Association between neuropsychiatric and autonomic dysfunction in Alzheimer's disease

We sought to determine whether there was an association between specific neuropsychiatric deficits and autonomic dysfunction in patients with Alzheimer's disease (AD). We studied 20 patients and 20 age-matched control subjects with neuropsychiatric tests (Blessed, Cornell depression and NPI scores) and autonomic tests (Deep breath (HRdb), 30:15 ratio and orthostatic hypotension (Bpoh)). The 30:15 ratio was consistently reduced in AD patients as compared to control subjects (1.05 ± 0.07 for patients and 1.18 ± 0.1 for controls, p 0.001). Whereas there were no significant differences in the HRdb and presence of Bpoh. In AD patients with an abnormal 30:15 ratio, there were significant abnormalities in the Blessed score and in the apathy, delusions and aberrant motor behavior items of the NPI. The other autonomic tests did not correlate with any neuropsychiatric score. The relationship between abnormal cortical function and impaired 30:15 ratio suggested that a lack of cortical modulation of autonomic circuits may underlie cardiovascular instability in these patients. Received: 24 January 2001, Accepted: 10 December 2001     

Executive dysfunction in early Alzheimer's disease.

Twenty five patients with probable mild Alzheimer''s disease were assessed for deficits in executive functioning and the impact of these deficits on performance in other neuropsychological domains. The Wisconsin card sorting test, the release from proactive interference paradigm, the verbal fluency test, and the Stroop test were adopted to classify patients with (AD+) and without (AD-) executive deficits. Seven of the patients showed an impairment in executive function (AD+), defined as a performance below the cut off score in at least two of these tests. There were no significant differences in clinical assessments, demographic features, or other cognitive functions between patients. Executive dysfunction may be an early additional feature in a subgroup of patients with mild Alzheimer''s disease. Impairment on frontal lobe tests does not seem to be related to the severity or duration of disease, or to a different pattern of impairment in other cognitive domains.     

Association between statin use and Alzheimer's disease

CONTEXT: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been associated with a decreased risk for Alzheimer's disease (AD). OBJECTIVE: To evaluate the association between statin use and AD adjusted for comorbid medical conditions. DESIGN: A nested case-control study. PATIENTS: Patients at the Veterans Affairs Medical Center in Birmingham, Ala., USA with a new diagnosis of AD (cases) between 1997 and 2001 (n = 309) and age-matched non-AD controls (n = 3,088). MAIN OUTCOME MEASURE: Odds ratio for association between AD and statin use. RESULTS: Statin users had a 39% lower risk of AD relative to nonstatin users (odds ratio 0.61, 95% confidence interval 0.42-0.87). This association appeared to be modified by the presence of certain chronic medical conditions (i.e., hypertension, ischemic heart disease and cerebrovascular disease) in that the reduced risk was observed among those with these diseases, whereas no association was observed among those without any of these conditions. CONCLUSIONS: In this study, following adjustment for confounding factors, a statistically significant inverse association between statin use and AD was observed. The results lend support to looking at AD outcomes in trials of statins to further evaluate their possible beneficial effects.     

An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction

White matter pathology has been documented in the brains of familial Alzheimer's disease (FAD)-afflicted individuals during presymptomatic and preclinical stages of AD. How these defects in myelination integrity arise and what roles they may play in AD pathophysiology have yet to be fully elucidated. We previously demonstrated that triple-transgenic AD (3xTg-AD) mice, which harbor the human amyloid precursor Swedish mutation, presenilin-1 M146V (PS1(M146V) ) knock-in mutation, and tau(P301L) mutation, exhibit myelin abnormalities analogous to FAD patients and that Aβ(1-42) contributes to these white matter deficits. Herein, we demonstrate that the PS1(M146V) mutation predisposes mouse oligodendrocyte precursor (mOP) cells to Aβ(1-42) -induced alterations in cell differentiation in vitro. Furthermore, PS1(M146V) expression compromised mOP cell function and MBP protein distribution, a process that is further aggravated with exposure to Aβ(1-42) . We found that the myelination defect and MBP subcellular mislocalization triggered by PS1(M146V) and Aβ(1-42) can be effectively prevented by treatment with the GSK-3β inhibitor, TWS119, thereby implicating GSK-3β kinase activity in this pathogenic cascade. Overall, this work provides further mechanistic insights into PS1(M146V) and Aβ(1-42) -driven oligodendrocyte dysfunction andmyelin damage during early presymptomatic stages of AD, and provides a new target in oligodendrocytes for developing therapies designed to avert AD-related white matter pathology.     

The case for blood-brain barrier dysfunction in the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease that leads to a progressive loss of integrative and memory capacities of the brain. This is the predominant form of neurodegenerative dementia, with a growing prevalence of between 1 in 50 and 1 in 100 in North America. Numerous hypotheses related to the etiology of AD have developed over the years. However, among the various published hypotheses, the predominant one is related to the progressive and prominent accumulation of central nervous system β-amyloid peptide and the ensuing brain burden created. It is, therefore, important to consider the homeostatic mechanisms underlying β-amyloid transport dynamics between the brain and blood vascular compartments. As well, there is a dynamic interrelationship between soluble and insoluble forms of the peptide. Factors that underlie and regulate these dynamic processes are likely relevant to the end accumulation of β-amyloid peptide in the brain compartment and ultimately in insoluble forms, which is characteristic of, and significant for, the pathophysiology of the Alzheimer's brain. Significantly, and in particular relation to the amyloid burden theory mentioned above, it has been postulated that a dysfunctioning blood-brain barrier (BBB) may play a significant, if not critical, role in the pathogenesis of AD. By allowing the influx of injurious materials or agents into the brain or by impeding or blocking the efflux of those materials and/or agents, BBB-related neuronopathies and their associated sequelae could, and do, ensue.     

Mitochondrial dysfunction and Alzheimer's disease

To date, one of the most discussed hypotheses for Alzheimer's disease (AD) etiology implicates mitochondrial dysfunction and oxidative stress as one of the primary events in the course of AD. In this review we focus on the role of mitochondria and mitochondrial DNA (mtDNA) variation in AD and discuss the rationale for the involvement of mitochondrial abnormalities in AD pathology. We summarize the current data regarding the proteins involved in mitochondrial function and pathology observed in AD, and discuss the role of somatic mutations and mitochondrial haplogroups in AD development.     

嗅觉障碍与阿尔茨海默病

阿尔茨海默病(AD)为老年期常见的退行性神经变性疾病,以进行性记忆力、智力和认知功能减退为主要表现,至今病因未明,现有药物仅对疾病早期有效,因此,早诊断、早治疗意义重大.     

Mitochondrial dysfunction and Alzheimer's disease

Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Abeta) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Abeta-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Abeta with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Abeta-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Abeta interaction may be a potential therapeutic strategy for Alzheimer's disease.     

Association between bleomycin hydrolase and Alzheimer's disease in caucasians

A recent study showed modest evidence for an increased frequency of the bleomycin hydrolase (BH) V/V genotype in Alzheimer's disease (AD) patients compared with nondemented controls. To test this hypothesis, we examined this polymorphism in 621 rigorously evaluated patients and 502 control subjects (all caucasian) but were unable to detect an association between BH and AD even after controling for age, gender, and apolipoprotein E (ApoE) genotype. We conclude that this polymorphism does not account for inherited susceptibility to AD in the populations represented in this sample.     

Association between tau polymorphism and male early-onset Alzheimer's disease

Neurofibrillary tangles, containing hyperphosphorylated microtubule-associated protein tau, are one of the major pathological hallmarks of Alzheimer's disease. To investigate a possible association between tau genotypes and the risk of Alzheimer's disease, we screened for polymorphisms in the tau gene and found a novel polymorphism IVS11 + 90G --> A. A case-control study (874 patients and 678 controls) showed a significant association between possession of the A allele and male Alzheimer's disease with early-onset (age of onset before 65, odds ratio = 2.65; 95% confidence interval 1.30-5.42), suggesting that age and gender modify the risk effect. However, we failed to replicate the reported association between the Saitohin gene located in the tau intron 9 and Japanese Alzheimer's disease.     

Mitochondrial dysfunction and immune activation are detectable in early Alzheimer's disease blood

Alzheimer's disease (AD), like other dementias, is characterized by progressive neuronal loss and neuroinflammation in the brain. The peripheral leukocyte response occurring alongside these brain changes has not been extensively studied, but might inform therapeutic approaches and provide relevant disease biomarkers. Using microarrays, we assessed blood gene expression alterations occurring in people with AD and those with mild cognitive changes at increased risk of developing AD. Of the 2,908 differentially expressed probes identified between the three groups (p < 0.01), a quarter were altered in blood from mild cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a peripheral response to pathology may occur very early. There was strong evidence for mitochondrial dysfunction with decreased expression of many of the respiratory complex I-V genes and subunits of the core mitochondrial ribosome complex. This mirrors changes previously observed in AD brain. A number of genes encoding cell adhesion molecules were increased, along with other immune-related genes. These changes are consistent with leukocyte activation and their increased the transition from circulation into the brain. In addition to expression changes, we also found increased numbers of basophils in people with MCI and AD, and increased monocytes in people with an AD diagnosis. Taken together this study provides both an insight into the functional response of circulating leukocytes during neurodegeneration and also identifies potential targets such as the respiratory chain for designing and monitoring future therapeutic interventions using blood.     

Alzheimer's disease: pathogenesis and prevention

Tau lesions (pretangles, neuropil threads, neurofibrillary tangles) in select neuronal types are essential to the pathogenesis of Alzheimer's disease. Pretangle formation marks the beginning of the pathological process and is of particular interest because it is temporally closer to the prevailing conditions that induce the pathological process underlying Alzheimer's disease in contrast to late-stage disease. However, not all pretangles convert into neurofibrillary tangles. We propose that the development of tau lesions in Alzheimer's disease is traceable to differences between early- versus late-maturing oligodendrocytes and to the exceptionally protracted myelination of late-developing portions of the human brain. Conclusions drawn from these considerations should encourage development of new preventative and disease-modifying strategies.     

The early contribution of cerebrovascular factors to the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) and cerebrovascular disorders are the leading causes of dementia in our ageing population. Given that the progression of neuropathological changes in the brains of AD patients initiates several years, and even decades, before the diagnosis of dementia, a great effort has been made to identify potentially modifiable factors that contribute to the pathogenesis of sporadic late-onset AD. Among these factors, cerebrovascular disease and microvascular alterations seem to bilaterally interact with the underlying AD pathology, affecting the progression of cognitive deficits. In addition, cerebrovascular dysfunction has emerged as an early event in AD, encompassing changes in virtually all cell types of the neurovascular unit, including bone marrow-derived cells, astrocytes, pericytes, vascular smooth muscle cells and endothelial cells. In this review, we discuss recent studies implicating cerebrovascular factors in the pathogenesis of AD. We also discuss how the impairment of mechanisms of brain regeneration, such as neurogenesis and angiogenesis, might be related to the vascular dysfunction. Finally, we briefly discuss several therapeutic options targeting the vascular system, which might represent an interesting strategy for preventing or delaying the onset of dementia in AD.     

载脂蛋白D基因多态与散发性阿尔茨海默病的相关性

目的 通过检测载脂蛋白D基因(apolipoprotein D gene,ApoD)单核苷酸多态位点,探讨其与北方汉族人群散发性阿尔茨海默病(sporadic Alzheimer's disease,SAD)的相关性.方法 应用聚合酶链反应(PCR)及直接测序筛查ApoD基因所有外显子及其两端内含子多态位点.选取等位基因频率大于10%的位点,利用PCR-限制性片段长度多态性(PCR-RFLP)技术,采用病例-对照相关性研究方法 ,研究256例SAD患者以及294名健康人的ApoD多态位点与SAD发病的关系.同时对位点间的连锁不平衡及构建的单体型进行相关性分析.结果 ApoD第2号外显子存在T/C多态性(rs5952),第3号内含子(rs1568566)存在C/T多态性.ApoD rs5952 T/C和rs1568566 C/T等位基因频率和基因型频率在SAD组和对照组间的分布差异有统计学意义.Logistic回归分析表明携带rs5952C或rs1568566T等位基因分别增加SAD发病风险:校正后rs5952 χ2=9.282(P=0.002);rs1568566 χ2=5.072(P=0.024).进一步分析证实性别和ApoD多态性存在交互作用.rs5952-rs1568566位点间存在连锁不平衡.结论 北方汉族人ApoD基因存在第2号外显子rs5952和第3号内含子rs1568566 2个多态位点;ApoD多态可增加SAD发病风险;携带rs5952T或rs1568566C单体型可能对SAD的发病有一定的保护作用.     

Association between tumor necrosis factor-alpha promoter polymorphism and Alzheimer's disease

Tumor necrosis factor-alpha (TNFalpha) gene polymorphisms have been reported to be associated with Alzheimer's disease (AD) in Caucasian populations. Three TNFalpha polymorphisms (-857, -863, and -1,031) were studied in a Chinese population. A high-risk TNFalpha haplotype (-1,031C-863C-857C) with an odds ratio of 2.54 (95% CI 1.37 to 4.79) for AD was identified. No interaction effect of APOE and TNFalpha genotypes was found, but both acted as important risk factors for AD.     

Association between Alzheimer's disease and the NOS3 gene.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder of later life. Genetic studies have demonstrated that the apolipoprotein E (ApoE) gene is an important susceptibility locus; however, other environmental and genetic factors operating alone or in combination with ApoE must also be involved. Among candidate genes that may contribute to this residual risk is the endothelial nitric oxide synthase (NOS3) gene. NO release from vascular endothelium accounts in large part for endothelium-derived relaxing factor bioactivity. Abnormalities of cerebral small vessels occur early in AD, and it has been demonstrated recently that beta-amyloid interacts with endothelial cells in blood vessels to produce an excess of superoxide radicals. We have genotyped 122 cases of early-onset AD (EOAD) and 317 cases of late-onset AD (LOAD) as well as 392 controls for a common structural polymorphism Glu/Asp at codon 298 in the NOS3 gene. We find a highly significant enrichment for Glu/Glu homozygotes in LOAD compared with controls. The effect appears to be independent of ApoE status. NOS3 may be a new genetic risk factor for LOAD.     

白介素-18基因启动子多态性与阿尔茨海默病的关联分析

目的 探讨IL-18基因启动子区位点单核苷酸多态性与散发性阿尔茨海默病(SAD)的相关关系.方法 采用病例对照的研究方法,共入选SAD患者109例和同期年龄、性别完全匹配的对照组109例.应用序列特异性引物-聚合酶链反应技术检测两组对象IL-18基囚启动子-607C/A位点单核苷酸多态性.结果 IL-18基囚启动子-607C/A位点等位基因和基因型分布在SAD组和对照组间比较差异有统计学意义(P=0.021,P=0.041).SAD组-607CC基因型分布频率明显高于对照组,比较差异有统计学意义(x2=4.109,P=0.043),携带-607CC基因型的人群患SAD的风险是非携带人群的1.90倍(OR=1.90,95%CI:1.017～3.550).结论 SAD与IL-18基因启动子-607C/A位点单核苷酸多态性相关,其中-607CC基因型的人群发生SAD的风险较其他基因型人群的风险高.