Increased aneuploidy in Alzheimer disease

The purpose of this study was to determine if cytogenetic changes are present in Alzheimer disease, one of the presenile dementias. The chromosomes of three groups of people were studied: 1) sporadic cases fo Alzheimer disease (eight cases), 2) familial cases of Alzheimer disease with affected individuals in at least two generations of their families (five cases), and 3) currently unaffected siblings of the affected individuals in these families (nine cases). One hundred cells per individual were examined using GTG banding to allow chromosome identification. A statistically significant increase in aneuploidy was found in five of eight patients in group 1 (P<0.05) and in each of five patients in group 2 (P<0.001) when compared with the rate of aneuploidy in age-and sex-matched controls. In addition, two individuals in group 3 exhibited a significant increase in aneuploidy over the control group, raising the possibility that finding increased aneuploidy may allow one to anticipate the clinical expression of the disease state.     

Chromosome studies of patients with Alzheimer disease

Ten patients with either the familial or sporadic form of Alzheimer disease (AD) were studied cytogenetically to confirm reports of aneuploidy and “long acentric fragments” associated with the disease. Findings in leukocytes of patients were compared with those in eight unaffected relatives and seven persons of similar age. Observations from encoded slides involving 3,800 conventionally stained and 1,396 G-banded metaphases (one patient) showed no significant increase in aneuploidy. The frequency of cells with hypermodal counts, a reliable measure of aneuploidy, was 4.2% and 1.1%, respectively, in women and men with familial AD and 4.0% and 2.3%, respectively, in women and men with the sporadic form of the illness. Similar frequencies of hypermodal cells occurred in female (2.6%) and in male (2.0%) control subjects. In contrast to the lack of aneuploidy, a small but significant number of false “long acentric fragments” was found in cells of women with AD (P <.05). These aberrations are thought to represent premature centromere division (PCD) in intact chromosomes, primarily supernumerary Xs. Often in multiple copies, PCD occurred in 2.8% of their cells and in 0.6% of cells from control women. PCD occurred in 3.6% of cells of women with the familial form and in 1.7% of cells of women with the sporadic type of dementia. Among unaffected relatives PCD increased with age. The rarity of PCD in G-banded metaphases from an affected female (3/1,396) suggests that metaphase spreading techniques also may affect observable frequency. Thus PCDs occur more frequently in, but are not unique to, AD and may represent an epiphenomenon of aging, a process also characterized by the occurrence of neurofibrillary tangles and senile plaques in the cerebral cortex.     

阿尔茨海默病与脑血管病痴呆患者的诱发电位比较研究

目的：观察阿尔茨海默病痴呆（AD）和脑血管病痴呆（VD）视觉及听觉诱发电位的特点。方法：收集25例AD组、24例VD及22名正常老年人（NC），完成听觉诱发电位（AEP）和视觉诱发电位（VEP）检查，并进行简易智力状态检查（MMSE）评分比较。结果：与NC组相比，AD组AEP的N1、P2，VEP的P1潜伏期延迟，AEP的P2、P2，VEP的P2、P3波幅降低；VD组VEP的P2潜伏期延迟，P2和P3波幅降低。AD组和VD组相比，AD组AEP的N1、P2潜伏期延迟于VD组。AD组VEP的P2波的潜伏期，VD组AEP的P3波幅及VEP的N1潜伏期改变与其MMSE评分有关联。结论：AD组和VD组的诱发电位有类似变化，两组的VEP和AEP变化与MMSE相关。     

Aneuploidy in recurrent spontaneous aborters: the tendency to parental nondisjunction

To test the hypothesis that parental aneuploidy, particularly involving sex chromosomes, indicates an increased risk of meiotic nondisjunction, we analyzed chromosome numbers from 283 parents who had had 2 or more spontaneous abortions and, if they had children, no abnormal offspring. A sample of 15 lymphocyte metaphases was examined per individual for a total of 4,245 metaphases. Two or more cells with the same abnormal chromosome complement were found in 19 individuals: 4 males with a minor number of 45, X cells and 15 females with minor numbers of 45, X and/or 47, XXX cells (p< 0.001). The most logical explanation is that mitosis may, in part, reflect meiosis. This group of parents appears predisposed to chromosome errors in meiosis leading to recurrent spontaneous abortion.     

Alzheimer disease is not associated with polymorphisms in the angiotensinogen and renin genes

Hypertension has been implicated as a risk factor for Alzheimer disease (AD) and dementia in epidemiological studies of humans. It is thus possible that there are common genetic determinants for hypertension and AD. Epidemiological, clinical, and experimental data suggest that the renin‐angiotensin‐aldosterone system is a critical regulator of blood pressure. The presence of an MboI site in an RFLP in the renin gene and the Thr at the Met/Thr polymorphism at codon 235 (M235T) of the angiotensinogen gene have been reported to be associated with hypertension. These variants were studied in autopsy‐confirmed AD cases and matched controls from the U.K. While no association was detected with the renin polymorphism, a weak deleterious effect was observed in cases homozygous for the angiotensinogen Thr allele. However, this association was not observed in a French cohort of clinically diagnosed AD cases and controls, suggesting that the initial observation was a type I error. Thus, these polymorphisms are unlikely to be associated with AD risk. © 2001 Wiley‐Liss, Inc.     

Linkage of an Alzheimer disease susceptibility locus to markers on human chromosome 21

We assessed linkage between Alzheimer disease (AD) and restriction fragment length polymorphisms (RFLPs) from human chromosome 21 in 8 families selected because of multiple occurrences of AD and large size. Sib-pair analysis demonstrated significant evidence for linkage between 2 markers (D21S1 and D21S11) and disease. Two markers, D21S13 and D21S52, did not yield evidence in favor of linkage to disease and a 5th, D21S16, was uninformative. The results confirm that a susceptibility locus for Alzheimer disease is located on chromosome 21. In contrast to other investigators who demonstrated linkage between AD and chromosome 21 loci, we found evidence in favor of linkage in both late- (greater than age 65) and earlyonset families.     

Alzheimer's disease and Alzheimer's dementia: distinct but overlapping entities

Much of the controversy about the “amyloid cascade hypothesis” may reflect unrecognized differences in the use of language, including the use of the word “cause.” This commentary proposes that the term Alzheimer disease refer to the neuropathological entity and the term Alzheimer dementia to clinical dementia in people who also have Alzheimer neuropathology. The ultimate causes of Alzheimer disease are proposed to be aging, environmental stresses, and genetic predispositions. The fundamental cause of Alzheimer dementia is proposed to be Alzheimer disease, i.e. the neurobiological abnormalities in Alzheimer brain. The neurobiology of Alzheimer disease includes changes that may initially be adaptive but can become excessive and thereby harmful; they include increased expression of APP with accumulation of potentially damaging peptides such as Aβ, inflammation, and increased ROS activity. The neurobiological abnormality that is the proximate cause of Alzheimer dementia appears to be decreases in cerebral metabolic rate. Decreased metabolism occurs not only in this but in essentially all dementias, and impairing brain metabolism induces neuropsychological deficits characteristic of dementias. The immediate cause of Alzheimer dementia is proposed to be deficiencies in signaling, both intracellular and intercellular (neurotransmission), that follow directly from the decrease in cerebrometabolic rate.     

What are the facts and artifacts of the pathogenensis and etiology of Alzheimer disease?

Over the past decade, an increased clinical awareness, together with advances in biochemical, cellular, and molecular analyses, have catapulted the study of Alzheimer disease to the forefront of biomedical research. During this time, a great number of theories, regarding disease pathogenesis, have come and gone but several have persisted. Here, we critically evaluate these theories in an attempt to delineate the facts from the artifacts.     

SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population

SORL1 has recently been identified as a major genetic contributor to increased risk for late-onset Alzheimer disease (AD). Here we aimed at replicating this finding in a large, well-characterized group of 550 Belgian late-onset AD patients and 637 healthy control individuals using a gene-wide genotyping approach across the SORL1 locus. We observed significant associations, both for individual SNPs (SNPs 6, 8, 9, 10 and 27; p-values ranging from 0.001 to 0.040) and 3-SNP haplotypes (SNPs 5-6-7 and SNPs 25-26-27; p-values ranging from 0.008 to 0.035). Moreover, the associations at SNP 8, 9 and 10 represented a direct replication of the initial association data. Two signals in distinct regions of the gene were shown to be mutually independent, supporting allelic heterogeneity at the SORL1 locus in the Belgian population. Our findings confirm that genetic variants in SORL1 may be important risk factors for late-onset AD.     

Linkage and haplotype analysis of familial early-onset Alzheimer disease in Japanese population

Summary Linkage and haplotype analysis of eleven early-onset Alzheimer disease (AD) families was performed in relation to D21S210 and microsatellite DNA polymorphisms localized on chromosome 14q24.3. Linkage analysis of eight informative families out of eleven early-onset AD families disclosed the highest LOD score of 3.45 (=0.00) at D14S77, while the locus of /A4 amyloid protein precursor gene was formally excluded within 10 cM from D21S210, given the evidence of recombinations in five families. Transmission disequilibrium study between the patients and controls without dementia indicated significant differences at D14S43 (p=0.0001) and D14S71 (p=0.02). Association study between genotypes linked or related to onset of AD and those of control also revealed a significant difference at D14S43 (p<0.05), suggesting the existence of linkage disequilibrium. Moreover, the haplotypes at D14S43 linked with the onset of AD indicated a significant relationship with the mean age at onset. These results support that the major locus of earlyonset familial AD is located on 14q24.3, and its close linkage to D14S43 and the existence of allelic heterogeneity were suggested.     

阿尔茨海默病、阿尔茨海默病混合型及血管性痴呆患者心理及行为症状的比较

目的 比较阿尔茨海默病(Alzheimer Disease，AD)、AD混合型痴呆(Mixed dementia，MD)、血管性痴呆(Vascular dementia，VD)心理和行为症状(Psychological and behavioral symptoms of dementia，PBSD)的特征。方法 AD、MD及VD患者各30名参加本研究。采用Alzheimer病行为症状评定量表(The Begavioral Pathlolgy in Alzheiner Disease Rating Scale，BEHAVE—AD)、Cohen—Masfield激惹性问卷(The Cohen Mansfield Agitation Inventory，CMAI)评定痴呆患者BPSD。结果 AD患者激惹、焦虑与恐惧发生率较高，VD患者无目的游荡发生率、严重程度较低，MD患者BPSD症状无特异性。结论 AD、VD患者BPSD症状有特异性，MD患者BPSD表现无特异性。     

Etoposide (VP-16): Cytogenetic studies in mice

Etoposide (VP 16-213), the epipodophyllotoxin derivative that is widely used in the treatment of cancer, forms complexes with DNA-topoisomerase type llα to exert its cytotoxicity. The drug was evaluated in vivo in Swiss albino mouse bone marrow cells for its ability to induce clastogenicity and sister chromatid exchanges (SCEs). Doses of 5, 10, 15, and 20 mg/kg body weight etoposide given intraperitoneally induced a dose-dependent significant increase of clastogenicity (Trend test, α ≦ 0.05). The aberrations induced were predominanty chromatid types. The drug shows specificity for S-phase cells: cells harvested 6 and 12 hr posttreatment showed a significantly increased number of damaged cells and aberrations per cell. Doses of 0.5, 1.0, 2.5, 5.0, and 10.0 mg etoposide/kg body weight induced a dose-dependent significant induction of SCEs (Trend test, α ≦ 0.05). The minimal effective concentration was 0.5 mg/kg body weight. Etoposide significantly prolonged the cell cycle time at all concentrations tested: 12-13 hr in treated animals vs. 11 hr in control. The results confirm in vivo cell cycle phase specificity of the drug and further designate etoposide as a potent clastogen and a genotoxic agent in mice. © 1994 Wiley-Liss, Inc.     

Preferential location of sex chromosomes, their aneuploidy in human sperm, and their role in determining sex chromosome aneuploidy in embryos after ICSI

BACKGROUND: In babies born after ICSI procedures, an increase of de-novo sex chromosome abnormalities has been observed. Several hypotheses have been proposed to explain these findings: an increased rate of sex chromosome aneuploidy in sperm of oligozoospermic men, or a preferential location of the sex chromosomes in the sub-acrosomal region of the sperm nucleus which leads to a reduced DNA decondensation of this region. In order to investigate which theory may be more reliable, we studied the localization of sex chromosomes and their aneuploidy rate in sperm in men undergoing ICSI. METHODS: Using fluorescent in-situ hybridization we studied sex chromosome localization and the aneuploidy rate for sex chromosomes and chromosome 18 in 20 oligospermic men undergoing ICSI and in 10 controls. RESULTS: In 40.94 and 52.92% of cases, the X and Y chromosomes respectively were localized in the sub-acrosomal region of the sperm nucleus compared with only 14.29% of cases of chromosome 18 (P < 0.001). An increase of sex chromosome aneuploidy in sperm of oligospermic men was observed; 2.91 versus 0.69% of controls (P < 0.001). CONCLUSIONS: Sex chromosomes are localized preferentially in the sub-acrosomal region of sperm and sex chromosome aneuploidy rate in the sperm of oligozoospermic men is higher than in controls.     

线粒体表观遗传调控与阿尔茨海默病的研究进展

正线粒体表观遗传调控(mitoepigenetic regulation)是指对线粒体基因组编码基因的表观遗传学修饰调控,可引起线粒体基因组编码基因表达的改变,致使线粒体功能异常,导致多种疾病的发生。近年研究表明,线粒体表观遗传调控与阿尔茨海默病(Alzheimer disease,AD)发病机制密切相关。AD是一种中枢神经退行性疾病,典型神经病理变化是β-淀粉样蛋白(amyloid-β,Aβ)沉淀形成老年斑和神经原纤维     

A strategic research alliance: Turner syndrome and sex differences

Sex chromosome constitution varies in the human population, both between the sexes (46,XX females and 46,XY males), and within the sexes (e.g., 45,X and 46,XX females, and 47,XXY and 46,XY males). Coincident with this genetic variation are numerous phenotypic differences between males and females, and individuals with sex chromosome aneuploidy. However, the molecular mechanisms by which sex chromosome constitution impacts phenotypes at the cellular, tissue, and organismal levels remain largely unexplored. Thus, emerges a fundamental question connecting the study of sex differences and sex chromosome aneuploidy syndromes: How does sex chromosome constitution influence phenotype? Here, we focus on Turner syndrome (TS), associated with the 45,X karyotype, and its synergies with the study of sex differences. We review findings from evolutionary studies of the sex chromosomes, which identified genes that are most likely to contribute to phenotypes as a result of variation in sex chromosome constitution. We then explore strategies for investigating the direct effects of the sex chromosomes, and the evidence for specific sex chromosome genes impacting phenotypes. In sum, we argue that integrating the study of TS with sex differences offers a mutually beneficial alliance to identify contributions of the sex chromosomes to human development, health, and disease.     

Evaluation of multiple presenilin 2 SNPs for association with early‐onset sporadic Alzheimer disease

The presenilin genes encode proteins that modify, mediate, or perform similar functions to γ‐secretase, the enzyme responsible for converting amyloid β precursor protein (APP) into beta‐amyloid. Mutations in the presenilin genes cause an increased production of Aβ42, the aberrant form of beta‐amyloid found in the neural plaques of Alzheimer disease patients. Previously reported association studies of presenilin 2 (PSEN2) polymorphisms with early‐onset Alzheimer disease (EOAD) have produced contradictory results. In an effort to resolve these differences, we tested eight single nucleotide polymorphisms in and around the 3′ region of the PSEN2 gene for association with EOAD. An initial set of Scottish EOAD cases (n = 121) and controls (n = 152) was screened using the genotyping method dynamic allele‐specific hybridization (DASH). No significant differences were seen between allele or genotype frequencies of cases and controls. However, when conditioned on the risk allele (ε4) APOE, three polymorphisms showed allelic association with a P value below 0.05. These same polymorphisms were in near 100% linkage disequilibrium with each other (P < 5 × 10^?5), and in each, one of the homozygous genotypes was absent in controls but present in the cases. Replication in an independent set of Scottish EOAD cases (n = 84) and controls (n = 173) did not confirm this finding. From this study we find no evidence to suggest that variations in the PSEN2 gene pose as major risk factors for sporadic EOAD. © 2002 Wiley‐Liss, Inc.     

Some considerations bearing on the doctrine of self-fulfilling prophecy in sex chromosome aneuploidy

The doctrine of self-fulfilling prophecy has been invoked in studies of the effects of sex chromosome aneuploidy on human development as a reason for routine concealment of the diagnosis from affected children and their families. It has been assumed that knowledge of the existence of risk for deviance from normal development automatically creates a self-defeating emotional climate. This communication attempts to delineate both advantageous and deleterious aspects of self-fulfilling prophecy in the medical management of sex chromosome aneuploidy, presents an alternative approach, and reviews the experience in a prospective study of 52 families where a policy of disclosure was followed.     

Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studies

Age-related cognitive changes often include difficulties in retrieving memories, particularly those that rely on personal experiences within their temporal and spatial contexts (i.e., episodic memories). This decline may vary depending on the studied phase (i.e., encoding, storage or retrieval), according to inter-individual differences, and whether we are talking about normal or pathological (e.g., Alzheimer disease; AD) aging. Such cognitive changes are associated with different structural and functional alterations in the human neural network that underpins episodic memory. The prefrontal cortex is the first structure to be affected by age, followed by the medial temporal lobe (MTL), the parietal cortex and the cerebellum. In AD, however, the modifications occur mainly in the MTL (hippocampus and adjacent structures) before spreading to the neocortex. In this review, we will present results that attempt to characterize normal and pathological cognitive aging at multiple levels by integrating structural, behavioral, inter-individual and neuroimaging measures of episodic memory.     

Cytogenetic studies of a male with sporadic intestinal lymphangiectasia: 45,X/46,XY mosaicism with pseudo- and hyperdiploid subpopulations in cultured tissues

45,X/46,XY mosaicism was found in peripheral blood, bone marrow, and tissue cultures of an adult male with intestinal lymphangiectasia (IL). Turner phenotype was not present; his meiotic metaphase analysis was normal, and his dermatoglyphics resembled those of his family. Ten separate tissue culture lines from three biopsies of skin and thyroid gland contained 45,X cells (14.8 to 78.3%). Autosomal aneuploidy, resulting in pseudo- or hyperdiploidy, was also present in 4.3 to 41.6% of the cells. A hyperdiploid clone with a 47,X,+10,+18 karyotype was found in 22.6% of cells in one line. A second hyperdiploid clone with a 48,X,+2,+18,+18 karyotype occurred in 7.6% of cells from another line containing a total of 41.6% pseudo- and hyperdiploid cells. Such clonal abnormalities were not typical of tissue cultures from other patients done in our laboratory. Growth of our patient's tissue cultures was subnormal, and none proliferated beyond the fourth subculture. The significance of this observation remains to be determined. Our results do not allow us to conclude whether our patient's mosaicism of somatic tissues arose during embryogenesis, or whether it originated post-natally. The secondary immunodeficiency which occurs in IL may explain persistence of cells with unusual combinations of autosomal aneuploidy in our patient's tissues.