Disease-modifying therapies in Alzheimer’s disease

Alzheimer’s disease (AD) is a chronic, progressive, neurodegenerative disorder that places a substantial burden on patients, their families, and society. The disease affects approximately 5 million individuals in the United States, with an annual cost of care greater than $100 billion. During the past dozen years, several agents have been approved that enhance cognition and global function of AD patients, and recent advances in understanding AD pathogenesis has led to the development of numerous compounds that might modify the disease process. A wide array of antiamyloid and neuroprotective therapeutic approaches are under investigation on the basis of the hypothesis that amyloid beta (Aβ) protein plays a pivotal role in disease onset and progression and that secondary consequences of Aβ generation and deposition, including tau hyperphosphorylation and neurofibrillary tangle formation, oxidation, inflammation, and excitotoxicity, contribute to the disease process. Interventions in these processes with agents that reduce amyloid production, limit aggregation, or increase removal might block the cascade of events comprising AD pathogenesis. Reducing tau hyperphosphorylation, limiting oxidation and excitotoxicity, and controlling inflammation might be beneficial disease-modifying strategies. Potentially neuroprotective and restorative treatments such as neurotrophins, neurotrophic factor enhancers, and stem cell–related approaches are also under investigation.     

Prospects for pharmacological intervention in Alzheimer disease

Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.     

Early intervention is key to successful management of Alzheimer disease

Because of the huge healthcare burden associated with Alzheimer disease (AD) and the increased lifespan in many industrialized countries, the costs associated with AD are expected to reach astronomical proportions in the next 50 years. Diagnosis, treatment and follow-up of AD patients from the earliest stage possible will reduce healthcare costs and increase quality of life. Indeed, progress in our clinical knowledge of AD has led to more reliable diagnostic criteria and diagnostic accuracy, and research efforts are expanding to uncover the earliest manifestations and even the presymptomatic phases of the disease. The initiating and propagating pathologic processes and the anatomic location of the earliest changes will become new targets of research and therapeutic development. The proposed precursor to AD, mild cognitive impairment, is currently under investigation as a possible therapeutic starting point. This paper reviews our current understanding of the early pathology and clinical manifestations associated with mild cognitive impairment and early AD. A discussion of the latest diagnostic techniques as well as promising therapeutic targets for early intervention also will be included.     

Opportunities and challenges in developing Alzheimer disease therapeutics

Alzheimer disease (AD) is a chronic, progressive disorder with an average disease progression of 7–10 years. However, the histopathological hallmark lesions of this disease, the extracellular Aβ plaques and the intraneuronal neurofibrillary tangles, start as early as childhood in the affected individuals. AD is multifactorial and probably involves many different etiopathogenic mechanisms. Thus, while AD offers a wide window of opportunity that practically includes the whole life span of the affected individuals, and numerous therapeutic targets, the multifactorial nature of this disease also makes the selection of the therapeutic targets an immensely challenging task. In addition to β-amyloidosis and neurofibrillary degeneration, the AD brain also is compromised in its ability to regenerate by enhancing neurogenesis and neuronal plasticity. An increasing number of preclinical studies in transgenic mouse models of AD show that enhancement of neurogenesis and neuronal plasticity can reverse cognitive impairment. Development of both drugs that can inhibit neurodegeneration and drugs that can increase the regenerative capacity of the brain by enhancing neurogenesis and neuronal plasticity are required to control AD.     

Cognitive intervention in Alzheimer disease: a randomized placebo-controlled study

The efficacy of a cognitive intervention consisting of training in face-name associations, spaced retrieval, and cognitive stimulation was tested in a sample of 37 patients (16 men, 21 women) with probable Alzheimer disease (AD). Patients with AD were randomly assigned to receive either the cognitive intervention or a mock (placebo) intervention for 5 weeks. The placebo group then crossed over to receive the intervention. During the intervention, AD patients showed significant improvement in recall of personal information, face-name recall, and performance on the Verbal Series Attention Test. Improvement did not generalize to additional neuropsychologic measures of dementia severity, verbal memory, visual memory, word generation, or motor speed, or to caregiver-assessed patient quality of life. Results suggest that although face-name training, spaced retrieval, and cognitive stimulation may produce small gains in learning personal information and on a measure of attention, improvement does not generalize to overall neuropsychologic functioning or patient quality of life.     

阿尔茨海默病患者的脑脊液tau蛋白及Aβ1-42水平

目的 探讨脑脊液(cerebrospinal fluid,CSF)中tau蛋白及β-淀粉样蛋白1-42(Aβ1-42)对诊断阿尔茨海默病(Alzheimer's disease,AD)的早期诊断价值,寻找AD理想的生物学标志.方法 采用酶联免疫吸附法检测36例AD、24例血管性痴呆患者(vascular dementia,VD)和26名正常对照者(对照组)CSF中tau蛋白及Aβ1-42浓度的变化.结果 CSF中tau蛋白平均浓度:AD组(336±126)ng/L,VD组(183±96)ng/L,对照组(98±54)ng/L,AD组CSF中tau蛋白浓度明显高于对照组,差异有统计学意义(P<0.05);CSF中Aβ1-42平均浓度:AD组(341β113)ng/L,VD组(457±132)ng/L,对照组(502±167)ng/L,AD组CSF中Aβ1-42浓度明显低于对照组.差异有显著性意义(P<0.05).结论 脑脊液Aβ1-42、tau蛋白浓度的变化,不仅对诊断阿尔茨海默病具有较高的敏感性和特异性,而且亦可作为阿尔茨海默病与血管性痴呆鉴别诊断的生物学指标.     

Microglia‐targeted stem cell therapies for Alzheimer disease: A preclinical data review

Alzheimer disease (AD) is a severe, life‐threatening illness characterized by gradual memory loss. The classic histological features of AD include extracellular formation of β‐amyloid plaques (Aβ), intracellular neurofibrillary tangles (NFT), and synaptic loss. Recently, accumulated evidence has confirmed the critical role of microglia in the development and exacerbation of AD. When Aβ forms deposits, microglia quickly respond to restore brain physiology by activating a series of repair mechanisms. However, prolonged microglial activation is considered detrimental and may aggravate AD progression. To date, there are no curative therapies for AD. The advent of stem cell transplantation offers novel strategies to treat AD in animal models. Furthermore, studies have reported that transplanted stem cells might ameliorate AD symptoms by regulating microglial functions, from detrimental to protective. This review focuses on the crucial functions of microglia in AD and examines the reactions of microglia to transplanted stem cells.     

Peripheral blood abnormalities in Alzheimer disease: evidence for early endothelial dysfunction

Clinical and epidemiologic studies demonstrate that vascular risk factors may be involved in Alzheimer disease (AD). To evaluate whether vascular abnormalities are an early feature of AD, several parameters of coagulation and fibrinolysis were assessed. Thirty patients with mild AD and 30 age-matched control subjects entered the study. All subjects performed a standardized clinical and laboratory protocol. Persons with vascular risk factors and systemic diseases were excluded. AD patients present significant increased levels of thrombomodulin (p < 0.0001) and sE-selectin (p < 0.03). In contrast, no difference was found between the two diagnostic groups in the levels of beta-thromboglobulin, prothrombin fragment 1+2, fibrinogen, and von Willebrand factor. No other association but diagnosis was found with thrombomodulin and sE-selectin. These findings suggest that endothelial dysfunction is an early event in AD patients.     

Disease-modifying drugs for the early treatment of multiple sclerosis

The introduction of new immunomodulatory therapies such as, interferon-beta, glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) and mitoxantrone (Ralenova, Wyeth Pharma; Novantrone, Immunex Corp.) has considerably improved the therapeutic options for patients with multiple sclerosis. These agents have been shown to reduce relapse rate, slow down progression of disability and prevent the accumulation of magnetic resonance imaging lesion load in clinically definite multiple sclerosis. Moreover, two formulations of interferon-beta delayed conversion into clinically definite multiple sclerosis in patients with clinically isolated syndromes suggestive of multiple sclerosis. Since axonal damage leading to irreversible neurological disability is already present early at the onset of the disease, immunomodulatory therapy should start as soon as possible. This article reviews the arguments for the early initiation of therapy and provides an overview of clinical studies dealing with the early treatment of multiple sclerosis.     

临床前期阿尔茨海默症的早期诊断与干预

随着人口老龄化的加剧,以阿尔茨海默病（Alzheimer Disease,AD）为主的老年认知障碍问题日趋严重.作为一种多因素、多阶段并有伴随疾病的临床综合征,老年认知障碍在临床症状出现后将进展成不可逆性痴呆.因此,在无症状性临床前期AD症（PCAD）阶段进行早期诊断与干预成为了国内外研究的热点.现对PCAD的危险因素和针对其诊断干预的探索性研究进行综述,试图寻找在早期病理进程中新的可用于临床早期诊断的生物标记物及早期干预的药物靶点.     

Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer’s disease

The pathophysiologic process leading to neurodegeneration in Alzheimer’s disease (AD) is thought to begin long before clinical symptoms develop. Existing therapeutics for AD improve symptoms, but increasing efforts are being directed toward the development of therapies to impede the pathologic progression of the disease. Although these medications must ultimately demonstrate efficacy in slowing clinical decline, there is a critical need for biomarkers that will indicate whether a candidate disease-modifying therapeutic agent is actually altering the underlying degenerative process. A number ofin vivo neuroimaging techniques, which can reliably and noninvasively assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise as biomarkers. These neuroimaging measures appear to relate closely to neuropathological and clinical data, such as rate of cognitive decline and risk of future decline. As this work has matured, it has become clear that neuroimaging measures may serve a variety of potential roles in clinical trials of candidate neurotherapeutic agents for AD, depending in part on the question of interest and phase of drug development. In this article, we review data related to the range of neuroimaging biomarkers of Alzheimer’s disease and consider potential applications of these techniques to clinical trials, particularly with respect to the monitoring of disease progression in trials of disease-modifying therapies.     

Complement activation in very early Alzheimer disease

The activation of the classical complement (C)-system in early-stage Alzheimer disease (AD) and nondemented aging was examined with immunohistochemistry in subjects assessed by the Clinical Dementia Rating (CDR). Activation (staining for C3 and C4 fragments) was found in all brains with amyloid deposits, including all nondemented (CDR 0) cases, with either small numbers of diffuse plaques or with sufficient plaques and tangles to indicate preclinical AD. Staining for C3 and C4 increased in parallel with plaque density in very mild to severe clinical AD. A subset of very mild AD (CDR 0.5) cases also showed C1q (on plaques) and C5b-9 (on neuritic plaques and tangles), whereas these C-fragments were consistently found in severe AD (CDR 3). Mirror section (split-face) analysis showed that C1q, C3, and apoJ (clusterin) occurred on the same plaques. However, C-system regulators CD59, CR1, DAF, and MCP were not detected on plaques or tangles at any stage, indicating that C-activation related to AD is incompletely controlled.     

Gene silencing through methylation: an epigenetic intervention on Alzheimer disease

Alzheimer disease (AD) is among the few diseases that may display high homocysteine (HCY) and low B12 and folate in blood. This observation has raised the suspect that amyloid-beta overproduction and accumulation, which may be the cause of the disease, could be due to the loss of epigenetic control in the expression of the genes involved in AbetaPP (amyloid-beta protein precursor) processing. We have shown, in cell culture, that two of the genes responsible for amyloid-beta production are controlled by the methylation of their promoters. The process is strictly related to S-adenosylmethionine (SAM) metabolism. SAM is a natural compound, mainly produced by the liver, which has been found at very low concentrations in AD brains. A further support to this thesis came from the observation that in elderly DNA methylations are consistently lower than in young and mid aged people. We are actually experimenting in transgenic mice the possibility to prevent or to arrest amyloid-beta accumulation, through SAM administration, and therefore its significance and the use of this drug for the treatment of the disease.