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(Stroke. 1995;26:749-754.)
© 1995 American Heart Association, Inc.

Articles

Anticardiolipin Antibodies in Normal Subjects

Neuropsychological Correlates and MRI Findings

R. Schmidt, MD; P. Auer-Grumbach, MD; F. Fazekas, MD; H. Offenbacher, MD P. Kapeller, MD

From the Departments of Neurology (R.S., F.F., H.O., P.K.) and Dermatology (P.A.-G.) and the MRI Center (R.S., F.F., H.O., P.K.), Karl Franzens University Graz (Austria).

Correspondence to Reinhold Schmidt, MD, Department of Neurology, Karl-Franzens University Graz, Auenbruggerplatz 22, A-8036 Graz, Austria.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Our aim was to assess the association of elevated anticardiolipin antibody (aCL) titers with silent brain damage and cognitive functioning in middle-aged and elderly normal subjects.

Methods We determined the IgM and IgG aCL titers from 233 randomly selected clinically normal participants of a population-based stroke prevention study (age range, 44 to 82 years). aCL titers were categorized into negative (0 to 10 U/L), low positive (10 to 20 U/L), and moderately high positive (>20 U/L). All participants underwent 1.5-T MRI and demanding neuropsychological testing. Semiautomated measurements of the total white matter hyperintensity area and the size of ventricles and cortical sulci were conducted.

Results There were 180 subjects (77.3%) with negative, 35 (15.0%) with low positive, and 18 (7.7%) with moderately high positive aCL titers. The frequency and extent of focal and diffuse brain abnormalities were not related to the aCL status of those examined. However, subjects with positive aCL results performed worse than those with negative findings on almost all tests administered, and this effect was mainly IgG titer related. When an ANCOVA test and partial correlations to correct for slight group differences in age and for the presence of major vascular risk factors were used, values of P<.05 were noted on tests assessing mnemonic and visuopractical abilities.

Conclusions Increased aCL titers in normal elderly persons may be associated with subtle neuropsychological dysfunction, but they do not appear to cause any morphological changes as demonstrated by MRI.

Key Words: aging • anticoagulants, anticardiolipin antibodies • neuropsychology • magnetic resonance imaging

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Anticardiolipin antibodies (aCL) have been linked to a plethora of symptoms including recurrent abortion, thrombocytopenia, livedo reticularis, and a prothrombotic state, with stroke being a common manifestation.^{1 2 3} Only recently the Antiphospholipid in Stroke Study (APASS) group demonstrated that this type of antibody may be a risk factor for cerebral ischemia not only in the young but also in the elderly.⁴ However, aCL were also seen in asymptomatic persons, and they become more common with increasing age.⁵ Some studies demonstrated an extremely high prevalence among subjects older than 65 years.⁶ The significance of this finding is still unclear. It has been suggested that aCL in the middle-aged and elderly partly belong to a class of "natural" autoantibodies without pathogenic implications.⁷ Conceivably, they could also be associated with clinically unexpected ischemic brain damage by causing some state of hypercoagulability. Focal changes of the brain parenchyma are a common MRI observation in normal subjects, and their frequency is strongly age related.^{8 9 10 11} Only recently has the presence of such abnormalities been linked to slowing of mental processing, which may be another accompaniment of aging.^{12 13} It might therefore be speculated that an association exists between the presence of aCL, silent cerebral damage, and cognitive impairment in older persons.

To test this hypothesis, the present study evaluated aCL in a large series of older asymptomatic community members in the setting of a stroke prevention study and correlated the aCL titers with the subjects' MRI findings and neuropsychological test performance.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The study population consisted of 233 participants (103 women, 130 men) of the Austrian Stroke Prevention Study (ASPS). They followed a written invitation after random selection from the official register of residents of the city of Graz, Austria. The response rate noted for the ASPS was 28%. A random sample of 200 nonresponders were interviewed by telephone and did not differ from responders in terms of age, sex, or educational level.¹⁴ Before study entry, all study participants underwent a structured clinical interview, a physical and neurological examination, three blood pressure measurements, electrocardiography, echocardiography, and laboratory testing including a blood cell count and a blood chemistry panel. The general criteria for enrollment into the ASPS were a history free of neuropsychiatric disease and a normal neurological examination. Persons reporting migraine attacks without aura were eligible for the study. The ages of study participants ranged from 44 to 82 years (mean age, 59.2 years). The sera of attendees were screened for autoantibodies known to have cross-reactivity with aCL. This included assessment of antinuclear antibodies by indirect immunofluorescence on Hep-2 cells and anti–double-stranded DNA antibodies by indirect immunofluorescence on Crithidia luciliae. For the present study, several inclusion criteria in addition to those of the ASPS were applied: (1) no severe general disease, including a recent history of myocardial infarction or prosthetic heart valves; (2) no drug or alcohol dependence disorder; (3) no clinical or laboratory evidence of systemic lupus erythematosus or other autoimmune disease; and (4) no autoantibodies with possible cross-reactivity with aCL. Diagnosis of cerebrovascular risk factors relied on the patients' history and appropriate laboratory findings, as described previously.^{13 15}

Commercially available purified cardiolipin (Elias) was used for the assessment of aCL in the patients' sera with a standardized synchronous enzyme-linked immunosorbent assay according to the methods defined by the International Workshop on Evaluation of the Anticardiolipin Test in 1986.^{16 17} Results were measured photometrically at 492 nm. The IgM and IgG isotype results were assessed in IgM (MPL) and IgG (GPL) phospholipid units, by which 1 unit is equal to 1 µg/mL of IgM or IgG. Following the interpretations of the APASS group,⁴ we categorized the results as negative (<10 MPL or GPL), low positive (10 to 20 MPL or GPL), and moderately high positive (>20 MPL or GPL). The coefficients of variance for intra-assay and interassay variabilities were 6.37 and 8.76, respectively. In all subjects with positive aCL titers the measurements were repeated after 3 months. Eight subjects with only transient aCL elevations were excluded from the study, and the results of the first examination were used for titer categorization in the remaining participants. We did not average titer results in subjects who underwent two assessments.

MRI was performed on 1.5-T superconducting magnets (Gyroscan S 15 or ACS, Philips) with the use of the spin-echo technique. Sagittal T₁-weighted images (repetition time [TR], 600 milliseconds; echo time [TE], 30 milliseconds) and transverse T₂-weighted scans (TR, 2500 milliseconds; TE, 30 or 60 milliseconds) were obtained with a slice thickness of 5 mm. All scans were reviewed by three experienced investigators (R.S., F.F., H.O.) who were unaware of the subjects' laboratory and clinical data. The scans were evaluated for focal and diffuse brain abnormalities. White matter hyperintensities (WMH) were graded according to our scheme^{18 19} as follows: 0, absent; 1, punctate; 2, beginning confluent; and 3, confluent. According to a recent publication demonstrating irregular periventricular hyperintensities to be ischemic in etiology, we also considered this type of abnormality as grade 3 WMH.²⁰ Caps and periventricular lining were disregarded because they most likely represent normal anatomic variants.^{13 21} For the assessment of total white matter hyperintensity area (TWMHA) (in square centimeters), we used the cursor-controlled stylus of our MRI console region-of-interest utility. This technique has been previously described.¹³ Lacunes were focal lesions that involved the basal ganglia, internal capsule, thalamus, or brain stem and were isointense to cerebrospinal fluid, with a maximum diameter of 10 mm or less.²²

The extent of ventricular and sulcal enlargement was subjectively rated as follows: 0, absent; 1, mild; 2, moderate; and 3, severe. Several objective measurements of the size of ventricles and cortical sulci were conducted. Ventricular indexes were (1) temporal horn width, (2) third ventricular ratio, and (3) ventricular–intracranial cavity ratio. Sulcal indexes included (1) sylvian fissure width and (2) frontal interhemispheric fissure width at the cella media level. A detailed description of these measures has been given elsewhere.^{23 24}

A neuropsychological test battery assessing verbal intelligence, mood, memory and learning abilities, conceptual reasoning, attention and speed, and visuopractical skills was administered to every subject. The tests employed have been widely used in the German-speaking area and were always applied in the same order and under the same laboratory conditions. Verbal intelligence was evaluated by the Mehrfachwahlwortschatztest (MWT-B),²⁵ a 35-item test requesting the individual to select the only meaningful term from among five options given for each item. Mood was evaluated by the test of Janke and Debus,²⁶ which is a self-administered questionnaire consisting of 136 adjectives describing states of activation, deactivation, extroversion, introversion, well-being, emotional stress, and anxiety. Bäumler's Lern-und Gedächtnistest (LGT-3)²⁷ assessed learning capacity and intermediate memory. It is a highly demanding paper-and-pencil procedure and consists of six subtests. Three subtests (word and digit association tasks and story recall) screen for verbal memory, and two (trail and design recall) screen for visuospatial memory. The sum of weighted scores from these subtests and of an image recognition paradigm was the total learning and memory performance score. The Wisconsin Card Sorting Test²⁸ was used as a measure of conceptual reasoning. Adhering to the criteria of Millner,²⁹ the measures computed were categories completed, perseverative errors, and total errors. Attention and speed were assessed with the Alters Konzentrations Test of Gatterer,³⁰ form B of the Trail Making Test,³¹ the Digit Span from the Wechsler Adult Intelligence Scale (Revised),³² and a complex reaction time task.³³ The Alters Konzentrations Test is a cancellation test particularly designed for use in elderly populations; it requests the proband to correctly identify a symbol repeatedly presented among five lines of slightly differing items. The variables used for analysis were the time needed to finish the test and the number of errors. The reaction time task was performed on a computerized system and tested the subject's ability to selectively react to a specific combination of visual and acoustic signals by pressing a button as quickly as possible. The computer records the number of erroneous responses and the reaction time. The Purdue Pegboard Test³⁴ evaluated visuopractical skills. The test consists of four subtests. In the first three subtests, the subject places as many pins as possible in a board containing two parallel rows of 25 holes within a 30-second period. The individual first uses the preferred hand, then the nonpreferred hand, and finally both hands. In the fourth subtest, both hands are used alternatively to construct "assemblies" consisting of a pin, a washer, a collar, and another washer during a 1-minute period.

We used the Statistical Package for Social Sciences (SPSS/PC+) for data analysis. Frequency distributions were compared by the ² test. One-way ANOVA was applied to assess significant differences of continuous variables among groups. An ANCOVA adjusted for the effects of age and vascular risk factors on the neuropsychological test scores. Partial correlations were used to identify the relationships between IgM and IgG titers and cognitive functioning. A Bonferroni correction for multiple outcome measures was not performed because this was a pilot study.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
One hundred eighty subjects (77.3%) had negative, 35 (15.0%) low positive, and 18 (7.7%) moderately high positive aCL titers. We identified 38 (16.3%) subjects with isolated IgG isotype and 11 (4.7%) with isolated IgM isotype elevations. Four participants (1.7%) were found to have both aCL isotypes increased. As seen in Table 1, aCL-positive subjects were slightly older and had a somewhat higher rate of cardiac disease than aCL-negative subjects. Length of education, sex distribution, and other major vascular risk factors as well as mood at the time of examination were almost equal among groups. Migraine without aura was reported by 15 subjects (8.3%) with negative, 4 (11.4%) with low positive, and 2 (11.1%) with moderately high positive titers. The aCL status of subjects had no influence on the MRI results (Table 2). Overall, silent ischemic brain damage defined as either infarcts, lacunes, or WMH was noted in 90 subjects (51.1%) with negative, 18 (51.4%) with low positive, and 12 (66.7%) with moderately high positive titers (P=.35). The frequency of ventricular and sulcal enlargement was also similarly distributed. These findings were confirmed by the semiquantitative MRI measurements of the TWMHA and the size of cerebrospinal fluid spaces (Table 3). The neuropsychological test results are shown in Table 4. aCL-positive study participants obtained worse scores than their aCL-negative counterparts on almost all tests. When ANCOVA was used to correct for group differences in age and vascular risk factors, values of P<.05 were seen on tasks that assessed mnemonic and visuopractical abilities. A similar trend was noted on attentional measures. As seen in Table 5, within these cognitive domains performance deteriorated significantly with increasing IgG isotype titers. A similar association did not exist for the IgM isotype.

View this table: [in this window] [in a new window]   Table 1. Demographic Data, Mood, and Cerebrovascular Risk Factors in Relation to Anticardiolipin Antibody Titer Categories

View this table: [in this window] [in a new window]   Table 2. MRI Findings in Relation to Anticardiolipin Antibody Titer Categories

View this table: [in this window] [in a new window]   Table 3. MRI Measurements in Relation to Anticardiolipin Antibody Titer Categories

View this table: [in this window] [in a new window]   Table 4. Neuropsychological Test Results in Relation to Anticardiolipin Antibody Titer Categories

View this table: [in this window] [in a new window]   Table 5. Partial Correlations Between Anticardiolipin Isotype Titers and Neuropsychological Test Results

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found positive aCL titers in 22.7% of clinically normal study participants, a rate higher than that seen in US studies, which indicated frequencies in the range of 0% to 14%.^{4 5 35 36} It is noteworthy that another European study also reported a very high aCL prevalence of 51.6%.⁶ Although no difference existed in terms of demographic characteristics between our study cohort and a random sample of nonresponders, some collection bias cannot be excluded for two reasons. First, the overall response rate noted for the ASPS was relatively low. Second, as in every stroke prevention study on volunteers, a disproportionately high response of persons with known risk factors might have occurred, and this could have led to an overestimation of aCL prevalence in our study. However, this is the first study on aCL findings among community-dwelling elderly persons and thus extends previous studies that focused either on blood donors^{4 5 35 36} or in one instance on healthy residents of a public nursing home.⁶ It is unlikely that methodological factors are responsible for the discrepancy in results, since most investigations, including our own, adhered to the international recommendations of aCL test standardization.^{16 17} Moreover, we repeated the measurements in all subjects with positive titers to exclude those with only transient titer elevations, which, for example, may occur during minor infectious diseases. Although the stock of affinity-purified cardiolipin may differ based on source and thus could have led to differences in assay results, it is also important to note that numerous authors have shown that aCL are heritable.^{37 38 39} Genetic differences among the populations investigated may therefore be another cause of the considerable variations in the prevalence rates reported.

The subjects with aCL in the present study had subtle neuropsychological deficits, which became particularly evident on tasks assessing mnemonic and visuopractical abilities. This finding cannot be attributed to potential confounders such as the slightly higher age of aCL-positive subjects and their increased frequency of heart disease because we used an ANCOVA for group comparison. Distorting effects of variations in the mood status between groups were also excluded. Although the differences in neuropsychological test performance could represent a type I statistical error induced by the multiple comparisons, this is unlikely since evidence of aCL was associated with impairment in virtually all cognitive domains. More importantly, a clear-cut negative relationship between cognitive test scores and the IgG isotype titer existed. A similar relation could not be substantiated for the IgM isotype, but one has to consider that only 15 subjects in our study had abnormal IgM levels.

Thus far there has been only one report on higher cortical dysfunction with antiphospholipid antibodies.⁴⁰ However, this study was conducted in patients with lupus erythematosus, and the parallels one might draw from neuropsychological abnormalities seen with this complex disorder and our cognitive findings in asymptomatic individuals are quite unclear. In contrast to the hypothesis of the present study, the frequency and extent of focal and diffuse brain abnormalities were unrelated to the participants' aCL titers. This lack of association is supported by a previous study by Fisher et al,⁴¹ who also failed to demonstrate a significant relationship between subcortical MRI changes of normal elderly subjects and various hemostasis factors, including aCL. Although microthrombotic events below the resolution of MRI still cannot be excluded with certainty, our results strongly suggest other than ischemic mechanisms for the observed aCL-related mental changes. One mechanism could be complement activation, which can result in membrane damage in various tissues. Davis and Brey⁴² evaluated complement activation directly using an enzyme-linked immunosorbent assay for SC5b-9 in young stroke patients with and without aCL and found a significant increase in the amount of this complex in those with aCL independent of thrombosis. SC5b-9 represents the terminal portion of the complement cascade and is responsible for its cytolytic effects.⁴³ If this mechanism occurred in the brains of our study participants with increased aCL titers, this would have been supported by more pronounced atrophy. However, as seen in many neurodegenerative disorders, morphological cerebral abnormalities may occur only late in the disease and are frequently anteceded by functional changes. The same has been observed in autoimmune diseases. Kushner et al⁴⁴ described lupus patients with neuropsychiatric symptoms with completely normal CT or MRI scans but marked multifocal perfusion deficits. An association with antiphospholipid antibodies such as the lupus anticoagulant was not assessed by these authors. We currently perform a single-photon emission CT study in our aCL-positive subjects to search for a functional correlate of their cognitive impairment. Recently Chapman et al⁴⁵ suggested another mechanism for neuronal dysfunction in the presence of aCL by demonstrating binding of antiphospholipid antibodies to ATP in a cohort of patients with dementia.

In conclusion, this study provides the first evidence of an aCL-related neuropsychological impairment in elderly normal subjects and therefore suggests that the spectrum of symptoms associated with this type of autoantibody may extend beyond what has been reported thus far. Replication of our results in different populations with a case-control design is imperative.

Received October 11, 1994; revision received December 22, 1994; accepted January 27, 1995.

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				A. Sabet, W. L. Sibbitt Jr, C. A. Stidley, J. Danska, and W. M. Brooks Neurometabolite Markers of Cerebral Injury in the Antiphospholipid Antibody Syndrome of Systemic Lupus Erythematosus Stroke, November 1, 1998; 29(11): 2254 - 2260. [Abstract] [Full Text] [PDF]

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