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1.  Alzheimer’s disease biomarkers in animal models: closing the translational gap 
The rising prevalence of Alzheimer’s disease (AD) is rapidly becoming one of the largest health and economic challenges in the world. There is a growing need for the development and implementation of reliable biomarkers for AD that can be used to assist in diagnosis, inform disease progression, and monitor therapeutic efficacy. Preclinical models permit the evaluation of candidate biomarkers and assessment of pipeline agents before clinical trials are initiated and provide a translational opportunity to advance biomarker discovery. Fast and inexpensive data can be obtained from examination of peripheral markers, though they currently lack the sensitivity and consistency of imaging techniques such as MRI or PET. Plasma and cerebrospinal fluid (CSF) biomarkers in animal models can assist in development and implementation of similar approaches in clinical populations. These biomarkers may also be invaluable in decisions to advance a treatment to human testing. Longitudinal studies in AD models can determine initial presentation and progression of biomarkers that may also be used to evaluate disease-modifying efficacy of drugs. The refinement of biomarker approaches in preclinical systems will not only aid in drug development, but may facilitate diagnosis and disease monitoring in AD patients.
PMCID: PMC3703123  PMID: 23844335
Alzheimer’s disease; biomarkers; animal models; drug development
2.  The Role of Biomarkers in Clinical Trials for Alzheimer Disease 
Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer’s Association’s Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.
doi:10.1097/01.wad.0000191420.61260.a8
PMCID: PMC1820855  PMID: 16493230
Alzheimer disease; amyloid beta; cerebrospinal fluid; clinical trials; cytokines; isoprostanes; positron emission tomography; tau; volumetric magnetic resonance imaging
3.  Comparison of analytical platforms for cerebrospinal fluid measures of Aβ1-42, total tau and p-tau181 for identifying Alzheimer’s disease amyloid plaque pathology 
Archives of neurology  2011;68(9):1137-1144.
OBJECTIVE
Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of ante-mortem diagnosis. Establishing biomarker validity requires demonstration that the assays are true markers of underlying disease pathology (e.g., amyloid plaques and/or neurofibrillary tangles) in living individuals.
DESIGN
We compared the performances of the two most commonly used platforms, INNOTEST® ELISA and INNO-BIA AlzBio3 for measurement of CSF amyloid-beta (Aβ) and tau(s), for identifying the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Aβ1-42, total tau and phosphorylated tau181 (p-tau181) using the two assay platforms were compared to brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent, Pittsburgh Compound B (PIB).
SUBJECTS
Research volunteers who are cognitively normal or have very mild to moderate AD dementia.
RESULTS
The two assay platforms yielded different (~2–6-fold) absolute values for the various analytes, but relative values were highly correlated. CSF Aβ1-42 correlated inversely, and tau and p-tau181 correlated positively, with the amount of cortical PIB binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau/Aβ1-42 and p-tau181/Aβ1-42 outperformed any single analyte, including Aβ1-2, in discriminating individuals with versus without cortical amyloid.
CONCLUSIONS
The INNOTEST® and INNO-BIA CSF platforms performed equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cut-point values.
doi:10.1001/archneurol.2011.105
PMCID: PMC3154969  PMID: 21555603
Alzheimer’s disease; amyloid; biomarkers; cerebrospinal fluid; imaging (PET, MRI) in dementias; Pittsburgh Compound B
4.  Evolution of the diagnostic criteria for degenerative and cognitive disorders 
Current Opinion in Neurology  2011;24(6):532-541.
Purpose of review
This review describes the evolution of the clinical criteria for Alzheimer’s disease over the past 25 years, with special emphasis on those recently published that have incorporated the use of biomarkers.
Recent findings
One of the most important advances in the knowledge of Alzheimer’s disease was the development of cerebrospinal fluid, PET and MRI biomarkers. These have shown that the Alzheimer’s disease is present in cognitively normal individuals, suggesting that there is a long incubation process that precedes the onset of the symptoms. Although there are diagnostic criteria for Alzheimer’s disease, the National Institute on Aging and the Alzheimer’s Association has proposed a set of diagnostic criteria oriented to provide a unified vision of the pathological process from preclinical, to mild cognitive impairment, and to full-blown dementia. These new criteria take advantage of different biomarkers to support the clinical diagnosis of the different stages of the disease.
Summary
The new guidelines provide a definition of the dementia syndrome and core diagnostic features to be used in research and clinical practice, although they caution about the use of biomarkers, since they still require validation, and the longitudinal interaction and dynamics of these biomarkers in relationship to the manifestation of the symptoms are not fully understood.
doi:10.1097/WCO.0b013e32834cd45b
PMCID: PMC3268228  PMID: 22071334
Alzheimer’s disease; dementia; diagnostic criteria; mild cognitive impairment; preclinical Alzheimer’s disease
5.  Evidence for Ordering of Alzheimer’s Disease Biomarkers 
Archives of Neurology  2011;68(12):1526-1535.
Objective
To empirically assess the concept that Alzheimer’s disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.
Design
Validation sample
Setting
Multi-site, referral centers
Patients
We studied 401 elderly cognitively normal (CN), Mild Cognitive Impairment (MCI) and AD dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative. We compared the proportions of three AD biomarkers – CSF Aβ42, CSF total tau (t-tau), and hippocampal volume adjusted by intra-cranial volume (HVa) - that were abnormal as cognitive impairment worsened. Cut-points demarcating normal vs. abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.
Interventions
None
Main Outcome measures
AD biomarkers
Results
Within each clinical group in the entire sample (n=401) CSF Aβ42 was abnormal more often than t-tau or HVa. Among the 298 subjects with both baseline and 12 month data, the proportion of subjects with abnormal Aβ42 did not change from baseline to 12 months in any group. The proportion of subjects with abnormal t-tau increased from baseline to 12 months in CN (p=0.05) but not in MCI or dementia. In 209 subjects with abnormal CSF AB42 at baseline, the percent abnormal HVa, but not t-tau, increased from baseline to 12 months in MCI.
Conclusions
Reduction in CSF Aβ42 denotes a pathophysiological process that significantly departs from normality (i.e., becomes dynamic) early, while t-tau and HVa are biomarkers of downstream pathophysiological processes. T-tau becomes dynamic before HVa, but HVa is more dynamic in the clinically symptomatic MCI and dementia phases of the disease than t-tau.
doi:10.1001/archneurol.2011.183
PMCID: PMC3387980  PMID: 21825215
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; CSF tau; CSF Abeta; Alzheimer’s disease staging
6.  Biomarkers in Alzheimer's Disease: A Review 
ISRN Pharmacology  2012;2012:984786.
Alzheimer's disease is the most common form of dementia affecting millions of individuals worldwide. It is currently diagnosed only via clinical assessments and confirmed by postmortem brain pathology. The development of validated biomarkers for Alzheimer's disease is essential to improve diagnosis and accelerate the development of new therapies. Biochemical and neuroimaging markers could facilitate diagnosis, predict AD progression from a pre-AD state of mild cognitive impairment (MCI), and be used to monitor efficacies of disease-modifying therapies. Cerebrospinal fluid (CSF) levels of Aβ40, Aβ42, total tau, and phosphorylated tau have diagnostic values in AD. Measurements of the above CSF markers in combination are useful in predicting the risk of progression from MCI to AD. New potential biomarkers are emerging, and CSF or plasma marker profiles may eventually become part of the clinician's toolkit for accurate AD diagnosis and management. These biomarkers along with clinical assessment, neuropsychological testing, and neuroimaging could achieve a much higher diagnostic accuracy for AD and related disorders in the future.
doi:10.5402/2012/984786
PMCID: PMC3395245  PMID: 22811931
7.  Diagnosing Alzheimer’s disease: are we any nearer to useful biomarker-based, non-invasive tests? 
Background: Alzheimer’s disease (AD) accounts for 60–80% of cases of dementia and causes significant morbidity in patients and carers, and expense for health and social services. There is a need for a validated, non-invasive and cheap test to diagnose early AD, as diagnosis may enable prompt treatment and service planning.
Aim: To identify emerging biomarker-based tests for the early diagnosis of AD which could be available for use in primary or generalist care in the near future.
Design: Horizon scanning review.
Methods: We searched online sources to identify emerging non-invasive, biomarker-based tests. Tests were included if they used blood, saliva or urine; and there was evidence of use in trials in patients with AD. For tests licensed for use in clinical or research settings we requested information from the developer on the intended place of use and plans for availability in Europe.
Results: We identified 6 biomarker-based tests of which 5 are available for research or clinical use. The closest to market were AclarusDX™ (ExonHit Therapeutics) a gene signature test, and INNO-BIA plasma Aβ forms assay (Innogenetics N.V.) which may be CE marked for clinical use in 2015. We found no evidence of clinical utility or cost.
Conclusion: Although biomarker-based tests are nearing clinical availability and may have a future role to help target AD-specific treatment and guide prognosis, they are not yet ready for trials of clinical utility in primary care.
doi:10.3205/hta000107
PMCID: PMC3677379  PMID: 23755087
Alzheimer's disease; diagnosis; biomarker; emerging health technology; primary health care; dementia
8.  Validation of new biomarkers in systemic autoimmune diseases 
Nature reviews. Rheumatology  2011;7(12):708-717.
Biomarkers have an important influence on the clinical decision-making processes involved in diagnosis, assessment of disease activity, allocation of treatment, and determining prognosis. The clinical usefulness of a biomarker is dependant on demonstration of its validity. Ideally, biomarkers should provide information not available from currently available tests and should be tested as they would be used in clinical practice; however, potential biomarkers could be affected by many different clinical or patient variables—such as disease activity, therapeutic intervention, or the presence of comorbidities—and validation studies might not include all the design features that are required to ensure that the biomarker is a true measure of the clinical process it is intended to reflect. In this Review, we appraise studies that have been conducted to validate six promising new biomarkers for diagnosis, disease activity assessment, or prognosis in patients with systemic autoimmune diseases. We discuss the validity of these six biomarkers with particular reference to the features of the studies that lend weight to or distract from their findings. The intent of this discussion is to draw attention to elements of validation study design that should be considered when evaluating the robustness of a biomarker, which differ according to the marker's intended use.
doi:10.1038/nrrheum.2011.157
PMCID: PMC3441180  PMID: 22045310
9.  Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria 
Background: Current research criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable.
Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD.
Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD.
Eligibility criteria: (1a) Systematic reviews with meta-analysis; (1b) Primary studies published after the new revised diagnostic criteria; (2) Evaluation of the diagnostic performance of at least one CSF core biomarker.
Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for mild cognitive impairment (MCI) prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia.
Limitations: (1) Use of clinical diagnosis as standard instead of pathological postmortem confirmation; (2) variability of methodological aspects; (3) insufficiently long follow-up periods in MCI studies; and (4) lower diagnostic accuracy in primary care compared with memory clinics.
Conclusion: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development.
doi:10.3389/fnagi.2014.00047
PMCID: PMC3970033  PMID: 24715863
Alzheimer’s disease; cerebrospinal fluid biomarkers; amyloid beta-protein (42); tau protein; sensitivity; specificity; meta-review; state-of-the-art review
10.  Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer's type 
Archives of neurology  2009;66(5):638-645.
Objective
Cerebrospinal fluid (CSF) levels of Aβ peptide 1-42 (Aβ42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer's disease (AD). We hypothesized that these biomarkers might predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT).
Design
Retrospective analysis of CSF biomarkers and clinical data.
Setting
An academic Alzheimer's Disease Research Center.
Participants
Research volunteers in a longitudinal study of aging and cognition. Participants (n=49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All participants had at least one follow-up assessment (mean years of follow-up = 3.5 ± 1.8 years).
Main outcome measures
Baseline CSF levels of Aβ42, Aβ40, tau and tau phosphorylated at threonine 181 (ptau181), rate of dementia progression as measured by CDR-sum of boxes (CDR-SB) and by psychometric performance,
Results
The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Aβ42, with higher tau or ptau181, or high tau/Aβ42 ratio. For example, the annual change in CDR-SB was 1.1 for the lowest two tertiles of Aβ42 values and 0.3 for the highest tertile of Aβ42 values.
Conclusions
In individuals with very mild DAT, lower CSF Aβ42, high tau or ptau181, or a high tau/Aβ42 ratio quantitatively predict more rapid progression of cognitive deficits and dementia. CSF biomarkers may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.
doi:10.1001/archneurol.2009.55
PMCID: PMC2759394  PMID: 19433664
amyloid beta; Aβ; tau; biomarker; dementia progression
11.  Predicting AD Conversion: Comparison between Prodromal AD Guidelines and Computer Assisted PredictAD Tool 
PLoS ONE  2013;8(2):e55246.
Purpose
To compare the accuracies of predicting AD conversion by using a decision support system (PredictAD tool) and current research criteria of prodromal AD as identified by combinations of episodic memory impairment of hippocampal type and visual assessment of medial temporal lobe atrophy (MTA) on MRI and CSF biomarkers.
Methods
Altogether 391 MCI cases (158 AD converters) were selected from the ADNI cohort. All the cases had baseline cognitive tests, MRI and/or CSF levels of Aβ1–42 and Tau. Using baseline data, the status of MCI patients (AD or MCI) three years later was predicted using current diagnostic research guidelines and the PredictAD software tool designed for supporting clinical diagnostics. The data used were 1) clinical criteria for episodic memory loss of the hippocampal type, 2) visual MTA, 3) positive CSF markers, 4) their combinations, and 5) when the PredictAD tool was applied, automatically computed MRI measures were used instead of the visual MTA results. The accuracies of diagnosis were evaluated with the diagnosis made 3 years later.
Results
The PredictAD tool achieved the overall accuracy of 72% (sensitivity 73%, specificity 71%) in predicting the AD diagnosis. The corresponding number for a clinician’s prediction with the assistance of the PredictAD tool was 71% (sensitivity 75%, specificity 68%). Diagnosis with the PredictAD tool was significantly better than diagnosis by biomarkers alone or the combinations of clinical diagnosis of hippocampal pattern for the memory loss and biomarkers (p≤0.037).
Conclusion
With the assistance of PredictAD tool, the clinician can predict AD conversion more accurately than the current diagnostic criteria.
doi:10.1371/journal.pone.0055246
PMCID: PMC3570420  PMID: 23424625
12.  Cerebrospinal fluid biomarkers of Alzheimer’s disease 
Biomarkers in medicine  2010;4(1):51-63.
Alzheimer’s disease will reach epidemic proportions within the next 20–30 years if left unchecked. Currently, there are no treatments that prevent or slow Alzheimer’s disease but many are being developed. Parallel efforts to develop biomarkers to aid in disease diagnosis and prognosis, and assess disease risk are currently underway. Clinicopathological and biomarker studies have demonstrated that Alzheimer’s disease pathology can be detected preclinically. Using biomarkers to identify affected individuals prior to the onset of clinical symptoms and associated synaptic/neuronal loss should enable novel clinical trial design and early mechanism-based therapeutic intervention. This article summarizes the most promising cerebrospinal fluid biomarkers, highlights novel applications and current challenges, and provides a prediction on how the field may evolve in 5–10 years.
doi:10.2217/BMM.09.83
PMCID: PMC2846664  PMID: 20361010
Alzheimer’s disease; amyloid-β; biomarkers; cerebrospinal fluid; preclinical Alzheimer’s disease; tau
13.  Biomarker-based diagnosis of mild cognitive impairment due to Alzheimer’s disease: how and what to tell. A kickstart to an ethical discussion 
New criteria for the diagnosis of Alzheimer’s disease (AD) based on biomarker results have recently been developed and are currently undergoing extensive validation. The next few years may represent a time window where the diagnostic validity of biomarkers will be studied in highly specialized research settings. Biomarkers results will be used to direct clinical diagnosis and, whenever appropriate, therapy and management. This piece aims to stimulate discussion by identifying the ethical challenges involved in the use of biomarkers to make a diagnosis of mild cognitive impairment due to AD and disclose it to patients. At the individual level, these challenges are related to (i) the ethical appropriateness of implementing an ecological diagnostic research protocol, (ii) the related informed consent process, and (iii) the diagnostic disclosure. We justify the ethical legitimacy of implementing a research diagnostic protocol by referring to the respect of patients’ subjectivity and autonomy, and we suggest guidelines for informed consent development and diagnostic disclosure. All of the above points are discussed in light of the unique features of AD, currently scanty treatment options, and knowledge and uncertainties regarding the diagnostic value of biomarkers.
doi:10.3389/fnagi.2014.00041
PMCID: PMC3959740  PMID: 24678299
prodromal Alzheimer’s disease; informed consent; diagnosis disclosure; translational research; bioethics guideline
14.  Preclinical Evidence of Alzheimer Changes: Convergent Cerebrospinal Fluid Biomarker and Fluorodeoxyglucose Positron Emission Tomography Findings 
Archives of neurology  2009;66(5):632-637.
Background
Alterations in cerebrospinal fluid (CSF) tau and β–amyloid peptide 1–42 (Aβ42) levels and rates of cerebral glucose (CMRglu) on fluorodeoxyglucose positron emission tomography (FDG PET) occur years before clinical symptoms of Alzheimer’s disease (AD) become manifest, but their relationship remains unclear.
Objective
To determine whether CSF AD biomarker levels and CMRglu in healthy individuals correlate in brain structures affected early in AD.
Design
Cohort study.
Setting
Alzheimer’s disease research center.
Participants
Twenty individuals without dementia, aged 46 to 83 years.
Interventions
Lumbar CSF sampling and FDG-PET imaging of CMRglu. The CSF Aβ42, tau, and tau phosphorylated at threonine 181 (p–tau181) levels were measured using immunobead–based multiplex assays.
Main Outcome Measures
Correlations between CMRglu and CSF biomarker levels were analyzed via voxel–based and volume–of–interest approaches.
Results
Voxel–based analyses demonstrated significant negative correlations between CSF tau and p–tau181 levels and CMRglu in the posterior cingulate, precuneus, and parahippocampal regions. In contrast, a limited positive correlation was found between CSF Aβ42 levels and CMRglu in the inferior temporal cortex. Volume–of–interest analyses confirmed negative associations between CSF tau and p–tau181 levels and CMRglu in the parietal and medial parietal lobes and a positive association between CSF Aβ42 levels and CMRglu in the parahippocampal gyrus.
Conclusions
In healthy individuals, higher CSF tau and p–tau181 concentrations were associated with more severe hypometabolism in several brain regions affected very early in AD, whereas lower CSF Aβ42 concentrations were associated with hypometabolism only in the medial temporal lobe. This suggests that early tau and Aβ abnormalities may be associated with subtle synaptic changes in brain regions vulnerable to AD. A longitudinal assessment of CSF and FDG–PET biomarkers is needed to determine whether these changes predict cognitive impairment and incipient AD.
doi:10.1001/archneurol.2009.59
PMCID: PMC2718788  PMID: 19433663
15.  Con: Can biomarkers be gold standards in Alzheimer's disease? 
As Alzheimer's disease remains a clinical diagnosis, and as clinical diagnosis can be difficult, it makes sense to look for so-called biomarkers. A biomarker predicts who is likely to have the illness and who is not. Some biomarkers might even correlate with a clinically meaningful response to treatment. Developing biomarkers is often characterized as searching for a diagnostic gold standard that can seem appealing in its promise of certainty. Even so, considering both the economic history of the gold standard and the results of neuropathological studies, framing the search for measurable, biological correlates of dementia syndromes in this way is likely to be self-defeating. Instead of considering biomarkers as providing certainty through referent criterion validation, currently it makes more sense to test their construct validity and their predictive ability. This means that while biomarkers should inform, they will not dictate clinical meaningfulness. For the foreseeable future, even were they to inform diagnosis, biomarkers cannot substitute for understanding whether patients and caregivers find a given dementia treatment effective. Instead, clinicians should recognize their own determining role, both in dementia diagnosis and in the evaluation of treatment. These roles will best be executed by hearing what patients and caregivers tell us about dementia, and its response to treatment.
doi:10.1186/alzrt40
PMCID: PMC2919696  PMID: 20587007
16.  Validation of Consensus Panel Diagnosis in Dementia 
Archives of neurology  2010;67(12):1506-1512.
Background
The clinical diagnosis of dementing diseases largely depends upon the subjective interpretation of patient symptoms. Consensus panels are frequently used in research to determine diagnoses when definitive pathological findings are unavailable. Nevertheless, research on group decision-making indicates many factors can adversely influence panel performance.
Objective
To determine conditions that improve consensus panel diagnosis.
Design
Comparison of neuropathological diagnoses with individual and consensus panel diagnoses based on clinical summaries, FDG-PET scans, and summaries with scans.
Setting
Expert and trainee individual and consensus panel deliberations using a modified Delphi method in a pilot research study of the diagnostic utility of FDG-PET imaging.
Patients and Methods
Forty-five patients with pathologically confirmed Alzheimer’s disease or frontotemporal dementia. Statistical measures of diagnostic accuracy, agreement, and confidence for individual raters and panelists before and after consensus deliberations.
Results
The consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive rather than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules.
Conclusions
Using a modified Delphi protocol to arrive at a consensus diagnosis is a reasonable substitute for pathologic information. This protocol improves diagnostic accuracy and certainty when panelist judgments differ and is easily adapted to other research and clinical settings while avoiding potential pitfalls of group decision-making.
doi:10.1001/archneurol.2010.301
PMCID: PMC3178413  PMID: 21149812
17.  Can peripheral leukocytes be used as Alzheimer’s disease biomarkers? 
Expert review of neurotherapeutics  2009;9(11):1623-1633.
Alzheimer’s disease (AD) is the leading cause of dementia in elderly populations throughout the world and its incidence is on the rise. Current clinical diagnosis of AD requires intensive examination that includes neuropsychological testing and costly brain imaging techniques, and a definitive diagnosis can only be made upon postmortem neuropathological examination. Additionally, antemortem clinical AD diagnosis is typically administered following onset of cognitive and behavioral symptoms. As these symptoms emerge relatively late in disease progression, therapeutic intervention occurs after significant neurodegeneration, thereby limiting efficacy. The identification of noninvasive diagnostic biomarkers of AD is becoming increasingly important to make diagnosis more widely available to clinics with limited access to neuropsychological testing or state-of-the-art brain imaging, reduce the cost of clinical diagnosis, provide a biological measure to track the course of therapeutic intervention, and most importantly, allow for earlier diagnosis – possibly even during the prodromal phase – with hopes of therapeutic intervention prior to appreciable neurodegeneration. Circulating leukocytes are attractive candidate AD biomarkers as they can be obtained in a minimally invasive manner and are easily analyzed by widely available flow cytometry techniques. In this review, we critically analyze the potential utility of peripheral leukocytes as biological markers for AD.
doi:10.1586/ern.09.118
PMCID: PMC2828773  PMID: 19903022
autoantibody; B lymphocyte; biological marker; cytokine; dementia; dendritic cell; granulocyte; immune; inflammation; macrophage; monocyte; natural killer cell; polymorphonuclear cell; T lymphocyte
18.  Biological markers of amyloid β-related mechanisms in Alzheimer’s disease 
Experimental neurology  2009;223(2):334-346.
Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer’s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid β (Aβ) production and aggregation. In drug development, it is important to co-develop biomarkers for Aβ-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Aβ isoforms (Aβ40/Aβ42), soluble APP isoforms, Aβ oligomers and β-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Aβ-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.
doi:10.1016/j.expneurol.2009.09.024
PMCID: PMC2896007  PMID: 19815015
Alzheimer’s disease (AD); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Amyloid β-peptide (Aβ); Amyloid precursor protein (APP); Biochemical markers; Biomarkers; β-Site APP-cleaving enzyme 1 (BACE1); Cerebrospinal fluid (CSF); Diagnosis; Drug development; Mild cognitive impairment (MCI); Mechanism of action; Neurochemistry; Oligomers; Plasma; Pre-clinical; Prediction; Presymptomatic; Stratification; US Food and Drug Administration (FDA); European Medicines Agency (EMEA)
19.  Neurochemical biomarkers in Alzheimer’s disease and related disorders 
Neurochemical biomarkers for diagnosing dementias are currently under intensive investigation and the field is rapidly expanding. The main protagonists and the best defined among them are cerebrospinal fluid levels of Aβ42, tau and its phosphorylated forms (p-tau). In addition, novel cerebrospinal fluid biomarkers are emerging and their multiparametric assessment seems most promising for increasing the accuracy in neurochemical dementia diagnostics. The combined assessment of Aβ42 and p-tau has recently shown value for diagnosing prodromal states of Alzheimer’s dementia, that is, mild cognitive impairment. Disease-specific biomarkers for other degenerative dementias are still missing, but some progress has recently been made. As lumbar puncture is an additional burden for the patient, blood-based neurochemical biomarkers are definitely warranted and promising new discoveries have been made in this direction. These diagnostic developments have implicit therapeutic consequences and give rise to new requirements for future neurochemical dementia diagnostics.
doi:10.1177/1756285612455367
PMCID: PMC3487531  PMID: 23139704
Alzheimer’s disease; biomarker; blood; cerebrospinal fluid; dementia
20.  Cerebrospinal Fluid Aβ and Tau Level Fluctuation in an Older Clinical Cohort 
Archives of Neurology  2012;69(2):246-250.
Objective
To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals.
Design
Biomarker validation in a clinical cohort.
Setting
University hospital inpatient unit.
Participants
Ten patients admitted for CSF drainage for diagnostic purposes.
Main Outcome Measures
The CSF levels of Aβ1–40, Aβ1–42, tau, and phosphorylated tau on threonine 181 (p-tau181) were measured every 6 hours for 24 or 36 hours.
Results
The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%–10.0%) for Aβ1–42, 12.2% (9.0%–24.2%) for Aβ1–40, 8.2% (5.7%–15.1%) for total tau, and 11.9% (8.5%–23.0%) for p-tau181. These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency.
Conclusion
In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.
doi:10.1001/archneurol.2011.732
PMCID: PMC3310240  PMID: 22332192
21.  Beyond PSA: The next generation of prostate cancer biomarkers 
Science translational medicine  2012;4(127):127rv3.
Since the introduction of serum prostate specific antigen (PSA) screening twenty-five years ago, prostate cancer diagnosis and management have been guided by this biomarker. Yet, PSA has proven controversial as a diagnostic assay due to its limitations. The next wave of prostate cancer biomarkers has emerged, introducing new assays in serum and urine that may supplement or, in time, replace PSA due to higher cancer specificity. This expanding universe of biomarkers has been facilitated, in large part, by new genomic technologies that have enabled an unbiased look at cancer biology. Such efforts have produced several notable success stories, moving biomarkers from the bench to the clinic rapidly. However, biomarker research has centered on disease diagnostics, rather than prognosis and prediction, which could work toward disease prevention—an important focus moving forward. We review the current state of prostate cancer biomarker research, including the PSA revolution, its impact on early prostate cancer detection, the recent advances in biomarker discovery, and the future efforts that promise to improve clinical management of this disease.
doi:10.1126/scitranslmed.3003180
PMCID: PMC3799996  PMID: 22461644
22.  Shapes of the Trajectories of Five Major Biomarkers of Alzheimer’s Disease 
Archives of neurology  2012;69(7):856-867.
Objective
To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.
Design
Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Patients
Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.
Main Outcome Measures
The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).
Results
Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.
Conclusions
Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.
doi:10.1001/archneurol.2011.3405
PMCID: PMC3595157  PMID: 22409939
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; cerebro spinal fluid; amyloid PET imaging; FDG PET imaging
23.  Multiplex assessment of a panel of 16 serum molecules for the differential diagnosis of Alzheimer’s disease 
One of the current challenge in Alzheimer’s disease (AD) is the identification of reliable biomarkers that might improve diagnostic accuracy, possibly correlating with the disease progression and patient’s response to therapy. As the clinically validated AD biomarkers evaluate cerebrospinal fluid (CSF) parameters, the need for less invasive diagnostic markers is well evident. To this respect, blood circulating cytokines or growth factors have provided some encouraging results, even though no clinically validated to date. In 2007 Ray et al suggested a panel of 18 circulating molecules that might increase AD diagnostic accuracy. In an attempt of replicating their data, we designed a multiplex fluorimetric assay comprising 16 independent analytes and covering 15 out of the 18 described proteins. We collected serum samples from three diagnostic groups: probable AD (n=33), matched healthy controls (CNT, n=23) and non AD demented (NAD, n=14). After correction for age, we found an increased level of EGF-1 in AD in comparison to CNT and NAD, while an increase of TRAIL-R4 was found in NAD. However, evaluation of specificity/sensitivity by ROC curve analysis gave weak evidence of diagnostic accuracy (area under the curve = 0.63 and 0.66 for EGF and TRAIL-R4, respectively). Finally, we tried to find a diagnostic classifier by a multivariate algorithm. We found indication of diagnostic evidence for AD only, while NAD samples did not show a diagnostic pattern.
PMCID: PMC3601470  PMID: 23515357
Alzheimer’s disease; diagnosis; peripheral biomarkers; multiplex analysis; EGF-1; multivariate classifier; machine learning; artificial neural networks
24.  Mechanistic biomarkers for clinical decision making in rheumatic diseases 
Nature reviews. Rheumatology  2013;9(5):267-276.
The use of biomarkers is becoming increasingly intrinsic to the practice of medicine and holds great promise for transforming the practice of rheumatology. Biomarkers have the potential to aid clinical diagnosis when symptoms are present or to provide a means of detecting early signs of disease when they are not. Some biomarkers can serve as early surrogates of eventual clinical outcomes or guide therapeutic decision making by enabling identification of individuals likely to respond to a specific therapy. Using biomarkers might reduce the costs of drug development by enabling individuals most likely to respond to be enrolled in clinical trials, thereby minimizing the number of participants required. In this Review, we discuss the current use and the potential of biomarkers in rheumatology and in select fields at the forefront of biomarker research. We emphasize the value of different types of biomarkers, addressing the concept of ‘actionable’ biomarkers, which can be used to guide clinical decision making, and ‘mechanistic’ biomarkers, a subtype of actionable biomarker that is embedded in disease pathogenesis and, therefore, represents a superior biomarker. We provide examples of actionable and mechanistic biomarkers currently available, and discuss how development of such biomarkers could revolutionize clinical practice and drug development.
doi:10.1038/nrrheum.2013.14
PMCID: PMC3673766  PMID: 23419428
25.  Role of family history for Alzheimer biomarker abnormalities in the adult children study 
Archives of Neurology  2011;68(10):1313-1319.
Objective
To assess whether family history (FH) of Alzheimer’s disease (AD) alone influences AD biomarker abnormalities.
Design
Adult Children Study (ACS).
Setting
Washington University's Knight Alzheimer's Disease Research Center.
Participants
Cognitively normal middle to older age individuals with and without a FH for AD (n=269).
Main Outcome Measures
Clinical and cognitive measures, magnetic resonance imaging (MRI)-based brain volumes, diffusion tensor imaging (DTI)-based white matter microstructure, cerebrospinal fluid (CSF) biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound-B (PIB).
Results
A positive FH for AD was associated with an age-related decrease of CSF Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted CSF Aβ42 was decreased for individuals with APOE4 compared with those without, and the decrease was larger for individuals with a positive FH compared with those without. The variation of CSF tau and PIB mean cortical binding potential (MCBP) increased by age. For individuals younger than 55, an age-related increase in MCBP was associated with APOE4, but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in MCBP. A positive FH was associated with decreased fractional anisotropy from DTI in the genu and splenium of the corpus callosum.
Conclusion
Independent of APOE4, FH is associated with age-related change of several CSF, PIB and DTI biomarkers in cognitively normal middle to older age individuals, suggesting that non-APOE susceptibility genes for AD influence AD biomarkers.
doi:10.1001/archneurol.2011.208
PMCID: PMC3327304  PMID: 21987546

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