Dutch hereditary cerebral amyloid angiopathy Structural lesions and apolipoprotein E genotype.код для вставкиСкачать
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Protection against Alzheimer’s disease with apoE €2. Lancet 1994;343:1432-1433 20. Rebeck GW, Perls TT, West HL, et al. Reduced apolipoprotein ~4allele frequency in the oldest old Alzheimer’s patients and cognitively normal individuals. Neurology 1994;44:1513-15 16 21. Schachter FS, Faure-Delanef L, Guenot F, et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 1994;6:29-32 22. Asada T, Yamagata Z, Kinoshita T, Asaka A. Apolipoprotein E allele of demented and non-demented centenarians: complete survey of centenarians in Yamanashi prefecture. Jpn J Geriatr 1995;32:134-13 5Brief Communication: Bornebroek et al: HCHWA-D Lesions and APOE Dutch Hereditary Cerebral Amyloid Angiopathy: Structural Lesions and Apolipoprotein E Genotype M. Bornebroek, MD,* J. Haan, M D , PhD,*I S. G. Van Duinen, MD, PhD,$ M. L. C. Maat-Schieman, MD,” M. A. Van Buchem, MD, PhD,$ E. Bakker, PhD,S C. Van Broeckhoven, PhD,*# and R. A. C. Roos, MD, PhD* Hereditary cerebral hemorrhage with amyloidosis-Dutch type is caused by a mutation at codon 693 of the p amyloid precursor protein gene. The disease is clinically characterized by strokes and dementia. In addition to cerebral plaques, cerebral amyloid angiopathy is the pathological hallmark. We investigated the correlation between radiological (white matter hyperintensities and focal lesions on magnetic resonance images) and pathological lesions (cerebrovascular amyloid angiopathy and plaques) and the apolipoprotein E genotype in patients with the disease. Twenty-five patients were studied using magnetic resonance imaging, and brain tissue from 8 patients was studied histopathologically. Neither the white matter hyperintensity scores nor the number of focal lesions on magnetic resonance images were associated with the presence of an ~4 allele. Nor was a correlation found between the number and type of plaques and the apolipoprotein E genotype. All patients had severe amyloid angiopathy in all cortical areas investigated. This study showed that the apolipoprotein E genotype does not modulate amyloidrelated structural lesions in hereditary cerebral hemorrhage with amyloidosis of the Dutch type. Bornebroek M, Haan J, Van Duinen SG, Maat-Schieman MLC, Van Buchem MA, Bakker E, Van Broeckhoven C, Roos RAC. Dutch hereditary cerebral amyloid angiopathy: structural lesions and apolipoprorein E genotype. Ann Neurol 1997;41:695-698 ___From the Departments of *Neurology, $Pathology, $Diagnostic Radiology, and ?Human Genetics, Leiden University Hospital, Leiden; ?Department of Neurology, Rijnland Hospital, Leiderdorp, the Netherlands; and #Laboratory o f Neurogenetics, Flanders Interuniversity for Biotechnology (VIB), Department of Biochemistry, Born-Bunge Institute (BBS), University of Antwerp (UIA), Belgium. Received Aug 28, 1996, and in revised form Oct 18. Accepted for publication Oct 23, 1996. Address correspondence to Dr Rornebroek, Department of Neurology, K5Q-97, Leiden University Hospital, P.O. Box 9600, 2300 RC Leiden, the Netherlands. Copyright 0 1997 by the American Neurological Association 695 Hereditary cerebral hemorrhage with amyloidosisDutch type (HCHWA-D) is an autosomal dominant disorder, caused by a mutation at codon 693 of the p amyloid precursor protein (PPP) gen’e located o n chromosome 21 [ l ] . Cerebral AP amyloid angiopathy (CAA) in leptomeningeal arteries and cortical arterioles is the histopathological hallmark of HCHWA-D . In addition, diffuse plaques, plaques with congophilia and abnormal neurites, and cored plaques have been found throughout the cortical gray nlatter .T h e disease is clinically characterized by strokes and dementia, and the age at onset ranges from 40 to 65 years . About one third of the patients die a.s a consequence of their first stroke, whereas others survive for many years and have recurrent strokes. Dementia often develops after the first stroke, but in some c:ases it may be the first symptom of HCHWA-D. The underlying causes of the phenotypic differences between HCHWA-D patients are nor known. T h e ~4 allele of the apolipoprotein E gene (apoE, protein; APOE, gene) is a genetic risk factor for Alzheimer’s disease (AD) . T h e presence of an APOE ~4 allele appears to reduce the age at onset of AD, a reduction that is probably more marked if subjects are homozygous for this allele. T h e presence of an APOE ~2 allele, on the other hand, may have a protective effect for AD. Histopathologically, in AD the presence of one or two APOE ~4 alleles is associated with increased and the ~2 allele with decreased plaque density [5, 61. CAA and CAA-related hemorrhages are also more frequent and severe in APOE €4 allele carriers with AD or sporadic CAA [7, 81. In H C H W A - D , clinical features, such as age at onset, age at death, occurrence of dementia, and the number of strokes, are not influenced by the APOE €2 or ~4 allele [9, I 01. However, these clinical parameters may not be the most valid measures of disease severity. T h e severity of the disease might be more accurately reflected by structural lesions such as CAA and plaques. It is difficult to quantity CAA postmortem, but it cannot be measured in vivo. Focal lesions reflect scars of old strokes and more recent hemorrhages including those that produce no clinical symptoms. Thus, the number of focal lesions could be an indicator of CAA severity in vivo. White matter hyperintensities (WMHs) on magnetic resonance images (MFUs) of HCHWA-D patients are a first sign of the disease and are chronically progressive. W M H s are the result of hypoperfusion of the deep white matter due to stenosis of the long perforating arterioles caused by amyloid angiopathy. They can, therefore, also be an index of CAA severity [ 1I]. Another indication of disease severity in HCHWA-D may be the type and the number of A@ plaques in the parenchyma. In the present study, we investigated the structural lesions ( W M H s and focal lesions o n MRI and CAA 696 Annals of Neurology Vol 41 No 5 May 1997 and plaques in brain tissue) in H C H W A - D patients, in relation to the APOE genotype. Patients and Methods A total of 31 HCHWA-D patients were studied: 23 with MRI, 6 by histopathological investigation, and 2 by both modalities. In all patients, the diagnosis of HCHWA-D was made by detection of the PPP codon 693 mutation [I]. APOE genotype was determined as described previously [?I. MRI was performed in 25 mutation carriers (12 men, 13 women; age range, 40-69 years; mean, 52 years). Eighteen had had one or more strokes, while 7 were presymptomatic and had not yet had a stroke. Fourteen of the patients had developed dementia as assessed by neuropsychological examination [ 121. One patient had non-insulin-dependent diabetes mellitus and 2 had hypertension. MRI was performed on a 1.5-T machine. T 1 - , T 2 - , and proton densiryweighted images were obtained in the axial plane. The number of focal lesions (scars of old hemorrhages, infarctions) was counted and WMHs were scored with a semiquantitative rating scale based on the one designed by Scheltens and colleagues . This scale (ranging from 0 to 24) provides a WMH score related to the size and the number of foci in four regions (frontal, temporal, parietal, and occipital). All scans were analyzed by two radiologists unaware of the clinical symptoms and APOE genotype. CAA and A P plaques were studied in the brains of 8 HCHWA-D patients (6 men, 2 women). The age of these patients at death ranged from 42 to 81 years. All had had one or more strokes and 4 had dementia. Formaldehyde-fixed and paraffin-embedded tissue of frontal, parietal, and temporal regions of the cerebral cortex was stained with a Bodian methenamine silver stain .In each 6-p,m-thick, nontangential section including all layers of the cortex, an area of 3.14 mm2 was selected as representing an average number of plaques. Amyloid angiopathy was rated semiquantitatively in each section of the cortex as described . Two observers (S. G. V. D. and M.L. C. M-S.), independently and unaware of the APOE genotype, scored the CAA and counted the number of plaques without coarse neuritic changes (diffuse plaques) and the number of plaques with neuritic changes (other plaques) in these areas. Statistics WMH scores and the number of focal lesions in ~4 carriers and noncarriers were subjected to multivariate regression analyses to control for the effect of age. Results Of the 25 mutation carriers investigated using MRI, 12 were €4 carriers and 13 had no €4 allele. Distribution of APOE genotype was as follows: ~ 2 1 ~ n3 = , 1; € 2 1 ~ 4n, 2; € 3 1 ~ 3n, = 12; ~ 3 1 ~ n4 ,= 7; € 4 1 ~ 4 , n = 3 . Distribution of the APOE genotype and mean WMH score and number of focal lesions are given in Table 1. T h e sum score of WMHs did not differ significantly ( p = 0.518) between €4 carriers (mean, 19.5; range, 14-24) and noncarriers (mean, 19.6; range, 14-24) and was, as expected, significantly cor=I Table 1. Distribution o f APOE Genotype dnd MRI Abnormalities in 25 HCHWA-D Patients Subcortical Genotype ~21~3 E3k3 ~21~4 ~31~4 €41~4 No. of Age Patients (yr) WMH Score" (0-24) No. of Focal Lesions" 1 12 2 22.0 19.7 (14-24) 20.0 (19-21) 20.0 (15-24) 20.7 (14-24) 3.0 1.5 (0-5) 5.0 (2-8) 0.8 (0-2) 2.1 (1-5) 7 3 58.0 53.1 47.5 51.1 53.0 "Mean (range). HCHWA-D = hereditary cerebral hemorrhage with amyloidosisDutch type; WMH = white matter hyperintensiry. related with age ( p = 0.034) on multivariate analysis . The sum score of WMHs in patients homozygous for ~4 (n = 3) did not differ from that in patients heterozygous for ~4 or non-&4 carriers. In patients with an ~4 allele, the mean number of focal lesions was 1.8 (range, 0-8) and in patients without an ~4 allele 1.6 (range, 0-5). The number of focal lesions was not associated with the presence or absence of an ~4 allele ( p = 0.514) or with age ( p = 0.26) in multivariate analyses. The MRI of the patient with an &2/&3genotype did not demonstrate less severe WMHs (score, 22) or a smaller number of focal lesions (3 focal lesions) than did MRIs of patients without the ~2 allele. Distribution of the APOE genotype in the 8 HCHWA-D brains studied was as follows: ~ 2 1 ~n3 = , 2; ~ 3 1 ~ n3 ,= 3; € 3 1 ~ 4 n, = 3. All 8 brains investigated had severe amyloid angiopathy in all cortical areas (>20 affected vesselslarea). This makes modulation by APOE genotype impossible to detect, but unlikely. The number and type of plaques are provided in Table 2 together with APOE genotype and age at death. The mean number of plaques in a cortical area did not difTable 2. Distribution of the APOE Genotype and Plaques in 8 HCHWA-D Patients Age at Death (yr) Genotype No1144 53 carriers 58 53 59 76 Mean 59.8 &4carriers 42 52 81 Mean 58.3 &2/&3 ~21~3 ~31~3 ~31~3 ~31~3 &3/&4 E31E4 ~31~4 No. of Diffuse Plaques (Frontall Parietal/ Temporal) No. of Othet Plaques (Frontall Parietal/ Temporal) 20/30/60 22/34/23 -127130 16/27/02 20/07/10 oo/oo/oo 2611 5110 -/00/00 00/1/00 07I46I23 19.5/25.0/25.0 8.3/12.4/6.6 -122135 --/oo/oo 31/37/16 00/00/00 15/10/15 32/11/31 23.0/23.0/22.0 16.0/3.7/10.4 HCHWA-D = hereditary cerebral hemorrhage with amyloidosis-Dutch type; - = parts of frontal lobe were not available. fer benveen patients with an €4 allele and those without an ~4 allele. The ~2 allele was not associated with a lower number of plaques. In 3 patients, other plaques were found: 1 had an € 3 1 ~ 4 1 , had an €31~3,and 1 had an € 2 1 ~ 3genotype. Discussion The ~4 allele frequency (50%) in the investigated group of HCHWA-D patients was higher than that in the general Dutch population (30%), confirming the finding in our earlier study . The higher €4 allele frequency can be explained, as all patients are members of a few large families with a common ancestor. In this study, we showed that the APOE genotype did not correlate with the structural lesions, as visualized by MRI, or with CAA and plaques in the brains of HCHWA-D patients. These findings extend those of our earlier studies, which showed no correlation of the APOE genotype with clinical parameters, such as age at onset, age at death, occurrence of dementia, and number of strokes "9, 101. In sporadic CAA as well as in familial and sporadic AD, the APOE genotype is a strong predictor of the clinical expression of the disease and the development of structural lesions, including vascular lesions. The ~4 allele is associated with larger numbers of plaques, more severe CAA, and the occurrence of hemorrhages in a dose-dependent manner [6, 171. In addition, there are indications that vascular lesions (multiple infarcts, WMHs, hemorrhagic infarcts) in AD are associated with the ~4 allele 181. Moreover, in patients with vascular dementia without AD pathology, a significantly higher frequency of the ~4 allele, compared to normal, is reported [I&].However, the results of studies are inconsistent; a few failed to demonstrate a significant correlation between the APOE genotype and the burden of the amyloid pathology . These findings indicate that the APOE genotype not only influences neuronal pathology, but also can probably modulate vascular changes. In this study of HCHWA-D patients, we found no association between APOE and amyloid-related structural lesions. In AD patients with PPP 670/671 and PPP 717 mutations there was no obvious effect of the APOE genotype on AP accumulation in the brain, although the number of patients studied was too small to allow a definite conclusion [2O]. The age at onset, however, does seem to be influenced by the APOE genotype, ~4 leading to earlier onset ages . We previously suggested two possible explanations for the lack of influence of APOE genotype on clinical features of HCHWA-D [9, lo]. First of all, clinical features may be an invalid measure of disease severity because superimposed external factors, at least partially, influence these clinical symptoms. In the present study, we minimized the influence of external factors by mea- Brief Communication: Bornebroek et al: HCHWA-D Lesions and APOE 697 suring structural lesions. Second, it is possible that apoE has a lower binding affinity for AP when the codon 693 mutation is present, and therefore may not influence AP deposition. This study did not, however, investigate the binding affinity of apoE for AP. 15. Ellis RJ, Olichney JM, Thal LJ, et al. Cerebral amyloid angi- Financial support was provided by the “Dutch Organisation for Scientific Research ( N W O M.B. project 903.52.124). 17. We thank Mrs S. de Bruine (Department of Diagnostic Radiology) for scoring the MRIs and Mr R. Brand (Department of Medical Statistics, Leiden University) for assistance with the statistical analyses. 18. 16. 19. References 1. Bakker E, Van Broeckhoveii C , Haan J, et al. DNA diagnosis for hereditary cerebral heniorrhage with atnyloidosis (Dutch type). Am J H u m Genet 1991;49:518-521 2. Maat-Schieman MLC, Van Duinen SC, Bornebroek M, et al. Hereditary cerebra! hemorrhage with amyloidosis-Dutch type (HCHWA-D): 11-a review of histop:tthological aspects. 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Apolipoprotein E in patienrs with dementia of the Alzheimer’s rype and vascular dementia. Acta Neurol Scand 1996;93:133-137 Heinonen 0 , Lehtovirta M , Soininen H, et al. Alzheimer pathology of patients carrying apohpoprotein E E4 allele. Neurobiol Aging 1995; 16:505-5 13 Mann DMA, Iwarsubo T, Ihara Y, er al. Predominant deposition of amyloid-P42(43j in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am J Pathol 1996; 148:1257-1266 Correction Two paragraphs were omitted from “Mitochondria1 Function in Muscle from Elderly Athletes” by Brierley and colleagues (Ann Neurol 1997;41:1 14-1 16) The first two paragraphs under Discussion should read as follows: In physically fit, health adults, respiratory chain function did not deteriorate with age. W e recently reported the same in a large group of sedentary subjects in whom physical activity was carefully controlled [91. This study is the first to use strict subject selection criteria similar to the SENIEUR protocol of immunological aging research [ 151 and studied a unique group of humans-athletes-a model choice for determining true aging within skeletal muscle. Our two studies cast doubt on the significance of initial reports that respiratory chain function declines dramatically with age in humans [6-81. The SENIEUR protocol was developed because many immunological changes seen with age are not due to age but are secondary to disease. In these earlier studies, many factors were uncontrolled, and it is likely that altered physical activity and disease are responsible. If mitochondria are involved in aging, it has to be through a more subtle mechanism than a global decline in respiratory function. Reference 15 is: Ligthart GJ, Coberand JX, Fourniers C , et a]. Admission criteria for immunogerontological studies in man: the SENIEUR protocol. Mech Ageing Dev 1984;28:47-5 5 . 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