Alzheimer Disease: Hampel H

Padberg F, Hampel H, Möller HJ. · No affiliation provided · MMW Fortschr Med. · Pubmed #11824167 No free full text.

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Padberg F, Hampel H, Möller HJ. · No affiliation provided · Fortschr Med Orig. · Pubmed #11789127 No free full text.

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Carrillo MC, Blackwell A, Hampel H, Lindborg J, Sperling R, Schenk D, Sevigny JJ, Ferris S, Bennett DA, Craft S, Hsu T, Klunk W. · Alzheimer's Association, Chicago, IL, USA. · Alzheimers Dement. · Pubmed #19328456 No free full text.

Abstract: The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

Buschert VC, Teipel SJ, Hampel H, Bürger K. · Alzheimer Gedächtniszentrum, Klinik und Poliklinik für Psychiatrie und Psychotherapie der LMU München, Nussbaumstrasse 7, 80336, München, Deutschland. · Nervenarzt. · Pubmed #19229510 No free full text.

Abstract: At present more than 1 million patients in Germany suffer from Alzheimer's disease (AD). This number is expected to double by 2050. The effectiveness of presently approved specific antidementive drugs for symptomatic treatment of AD is still not satisfactory. The question arises whether cognition-based nonpharmacologic measures may constitute an effective intervention in AD and its prodromal stages. The paper at hand defines theoretical general principles of cognitive training and gives an overview of recent findings that provide evidence of its effectiveness. We finally present recommendations for future studies and establishment of cognitive training.

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.

Hampel H, Shen Y. · 1Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. · Scand J Clin Lab Invest. · Pubmed #18609117 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the amyloid beta-peptide (Abeta) in the brain. Pathological mechanisms are already active early in the presymptomatic stage of AD. BACE1, beta-secretase, is one of the two key enzymes in amyloid precursor protein (APP) processing; the other being gamma-secretase. The Abeta peptide results from cleavage of APP initially by BACE1 to produce the C99 fragment and releases soluble APPbeta (sAPPbeta); C99 is then further cleaved by gamma-secretase leading to the Abeta peptide. Increased BACE1 activity and elevated levels of insoluble Abeta peptide have been shown in brain tissue of patients with sporadic AD. Since the CSF is in direct contact with the extracellular space of the central nervous system, biochemical changes in the brain can potentially be reflected in CSF. Therefore, CSF-based detection of BACE1 levels and activity might be valuable in aiding early detection and prediction, particularly in preclinical or even presymptomatic subjects who are at risk of AD. Recently, we were among the first groups to quantitatively analyse the enzymatic activities and protein levels of BACE1 in the CSF. Preliminary research using recently developed BACE1 ELISAs, BACE1 enzymatic activity, sAPPbeta and total Abeta1-x ELISAs were used by examining these hypothesis driven functional candidate markers in subjects with clinically diagnosed AD and amnestic MCI. Two sandwich ELISAs were used and BACE1 enzymatic activities were seen by synthetic fluorescence substrate and total Abeta levels by sandwich-ELISA. Moreover, elevated CSF levels of BACE1 protein were associated with an increased risk ratio in MCI. Interestingly, amnestic MCI subjects showed increased levels of BACE1 activity compared to HC and AD patients. For total Abeta and tau, increased CSF levels were associated with a higher risk of MCI compared to HC as well. BACE1 activity was significantly correlated with BACE1 protein concentration and total Abeta levels, with Abeta being itself correlated with the BACE1 protein level. Currently, independent studies are ongoing to validate BACE1 and functionally associated proteins as candidate biomarkers for early detection, prediction, progression as well as for biological activity in AD.

Teipel SJ, Meindl T, Grinberg L, Heinsen H, Hampel H. · Dementia and Neuroimaging Section, Department of Psychiatry, Alzheimer Memorial Center, Ludwig-Maximilian University, Nussbaumstrasse 7, Munich, Germany. · Eur J Nucl Med Mol Imaging. · Pubmed #18205002 No free full text.

Abstract: INTRODUCTION: Positive markers of Alzheimer's disease (AD) have been established in MRI that may allow early detection of AD in at-risk groups. In the near future, these markers will be of high relevance for the selection of at-risk subjects in secondary preventive trials. METHODS: We describe the methodology and diagnostic value of manual volumetry of the hippocampus and entorhinal cortex, automated voxel-based morphometry, cortical thickness measurement, basal forebrain volumetry and deformation-based morphometry, implementing multivariate statistics and machine learning algorithms to improve group separation and prediction of AD in at-risk groups. We also describe the methodological basis and results obtained in AD using the recently developed technique of diffusion tensor-based morphometry (DTI). This technique gives access to the integrity of subcortical fibre systems in the human brain. RESULTS: The best established structural biomarker of AD to date is hippocampus volume that already has been implemented as secondary endpoint in clinical trials on disease modification in AD. Automated approaches will gain an increasing role as endpoints of clinical trials in the near future given the interest in these techniques expressed by the regulatory authorities. DTI is still a developing field where analysis techniques are presently being devised to make optimal use of the multivariate data. Data on changes of fibre tract in preclinical AD are still limited, but the first results are promising in respect to a further enhancement of diagnostic accuracy by combining MRI and DTI. CONCLUSION: Besides their diagnostic use, MRI and DTI will broaden our understanding of the pathophysiology of AD and the structural and functional basis of normal cognition.

Omerovic M, Hampel H, Teipel SJ, Buerger K. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany. · World J Biol Psychiatry. · Pubmed #17886162 No free full text.

Abstract: Alzheimer's disease (AD) is one of the most frequent disorders of the central nervous system characterised by a progressive cognitive decline. The demographic changes of our aging population lead to increased numbers of patients and a need of early diagnosis and treatment of cognitive and behavioural symptoms of AD. Drugs are available for symptomatic treatment of AD. The pharmacological treatment of behavioural disturbances experienced dynamic changes in the last years. In this paper, we present the current state and future perspectives in the treatment of AD. Furthermore, we discuss current difficulties regarding AD treatment by looking for explanations for a still unsatisfying rate of state-of-the-art treatment of AD-patients.

Hampel H, Teipel SJ, Bürger K. · Alzheimer Gedächtniszentrum, Forschungsgruppe Dementielle Erkrankungen und Bildgebende Verfahren, Klinik und Poliklinik für Psychiatrie und Psychotherapie der Ludwig-Maximilians-Universität, München. · Nervenarzt. · Pubmed #17611728 No free full text.

Abstract: In order to improve diagnosis of Alzheimer's disease (AD), candidate biological markers in CSF as well as structural and functional imaging were investigated. Biomarkers are clearly needed to support detection of incipient AD in subjects with mild cognitive impairment (MCI). To date the most promising core candidate markers are total and hyperphosphorylated tau protein and amyloid beta peptides in the CSF, as well as hippocampus and whole brain volumetry using MRI. None of the candidates has been finally validated and established for clinical routine so far. International controlled multicenter cooperative studies are ongoing to further develop these core diagnostic marker candidates (phase III). The core markers are reviewed in detail. Promising novel approaches are discussed.

Sunderland T, Hampel H, Takeda M, Putnam KT, Cohen RM. · Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16880359 No free full text.

Abstract: Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer's disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer's disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer's disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions.

Teipel SJ, Hampel H. · Alzheimer Memorial Center and Geriatric Psychiatry Branch, Dementia and Neuroimaging Section, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · Behav Genet. · Pubmed #16485178 No free full text.

Abstract: Aging in Down syndrome (DS) is accompanied by neuropathological features of Alzheimer's disease (AD). Therefore, DS has been proposed as a model to study predementia stages of AD. MRI-based measurement of grey matter atrophy is an in vivo surrogate marker of regional neuronal density. A range of neuroimaging studies have described the macroscopic neuroanatomy of DS. Recent studies using sensitive quantitative measures of region-specific atrophy based on high-resolution MRI suggest that age-related atrophy in DS resembles the pattern of brain atrophy in early stages of AD. The pattern of atrophy determined in predementia DS supports the notion that AD-type pathology leads to neuronal degeneration not only in allocortical, but also in neocortical brain areas before onset of clinical dementia. This has major implications for our understanding of the onset and progression of AD-type pathology both in DS and in sporadic AD.

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.

Frölich L, Schmitt B, Calabrese P, Diener H, Förstl H, Gertz HJ, Hallauer JF, Hampel H, Ihl R, Rieke K, Riepe M, Supprian T. · Zentralinstitut für Seelische Gesundheit Mannheim, Universität Heidelberg. · Dtsch Med Wochenschr. · Pubmed #15717252 No free full text.

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Hampel H, Teipel SJ. · Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Munich, Germany. · Dement Geriatr Cogn Disord. · Pubmed #15178952 No free full text.

Abstract: An ever increasing number of patients with neurodegenerative disorders calls for the evaluation of potential diagnostic markers that allow an early diagnosis and an early initiation of specific therapy. Clinical diagnosis of Alzheimer's disease (AD), the most common neurodegenerative disorder, reaches 80-90% accuracy upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical or preclinical stages is far less accurate, as is the differential diagnosis between AD and other primary dementias, such as frontotemporal dementia (FTD). Microtubule-associated tau protein is abnormally phosphorylated in AD and aggregates as paired helical filaments in neurofibrillary tangles. Recently, immunoassays have been developed detecting tau phosphorylated at specific epitopes in cerebrospinal fluid (CSF). Four years of clinical research consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased in AD compared to healthy controls and may differentiate AD from its most relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau(231)) shows excellent differentiation between AD and FTD, whereas serine 181 (p-tau(181)) enhances accurate differentiation between AD and dementia with Lewy bodies. Moreover, p-tau(231) levels decline with disease progression, correlating with cognitive performance at baseline. Total tau (t-tau) is regarded as a general marker of neurodegeneration for evaluation in future population-based studies. p-tau(231) and p-tau(181) yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker candidate for future evaluation in large national and international multicenter networks.

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.

Frölich L, Fox J, Padberg F, Maurer K, Möller HJ, Hampel H. · Klinik für Psychiatrie und Psychotherapie I Johann Wolfgang Goethe-Universität, Heinrich-Hoffmann-Str 10, 60528 Frankfurt am Main, Germany. · Curr Pharm Des. · Pubmed #14754383 No free full text.

Abstract: Diagnosis and therapy of dementia have made considerable progress in recent years. Drugs have been developed which improve cognitive performance, delay the loss of abilities of daily living and prevent early nursing home placement in a considerable number of patients. With the various pharmacological and non-pharmacological approaches, effective treatment options of AD are available at present and the therapeutic potential will even increase in future. Thus, the treatment of dementia should more focused and explicit in its goals for the doctor, the patient and the relatives. Therapeutic targets must be defined on the basis of the individual needs and deficits and with regard to different levels of the disease process. Ideally, treatment should always aim at an etiological and/or a pathophysiological level. At present, however, aiming at the neurotransmitter level, the core syndrome of cognitive deficits can be approached by treatment options. Further therapeutic targets can be defined on the level of activities of daily living, following a resource focused approach, as well as on the level of behavioral disturbances. Additional therapeutic targets should be seen under a humanitarian or palliative perspective. And finally, family members are also targets for therapy in dementia, even if such therapy is not directed towards the demented patient. All these treatment targets have to be evaluated and adapted under the perspective of time because prominent symptoms in AD change considerably with disease progression. Selection and adaptation of medication becomes easier if such targets are considered and if therapeutic effects are monitored target-specifically.

Fuchsberger T, Möller HJ, Hampel H. · Klinik und Poliklinik für Psychiatrie und Psychotherapie, LMU München. · MMW Fortschr Med. · Pubmed #14579485 No free full text.

Abstract: In recent years, the efficacy of symptomatic treatment in patients with Alzheimer's disease has repeatedly been demonstrated in a number of multicenter studies. Such treatment aims both to improve the patient's cognitive abilities and to preserve his or her quality of life and ability to cope with the activities of daily life. In this way the burden on relatives and caregivers is reduced, and the need for home or institutionalized care delayed. Causally effective therapeutic strategies resulting in a cure or the delaying of pathophysiological progression are currently not available, but are being investigated in ongoing clinical and experimental studies. Presently available treatments should be initiated early on, and applied as long as needed, which requires the earliest possible clinical diagnosis by the primary-care physician. The results of initial studies reveal an effect of antidementia agents also in mixed Alzheimer's and vascular dementia, as well as vascular and lewy-body dementia. Efforts to obtain approval for these indications are underway.

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.

Leinsinger G, Teipel S, Wismüller A, Born C, Meindl T, Flatz W, Schönberg S, Pruessner J, Hampel H, Reiser M. · Institut für Klinische Radiologie, Klinikum der Ludwig-Maximilians-Universität München, Munich. · Radiologe. · Pubmed #12955216 No free full text.

Abstract: PURPOSE. Volumetric analysis of the corpus callosum and hippocampus using MRI in Alzheimer's disease (AD) to evaluate the regional pattern and progression of neocortical neurodegeneration. METHODS. In subsequent studies we investigated patients with AD and healthy controls. Volumetry was based on MRI-data from a sagittal 3D T1w-gradient echo sequence. The corpus callosum (CC) was measured in a midsagittal slice, and subdivided into 5 subregions. Volumetry of the hippocampus/amygdala-formation (HAF) was performed by segmentation in coronary reoriented slices. RESULTS. In AD patients we found a significant atrophy in the rostrum und splenium of CC. The atrophy was correlated with the severity of dementia, but no correlation was found with the load of white matter lesions. In comparison with (18)FDG-PET, we found a significant correlation of regional CC-atrophy with the regional decline of cortical glucose metabolism. A ROC-analysis demonstrated no significant differences in the diagnostic accuracy of HAF volumetry and regional CC volumetry of the splenium (region C5) even in mild stages of dementia. CONCLUSION. Regional atrophy of CC can be used as a marker of neocortical degeneration even in early stages of dementia in AD.

Hampel H, Goernitz A, Buerger K. · Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, D-80336 Munich, Germany. · Brain Res Bull. · Pubmed #12909294 No free full text.

Abstract: Advances have been made to establish biological markers of Alzheimer's disease (AD). Measurement of total tau (t-tau) and beta-amyloid(1-42) (Abeta(1-42)) in the cerebrospinal fluid (CSF) seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. New immunoassays to detect different phosphorylated tau epitopes (p-tau) have recently been developed. P-tau phosphorylated at threonine 231 (p-tau(231)) showed improvements compared to t-tau in the early detection of AD in subjects with mild cognitive impairment. As p-tau(231) declined during the course of AD, it may have potential to track disease progression. Additionally, p-tau(231) improved differential diagnosis between AD, frontotemporal dementia, and geriatric major depression. P-tau phosphorylated at threonine 181 improved diagnostic accuracy between AD and dementia with Lewy bodies. P-tau phosphorylated at serine 199 demonstrated high discriminative power between AD and non-Alzheimer's dementia. P-tau phosphorylated at serine 306/serine 404 improved differential diagnosis between AD and vascular dementia. A comparative study of the different p-tau epitopes is currently under way.In summary, first clinical multi-center studies suggest that measurement of phosphorylated tau proteins may significantly improve early and differential diagnosis and may come close to fulfilling proposed criteria of a biological marker for AD.

Dodel RC, Hampel H, Du Y. · Department of Neurology, Friedrich-Wilhelms-University Bonn, Germany. <> · Lancet Neurol. · Pubmed #12849209 No free full text.

Abstract: Recent studies in murine models of Alzheimer's disease (AD) have found that active immunisation with amyloid-beta peptide (Abeta) or passive immunisation with Abeta antibodies can lessen the severity of Abeta-induced neuritic plaque pathology through the activation of microglia. These antibodies can be detected in the serum and CSF. Whether they slow down or speed up the development and progression of AD has not been determined. Furthermore, the conditions that induce formation of such antibodies are unknown, or how specific they are to AD. However, the evidence suggests at least a potential beneficial role for some features of neuroinflammation in AD. A clinical phase II study of an active immunisation approach with AN1792 was started in 2001, but was recently suspended after some patients developed serious adverse events. These were most likely caused by the activation of the proinflammatory cascade. Immunotherapy approaches represent fascinating ways to test the amyloid hypothesis and may offer genuine opportunities to modify disease progression. This review focuses on immunisation strategies and details of the pathways involved in antibody clearance of Abeta.

Frank RA, Galasko D, Hampel H, Hardy J, de Leon MJ, Mehta PD, Rogers J, Siemers E, Trojanowski JQ, Anonymous00193. · Pharmacia Corporation, Mailstop 134, Peapack, NJ 07977, USA. · Neurobiol Aging. · Pubmed #12714109 No free full text.

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Hüll M, Hampel H. · Department of Psychiatry, University of Freiburg, Medical School, Hauptstr. 5, 79104 Freiburg, Germany. · Ernst Schering Res Found Workshop. · Pubmed #12066411 No free full text.

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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.

Frölich L, Padberg F, Kratzsch T, Maurer K, Möller HJ, Hampel H. · Klinik für Psychiatrie und Psychotherapie der Univ. Frankfurt/M. · MMW Fortschr Med. · Pubmed #10920665 No free full text.

Abstract: In recent years, considerable progress has been made both in the diagnosis and treatment of dementia. Drugs have been developed which enhance cognitive performance in a large percentage of those afflicted, delay impairment of the ability to cope with the tasks of daily life, and avoid premature admission to a nursing home. In the practical medical care setting, however, these advantages are being utilized to only a limited extent, and this despite the fact that numerous therapeutic options are now available for the treatment of AD. New therapeutic approaches are aimed at inhibiting the pathological cleavage and extracellular and intracellular deposition of amyloid, preventing the toxic effects of amyloid accumulation around the neurons, and re-establishing intracellular transport deranged by the aggregation of neurofibrils. A further approach is the use of combinations of available substances with differing, possibly synergic, effects. Over and beyond this, treatment of AD in the "presymptomatic stage", or in the stage of only mild cognitive disturbance, is currently the subject of clinical trials.