12 (4.92) 18.72 (5.29) NPH indicates no periventricular hyperintensities; PH, periventricular hyperintensities. Variable

=

Table 5.—Wechsler

=

Memory Scale*

NPH,

PH,

_Variable_ (SD)_ (SD)_f Test

Mann-

Whitney

U

3.05 (2.26) 4.89 (2.07) .01 Logical memory, immediatet .02 Logical memory, delayedf_0.79 (1.13)_2.08 (1.79)_.Oí_.01 Visual reproduction, immediate_4.89 (4.88)_6.26 (3.50)_.32_.21 Visual reproduction, 2.00 (2.41)_ 8_ 2 delayedt_0.79 (1.62) 8.62 (4.01) 8.66 (4.34) Paired associates, immediatet .98 .99 .07 Paired associates, delayedt .09 2.53(1.66) 3.58(1.90) * NPH indicates no periventricular hyperintensities; PH, periventricular hyperintensities. tDiscriminating variable.

Table 6.—Wechsler Adult Intelligence Scale-Revised* NPH,

=

16,

PH,

=

14,

_Variable_ (SD)_ (SD) Full scale IQ_81.73 (13.01)_83.57 (9.84) Verbal IQ_85.47 (14.38)_88.07 (10.82) Performance IQ_78.00 (11.53)_79.36 (10.46) Information_7.20 (1.82)_7.79 (2.22) Vocabulary_9.14 (2.82)_8.55 (1.99) Arithmetic_7.00 (2.67)_7.64 (2.10) Comprehension_7.28 (3.26)_7.71 (3.71) Similarities_7.00 (2.51)_7.29 (2.89) Picture completion_6.13 (2.77)_6.14 (3.42) Picture arrangement_6.60 (3.20)_5.86 (2.68) Block design_6.27 (2.87)_6.29 (2.37) Object assembly_5.27 (3.15)_6.15 (2.96) Digit symbol *

NPH indicates

5.10(2.96) no

6.45(2.17)

periventricular hyperintensities; PH, periventricular hyperintensities.

BD may show more language change. In contrast, our findings indicate more language changes with PH than with¬ out PH in this early dementia popula¬ tion. In the subcortical variety of certain forms of vascular dementia, such as BD, language decline may be early and loss of comprehension may turn out to be a marker for this type of subcor¬ tical pathology. This finding may be an apparent departure from the defini¬ tion of subcortical dementia by

Albert46 who observed that patients with predominantly subcortical pa¬ thology such as progressive supranu¬ clear palsy and Parkinson's disease have less language disturbance than those with cortical dementia or AD. This principle is generally valid if pa¬ tients with later stage AD are consid¬ ered. However, there is a clinical and pathological difference between the neuronal system disorders, such as Parkinson's disease and progressive supranuclear palsy, and the periven¬ tricular subcortical lesions with sub¬ stantive, although patchy, disconnec¬ tions of the language network. Memory tests showed a significantly worse performance in AD patients without PH. All memory subtests, including visual reproduction, were worse in this group although the dif¬ ferences were the greatest in the logi¬ cal memory subtests and in delayed memory. Therefore, the performance on the Wechsler Memory Scale, as well as the memory subtest of the MDRS, are useful to discriminate patients with and without white matter in¬

volvement,

even

though they

are

matched for dementia severity. The combination of language tests with memory tests provides more discrimi¬ nating power than using only one test. Simple, brief tests, such as the MiniMental State Examination or encoding 10 words in sentences is not likely to provide sufficient clinical information in the early assessment of dementia to distinguish between various sub¬ groups with possible different patho¬

genesis.

criteria of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition,3' include radiological features. Multi-infarct dementia is a syndrome of acquired intellectual im¬ pairment with stepwise deteriorating course with variable mental status deficits. This includes, however, a het¬ erogeneous group of aphasie, apraxie, and agnosie patients who differ from patients with progressive diffuse vas¬ cular dementia. We were careful to ex¬ clude stroke patients and include only those who were referred with

primary dementia. We studied early dementia at pre¬ sentation, distinct from retrospective studies comparing different stages of

vascular dementia with AD. The dura¬ tion and severity of illness were matched, as the stage of disease is im¬ portant to determine the nature of the cognitive deficit. Language impair¬ ment, for instance, invariably develops in later stages of AD,43"45 therefore, a patient with a later stage of AD com¬ pared with a relatively early case of nonprogressive vascular dementia or

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There is evidence for the coexist¬ of AD pathology with vascular changes.13-1518 Magnetic resonance im¬ aging appears to be particularly sensi¬ tive to the white matter hyperintensi¬ ties even in some of those cases that ence

are clinically diagnosed as primary degenerative dementia or AD.9-12-17-18-30 Recently, the term senile dementia of the Binswanger type was proposed to suggest that patients who show these changes should be considered sep¬ arately.11 Even though AD may coexist with vascular pathology, our study suggests that patients with or without

white matter

changes may be distin¬ guishable neuropsychologically. More detailed studies with extensive cogni¬ tive correlations are needed to estab¬ lish the early diagnosis of BD and whether separation from AD is justi¬ fied on the basis of MRI appearance. Binswanger's disease or full-blown ischemie periventricular leukoenceph¬ alopathy is characterized by dementia with focal deficits, frontal lobe signs, pseudobulbar palsy, and gait difficul¬ ties with or without urinary incon¬ tinence.10-23 However, the majority of patients who present with radiological signs and mild dementia do not have the full syndrome. Pathological stud¬ ies of BD include a wide spectrum of

clinical disease, and correlation with neuropathological, clinical, and MRI patterns is still lacking. Since this is a potentially preventable and treatable form of dementia, its early identifica¬ tion has great clinical significance, even without pathological confirma¬ tion. It is too early to equate PH on the MRI or leuko-araiosis on CT with BD. Some have come to believe that MRI provides a nonspecific index of brain parenchymal alterations caused by aging and chronic cerebrovascular disease.47 Careful clinical follow-up of these patients will certainly be re¬ quired to clarify the issue. One study followed up a few patients with PH on

MRI and did not find significant deterioration.48 For the time being, the designation of these patients as having possible dementia of the Binswanger type may be a useful distinction from those demented patients without the white matter changes. Our results sug¬ gest that some of the distinctions de¬ tected by systematic language and cog¬ nitive tests may be related to different pathologies, at least as they are dis¬ tinguished by the MRI. This study was supported by the Physician's Services Ine Foundation Grant No. 88-15 to Dr Kertesz. We are grateful for the assistance of Linda Carter, Bonita Caddel, Barbara Robertson, Patri¬ cia McCabe, and Larry Nicholson.

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