PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials

The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.     

Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders

Neurodegenerative diseases are devastating mental illnesses without a cure. Alzheimer's disease (AD) characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. Although tremendous progress has made in understanding the basic biology in disease processes in AD and PD, we still do not have early detectable biomarkers for these diseases. Just in the United States alone, federal and nonfederal funding agencies have spent billions of dollars on clinical trials aimed at finding drugs, but we still do not have a drug or an agent that can slow the AD or PD disease process. One primary reason for this disappointing result may be that the clinical trials enroll patients with AD or PD at advances stages. Although many drugs and agents are tested preclinical and are promising, in human clinical trials, they are mostly ineffective in slowing disease progression. One therapy that has been promising is ‘stem cell therapy’ based on cell culture and pre-clinical studies. In the few clinical studies that have investigated therapies in clinical trials with AD and PD patients at stage I. The therapies, such as stem cell transplantation – appear to delay the symptoms in AD and PD. The purpose of this article is to describe clinical trials using 1) stem cell transplantation methods in AD and PD mouse models and 2) regenerative medicine in AD and PD mouse models, and 3) the current status of investigating preclinical stem cell transplantation in patients with AD and PD.     

Targeted proteomics in Alzheimer's disease: focus on amyloid-beta

Diagnosis and monitoring of sporadic Alzheimer's disease (AD) have long depended on clinical examination of individuals with end-stage disease. However, upcoming anti-AD therapies are optimally initiated when individuals show very mild signs of neurodegeneration. There is a developing consensus for cerebrospinal fluid amyloid-beta (Abeta) as a core biomarker for the mild cognitive impairment stage of AD. Abeta is directly involved in the pathogenesis of AD or tightly correlated with other primary pathogenic factors. It is produced from amyloid precursor protein (APP) by proteolytic processing that depends on the beta-site APP-cleaving enzyme 1 and the gamma-secretase complex, and is degraded by a broad range of proteases. This review summarizes targeted proteomic studies of Abeta in biological fluids and identifies clinically useful markers of disrupted Abeta homeostasis in AD. The next 5 years will see a range of novel assays developed on the basis of these results. From a longer perspective, establishment of the most effective combinations of different biomarkers and other diagnostic modalities may be foreseen.     

Targeted proteomics in Alzheimer’s disease: focus on amyloid-β

Diagnosis and monitoring of sporadic Alzheimer’s disease (AD) have long depended on clinical examination of individuals with end-stage disease. However, upcoming anti-AD therapies are optimally initiated when individuals show very mild signs of neurodegeneration. There is a developing consensus for cerebrospinal fluid amyloid-β (Aβ) as a core biomarker for the mild cognitive impairment stage of AD. Aβ is directly involved in the pathogenesis of AD or tightly correlated with other primary pathogenic factors. It is produced from amyloid precursor protein (APP) by proteolytic processing that depends on the β-site APP-cleaving enzyme 1 and the γ-secretase complex, and is degraded by a broad range of proteases. This review summarizes targeted proteomic studies of Aβ in biological fluids and identifies clinically useful markers of disrupted Aβ homeostasis in AD. The next 5 years will see a range of novel assays developed on the basis of these results. From a longer perspective, establishment of the most effective combinations of different biomarkers and other diagnostic modalities may be foreseen.     

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer’s disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.     

Alzheimer 病生物标志物表达的研究进展

目前,对阿尔茨海默病（AD）的诊断和治疗还存在一定的局限性和困难,临床上筛选出敏感性和特异性高的生物标志物有助于对AD的诊断和鉴别诊断,本文就与淀粉样变过程、胆固醇代谢过程及氧化应激过程的标志物的研究现状及其对临床的价值作一综述。     

Diagnostic function of the neuroinflammatory biomarker YKL-40 in Alzheimer’s disease and other neurodegenerative diseases

Introduction: Neuroinflammation is a crucial mechanism in the pathophysiology of neurodegenerative diseases pathophysiology. Cerebrospinal fluid (CSF) YKL-40 – an indicator of microglial activation ? has recently been identified by proteomic studies as a candidate biomarker for Alzheimer’s disease (AD).

Areas covered: We review the impact of CSF YKL-40 as a pathophysiological biomarker for AD and other neurodegenerative diseases. CSF YKL-40 concentrations have been shown to predict progression from prodromal mild cognitive impairment to AD dementia. Moreover, a positive association between CSF YKL-40 and other biomarkers of neurodegeneration – particularly total tau protein ? has been reported during the asymptomatic preclinical stage of AD and other neurodegenerative diseases. Albeit preliminary, current data do not support an association between APOE-ε4 status and CSF YKL-40 concentrations. When interpreting the diagnostic/prognostic significance of CSF YKL-40 concentrations in neurodegenerative diseases, potential confounders – including age, metabolic and cardiovascular risk factors, diagnostic criteria for selecting cases/controls – need to be considered.

Expert opinion/commentary: CSF YKL-40 represents a pathophysiological biomarker reflecting immune/inflammatory mechanisms in neurodegenerative diseases, associated with tau protein pathology. Besides being associated with tau pathology, CSF YKL-40 adds to the growing array of biomarkers reflecting distinct molecular brain mechanisms potentially useful for stratifying individuals for biomarker-guided, targeted anti-inflammatory therapies emerging from precision medicine.     

The Alzheimer's disease mitochondrial cascade hypothesis: Progress and perspectives

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.     

Biomarkers of Alzheimer’s disease in body fluids

Various innovative diagnostic methods for Alzheimer’s disease (AD) have been developed in view of the increasing preva-lence and consequences of later-life dementia. Biomarkers in cerebrospinal fluid (CSF) and blood for AD are primarily based on the detection of components derived from amyloid plaques and neurofibrillary tangles (NFTs). Published reports on CSF and blood biomarkers in AD indicate that although biomarkers in body fluids may be utilized in the clinical diagnosis of AD, there are no specific markers that permit accurate and reliable diagnosis of early-stage AD or the monitoring of disease pro-gression.     

Urinary proteomics and molecular determinants of chronic kidney disease: possible link to proteases

Chronic kidney disease (CKD) is the gradual decrease in renal function. Currently available biomarkers are effective only in detecting late stage CKD. Biomarkers of early stage CKD and prognostic biomarkers are required. We review the major findings in urinary proteomics in CKD during the last five years. Significant progress has been made and today urinary proteomics is applied in large randomized trials, and in patient management. Many of the biomarkers indicate altered protease activity. We therefore also review the literature on proteases associated with renal function loss. We anticipate in silico prediction tools of protease activity and additional system biology studies may contribute to biomarker discovery and elucidate the role of proteases in CKD development and progression. These approaches will enable the deciphering of the molecular pathophysiology of CKD, and hence definition of the most appropriate therapeutic targets in the future. Together with stable biomarker panels available today, this will significantly improve patient management.     

Neuroimaging Results Impose New Views on Alzheimer’s Disease—the Role of Amyloid Revised

Huge progress has been made in unraveling the mysteries of Alzheimer’s disease (AD), but we still do not understand the basic mechanisms that set off the cascade of pathological events. In May 2011, the National Institute on Aging–Alzheimer’s Association published new diagnostic guidelines, expected to have huge impact on AD research and clinical practice. However, the new guidelines are already criticized for being biased in favor of a specific theory of the pathophysiological origins of AD—the amyloid cascade hypothesis. Shortly before publication of the guidelines, a hypothetical model of the dynamic biomarkers of the Alzheimer’s pathological cascade was published, taking as starting point that biomarkers reflecting brain levels of amyloid become deviant long before brain atrophy, cognitive dysfunction, or clinical symptoms are manifest. This model has already attracted substantial interest and arguably represents a dominating view within human research on AD. Here we critically review the evidence for the view of amyloid as an initiating event in the pathological cascade and discuss how central assumptions of this hypothesis affect how results from contemporary human AD research are understood. Interpretations of new results are greatly impacted by researchers’ view on the role of amyloid, and identical observations are sometimes taken to support radically opposing views on the amyloid hypothesis. We argue that the canonical view of the role of amyloid as the main causal factor in AD may not be correct and that evidence from recent neuroimaging studies indicates that amyloid is neither necessary nor sufficient, for the manifestation of AD-like brain atrophy.     

The impact of cerebrospinal fluid biomarkers on the diagnosis of Alzheimer's disease

The cerebrospinal fluid (CSF) biomarkers β-amyloid(1-42) (Aβ(1-42)), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau(181P)) are gradually finding their way into routine clinical practice as an affirmative diagnostic tool for Alzheimer's disease (AD). These biomarkers have also been implemented in the revised diagnostic criteria for AD. The combination of the CSF biomarkers Aβ(1-42), T-tau, and P-tau(181P) leads to high (around 80%) levels of sensitivity, specificity, and diagnostic accuracy for discrimination between AD and controls (including psychiatric disorders like depression) and can be applied for diagnosing AD in the predementia phases of the disease (mild cognitive impairment). The added value of CSF biomarkers could lie within those cases in which the clinical diagnostic work-up is not able to discriminate between AD and non-AD dementias. However, their discriminatory power for the differential diagnosis of dementia is suboptimal. Other CSF biomarkers, especially those that are reflective of the pathology of non-AD dementia etiologies, could improve the accuracy of differential dementia diagnosis. CSF biomarkers will be of help to establish a correct and early AD diagnosis, even in the preclinical stages of the disease, which will be of importance once disease-modifying drugs for AD become available. Variation in biomarker measurements still jeopardize the introduction of CSF biomarkers into routine clinical practice and clinical trials, but several national and international standardization initiatives are ongoing.     

阿尔茨海默病免疫治疗的临床研究进展

阿尔茨海默病免疫治疗以淀粉样蛋白Aβ或tau蛋白为治疗靶点。通过疫苗刺激产生靶标抗体的主动免疫或直接给予抗体的被动免疫,可减轻AD病理改变,有望延缓或阻止AD病程进展。动物研究显示了广阔的治疗前景,临床免疫治疗的部分药物已完成III期试验,但未达到预期效果。综述近年来免疫治疗AD的临床研究进展。     

Peptides and proteins in plasma and cerebrospinal fluid as biomarkers for the prediction, diagnosis, and monitoring of therapeutic efficacy of Alzheimer's disease

Alzheimer's disease (AD) affects millions of persons worldwide. Earlier detection and/or diagnosis of AD would permit earlier intervention, which conceivably could delay progression of this dementing disorder. In order to accomplish this goal, reliable and specific biomarkers are needed. Biomarkers are multidimensional and have the potential to aid in various facets of AD such as diagnostic prediction, assessment of disease stage, discrimination from normally cognitive controls as well as other forms of dementia, and therapeutic efficacy of AD drugs. To date, biomarker research has focused on plasma and cerebrospinal fluid (CSF), two bodily fluids believed to contain the richest source of biomarkers for AD. CSF is the fluid surrounding the central nervous system (CNS), and is the most indicative obtainable fluid of brain pathology. Blood plasma contains proteins that affect brain processes from the periphery, as well as proteins/peptides exported from the brain; this fluid would be ideal for biomarker discovery due to the ease and non-invasive process of sample collection. However, it seems reasonable that biomarker discovery will result in combinations of CSF, plasma, and other fluids such as urine, to serve the aforementioned purposes. This review focuses on proteins and peptides identified from CSF, plasma, and urine that may serve as biomarkers in AD.     

Beta-amyloid (Abeta) protein in cerebrospinal fluid as a biomarker for Alzheimer's disease

With the arrival of symptomatic treatment (acetylcholine esterase inhibitors) and the promise of drugs that may delay disease progression, development of diagnostic biomarkers for Alzheimer's disease (AD) are important. Beta-Amyloid (Abeta) protein is the main component of senile plaques. A marked reduction in cerebrospinal fluid (CSF)-Abeta42 in AD has been found in numerous studies. Importantly, reduced CSF-Abeta42 is also found very early in the disease process, before the onset of clinical symptoms. Recent studies suggest that CSF-Abeta42 have a satisfactory performance when used as a diagnostic marker for AD in clinical routine. This paper reviews CSF-Abeta42 as a biomarker for AD.     

Stimulation of the amyloidogenic pathway by cytoplasmic superoxide radicals in an Alzheimer's disease mouse model

Oxidative stress is involved in the pathogenesis of neurodegeneration. Amyloid β (Aβ) oligomer as an intermediate of aggregates causes memory loss in Alzheimer's disease (AD). We have suggested that oxidative stress plays an important role in Aβ oligomerization and cognitive impairment using a human amyloid precursor protein (hAPP) transgenic AD mice lacking cytoplasmic superoxide dismutase (hAPP/Sod1-/-). Recently, clinical trials revealed inhibitors of Aβ production from hAPP as promising therapeutics, but the relationship between oxidative stress and Aβ metabolism remains unclear. Here we found that Sod1 deficiency enhanced β-cleavage of hAPP, suggesting that it increased Aβ production in hAPP/Sod1-/- mice. In contrast, Aβ degradation did not decrease in hAPP/Sod1-/- as compared with hAPP/Sod1+/+ mice. Furthermore, we successfully detected in situ superoxide radicals associated with increased protein carbonylation in hAPP/Sod1-/-. These results suggest that cytoplasmic oxidative stress is involved in Aβ production as well as aggregation during AD progression.     

Distribution and binding of 18F-labeled and 125I-labeled analogues of ACI-80, a prospective molecular imaging biomarker of disease: a whole hemisphere post mortem autoradiography study in human brains obtained from Alzheimer's disease patients

One of the major pathological landmarks of Alzheimer's disease and other neurodegenerative diseases is the presence of amyloid deposits in the brain. The early non-invasive visualization of amyloid is a major objective of recent diagnostic neuroimaging approaches, including positron emission tomography (PET), with an eye on follow-up of disease progression and/or therapy efficacy. The development of molecular imaging biomarkers with binding affinity to amyloid in the brain is therefore in the forefront of imaging biomarker and radiochemistry research. Recently, a dodecamer peptide (amino acid sequence=QSHYRHISPAQV; denominated D1 or ACI-80) was identified as a prospective ligand candidate, binding with high ex vivo affinity to L-Aβ-amyloid (K(d): 0.4 μM). In order to assess the ligand's capacity to visualize amyloid in Alzheimer's disease (AD), two (125)I labeled and three (18)F labeled analogues of the peptide were synthesized and tested in post mortem human autoradiography experiments using whole hemisphere brain slices obtained from deceased AD patients and age matched control subjects. The (18)F-labeled radioligands showed more promising visualization capacity of amyloid that the (125)I-labeled radioligands. In the case of each (18)F radioligands the grey matter uptake in the AD brains was significantly higher than that in control brains. Furthermore, the grey matter: white matter uptake ratio was over ~2, the difference being significant for each (18)F-radioligands. The regional distribution of the uptake of the various radioligands systematically shows a congruent pattern between the high uptake regions and spots in the autoradiographic images and the disease specific signals obtained in adjacent or identical brain slices labeled with histological, immunohistochemical or autoradiographic stains for amyloid deposits or activated astrocytes. The present data, using post mortem human brain autoradiography in whole hemisphere human brains obtained from deceased AD patients and age matched control subjects, support the visualization capacity of the radiolabeled ACI-80 analogues of amyloid deposits in the human brain. Further studies are warranted to explore the usefulness of the (18)F-labeled analogues as in vivo molecular imaging biomarkers in diagnostic PET studies.     

β-amyloid PET neuroimaging: A review of radiopharmaceutical development

Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposition of amyloid-β plaques that occurs even before symptoms of brain failure are clinically detectable. Whereas previously the diagnosis of AD was only routinely based on clinical assessment, an improvement over the past few years in imaging biomarkers has now led to reconsider the core of the AD diagnostic pathway. Therefore, positron emission tomography (PET) radiotracers for the in vivo imaging of amyloid plaques have been the focus of intense research. Many chemical compounds, mostly derived from the chemistry of amyloid histological staining dyes, have permitted to obtain promising brain amyloid radiopharmaceuticals. Three of them have been approved by the FDA and European regulatory bodies. The present review focuses on the development of these compounds not only as a suitable imaging biomarker to improve AD diagnosis, but also to evaluate new potential therapy.