Alzheimer Disease: Blennow K

Zetterberg H, Andreasen N, Blennow K. · Sahlgrenska Universitetssjukhuset Mölndal. · Lakartidningen. · Pubmed #19585836 No free full text.

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Wasling P, Daborg J, Riebe I, Andersson M, Portelius E, Blennow K, Hanse E, Zetterberg H. · Department of Physiology, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. · J Alzheimers Dis. · Pubmed #19158416 No free full text.

Abstract: Pathological hallmarks of Alzheimer's disease (AD) include synaptic and neuronal degeneration and the presence of extracellular deposits of amyloid-beta (Abeta) in senile plaques in the cerebral cortex. Although these brain lesions may be seen also in aged non-demented individuals, the increase in brain Abeta is believed by many to represent the earliest event in the disease process. Accumulating evidence suggests that Abeta, which is highly conserved by evolution, may have an important physiological role in synapse elimination during brain development. An intriguing idea is that this putative function can become pathogenic if activated in the aging brain. Here, we review the literature on the possible physiological roles of Abeta and its precursor protein AbetaPP during development with special focus on electrophysiological findings.

Hampel H, Bürger K, Teipel SJ, Bokde AL, Zetterberg H, Blennow K. · School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Trinity Centre for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital, Dublin, Ireland. · Alzheimers Dement. · Pubmed #18631949 No free full text.

Abstract: BACKGROUND: In the earliest clinical stages of Alzheimer's disease (AD) when symptoms are mild, clinical diagnosis can be difficult. AD pathology most likely precedes symptoms. Biomarkers can serve as early diagnostic indicators or as markers of preclinical pathologic change. Candidate biomarkers derived from structural and functional neuroimaging and those measured in cerebrospinal fluid (CSF) and plasma show the greatest promise. Unbiased exploratory approaches, eg, proteomics or cortical thickness analysis, could yield novel biomarkers. The objective of this article was to review recent progress in selected imaging and neurochemical biomarkers for early diagnosis, classification, progression, and prediction of AD. METHODS: We performed a survey of recent research, focusing on core biomarker candidates in AD. RESULTS: A number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy, hold promise as biomarkers. These neurobiologic measures appear to relate closely to pathophysiologic, neuropathologic, and clinical data, such as hyperphosphorylation of tau, amyloid beta (Abeta) metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, functional and cognitive decline, as well as risk of future decline. Current advances in the neuroimaging of mediotemporal, neocortical, and subcortical areas of the brain of mild cognitive impairment (MCI) and AD subjects are presented. CSF levels of Abeta42, tau, and hyperphosphorylated tau protein (p-tau) can distinguish subjects with MCI who are likely to progress to AD. They also show preclinical alterations that predict later development of early AD symptoms. Studies on plasma Abeta are not entirely consistent, but recent findings suggest that decreased plasma Abeta42 relative to Abeta40 might increase the risk of AD. Increased production of Abeta in aging is suggested by elevation of BACE1 protein and enzyme activity in the brain and CSF of subjects with MCI. CSF tau and p-tau are increased in MCI as well and show predictive value. Other biomarkers might indicate components of a cascade initiated by Abeta, such as oxidative stress or inflammation. These merit further study in MCI and earlier. CONCLUSIONS: A number of neuroimaging candidate markers are promising, such as hippocampus and entorhinal cortex volumes, basal forebrain nuclei, cortical thickness, deformation-based and voxel-based morphometry, structural and effective connectivity by using diffusion tensor imaging, tractography, and functional magnetic resonance imaging. CSF Abeta42, BACE1, total tau, and p-tau are substantially altered in MCI and clinical AD. Other interesting novel marker candidates derived from blood are being currently proposed (phase I). Biomarker discovery through proteomic approaches requires further research. Large-scale international controlled multicenter trials (such as the U.S., European, Australian, and Japanese Alzheimer's Disease Neuroimaging Initiative and the German Dementia Network) are engaged in phase III development of the core feasible imaging and CSF biomarker candidates in AD. Biomarkers are in the process of implementation as primary outcome variables into regulatory guideline documents regarding study design and approval for compounds claiming disease modification.

Portelius E, Zetterberg H, Gobom J, Andreasson U, Blennow K. · Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, The Sahlgrenska Academy at Göteborg University, Mölndal, Sweden. · Expert Rev Proteomics. · Pubmed #18466053 No free full text.

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

Höglund K, Blennow K. · Department of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry at the Sahlgrenska Academy, Göteborg University, Göteborg, Sweden. · CNS Drugs. · Pubmed #17521225 No free full text.

Abstract: To date, a number of hypotheses of the cause of Alzheimer's disease, the most common form of dementia, have been postulated. The beta-amyloid peptide (Abeta) is the major constituent of senile plaques, which together with atrophy and neurofibrillary tangles, is the main neuropathological finding in Alzheimer's disease. It is a widely accepted theory that aggregation of Abeta into plaques is an initial event in the pathogenesis of Alzheimer's disease, driving neurodegeneration. The cholesterol hypothesis, primarily based on in vitro and animal studies, states that increased levels of cholesterol promote the production of Abeta. Furthermore, treating animals with HMG-CoA reductase inhibitors ('statins'; cholesterol-lowering agents), or adding these agents to cell culture, results in decreased production of Abeta. This 'positive' effect of statin treatment has further been verified by some, but not all, longitudinal studies where a reduced prevalence of Alzheimer's disease is seen among patients taking statins. These findings have together been interpreted to indicate that statins act via a cholesterol-dependent mechanism, reducing the production of Abeta and, hence, the risk of developing Alzheimer's disease.This review focuses on the cholesterol hypothesis of Alzheimer's disease and investigations into its validity in the clinical setting, i.e. the outcome of clinical trials where the effect of statin treatment on Abeta production has been studied. To date, the cholesterol hypothesis has not been shown to be valid in clinical trials. We hypothesise that the vascular contributions in Alzheimer's disease may be one possible mechanism for statins to interfere with the disease process and reduce the prevalence of Alzheimer's disease. We also suggest that statins may act through the inflammatory pathway. Both of these mechanistic suggestions are good candidates, supported by the literature, for the underlying mechanistic link between statin treatment and a reduced prevalence for Alzheimer's disease.

de Leon MJ, Mosconi L, Blennow K, DeSanti S, Zinkowski R, Mehta PD, Pratico D, Tsui W, Saint Louis LA, Sobanska L, Brys M, Li Y, Rich K, Rinne J, Rusinek H. · Center for Brain Health, NYU School of Medicine, Department of Psychiatry, 560 First Ave., New York 10016, USA. · Ann N Y Acad Sci. · Pubmed #17413016 No free full text.

Abstract: It is widely believed that the path to early and effective treatment for Alzheimer's disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG-PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG-PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials.

Wahlund LO, Almkvist O, Blennow K, Engedahl K, Johansson A, Waldemar G, Wolf H. · Department of Neurobiology, Caring Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden. · Top Magn Reson Imaging. · Pubmed #17088692 No free full text.

Abstract: BACKGROUND: The diagnostic utility of magnetic resonance imaging in dementia workups has increased recently. The basic use is to exclude space-occupying processes in the brain. However, magnetic resonance imaging offers major opportunities for studying atrophy of specific brain areas. A great interest has been put in whether atrophy in the medial temporal lobe can serve as an early diagnostic marker for Alzheimer disease. METHODS AND RESULTS: In this evaluation, we used evidence-based techniques and reviewed more than 400 articles that address this issue. Our main finding is that a variety of methods in studying brain areas were used, and this made it difficult to extract conclusive information in a systematic way. CONCLUSION: However, we were able to conclude that atrophy of the hippocampus can distinguish patients with Alzheimer disease from healthy subjects, but there was a lack of evidence because of insufficient studies concerning the usefulness of medial temporal lobe atrophy as a diagnostic marker in a more general setting.

Blennow K, de Leon MJ, Zetterberg H. · Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren's University Hospital, Mölndal, Sweden. · Lancet. · Pubmed #16876668 No free full text.

Abstract: Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.

Höglund K, Wallin A, Blennow K. · Section of Experimental Neurochemistry, Institute of Clinical Neuroscience, Göteborg University, Sweden. · Acta Neurol Scand Suppl. · Pubmed #16866916 No free full text.

Abstract: According to the amyloid cascade hypothesis, both familial and sporadic Alzheimer's disease (AD) is caused by the toxic effect of over-production and/or aggregation of beta-amyloid (Abeta). Recent cell and animal studies have linked the production of Abeta to high levels of cholesterol and the use of statins, compounds inhibiting the de novo synthesis of cholesterol. Epidemiological studies have also supported such linkage by showing a reduced prevalence of AD for subjects taking statins. A limited number of clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in AD in humans and this review focuses on the current state of these clinical studies. The results are contradictory, but the overall interpretation suggests that statin treatment probably does not have a direct impact through lowering of cholesterol on the APP processing and Abeta production in humans. To confirm this, further clinical studies needs to be performed with extended treatment periods and where several parameters (lipid profile, lipoproteins, sterols, biomarkers related to AD and APP metabolites) are analyzed, both in the cerebrospinal fluid and plasma. The pleiotropic effects of statins should be investigated further. One approach is presented in this review.

Blennow K, Popa C, Rasulzada A, Minthon L, Wallin A, Zetterberg H. · Institutionen för klinisk neurovetenskap, Sahlgrenska Universitetssjukhuset/Mölndal, Sweden. · Lakartidningen. · Pubmed #16196432 No free full text.

Abstract: The clinical symptomatology and pathogenic mechanisms of chronic traumatic brain injury associated with boxing (CTBI-B) is reviewed. This syndrome is also known as punch drunk syndrome or dementia pugilistica. Since even milder forms of CTBI-B are rare among amateur boxers, we make a distinction between amateur and professional boxing throughout the review. Focus is also set on the interesting similarities in neurochemical changes and pathogenic mechanisms between CTBI-B, acute traumatic brain injury (e.g. road traffic accidents) and Alzheimer's disease.

Sjögren M, Blennow K. · Section of Experimental Geriatrics, Neurotec, Karolinska Institute KFC, Novum Plan 4, SE-14186 Huddinge, Sweden. · World J Biol Psychiatry. · Pubmed #16156481 No free full text.

Abstract: A leading hypothesis on the pathophysiology of Alzheimer's disease (AD) is the mis-metabolism of amyloid precursor protein. This mis-metabolism causes the 42-amino acid form of A beta(Abeta42) to form oligomers that in turn start a chain of events leading to the accumulation of amyloid plaques. Vascular factors such as hypertension, hypercholesterolemia and diabetes as well as the inheritance of the epsilon4 allele of the ApoE gene are risk factors for AD. These risks are thought to promote the production of beta-amyloid (Abeta). An association between cholesterol and the development of AD was suggested in 1994 and since then, research has confirmed a link between cholesterol and the development of AD. A high cholesterol level in mid-life is a risk for AD and statins i.e. cholesterol-lowering drugs, reduce this risk. Statins inhibit enzymes involved in the endogenous synthesis of cholesterol and evidence is mounting that they also affect enzymes in Abeta metabolism i.e. beta-secretase. This normalises the breakdown of the precursor of Abeta, amyloid precursor protein, thereby promoting the nonamyloidogenic pathway. This review focusses on the link between cholesterol and Alzheimer's disease.

Wiltfang J, Lewczuk P, Riederer P, Grünblatt E, Hock C, Scheltens P, Hampel H, Vanderstichele H, Iqbal K, Galasko D, Lannfelt L, Otto M, Esselmann H, Henkel AW, Kornhuber J, Blennow K. · Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. · World J Biol Psychiatry. · Pubmed #16156480 No free full text.

Abstract: Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Blennow K. · The Sahlgrenska Academy at Göteborg University, Department of Clinical Neuroscience, Section of Experimental Neuroscience, Sahlgrenska University Hospital, SE-431 80 Mölndal, Sweden. · Expert Rev Mol Diagn. · Pubmed #16149870 No free full text.

Abstract: Early diagnosis of Alzheimer's disease is important in initiating symptomatic treatment with acetylcholine esterase inhibitors, and will be of even greater significance if drugs with a potential to slow down the degenerative process, such as beta-secretase inhibitors and beta-amyloid vaccination, prove to have a clinical effect. During the last decade, research efforts have focused on developing cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease. In this review, the background and principles for, and the diagnostic performance of, the CSF biomarkers total tau, phosphorylated tau and the 42-amino acid form of beta-amyloid, are reviewed. New candidate CSF biomarkers and new strategies, including multiparameter immunoassays and CSF proteomics techniques, in the search of additional CSF biomarkers are also reviewed. Finally, the rationale for the use of CSF biomarkers to identify and monitor the biochemical effect of new drug candidates is reviewed.

Andreasen N, Blennow K. · Karolinska Institutet, Department of NEUROTEC, Section of Geriatric Medicine, M51, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. · Clin Neurol Neurosurg. · Pubmed #15823670 No free full text.

Abstract: A correct clinical diagnosis, early in the course of Alzheimer's disease (AD), is of importance given the currently available symptomatic treatment with acetylcholine esterase inhibitors. The development of disease-modifying drugs like beta-sheet breakers or gamma- and beta-secretase inhibitors, emphasizes the need of improved diagnostic accuracy, especially in patients with mild cognitive impairment (MCI) that have incipient AD. Therefore, diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field. Three cerebrospinal fluid biomarkers (the 42 amino acid form of beta-amyloid (A beta), total tau, and phospho tau) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal aging, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. If these biomarkers are used in combination with a careful medical history, clinical examination, standard laboratory tests and imaging techniques of the brain, the diagnostic accuracy may be appropriate for the clinical evaluation of MCI cases.

Blennow K. · Department of Clinical Neuroscience, Section of Experimental Neuroscience, The Sahlgrenska Academy at Göteborg University, SE-43180 Göteborg, Sweden. · NeuroRx. · Pubmed #15717022 links to  free full text

Abstract: The introduction of acetylcholine esterase (AChE) inhibitors as a symptomatic treatment of Alzheimer's disease (AD) has made patients seek medical advice at an earlier stage of the disease. This has highlighted the importance of diagnostic markers for early AD. However, there is no clinical method to determine which of the patients with mild cognitive impairment (MCI) will progress to AD with dementia, and which have a benign form of MCI without progression. In this paper, the performance of cerebrospinal fluid (CSF) protein biomarkers for AD is reviewed. The diagnostic performance of the three biomarkers, total tau, phospho-tau, and the 42 amino acid form of beta-amyloid have been evaluated in numerous studies and their ability to identify incipient AD in MCI cases has also been studied. Some candidate AD biomarkers including ubiquitin, neurofilament proteins, growth-associated protein 43 (neuromodulin), and neuronal thread protein (AD7c) show interesting results but have been less extensively studied. It is concluded that CSF biomarkers may have clinical utility in the differentiation between AD and several important differential diagnoses, including normal aging, depression, alcohol dementia, and Parkinson's disease, and also in the identification of Creutzfeldt-Jakob disease in cases with rapidly progressive dementia. Early diagnosis of AD is not only of importance to be able to initiate symptomatic treatment with AChE inhibitors, but will be the basis for initiation of treatment with drugs aimed at slowing down or arresting the degenerative process, such as gamma-secretase inhibitors, if these prove to affect AD pathology and to have a clinical effect.

Blennow K. · Department of Clinical Neuroscience, Section of Experimental Neuroscience, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. · J Intern Med. · Pubmed #15324365 No free full text.

Abstract: A correct clinical diagnosis of Alzheimer's disease (AD) early in the course of the disease is of importance to initiate symptomatic treatment with acetylcholine esterase inhibitors, and will be even more important when disease-arresting drugs, such as beta-sheet breakers or gamma-secretase inhibitors, will reach the clinic. However, there is no clinical method to determine if a patient with mild cognitive impairment (MCI) has incipient AD, i.e. will progress to AD with dementia, or have a benign form of MCI without progression. Thus, there is a great clinical need for diagnostic biomarkers to identify incipient AD in MCI cases. Three cerebrospinal fluid (CSF) biomarkers; total-tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of beta-amyloid (Abeta42) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal ageing, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. However, if the CSF biomarkers are used in the right clinical context, i.e. together with the cumulative information from the clinical examination, standard laboratory tests and brain-imaging techniques [single photon emission tomography (SPECT) and magnetic resonance tomography (MRT) scans], they may have a role in the clinical evaluation of MCI cases.

Hampel H, Mitchell A, Blennow K, Frank RA, Brettschneider S, Weller L, Möller HJ. · Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · J Neural Transm. · Pubmed #14991453 No free full text.

Abstract: Alzheimer's disease (AD) is a complex neurodegenerative dementing illness. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in the development of biomarkers. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease specific pathology hold the potential to provide effective measures of natural history (marker of disease that is predictive of outcome), biological activity (such as magnitude and frequency of response correlating with drug potency) and markers of surrogate endpoints (single or composite marker that accounts for clinical benefit of the therapy). Markers of biological activity should be also evaluated regarding their value to reflect disease progression, heterogeneity of the clinical population, for early decision making and characterization of new treatments. We focussed on the current status of core analytes which provide reasonable evidence for association with key mechanisms of pathogenesis or neurodegeneration in AD. In addition, feasibility was important, such as availability of a validated assay for the biological measure in question, with properties that included high precision and reliability of measurement, reagents and standards well described. On this basis we reviewed the body of literature that has examined CSF total tau (t-tau) and beta-amyloid 1-42 (Abeta(1-42)), phosphorylated tau (p-tau) and beta-amyloid-antibodies as diagnostic tests for AD versus clinically representative comparison groups. Measurement of t-tau and Abeta(1-42) in the CSF seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. First studies showed that measurement of p-tau proteins significantly improves early and differential diagnosis, as well as disease prediction in subjects at risk for AD and comes closest to fulfilling proposed criteria of a biological marker for AD. However, the nature of the majority of reported findings are still preliminary and retrospective. General issues for biomarkers have to be adequately addressed, such as sensitivity of the method, frequency of assessments, stability of the method, standardization of methods and dynamic range. There is still a partial lack of comparison patient populations that must be addressed in future studies. International dementia networks have been recently established to advance the establishment of core biomarker candidates of AD as potential surrogate endpoints for clinical trials and their clinical use for predictive and diagnostic purposes.

Andreasen N, Sjögren M, Blennow K. · Karolinska Institute NEUROTEC, Neurotec, Huddinge University Hospital, Sweden. · World J Biol Psychiatry. · Pubmed #14608585 No free full text.

Abstract: Today we have the first therapeutic compounds for treatment of Alzheimer's disease (AD) e.g. acetylcholine esterase inhibitors and in the near future we may expect new compounds such as gamma- and beta-secretase inhibitors. This has demanded increased accuracy in the diagnosis of AD and thus, among other possible approaches, diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field. Especially early in the course of the disease, when correct diagnosis is most difficult, such biomarkers would be especially valuable as one might expect the compounds to have the greatest potential of being effective. Two of the defining lesions in AD brains are senile plaques and neurofibrillary tangles with beta-amyloid (Abeta) and tau proteins as the main components respectively. Abeta and tau proteins are secreted to body fluids including plasma and cerebrospinal fluid (CSF). In this paper we review CSF markers for AD, with focus on their role in the clinical diagnosis. Reduced CSF levels of the 42 amino acid form of Abeta (Abeta42) and increased CSF levels of total tau (T-tau) in AD have been found in numerous studies, with high sensitivity figures. However, the specificity against other dementias is lower. The addition of phospho-tau (P-tau) seems to increase the specificity, since normal levels are found in other dementias and in cerebrovascular disease. An increasing number of studies suggests that these CSF markers perform well enough to have a role in the clinical work-up of patients with dementia if used together. We stress that the CSF markers should be combined with the clinical information and brain-imaging techniques.

Blennow K, Hampel H. · Department of Clinical Neuroscience, Sahlgrenska Academy, Gothenburg University, Sweden. · Lancet Neurol. · Pubmed #14505582 No free full text.

Abstract: Early diagnosis of Alzheimer's disease (AD) is needed to initiate symptomatic treatment with acetylcholinesterase inhibitors, and will be of even greater significance if drugs aimed at slowing down the degenerative process, such as vaccination regimes and beta-secretase and gamma-secretase inhibitors, prove to affect AD pathology and to have clinical effect. However, there is no clinical method to determine in which patients mild cognitive impairment (MCI) will progress to AD with dementia, and in which patients MCI is benign. Hence, there is a great clinical need for biomarkers to identify incipient AD in patients with MCI. The CSF biomarkers total tau protein, phosphorylated tau protein, and the 42 amino-acid residue form of amyloid-beta may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet this challenge.

Blennow K, Vanmechelen E. · Department of Clinical Neuroscience, University of Göteborg, SE-431 80 Mölndal, Sweden. · Brain Res Bull. · Pubmed #12909293 No free full text.

Abstract: In view of current (acetylcholine esterase (AChE) inhibitors) and future (e.g. gamma-secretase inhibitors) therapeutic compounds for treatment of Alzheimer's disease (AD), the development and evaluation of cerebrospinal fluid (CSF) biomarkers for AD has become a rapidly growing research field. Diagnostic biomarkers for AD would be especially valuable as aids to diagnosis early in the course of the disease, when correct diagnosis is difficult, and when therapeutic compounds have the greatest potential for being effective. This paper reviews CSF biomarkers for AD, with emphasis on their role in the clinical diagnosis. The two most studied biochemical markers, CSF-tau and CSF-Abeta42, have high sensitivity to identify AD, but the specificity against other dementias is lower. The addition of phosphorylated tau (P-Tau) seems to increase the specificity for the diagnosis of AD, since normal levels are found in both frontotemporal and Lewy body dementia, and in cerebrovascular disease. These CSF markers may be useful as diagnostic aids, especially to discriminate early or incipient AD from age-associated memory impairment, depression, and some secondary dementias.

Sjögren M, Andreasen N, Blennow K. · Institute of Clinical Neuroscience, Göteborg University, SE 431 80, Göteborg, Sweden. · Clin Chim Acta. · Pubmed #12763273 No free full text.

Abstract: The diagnosis of Alzheimer's disease (AD) is still made by excluding other disorders with a similar clinical picture. In addition, an analysis of symptoms and signs, blood analyses and brain imaging are the major ingredients of the clinical diagnostic work-up. However, the sensitivity of a clinical diagnosis using these instruments is unsatisfactory and disease markers with high sensitivity and specificity for AD would be a welcome supplement. Ideally, such markers should reflect the pathophysiological mechanisms of AD, that is, according to the currently predominant hypothesis mismetabolism of beta-amyloid and neurofibrillary degeneration. Among several, we have focused on three candidates that have been suggested to fulfil the requirements for biomarkers of AD: beta-amyloid42 (Abeta42), total tau (T-tau) and tau phosphorylated at various epitopes (P-tau). The cerebrospinal fluid (CSF) levels of these proteins reflect the metabolism of these proteins in the central nervous system. Only published articles using established ELISA methods for the quantification of these markers in CSF and preferably also presenting sensitivity and specificity figures have been included in this review. The number of patients included in the different studies varies; some having included only a few patients. Furthermore, diagnostic criteria vary and clinicopathological studies are scarce. However, there are some large studies, including even minor studies, and most have found reduced CSF levels of Abeta42 and increased CSF levels of T-tau in AD. The sensitivity and specificity of these measures are high for separation of AD patients from controls, but their specificity against other dementias is moderate. It increases if P-tau is added. An increasing number of studies suggest that supplementary use of these CSF markers, preferably in combination, adds to the accuracy of an AD diagnosis.

Andreasen N, Blennow K. · Department of Geriatric Medicine, Neurotec, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Stockholm, Sweden. · Peptides. · Pubmed #12128078 No free full text.

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

Blennow K, Vanmechelen E, Hampel H. · Department of Clinical Neuroscience, Unit of Neurochemistry, University of Göteborg, Sweden. · Mol Neurobiol. · Pubmed #11831556 No free full text.

Abstract: With the arrival of effective symptomatic treatments and the promise of drugs that may delay progression, we now need to identify Alzheimer's disease (AD) at an early stage of the disease. To diagnose AD earlier and more accurately, attention has been directed toward peripheral biochemical markers. This article reviews promising potential cerebrospinal fluid (CSF) biomarkers for AD focussing on their role in clinical diagnosis. In particular, two biochemical markers, CSF total tau (t-tau) protein and the 42 amino acid form of beta-amyloid (Abeta42), perform satisfactorily enough to achieve a role in the clinical diagnostic settings of patients with dementia together with the cumulative information from basic clinical work-up, genetic screening, and brain imaging. These CSF markers are particularly useful to discriminate early or incipient AD from age-associated memory impairment, depression, and some secondary dementias. In order to discriminate AD from other primary dementia disorders, however, more accurate and specific markers are needed. Preliminary evidence strongly suggests that quantification of tau phosphorylated at specific sites in CSF improves early detection, differential diagnosis, and tracking of disease progression in AD.

Blennow K, Minthon L, Wallin A. · Institutionen för klinisk neurovetenskap, Sahlgrenska Universitetssjukhuset, Mölndal. · Lakartidningen. · Pubmed #10668317 No free full text.

This publication has no abstract.

Wallin A, Blennow K, Rosengren L. · Institute of Clinical Neuroscience, Göteborg University, Sahlgrenska University Hospital, Mölndal, Sweden. · Alzheimer Dis Assoc Disord. · Pubmed #10609688 No free full text.

Abstract: There is a need for improvement of the diagnosis of vascular dementia (VaD). Today, the clinician has to rely on clinical examination, history, and, possibly, brain imaging to identify cerebrovascular damage and other signs of VaD. The clinical diagnosis of subcortical VaD may be difficult because the clinical manifestation of this disorder is often similar to that of Alzheimer disease. There are also mixed forms of the two disorders. Biochemical diagnostic markers, which reflect the pathogenetic processes in the brain, would add to the accuracy of the diagnosis. There are some interesting candidate markers: the cerebrospinal fluid (CSF)/serum albumin ratio could be used to identify blood-brain barrier damage to the small intracerebral vessels, CSF sulfatide to identify ongoing demyelination of the white matter, CSF neuron-specific enolase to identify ongoing neuronal degeneration, and CSF tau protein and CSF neurofilament light protein to identify ongoing axonal degeneration. None of these potential markers is specific to subcortical VaD, but together and used in conjunction with the conventional diagnostic workup, they may be of diagnostic value.