Abstract The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have ...significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.
Abstract The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early ...detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, 18 F-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU , and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.
Development of new therapies for Alzheimer's disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of ...AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials.
Partial least squares regression with a longitudinal clinical decline model identified items from commonly used clinical scales with the highest combined sensitivity to change over time in aMCI and weighted these items according to their relative contribution to detecting clinical progression in patients' early stages of AD. The resultant AD Composite Score (ADCOMS) was assessed for its ability to detect treatment effect in aMCI/prodromal AD (pAD) clinical trial populations.
ADCOMS consists of 4 Alzheimer's Disease Assessment Scale-cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating-Sum of Boxes items. ADCOMS demonstrated improved sensitivity to clinical decline over individual scales in pAD, aMCI and in mild AD dementia. ADCOMS also detected treatment effects associated with the use of cholinesterase inhibitors in these populations. Improved sensitivity predicts smaller sample size requirements when ADCOMS is used in early AD trials.
ADCOMS is proposed as new standard outcome for pAD and mild AD dementia trials, and is progressing in a CAMD-sponsored qualification process for use in registration trials of pAD.
The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of ...disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.
Introduction
Cerebrospinal fluid (CSF) biomarkers can identify individuals with Alzheimer's disease (AD) pathology (eg, amyloid plaques, neurofibrillary tangles), but defined analyte cut‐points using ...high‐throughput automated assays are necessary for general clinical use.
Methods
CSF amyloid β42 peptide (Aβ42), t‐tau, and t‐tau/Aβ42 were quantified by the Lumipulse platform in two test cohorts (A/B: Eisai BAN2401‐201/MISSION AD E2609‐301/302, n = 138; C: Knight Alzheimer's Disease Research Center (ADRC), n = 198), and receiver operating characteristic (ROC) curve analyses defined cut‐points corresponding best to amyloid determinations using positron emission tomography (PET) imaging. The best‐performing cut‐point was then validated as a predictor of amyloid status in an independent cohort (D: MISSION AD E2609‐301/302, n = 240).
Results
Virtually identical t‐tau/Aβ42 cut‐points (∼0.54) performed best in both test cohorts and with similar accuracy (areas under ROC curve AUCs A/B: 0.95; C: 0.94). The cut‐point yielded an overall percent agreement with amyloid PET of 85.0% in validation cohort D.
Discussion
Lumipulse CSF biomarker measures with validated cut‐points have clinical utility in identifying AD pathology.
Trimethyltin (TMT) chloride induces limbic system neurodegeneration, resulting in behavioral alterations including cognitive deficits. Different factors related to Alzheimer's disease (AD) were ...studied after TMT lesion in Sprague-Dawley rats. The expression of amyloid precursor protein (APP) containing 695 amino acids (APP695), APP containing the Kuniz protease inhibitor domain (APP- KPI), presenilin 1 (PS1), c- fos and IL- 1Beta was investigated at different timepoints after a single TMT injection (7 mg/kg i.p.) using in situ hybridization and immunohistochemistry. After the TMT treatment, extensive degeneration of pyramidal neurons was observed in the CA3 region of the hippocampus, concomitant with neurodegeneration in the outer layer of the CA1 region and layer II of entorhinal and piriform cortex. The affected regions showed abundant condensed eosinophilic and TUNEL-positive neuronal cells, that were apparent at day 4 after TMT, increasing to day 7 and subsequently disappearing. In the affected regions the levels of APP695 mRNA gradually declined with time after the TMT injection. While there was no apparent alteration in the overall expression of APP- KPI or PS1 mRNA, detailed analysis of the CA3c region showed that the mRNA expression shifted from neurons to glial cells. Three days after TMT, neurons in the piriform cortex, the CA3 region and DG expressed high levels of c-fos mRNA that slowly declined to become normalized when analyzed at day 28. At day 7 after TMT a few distinct IL- 1Beta mRNA expressing glial cells were observed in the CA3c region. Thus, TMT exposure leads to alterations in the expresson of APP, APP- KPI, PS1, c-fos and IL- 1Beta in the limbic system. These findings suggest that TMT lesions, not only share certain key features of AD symptomatology and regional neurodegeneration, but also induce effects on important factors related to the pathophysiology of AD.
Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta -protein (A beta ) levels. Here we present studies of a pathogenic amyloid ...precursor protein (APP) mutation, located within the A beta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased A beta 42 and A beta 40 levels in plasma. Additionally, low levels of A beta 42 were detected in conditioned media from cells transfected with APP sub(E693G). Fibrillization studies demonstrated no difference in fibrillization rate, but A beta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) A beta . The finding of increased protofibril formation and decreased A beta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid A beta protofibril formation leading to accelerated buildup of insoluble A beta intra- and/or extracellularly.
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