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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63:510-517 (2008)
© 2008 The Gerontological Society of America

Association of Blood Pressure and Genetic Background With White Matter Lesions in Patients With Mild Cognitive Impairment

Samantha Galluzzi, Cristina Geroldi, Luisa Benussi, Roberta Ghidoni, Cristina Testa, Genoveffa Borsci, Matteo Bonetti, Dario Manfellotto, Giuseppe Romanelli, Roberto Zulli, Giuliano Binetti and Giovanni B. Frisoni

1 LENITEM-Laboratory of Epidemiology, Neuroimaging and Telemedicine, 2 Psychogeriatric Unit, and 3 NeuroBioGenLab–Memory Clinic, IRCCS San Giovanni di Dio–Fatebenefratelli, Brescia, Italy.
4 AFaR, Associazione Fatebenefratelli per la Ricerca, Rome, Italy.
5 Institute of Internal Medicine, Department of Medical Sciences, University of Brescia, Italy.
6 Service of Neuroradiology, Istituto Clinico Città di Brescia, Italy.

Address correspondence to Giovanni B. Frisoni, MD, IRCCS Centro San Giovanni di Dio–Fatebenefratelli, National Centre for Research and Care of Alzheimer's and Mental Diseases, via Pilastroni 4, 25125 Brescia, Italy. E-mail: gfrisoni{at}fatebenefratelli.it


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Background. White matter lesions (WMLs) may contribute to cognitive deficits in patients with mild cognitive impairment (MCI), but their pathogenesis is complex. Fluctuations of blood pressure (BP) over 24 hours and genetic predisposition to develop vascular damage have been implicated.

Methods. In 63 MCI patients 65 years old or older, BP was measured both clinically and with ambulatory BP monitoring. Patients were classified in two groups: no/very mild (n = 34) and mild to severe (n = 29) WMLs, based on a visual scale on magnetic resonance (mean age 71.8 ± 4.7 vs 74.6 ± 5.1, and female gender 53% vs 66%, respectively). The volume of WMLs was measured by a semi-automatic method, separately for periventricular caps and rim, periventricular confluent, subcortical punctate, and subcortical confluent. Polymorphisms of cystatin C (CST3) and cholesterol 24-hydroxylase (CYP46) genes, putative risk factors for cerebrovascular disease, were determined.

Results. The prevalence of cerebrovascular risk factors was similar in the two MCI groups of different WML severity, as well as clinic and ambulatory BP. In patients with mild to severe, but not in those with no/very mild WMLs, the volume of periventricular confluent WMLs increased with increasing daytime systolic BP (regression coefficient.47, 95% confidence interval [CI],.13 to.71 vs.02, 95% CI, –.32 to.36, p =.003 for the difference between slopes). The volume of other WML subtypes was not associated with ambulatory BP. Participants carrying both CST3*B and CYP46*T alleles were overrepresented in the MCI group with mild to severe WMLs (43% vs 17%, p.03).

Conclusions. BP and gene putative risk factors for cerebrovascular disease are differentially associated with WMLs in two MCI groups of different WML severity. WMLs might develop for the convergence of innate with acquired factors.

Key Words: Blood pressure • White matter lesions • Mild cognitive impairment • Genotype • Cystatin c

MILD cognitive impairment (MCI) is an etiologically heterogeneous syndrome of older persons that often precedes dementia. The most frequent causes of MCI are neurodegeneration due to Alzheimer's disease (AD) (1) and white matter damage due to small vessel disease (2,3) that can be appreciated as white matter lesions (WMLs) on magnetic resonance (MR).

A large body of evidence has shown that vascular risk factors, especially elevated blood pressure (BP), is associated with the development of WMLs (4–6). In hypertensive patients, some factors seem to be associated with the presence of WMLs, such as the duration (7) and severity (8) of hypertension. In addition, studies on ambulatory BP monitoring evidenced the contribution of BP variability to cerebrovascular damage (9–11). In particular, steady and pulsatile components of daytime, nighttime, and 24-hour BP have gained interest in the prediction of WMLs (12).

However, not all hypertensive persons develop WMLs, as suggested by clinical observations of elderly patients with a long history of hypertension, sometimes badly treated, who have only few or no WMLs. It is reasonable to hypothesize that other factors, such as genetic background, might facilitate the expression of WMLs, as suggested by genetic disorders leading to severe WMLs in the absence of vascular risk factors (13,14) and by a twin study finding that WMLs are highly heritable (15).

Previous studies point to some genes as potential candidates for WMLs. The apoE e4 allele, the strongest risk factor for AD, has been inconsistently found to be associated with WMLs (16–19). The cystatin C (CST3) gene encodes a protein implicated in the repair processes of the nervous system (20). Moreover, it has been found associated with amyloid deposits in cerebral amyloid angiopathy (21), a condition in which WMLs develop due to intimal thickening of the small vessels and ischemia of the surrounding white matter (22). The cholesterol 24-hydroxylase (CYP46) gene expresses a brain-specific enzyme involved in cholesterol metabolism and has been associated with brain amyloid load in AD (23). This literature suggests that genes might predispose to microvascular damage by either increasing amyloid deposition in cerebral blood vessels or influencing brain response to vascular damage.

The aim of this study is to evaluate the association of ambulatory BP and candidate genes for microvascular damage with WMLs in MCI patients. BP will be measured with 24-hour ambulatory BP monitoring, daytime and nighttime BP will be studied separately, and pulse pressure will also be addressed. The genetic predisposition to develop WMLs will be assessed through polymorphisms of CST3, CYP46, and apoE genes. MCI patients rather than cognitively normal elders will be studied as the higher prevalence of WMLs in the former group may improve the power to detect an association with BP.


   MATERIALS AND METHODS
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Population and Study Design
Sixty-three consecutive patients seen at the Alzheimer's Unit of the IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico–Scientific Institute of Research and Care) San Giovanni di Dio–Fatebenefratelli, Brescia, were recruited in a prospective study on the natural history of MCI. The study protocol was approved by the local ethics committee, and all participants signed an informed participation consent.

Inclusion criteria in the study were all of the following: (i) complaint by the patient or report by a relative or the general practitioner of memory or other cognitive disturbances; (ii) Mini-Mental State Examination (MMSE) (24) score of 24–27 or MMSE of ≥28 with low performance on the clock drawing test (25) (score of 2/6 or lower); (iii) preservation of instrumental and basic activities of daily living. More details have been published elsewhere (26). Patients with history or neurological signs of major stroke have been excluded. From April 2002 through March 2005, 138 patients were enrolled, and we selected for the present study those 100 older than 65 years. Of these, 37 were excluded due to invalid ambulatory BP measurements (n = 7) or logistic problems or refusal to perform the exam (n = 30). Finally, 63 MCI patients were included.

We divided the whole sample into two groups of different WML severity based on an exploratory analysis of the relationship between BP and WMLs assessed with a validated visual rating scale (see MR Imaging, Visual Assessment). The analysis suggested a peculiar phenotype in which a sizeable subgroup (12 of 34, i.e., 35% of patients) had no or very mild WMLs even with high daytime systolic BP values (>135 mmHg). This observation was confirmed in the analysis of WML volumes, where a subgroup of patients had very low total and periventricular WML volumes even with extreme BP values. This observation encouraged us to isolate the group of patients with minimal or no WMLs to study possible differential associations of BP variables and genetic background with WML severity.

Clinical Assessment
We assessed vascular diseases and risk factors such as hypertension, heart diseases, diabetes, and hyperlipidemia. Hypertension was defined as high values of 24-hour mean BP (systolic ≥135 or diastolic ≥85) (27) or antihypertensive therapy. Heart diseases were defined as previous diagnosis and current treatment for coronary artery disease, primary arrhythmias, or heart failure. Cardiovascular medications were recorded and coded according to the Anatomic, Therapeutic, and Chemical (ATC) classification system (C01–C08) (28). Diabetes and hyperlipidemia were defined as previous diagnosis and current treatment. Duration of hypertension and diabetes was computed since the time of first diagnosis.

Nonvascular physical diseases were ascertained through history and clinical and instrumental exams. The number of nonvascular physical diseases was computed as the sum of the following: peripheral venous, respiratory, hepatobiliary, renal, musculoskeletal, gastrointestinal, endocrine, and autoimmune diseases and malignancies.

BP Measurement
Clinic BP measurement was obtained with the participant seated after at least 2 minutes of rest using a traditional sphygmomanometer from three consecutive measurements on both arms. The highest of the six measurements was defined as clinic BP.

Ambulatory BP monitoring was performed with an automatic portable device (Schiller BR-102; Schiller AG, Baar, Switzerland). Measurements were obtained with an adult-size cuff place around the nondominant arm, unless a right–left difference of systolic BP ≥10 mmHg was detected, in which case the cuff was placed around the arm with the higher measurement. The measurements were made at fixed intervals of 20 minutes during daytime and nighttime. Data were considered to be adequate for analysis if at least 70% of the 72 readings over the 24 hours were valid (29). The 24 hours were divided into day and night based on patients' activity diaries. Daytime and nighttime BPs were the average of the valid daytime and nighttime measurements. Pulse pressure was the average of the differences between 24-hour systolic and diastolic values at each time point.

MR Imaging
MR images were acquired at the Service of Neuroradiology, Istituto Clinico Città di Brescia, Brescia, using a 1.0 Tesla Philips Gyroscan (Philips Medical Systems, Milan, Italy). Axial T2-weighted, proton density, fluid-attenuated inversion recovery (FLAIR), and gradient echo 3D images (TR 20 ms, TE 5 ms, flip angle 30°, field of view 220 mm, acquisition matrix 256 x 256, slice thickness 1.3 mm) were acquired.

Visual Assessment
WMLs were assessed using the rating scale for age-related white matter changes (ARWMC) (30) on T2-weighted and FLAIR MR images. WMLs were rated separately in frontal, parieto-occipital, temporal, infratentorial areas and in basal ganglia on a 4-point scale. The total score is the sum of subscores for each area (score range 0–3) in the left and right hemisphere, ranging from 0 to 30.

MCI Groups of Different WML Severity
WMLs were considered as mild to severe when the ARWMC scale total score was 4 or more, or when beginning confluence of lesions (subscore 2) was observed in at least one area. Otherwise, WMLs were considered absent or very mild. Based on this criterion, patients were divided into 34 with no/very mild WMLs and 29 with mild to severe WMLs. WML volume was computed with an in-home semiautomatic software. A description of images preprocessing, tracing, and volume computation is available at http://www.centroalzheimer.it/public/additional_WMLvol.doc. WMLs were classified based on localization and morphology, allowing differentiation of four subtypes of WMLs: (i) periventricular caps and rim were symmetrical and regular caps around the horns of the lateral ventricles and continuous lining surrounding the wall of lateral ventricles (Figure 1a); (ii) periventricular confluent were WMLs connected to the periventricular caps and rim but extending into deep white matter with irregular shape (Figure 1a); (iii) subcortical punctate were small (≥5 mm) focal WMLS with regular shape located in deep white matter (Figure 1b); (iv) subcortical confluent were large and irregular WMLs arising from confluence of multiple lesions located in the deep white matter not adjacent to lateral ventricles (Figure 1b).


Figure 01
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  		Figure 1. Examples of definition of white matter lesion localization and morphology. a, Subcortical punctate (A) and confluent (B). b, Periventricular caps (A1), caps and rim (A2), and confluent (B)

 
Covariates
The total intracranial volume (TIV) was obtained by manual tracing of coronal MRs using Display 1.3 tools (McConnel Brain Imagery Centre, Montreal Neurological Institute, McGill University, Montreal, Canada). The brain volume was the sum of gray and white matter volumes automatically computed with statistical parametric mapping 2 (http://www.fil.ion.ucl.ac.uk/spm/software/spm2/).

Genetic Analyses
Blood samples were available in 32 patients with no/very mild and 28 with mild to severe WMLs. Genomic DNA was extracted from whole-blood samples according to standard procedures, and apoE genotyping was carried out by PCR amplification and HhaI restriction enzyme digestion. The genotype was resolved on 4% Metaphor Gel (BioSpa, Milan, Italy) and visualized by ethidium bromide staining (31). The DNA was analyzed for CST3 and CYP46 polymorphisms as previously described (32,23). Two CST3 analyses were missing because genotyping did not work.

Statistical Analysis
The data were analyzed using SPSS version 13.0 (SPSS, Chicago, IL). Sociodemographic, clinical, and genetic differences between the two MCI groups of different WML severity were assessed with t test for continuous and with chi-square for categorical variables. The association between WML volume and BP variables was assessed with multiple linear regression analysis adjusted for age, TIV, and brain volume. Generalized linear models (analysis of covariance [ANCOVA]) were built regressing each BP variable on WMLs to assess the significance of the difference between the regression coefficients of the two MCI groups of WML severity. Age, TIV, and brain volume were included as covariates.


   RESULTS
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Table 1 shows that patients with mild to severe WMLs were about 3 years older than those with no/very mild WMLs, whereas global cognitive performance was similar. There were no significant differences in vascular diseases, risk factors, or cardiovascular drug use, although diabetes was about twice as frequent in the group with mild to severe WMLs (17% vs 9%). The number of nonvascular diseases was also similar, including renal diseases (3% vs 6%) and levels of creatininemia (1.03 ±.20 mg/dL in both groups). In hypertensive patients, there was no correlation between duration of hypertension and WMLs (r =.02, p =.92).


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  		Table 1. Sociodemographic and Clinical Characteristics of 34 MCI Patients With No/Very Mild White Matter Lesions and 29 With Mild to Severe White Matter Lesions.

 
Table 2 shows that mean clinic and ambulatory BP values were not different in the two MCI groups. In those 18 hypertensive patients with mild to severe and 17 with no/very mild WMLs, the mean clinic (systolic 156 ± 16 vs 148 ± 27, p.25; diastolic 87 ± 12 vs 84 ± 10, p.56) and ambulatory BP values (systolic 131 ± 13 vs 129 ± 16, p.72; diastolic 79 ± 8 vs 79 ± 9, p.96) were also similar, suggesting that hypertension was treated equally well in both MCI groups with different WML severity. ApoE alleles had similar frequency in the two MCI groups. An almost significant higher frequency of CST3*B carriers was observed in MCI with mild to severe WMLs (46% vs 23%, p.06). Participants carrying both the CST3*B and CYP46*T alleles were overrepresented in the MCI group with mild to severe WMLs (43% vs 17%, p.03). This result remained significant when diabetic patients were not considered in the analysis (44% vs 18%, p.046).


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  		Table 2. Clinic and Ambulatory Blood Pressure (mmHg) and Genetic Features of 34 MCI Patients With No/Very Mild White Matter Lesions and 29 With Mild to Severe White Matter Lesions.

 
In the whole MCI sample (the two groups of different WML severity being considered together), we did not find any association between total WML volume or WML subtypes and BP. The relationship of BP variables with total WML volume was significant for daytime systolic BP in MCI with mild to severe WMLs (Table 3, adjusted B =.38, 95% CI,.02 to.66; p.03). No association was found for the other BP variables. When WML subtypes were taken into account, the strongest association of daytime systolic BP was found with periventricular confluent lesions. The association was significant both within the group with mild to severe WMLs and between the two groups of WML severity (Table 3). Figure 2 illustrates the association of daytime systolic BP with WML subtype volumes in the two MCI groups of different WML severity.


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  		Table 3. Regression Coefficients (B) and 95% Confidence Interval (CI) of Daytime Systolic Blood Pressure With Severity of White Matter Lesions (WML) (Total and Subtypes) Volume in 34 Mild Cognitive Impairment (MCI) Patients With No/Very Mild WMLs and 29 With Mild to Severe WMLs.

 

Figure 02
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  		Figure 2. Association of daytime systolic blood pressure values with severity of white matter lesion (WML) subtypes in 34 mild cognitive impairment (MCI) patients with no/very mild (open circles) and 29 with mild to severe (solid circles) WMLs

 
To rule out the possible confounding effect of higher, although statistically not significant, prevalence of diabetes in MCI with mild to severe WMLs, we repeated the analyses by excluding diabetic patients (n = 8), but the results remained unchanged. In particular, adjusted regression coefficients of daytime systolic BP on periventricular confluent WMLs were.37 (95% CI, –.04 to.67) in MCI with mild to severe and –.04 (95% CI, –.39 to.32) in MCI with no/very mild WMLs (p =.009 for the difference between slopes).


   DISCUSSION
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The main finding of this study is that BP was differentially associated with WMLs in MCI groups with different WML load. In the group with greater WML severity, higher values of daytime systolic BP were associated with higher volume of periventricular confluent WMLs, whereas the other high and low values of BP were associated with a low burden of WMLs. The association cannot be attributed to factors such as duration of hypertension or antihypertensive treatment, as these were equally distributed in the two groups or to diabetes as the association held also when the analyses were repeated after exclusion of diabetic patients. Interestingly, the two MCI groups had different genetic features, the one with greater WML severity showing greater frequency of alleles with a putative detrimental effect on cerebral small vessels (CST3*B and CYP46*T alleles). Caps and rim, punctate, and subcortical confluent WMLs were never associated with BP.

Findings of the association between daytime systolic BP and WML severity and of different distribution of CST3 B and CYP46 T polymorphisms in MCI groups with different WML load led us to speculate that this particular genetic profile might carry an increased susceptibility to the detrimental effects of BP on small vessels. Several observations suggested that CST3 can exert a protective role on neurons: Different brain injuries, including ischemia, axotomy, surgery, and epilepsy, led CST3 expression levels to increase, both in activated glial cells and in neurons. We previously demonstrated that, in humans, the CST3 B allele was associated with reduced secretion of CST3 (33) and abnormal cortical rhythms in dementia and MCI (20). The CYP46 T polymorphism was associated with increased cerebral β-amyloid load and cerebrospinal fluid levels of β-amyloid peptides and phosphorylated {tau} protein, as well as increased risk of AD in nondemented elderly persons (23), indicating a detrimental effect on the brain possibly mediated by β-amyloid. Our findings might suggest a synergistic interaction of CST3 and CYP46. We hypothesize that decreased production of CST3 together with increased amyloid production might result in an increased susceptibility to vascular damage.

The differential association of daytime systolic BP with WML subtypes deserves comment. There is much debate in the literature on the pathophysiology of WMLs. Some histological data (34) and clinical studies (35) have suggested that caps and rim lesions were caused by minor pathological changes of nonischemic origin and some punctate WMLs may even correspond to no detectable change on pathology (34,36). On the contrary, confluent WMLs seemed to have almost invariably a microvascular ischemic origin (37). The present data supported the view that the pathophysiology of periventricular confluent was different from that of caps and rim and punctate lesions. Subcortical confluent WMLs showed a trend toward the association of BP with mild to severe WMLs, being significant only in the differential association between the two groups of WML severity.

This study has some methodological limitations. First, the significant associations of this study cannot be taken to point to causal relationships due to the cross-sectional nature of the study and its design, which does not directly address the pathophysiological pathway leading from genes to BP to WMLs. Second, the small sample size prevented us from adjusting analyses for potential confounders such as hypertension, which was slightly more prevalent in the MCI with mild to severe WMLs. Third, uncontrolled hypertension-related variables such as dipping (38) and BP variability (39), and other vascular risk factors such as plasma homocysteine levels and inflammatory markers (40,41) might be associated with WMLs. Fourth, the clinical setting where the study was carried out prevented generalizability before the results were replicated in a large population-based sample of older persons. Last, we measured WMLs on conventional T2-weighted and FLAIR MR scans, which are known to capture only part of the phenotypic expression of WMLs. Novel MR techniques such as diffusion tensor imaging, sensitive to microstructural changes of white matter axons invisible to traditional imaging, might provide greater insight into the pathophysiology of WMLs (42).

Conclusion
Our study identified two MCI groups of different WML load in which BP was differentially associated with WMLs. The different distribution of genes possibly involved in microvascular damage might underlie this differential association. Further studies in larger samples of patients are warranted to confirm these results.


   Acknowledgments
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 
This study was funded in part by an ad hoc grant of the Italian Ministry of Health Ricerca Finalizzata "Decadimento cognitivo lieve non dementigeno: stadio preclinico di malattia di Alzheimer e demenza vascolare. Caratterizzazione clinica, strumentale, genetica e neurobiologica e sviluppo di criteri diagnostici utilizzabili nella realtà nazionale" (RA 00.61).


   Footnotes
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 
Decision Editor: Luigi Ferrucci, MD, PhD

Received February 7, 2007

Accepted August 16, 2007


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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