Biomarker Commons

The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception.

Alzheimers Dement. 2012 Feb;8(1 Suppl):S1-68

Authors: Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ,

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 study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. 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 consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers 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 combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) 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; (5) 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. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI 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 (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.

PMID: 22047634 [PubMed - indexed for MEDLINE]

Human serum transthyretin levels correlate inversely with Alzheimer's disease.

J Alzheimers Dis. 2011;25(1):77-84

Authors: Han SH, Jung ES, Sohn JH, Hong HJ, Hong HS, Kim JW, Na DL, Kim M, Kim H, Ha HJ, Kim YH, Huh N, Jung MW, Mook-Jung I

Abstract
Alzheimer's disease (AD) is the fastest growing neurodegenerative disease in the elderly population, and the search for therapeutic targets and diagnostic AD biomarkers is an exigent issue. Because amyloid-β (Aβ) aggregation constitutes the epicenter of AD pathology, Aβ-binding proteins that regulate Aβ aggregation, such as transthyretin (TTR), have attracted much attention. TTR binds to Aβ, prevents its aggregation, and consequently inhibits Aβ-induced cellular toxicity. Decreased TTR levels in cerebrospinal fluid (CSF) from AD patients suggest that TTR is a biomarker of AD. But, studies on TTR as a biomarker have focused on CSF; no study has evaluated peripheral levels of TTR in AD. Here, we examined the relationship between serum TTR levels and AD. We measured TTR levels in serum samples from 90 nondemented controls and 111 AD patients and observed significantly lower serum TTR levels in AD (p < 0.001). Notably, females in the control group had lower serum TTR levels compared with male in the control (p = 0.006), while no difference in gender was noted in the AD group. There were no age-related changes in serum TTR levels. Thus, this study demonstrates a clear negative correlation between serum TTR levels and AD, suggesting that TTR is not only involved in AD pathological process but also suggested as possible peripheral biomarker for AD diagnosis in serum level.

PMID: 21335655 [PubMed - indexed for MEDLINE]

Reduced levels of IgM autoantibodies against N-truncated pyroglutamate Aβ in plasma of patients with Alzheimer's disease.

Neurobiol Aging. 2011 Aug;32(8):1379-87

Authors: Marcello A, Wirths O, Schneider-Axmann T, Degerman-Gunnarsson M, Lannfelt L, Bayer TA

Abstract
In the present work, we investigated the level of IgM autoantibodies directed against different Aβ epitopes as potential diagnostic biomarker for Alzheimer's disease (AD). Anti-Aβ autoantibody levels were measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To validate the presence of anti-Aβ IgMs, pooled plasma samples were subjected to gel-filtration analysis. The mean level of pGluAβ-IgM (N-terminal truncated starting at position three with pyroglutamate) was significantly decreased in AD patients as compared to HC. In the group of MCI patients there was a significant positive correlation between pGluAβ-IgM and cognitive decline analyzed by MMSE (rho = 0.58, d.f. = 13, p = 0.022). These observations indicate that the level of IgM autoantibodies against pGluAβ is a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk to develop AD.

PMID: 19781815 [PubMed - indexed for MEDLINE]

[Predementia Alzheimer's disease. Benefits of early diagnosis].

Rev Esp Geriatr Gerontol. 2011 Oct;46 Suppl 1:47-54

Authors: Viloria A

Abstract
Given population aging and the rise in the number of persons with Alzheimer's disease, measures that aim not only to delay but also to prevent the development of this disease are increasingly required. Advances in the diagnosis of Alzheimer's disease support the need for a review of current clinical standards for mild cognitive impairment and provide new goals in the early treatment of this disease. The current diagnostic process should be refocussed toward the pathological substrate of this disease rather than symptoms in order to initiate therapeutic measures as soon as possible without waiting for clinical manifestations to appear. Such an approach is essential in patients with greater cognitive reserve, in whom the lesions are usually more severe at diagnosis and treatment is less effective. To identify disease-modifying therapies to delay the onset of the clinical symptoms of Alzheimer's disease in cognitively intact persons at high risk, biomarkers for this disease must be validated. A single biomarker is unlikely to provide the required diagnostic accuracy and therefore a multimodal approach, incorporating biochemical, neuropathological and anatomical and metabolic neuroimaging methods, should be employed. To optimize the results of drugs under investigation, a combination of biomarkers should be used to select appropriate participants in the earliest phases of the disease, and disease progression should be followed-up. Early diagnosis might clarify essential questions in the care of patients with Alzheimer's disease, such as the possibility of distinguishing among various subtypes, thus encouraging the development of optimal treatments for each. The ultimate goal is to develop disease-modifying treatments that could be initiated early, while patients are asymptomatic or only minimally symptomatic, to maintain their quality of life.

PMID: 22152916 [PubMed - indexed for MEDLINE]

Effects of Alzheimer's disease transgenes on neurochemical expression in the mouse brain determined by ¹H MRS in vitro.

NMR Biomed. 2012 Jan;25(1):52-8

Authors: Forster DM, James MF, Williams SR

Abstract
Transgenic models of human disease can be used to understand pathology and to discover biomarkers of disease presence, progression and response to therapy. Here we report a study of longitudinal metabolic differences between TASTPM transgenic Alzheimer's disease (AD) mice and their wild type counterparts using (1)H magnetic resonance spectroscopy (MRS) to look for potential biomarkers for use in AD research and drug discovery. Chloroform methanol extractions were performed on the brains of mice aged between 3 and 18 months. (1)H MR spectra were recorded from the aqueous fractions. Absolute metabolite concentrations, determined from resonance integrals relative to an internal standard, were analysed by 2-way ANOVA (genotype x age). Significant effects of age alone were identified for creatine, glutamine and total choline-containing compounds. There was a marked increase in creatine in the oldest (15-18 mo) TASTPM mice. The increase in creatine was unexpected and may be caused by osmotic stress in older animals as plaque load increases. Care should be taken when using creatine as a reference metabolite during scans of these animals in vivo. A significant effect of genotype alone was identified for myo-inositol (MI), which was higher in TASTPM mice at all ages. Succinate, glycerophosphocholine and choline all showed significant effects of age and genotype. No significant effects were detected in N-acetylaspartate (NAA) levels. Increased MI could be a marker of gliosis or microglial activation in TASTPM mice, but the absence of an age dependence for MI levels means it may be a biomarker of disease, but not of disease progression. Decreased succinate is indicative of disrupted neuronal energy metabolism, an effect that has been seen in human AD.

PMID: 22241671 [PubMed - indexed for MEDLINE]

Coordinated increase of γ-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer's disease patients: quantitative analysis of p3-Alcα with a new ELISA system.

Mol Neurodegener. 2011;6:76

Authors: Konno T, Hata S, Hamada Y, Horikoshi-Sakuraba Y, Nakaya T, Saito Y, Yamamoto T, Yamamoto T, Maeda M, Ikeuchi T, Gandy S, Akatsu H, Suzuki T,

Abstract
BACKGROUND: Aggregatable amyloid β-peptide (Aβ) and non-aggregatable p3-Alcα are metabolic products of the γ-secretase cleavage of amyloid β-protein precursor (APP) and Alcadeinα (Alcα), respectively. Familial AD (FAD) -linked mutations in the presenilin 1 or 2 (PS1 or PS2) component of γ-secretase can cause alternative intramembranous processing of APP and Alcα, leading to a coordinated generation of variants of both Aβ and p3-Alcα. Variant Alcα peptides have been observed in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and sporadic Alzheimer's disease (AD). Since, like APP, Alcα is largely expressed in brain, one might predict that alternative processing of Alcα would be reflected in body fluids of some AD patients. These patients with misprocessing of multiple γ-secretase substrates might define an endophenotype of p3-Alcα, in whom AD is due either to dysfunction of γ-secretase or to a disorder of the clearance of hydrophobic peptides such as those derived from transmembrane domains.
RESULTS: We developed a simple procedure for extraction of p3-Alcα from plasma and for analyzing this extract in a sensitive, p3-Alcα-specific sandwich enzyme-linked immunosorbent assay (ELISA) system. Plasma p3-Alcα levels and Aβ40 levels were examined in sporadic AD subjects from two independent Japanese cohorts. In some of these patients, levels of plasma p3-Alcα were significantly higher, and were accompanied by parallel changes in Aβ40 levels. This AD-related difference was more marked in female subjects, but this phenomenon was not observed in subjects with frontotemporal lobar degeneration (FTLD).
CONCLUSION: Reagents and procedures have been established that enable extraction of p3-Alcα from plasma and for quantification of plasma p3-Alcα levels by ELISA. Some populations of AD subjects apparently show increased levels of both p3-Alcα and Aβ40. Quantification of p3-Alcα level may be useful as a readily accessible biomarker for a population of sporadic AD patients in which disease pathogenesis is associated with either dysfunction of γ-secretase or with a disorder of the clearance of transmembrane domain-derived peptides.

PMID: 22067061 [PubMed - indexed for MEDLINE]

Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease.

Neurology. 2012 Feb 21;78(8):569-77

Authors: Watabe-Rudolph M, Song Z, Lausser L, Schnack C, Begus-Nahrmann Y, Scheithauer MO, Rettinger G, Otto M, Tumani H, Thal DR, Attems J, Jellinger KA, Kestler HA, von Arnim CA, Rudolph KL

Abstract
OBJECTIVE: DNA damage accumulation in brain is associated with the development of Alzheimer disease (AD), but newly identified protein markers of DNA damage have not been evaluated in the diagnosis of AD and other forms of dementia.
METHODS: Here, we analyzed the level of novel biomarkers of DNA damage and telomere dysfunction (chitinase activity, N-acetyl-glucosaminidase activity, stathmin, and EF-1α) in CSF of 94 patients with AD, 41 patients with non-AD dementia, and 40 control patients without dementia.
RESULTS: Enzymatic activity of chitinase (chitotriosidase activity) and stathmin protein level were significantly increased in CSF of patients with AD and non-AD dementia compared with that of no dementia control patients. As a single marker, chitinase activity was most powerful for distinguishing patients with AD from no dementia patients with an accuracy of 85.8% using a single threshold. Discrimination was even superior to clinically standard CSF markers that showed an accuracy of 78.4% (β-amyloid) and 77.6% (tau). Combined analysis of chitinase with other markers increased the accuracy to a maximum of 91%. The biomarkers of DNA damage were also increased in CSF of patients with non-AD dementia compared with no dementia patients, and the new biomarkers improved the diagnosis of non-AD dementia as well as the discrimination of AD from non-AD dementia.
CONCLUSIONS: Taken together, the findings in this study provide experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. The biomarkers identified outperformed the standard CSF markers for diagnosing AD and non-AD dementia in the cohort investigated.

PMID: 22323746 [PubMed - indexed for MEDLINE]

Use of biomarkers in clinical trials of Alzheimer disease: from concept to application.

Mol Diagn Ther. 2011 Dec 1;15(6):313-25

Authors: Wu L, Rosa-Neto P, Gauthier S

Abstract
Research progress during the last decades has resulted in an unprecedented accumulation of knowledge regarding the molecular pathogenesis of Alzheimer disease (AD). These important achievements toward clarifying the mechanistic processes underlying AD are being translated into ongoing development of biomarkers and their use in clinical trials. AD biomarkers are biochemical and anatomical variables (e.g. cerebrospinal fluid, positron emission tomography, and structural MRI) that measure AD-related pathologic features (i.e. amyloid deposition and neurodegeneration) in vivo. Biomarkers are utilized as 'diagnostic biomarkers' and/or 'endpoint biomarkers' in symptomatic or disease-modifying clinical trials. Diagnostic biomarkers play an important role in population enrichment by refining selection criteria, stratifying populations, and increasing the statistical power of trials. Endpoint biomarkers may be used as outcome measures to monitor the rate of disease progression and detect treatment effects. AD biomarkers do not reach abnormal levels or peak simultaneously, but do so in a time-dependent order. The choice of biomarkers for a clinical trial must take into consideration the type of therapeutic intervention, the clinical stage of AD, and the time dependence of biomarker changes during disease progression. The combination of amyloid and neurodegeneration biomarkers is highly desirable since they capture different aspects of the disease. Clinical trials for every clinical stage of AD would benefit from quantification and standardization of biomarkers. However, this is still a work in progress.

PMID: 22188635 [PubMed - indexed for MEDLINE]

Endogenous conversion of omega-6 into omega-3 fatty acids improves neuropathology in an animal model of Alzheimer's disease.

J Alzheimers Dis. 2011;27(4):853-69

Authors: Lebbadi M, Julien C, Phivilay A, Tremblay C, Emond V, Kang JX, Calon F

Abstract
Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) and tau pathology and improves cognitive performance in animal models of Alzheimer's disease (AD). To exclude confounding variables associated with the diet, we crossed 3 × Tg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.001), including docosahexaenoic acid (DHA; +5%, p < 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels of soluble Aβ₄₂ (-41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ₄₀ and Aβ₄₂ in the brain of 3 × Tg-AD mice. The 3 × Tg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (-25%, p < 0.05) and insoluble phosphorylated tau (-55%, p < 0.05) compared to 3 × Tg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3 × Tg-AD/Fat-1 mice (-039%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, cyclin-dependent kinase 5, or protein phosphatase type 2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (-37%, p < 0.01) observed in 20 month-old 3 × Tg-AD mice. In conclusion, the expression of fat-1 in 3 × Tg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology.

PMID: 21914946 [PubMed - indexed for MEDLINE]

Homocysteine, vitamin B12, and folic acid levels in Alzheimer's disease, mild cognitive impairment, and healthy elderly: baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study.

J Alzheimers Dis. 2011;27(4):909-22

Authors: Faux NG, Ellis KA, Porter L, Fowler CJ, Laws SM, Martins RN, Pertile KK, Rembach A, Rowe CC, Rumble RL, Szoeke C, Taddei K, Taddei T, Trounson BO, Villemagne VL, Ward V, Ames D, Masters CL, Bush AI

Abstract
There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.

PMID: 21891867 [PubMed - indexed for MEDLINE]

Cerebrospinal fluid biomarkers in Progranulin mutations carriers.

J Alzheimers Dis. 2011;27(4):781-90

Authors: Carecchio M, Fenoglio C, Cortini F, Comi C, Benussi L, Ghidoni R, Borroni B, De Riz M, Serpente M, Cantoni C, Franceschi M, Albertini V, Monaco F, Rainero I, Binetti G, Padovani A, Bresolin N, Scarpini E, Galimberti D

Abstract
Cerebrospinal fluid (CSF) biomarkers (Aβ₁₋₄₂, total tau, P-181 tau) are currently used to support a clinical diagnosis of Alzheimer's disease (AD). The CSF profile in frontotemporal lobar degeneration (FTLD) caused by Progranulin (GRN) mutation is unknown. We assessed CSF biomarkers in 145 AD, 140 FTLD (20 GRN positive, 120 GRN negative) patients, and 38 controls. Taking into account the reference values used in clinical practice, GRN mutation carriers and controls did not differ significantly for any biomarker, whereas GRN negative FTLD patients had higher tau levels than controls (p < 0.001) and patients carrying GRN Thr272fs mutation (p = 0.033, Chi-Square test). Comparing CSF biomarkers mean values among groups, total tau was significantly increased in GRN negative FTLD and in mutation carriers compared with controls (p < 0.001). P-181 tau CSF was increased in AD patients and in GRN negative FTLD compared with controls (p < 0.001), but not in 17 patients carrying the Thr272fs mutation. 88.2% of mutation carriers had normal CSF tau, despite the neurodegenerative nature of FTLD. Our results suggest that GRN mutation carriers have normal or borderline CSF biomarkers. In patients with an AD-like phenotype but normal or borderline CSF biomarkers, a diagnosis of FTLD-U caused by GRN mutations should be considered.

PMID: 21891865 [PubMed - indexed for MEDLINE]

Amyloid-β toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease.

J Alzheimers Dis. 2011;27(4):701-9

Authors: Lloret A, Badia MC, Giraldo E, Ermak G, Alonso MD, Pallardó FV, Davies KJ, Viña J

Abstract
Amyloid-β peptide (Aβ) toxicity and tau hyperphosphorylation are hallmarks of Alzheimer's disease (AD). How their molecular relationships may affect the etiology, progression, and severity of the disease, however, has not been elucidated. We now report that incubation of fetal rat cortical neurons with Aβ upregulates expression of the Regulator of Calcineurin gene RCAN1, and this is mediated by Aβ-induced oxidative stress. Calcineurin (PPP3CA) is a serine-threonine phosphatase that dephosphorylates tau. RCAN1 proteins inhibit this phosphatase activity of calcineurin. Increased expression of RCAN1 also causes upregulation of glycogen synthase kinase-3β (GSK3β), a tau kinase. Thus, increased RCAN1 expression might be expected to decrease phospho-tau dephosphorylation (via calcineurin inhibition) and increase tau phosphorylation (via increased GSK3β activity). Indeed, we find that incubation of primary cortical neurons with Aβ results in increased phosphorylation of tau, unless RCAN1 gene expression is silenced, or antioxidants are added. Thus we propose a mechanism to link Aβ toxicity and tau hyperphosphorylation in AD: In our hypothesis, Aβ causes mitochondrial oxidative stress and increases production of reactive oxygen species, which result in an upregulation of RCAN1 gene expression. RCAN1 proteins then both inhibit calcineurin and induce expression of GSK3β. Both mechanisms shift tau to a hyperphosphorylated state. We also find that lymphocytes from persons whose ApoE genotype is ε4/ε4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE ε3/ε3 or ε3/ε4 genotypes. Thus upregulation of RCAN1 may be a valuable biomarker for AD risk.

PMID: 21876249 [PubMed - indexed for MEDLINE]

Parietal cortex matters in Alzheimer's disease: an overview of structural, functional and metabolic findings.

Neurosci Biobehav Rev. 2012 Jan;36(1):297-309

Authors: Jacobs HI, Van Boxtel MP, Jolles J, Verhey FR, Uylings HB

Abstract
Atrophy of the medial temporal lobe, especially the hippocampus and the parahippocampal gyrus, is considered to be the most predictive structural brain biomarker for Alzheimer's Dementia (AD). However, recent neuroimaging studies reported a possible mismatch between structural and metabolic findings, showing medial temporal lobe atrophy and medial parietal hypoperfusion as biomarkers for AD. The role of the parietal lobe in the development of AD is only recently beginning to attract attention. The current review discusses parietal lobe involvement in the early stages of AD, viz. mild cognitive impairment, as reported from structural, functional, perfusion and metabolic neuroimaging studies. The medial and posterior parts of the parietal lobe seem to be preferentially affected, compared to the other parietal lobe parts. On the basis of the reviewed literature we propose a model showing the relationship between the various pathological events, as measured by different neuroimaging techniques, in the development of AD. In this model myelin breakdown is a beginning of the chain of pathological events leading to AD pathology and an AD diagnosis.

PMID: 21741401 [PubMed - indexed for MEDLINE]

Demyelination of superficial white matter in early Alzheimer's disease: a magnetization transfer imaging study.

Neurobiol Aging. 2012 Feb;33(2):428.e7-19

Authors: Fornari E, Maeder P, Meuli R, Ghika J, Knyazeva MG

Abstract
Assuming selective vulnerability of short association U-fibers in early Alzheimer's disease (AD), we quantified demyelination of the surface white matter (dSWM) with magnetization transfer ratio (MTR) in 15 patients (Clinical Dementia Rating Scale [CDR] 0.5-1; Functional Assessment Staging [FAST]: 3-4) compared with 15 controls. MTRs were computed for 39 areas in each hemisphere. We found a bilateral MTR decrease in the temporal, cingulate, parietal, and prefrontal areas. With linear discriminant analysis, we successfully classified all the participants with 3 variates including the cuneus, parahippocampal, and superior temporal regions of the left hemisphere. The pattern of dSWM changed with the age of AD onset. In early onset patients, we found bilateral posterior demyelination spreading to the temporal areas in the left hemisphere. The late onset patients showed a distributed bilateral pattern with the temporal and cingulate areas strongly affected. A correlation with Mini Mental State Examination (MMSE), Lexis, and memory tests revealed the dSWM impact on cognition. A specific landscape of dSWM in early AD shows the potential of MTR imaging as an in vivo biomarker superior to currently used techniques.

PMID: 21190758 [PubMed - indexed for MEDLINE]

Multivariate analysis of differential lymphocyte cell cycle activity in Alzheimer's disease.

Neurobiol Aging. 2012 Feb;33(2):234-41

Authors: Stieler J, Grimes R, Weber D, Gartner W, Sabbagh M, Arendt T

Abstract
Mounting evidence suggests cell cycle dysregulation is involved in the pathogenesis of Alzheimer's disease (AD) and that this failure is systemic, affecting not only neurons but also peripheral blood lymphocytes (PBLs). This study analyzed if differences in PBL proliferation activity could be used as a diagnostic biomarker for AD. CD69 and CD28 expressions on PBL T, B, and monocyte cells were measured by flow cytometry with and without mitogenic stimulation in healthy controls (HC), probable AD, and Parkinson's disease dementia (PDD) subjects. Univariate and multivariate scoring models were employed to evaluate the data relative to the clinical diagnoses. Eleven CD expression markers were significantly altered in AD subjects compared with a mixed pool of PDD and HC subjects using univariate models. Using multivariate models, seven CD expression markers were significantly altered in AD subjects compared with PDD subjects. Multivariate scoring demonstrated up to a 91% positive and 92% negative agreement with subject clinical diagnosis and had little correlation with the severity of dementia. Present findings suggest that with further development this analytical and multivariate modeling procedure could aid the current differential diagnosis of Alzheimer's disease.

PMID: 20395014 [PubMed - indexed for MEDLINE]

Cerebrospinal fluid Aβ and tau level fluctuation in an older clinical cohort.

Arch Neurol. 2012 Feb;69(2):246-50

Authors: Moghekar A, Goh J, Li M, Albert M, O'Brien RJ

Abstract
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-tau(181)) 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-tau(181). 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.

PMID: 22332192 [PubMed - indexed for MEDLINE]

Ethical considerations of biomarker use in neurodegenerative diseases--a case study of Alzheimer's disease.

Prog Neurobiol. 2011 Dec;95(4):517-9

Authors: Prvulovic D, Hampel H

Abstract
A major issue in current Alzheimer research presents in a growing dysbalance between a swiftly advancing biological marker and diagnostic research field (including advances in genetic research towards genetic profiling), key aspects of which have already found their way into newly proposed diagnostic criteria and international clinical dementia guidelines, and still rather limited and stagnating therapeutic and preventive options for physicians and patients worldwide. While Alzheimer's disease (AD) to date can be diagnosed with high accuracy years ahead of the late stage clinical syndromal dementia manifestation supported by biomarker guided detection of AD-characteristic pathophysiological features, there are currently no approved preventive or disease-modifying therapies available and the existing approved symptomatic therapy options provide only modest effect sizes in already demented patients without affecting the overall course and progression of the chronically progressive and complex brain disease. This unsatisfactory situation brings along a number of important ethical issues that need to be addressed. We outline some of the relevant ethical implications mainly related to the patient's best interest as well as to the patient's autonomy in the specific context of medical, psychological and social consequences of predicting AD using multi-modal biological markers. Consent, disclosure, or failure to disclose, information from genetic and predictive biomarker results raises significant ethical concerns among IRBs, regulators and advocacy groups. With the swift advances in ever earlier detection, diagnosis and classification in AD, a worldwide debate on ethical issues and consensus processes to reach a common ethical framework is warranted to safely and responsibly bring the best possible diagnostic measures as early as possible to patients and to the health care system.

PMID: 22137044 [PubMed - indexed for MEDLINE]

Functional magnetic resonance imaging as a dynamic candidate biomarker for Alzheimer's disease.

Prog Neurobiol. 2011 Dec;95(4):557-69

Authors: Prvulovic D, Bokde AL, Faltraco F, Hampel H

Abstract
During the last two decades, imaging of neural activation has become an invaluable tool for assessing the functional organization of the human brain in vivo. Due to its widespread application in neuroscience, functional neuroimaging has raised the interest of clinical researchers in its possible use as a diagnostic biomarker. A hallmark feature of many neurodegenerative diseases is their chronic non-linear dynamic and highly complex preclinical course. Neurodegenerative diseases unfold over years to decades through clinically silent and asymptomatic stages of early adaptive, compensatory to pathophysiological (i.e. actively neurodegenerative) and decompensatory mechanisms in the brain - phases that are increasingly being considered as critical for primary and secondary preventive and therapeutic measures. Emerging evidence supports the concept of a potentially fully reversible functional phase that may precede the onset of micro- and macrostructural and cognitive decline, a potentially late-stage "neurodegenerative" phase of a primary neurodegenerative disorder. Alzheimer's disease serves as an ideal model to test this hypothesis supported by the neural network model of the healthy and diseased brain. Being highly dynamic in nature, brain activation and neuronal network functional connectivity represent not only candidate diagnostic but also candidate surrogate markers for interventional trials. Potential caveats of functional imaging are critically reviewed with focus on confound variables such as altered neurovascular coupling as well as parameters related to task- and study design.

PMID: 21722703 [PubMed - indexed for MEDLINE]

The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

Alzheimers Dement. 2011 May;7(3):263-9

Authors: McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH

Abstract
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

PMID: 21514250 [PubMed - indexed for MEDLINE]

The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

Alzheimers Dement. 2011 May;7(3):270-9

Authors: Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH

Abstract
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

PMID: 21514249 [PubMed - indexed for MEDLINE]