MRI white matter hyperintensities

Individuals and study design.

The study population consisted of participants of the Austrian Stroke Prevention Study, a single-center, prospective follow-up study on the cerebral effects of vascular risk factors in the normal elderly population of the city of Graz, Austria. The study is purely descriptive. We selected randomly a sample of 8,193 individuals age 50 to 75 years stratified by gender and 5-year age groups from the official community register. Between September 1991 and March 1994, individuals received a written invitation to participate in the study that described the purpose of the investigation. Overall, 2,794 of the invited returned a card stating their willingness to participate. Recruitment into the study was stopped after enrollment of 1,998 eligible participants. Individuals were excluded from the study if they had a history of neuropsychiatric disease, including previous cerebrovascular attacks and dementia, or an abnormal neurologic examination determined on the basis of a structured clinical interview and a physical and neurologic examination. A random age- and sex-stratified sample of nonresponders was interviewed by telephone and did not differ in terms of length of education, occupational status, and history of vascular risk factors including arterial hypertension, diabetes mellitus, and cardiac disease. All study participants underwent three blood pressure readings, EKG, echocardiography, and laboratory testing including blood cell count and a complete blood chemistry panel. Every fourth study participant or the next was invited to enter phase II of the study, which included MRI, Doppler sonography, SPECT, and neuropsychological testing. From a total of 498 phase II participants, 458 volunteered to undergo MRI. During the second study panel, 3 years after baseline, 345 phase II attendees agreed to be reexamined following the same protocol. From the 113 individuals that could not be reexamined, 7 died and another 7 experienced a stroke, which is an end point in our study. Seventy-two subjects underwent all other examinations but refused to undergo a second MR image because they experienced claustrophobic sensations during the initial evaluation. The remaining 27 individuals were contacted by telephone but did not want to undergo the extensive diagnostic workup a second time. The current study cohort is comprised of those 273 study participants, with a baseline and 3-year follow-up MRI. There were 142 women and 131 men. The mean age was 60 ± 6.1 years (median, 60.0 years). The sample consisted exclusively of whites of central European origin, and the length of education ranged from 9 to 18 years (mean, 11.7 years). At the time of examination, 48% of study participants were retired, 12% were blue-collar and 29% were white-collar workers, and 11% were housewives or housemen. No unemployed individual participated in the study. Overall, 76.6% of study participants were married, 8.4% were unmarried, 8.4% were divorced, and 6.6% were widowed. The individuals who participated in the follow-up MRI study did not differ from those who dropped out in terms of age, gender, educational and occupational status, and risk factors for stroke.

Vascular risk factors.

Historic information and laboratory findings at baseline and follow-up were considered for risk factor diagnosis. Arterial hypertension was considered present if an individual had a history of arterial hypertension with repeated blood pressure readings higher than 160/95 mm Hg, if an individual was treated for arterial hypertension, or if the two readings at the examinations exceeded this limit. Diabetes mellitus was coded present if an individual was treated for diabetes at the time of examination or if the fasting blood glucose level at one examination exceeded 140 mg/dL. Cardiac disease was assumed to be present if there was evidence of cardiac abnormalities known to be a source for cerebral embolism,22 evidence of coronary heart disease according to the Rose questionnaire,23 or appropriate EKG findings24 (Minnesota codes: I, 1 to 3; IV, 1 to 3; or V, 1 to 2), or if an individual presented signs of left ventricular hypertrophy on echocardiogram or EKG (Minnesota codes: III, 1; or IV, 1 to 3). Study participants were asked whether they ever smoked and if they currently smoked. The body mass index (BMI; in kilograms per square meters) was determined at both examinations. The means of systolic and diastolic blood pressure, fasting blood sugar, and BMI of baseline and follow-up measurements were calculated and used for data analyses.

Laboratory measurements.

During both examinations a lipid status, including the level of triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, as well as Lp(a) lipoprotein, was determined for each study participant. Thirty minutes after venipuncture the coagulated blood samples were centrifuged at 1,600 g for 10 minutes, then the serum was transferred to plastic tubes and analyzed within 4 hours. Triglycerides and total cholesterol were determined enzymatically using commercially available kits (Uni-Kit III “Roche” and MA-Kit 100 “Roche,” Hoffman-La-Roche, Vienna, Austria). HDL cholesterol was measured by using the TDx REA Cholesterol assay (Abbott, Vienna Austria). LDL cholesterol was calculated by the equation of Friederwald. Lp(a) lipoprotein concentration was determined by the electroimmunodiffusion method using a reagent kit containing monospecific anti-Lp(a) antiserum and the Rapidophor M3 equipment (Immuno AG, Vienna, Austria). The levels of apolipoprotein B and A-I were assessed with an immunoturbidometric method utilizing polyclonal antibodies and a laser nephelometer (Behringwerke AG, Marburg, Germany). We also measured the plasma fibrinogen concentration of study participants according to the Clauss method, using the prescription and reagents of Behringwerke AG. For data analysis we used the means of the baseline and follow-up lipid and fibrinogen values.

Magnetic resonance imaging.

MRI was performed on 1.5-T supraconducting magnets (Gyroscan S 15 and ACS, Philips, Eindhoven, The Netherlands) using proton density- and T2-weighted sequences (repetition time [TR]/echo time [TE], 2,000 to 2,500 msec/30 to 90 msec) in the transverse orientation. T1-weighted images (TR/TE, 600/30 msec) were generated in the sagittal plane. The slice thickness was 5 mm and the matrix size was 128 × 256 pixels. At baseline and the 3-year follow-up, the MRI protocols were identical. The scanning plane was always determined by a sagittal and coronal pilot to ensure consistency in image angulation throughout the study. The baseline and follow-up scans of each study participant were read independently by three experienced investigators blinded to the clinical data of study participants. Blinding of the readers for the date of the examinations was impossible because the format of hard copies changed from baseline to follow-up. Only proton density-weighted images were used for WMH reading. WMH were specified and graded according to our scheme8,25 into absent (grade 0), punctate (grade 1), early-confluent (grade 2), and confluent (grade 3) abnormalities. The number of WMH was recorded and categorized into zero, one to four, five to nine, and more than nine lesions. We disregarded caps and “pencil-thin” periventricular lining because they represent normal anatomic variants.5,26 Change of WMH in grade and number from baseline was determined by direct scan comparison. The change in number was again categorized into zero, one to four, five to nine, and more than nine lesions. Regression or progression of WMH was then graded as absent, minor, or marked. A change from baseline by one to four punctate lesions was defined as minor. If there was a difference of more than four lesions, or a transition to early-confluent or confluent WMH, the change was considered to be marked.

Examples for minor and marked progression of abnormalities are shown in figures 1 and 2⇓. The final rating of WMH evolution relied on the majority judgment of the three assessors. In case of complete disagreement, consensus was found in a joint reading session. During the baseline examination, four participants were found to have silent thromboembolic infarcts and 18 had lacunes, defined as focal lesions involving the basal ganglia, the internal capsule, the thalamus, or the brainstem not exceeding a maximum diameter of 10 mm. These individuals were not excluded from additional study.

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Figure 1. Minor white matter hyperintensity progression in a 59-year-old female study participant. The baseline scan was normal (left). One punctate white matter abnormality in the frontal subcortical white matter (arrow) was noted at the 3-year follow-up examination (right).

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Figure 2. Marked white matter hyperintensity progression in a 67-year-old female study participant. The composite shows baseline scans (left) and the corresponding follow-up studies (right). Several punctate foci were seen at baseline. After 3 years multiple, new, and partly confluent abnormalities occurred.

Neuropsychological testing.

During the baseline and 3-year follow-up, an identical neuropsychologic test battery assessing memory and learning abilities, conceptional reasoning, attention, and speed as well as visuopractical skills was administered to every subject. For tests of memory and learning as well as conceptional reasoning we administered validated parallel forms at follow-up. The tests employed have been widely used in the German-speaking area and were always applied in the same order and under same laboratory conditions. Bäumler’s “Lern-und Gedächtnistest”27 assessed for learning capacity and intermediate memory. It is a highly demanding, paper–pencil procedure and consists of six subtests. Three subtests (word and digit association tasks, and story recall) screen for verbal memory, and two subtests (trail and design recall) screen for visuospatial memory. The sum of weighted scores from these subtests and of an image recognition paradigm result in the total learning and memory performance score. The stimulus sets of the word association task (German–Turkish word pairs), the story (facts about construction of a library), and design recall (core symbol and frame), and the recognition paradigm (objects) consist of 20 items each. A trail in an abstracted city map serves as the trail recall test. These sets of stimuli were presented to the person being tested for 1 minute. Two minutes were given for learning the 13 items of the digit association task (three-digit telephone numbers and names of extension holders). During a learning phase the six sets of stimuli are subsequently presented to the person being tested. The recall phase starts immediately thereafter and follows the same order. The delay between presentation and recall for a given subtest ranges between 7 and 11 minutes. The Wisconsin Card Sorting test28 was used as a measure of conceptional reasoning. Adhering to Millner’s criteria,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 Test from the Wechsler Adult Intelligence Scale–Revised,32 and a complex reaction time task.33 The Alters–Konzentrations–Test is a cancellation test that has been designed particularly for use in elderly populations. The test is composed of 5 lines with 11 symbols each. The target symbol is a semicircle with the base on the bottom and a black quadrant on the right. Distractors are semicircles that are either positioned differently or positioned with the black quadrant on the left. The persons being tested were instructed to work as quickly and as accurately as possible. The variables used for analysis were the time needed to finish the test and the number of correct responses. The reaction time task was performed on a computerized system that tested the subject’s ability to react selectively to a specific combination of a visual and acoustic signal by pressing a button as quickly as possible. The computer records the number of correct responses and the reaction time. Visuopractical skills were evaluated with the Purdue Pegboard Test.34

Statistical analyses.

We used the Statistical Package of Social Sciences (PC+) (version 8.0.0; SPSS Inc., Chicago, IL) for data analysis. The degree of agreement for WMH rating at baseline and for WMH progression rating among observers was expressed by the means of kappa statistics. According to Fleiss,35 a kappa value less than 0.40 reflects poor agreement, a value between 0.40 and 0.75 indicates fair to good agreement, and a kappa value higher than 0.75 reflects excellent agreement. The kappa statistic was calculated for the agreement between each pair of raters. Categoric variables among the subgroups of individuals with various degrees of WMH progression were compared using the Mantel–Haenszel test for linear trend. Assumptions of normal distribution for continuous variables were tested by Lillifors statistics. Normally distributed continuous variables were compared with one-way analysis of variance (ANOVA), and the Kruskall–Wallis test was used to compare abnormally distributed variables. Multiple logistic regression analysis was used to assess the relative and independent contribution of demographics, vascular risk factors, and baseline MRI findings on total WMH progression. We simultaneously entered age, sex, and all variables for which the p value was less than 0.10 after univariate testing. The selected factors were used as independent variables, and the presence or absence of WMH progression was used as a dependent variable. Odds ratios and 95% CIs were calculated from the beta coefficients and their standard errors. ANOVA for repeated measures, with adjustment for age and duration of education, was applied to evaluate the effect of WMH progression × time on neuropsychological test performance.