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Articles by Philip Scheltens
Total Records ( 10 ) for Philip Scheltens
  Serge Gauthier and Philip Scheltens
  The past 30 years have seen multiple attempts at demonstrating the safety and efficacy of drugs for Alzheimer's disease (AD), predominantly to improve symptoms. Only five drugs (tacrine, donepezil, rivastigmine, galantamine, memantine) have obtained regulatory approval in most countries. Their cost-effectiveness from a societal perspective has not been universally recognized, and anybody who thinks these drugs are useful for individual patients will have to agree that the improvement above the starting point of treatment is moderate. Most of the benefit has been in slowing down progression of symptoms rather than a readily detectable improvement above baseline. There have also been attempts at arresting progression of AD, but all have failed until now. Should we change our approach to developing new drugs for AD so as to move forward? This review will highlight some options to consider in the development of future drugs for AD, with emphasis on strategies to prevent AD or arrest its progression.
  Guy M. McKhann , David S. Knopman , Howard Chertkow , Howard Chertkow , Clifford R. Jack , Claudia H. Kawas , William E. Klunk , Walter J. Koroshetz , Jennifer J. Manly , Richard Mayeux , Richard C. Mohs , John C. Morris , Martin N. Rossor , Philip Scheltens , Maria C. Carrillo , Bill Thies , Sandra Weintraub and Creighton H. Phelps
  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.
  Reisa A. Sperling , Clifford R. Jack , Sandra E. Black , Matthew P. Frosch , Steven M. Greenberg , Bradley T. Hyman , Philip Scheltens , Maria C. Carrillo , William Thies , Martin M. Bednar , Ronald S. Black , H. Robert Brashear , Michael Grundman , Eric R. Siemers , Howard H. Feldman and Rachel J. Schindler
  Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-β burden in Alzheimer‘s disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer‘s Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent ”vasogenic edema“ and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2∗ thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research.
  Clifford R. Jack , Frederik Barkhof , Matt A. Bernstein , Marc Cantillon , Patricia E. Cole , Charles DeCarli , Bruno Dubois , Simon Duchesne , Nick C. Fox , Giovanni B. Frisoni , Harald Hampel , Derek L.G. Hill , Keith Johnson , Jean-Francois Mangin , Philip Scheltens , Adam J. Schwarz , Reisa Sperling , Joyce Suhy , Paul M. Thompson , Michael Weiner and Norman L. Foster
  Background The promise of Alzheimer‘s disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer‘s disease and thus represents the most rational target for an initial effort at standardization. Methods and Results The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer‘s Disease Centers–Alzheimer‘s Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer‘s Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. Conclusions Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.
  Philip Scheltens and Kenneth Rockwood
  Current Alzheimer‘s disease (AD) criteria state that a definite diagnosis can only be made by postmortem examination. The neuropathological confirmation is often referred to as the ”gold standard.“ In this article, we review what constitutes a gold standard and how the neuropathological examination of AD lives up to that standard. We conclude that there is no evidence for this notion because results between different laboratories differ to an important extent, especially when the clinical picture is in doubt, for example, when the dementia is mild. As an alternative, we propose to abandon thinking in standards and value neuropathology as any other biomarker, and to strive to use and integrate multiple sources of information to make the diagnosis of AD in all its complexity.
  Sietske A.M. Sikkes , Elly S.M. de Lange-de Klerk , Yolande A.L. Pijnenburg , Freek Gillissen , Rolinka Romkes , Dirk L. Knol , Bernard M.J. Uitdehaag and Philip Scheltens
  Background Interference in everyday functioning is part of the diagnostic criteria for dementia. Questionnaires measuring ”instrumental activities of daily living“ (IADL) are used to measure this interference, but the psychometric quality of these questionnaires is often questioned. In addition, these questionnaires are less suited for early-onset patients. This is problematic, given the high frequency of relatively young patients in memory clinics. In this article, we describe the development and psychometric properties of a new informant-based IADL questionnaire aimed at detecting incipient dementia and appropriate for a broad age range. Methods We defined IADL in consensus with experts and constructed items based on existing items and suggestions from experts and informants. Informants of subjects (n = 206) who visited the Alzheimer Center of the VU University Medical Center completed the questionnaire. Factor structure was investigated using classical exploratory factor analysis and item response theory. We assessed test–retest reliability in 73 informants using weighted κ values. Results The questionnaire consisted of 75 items and was computerized to enhance ease of administration. Exploratory factor analysis supported a single-factor model, with 48.3% of the variance being explained by the first factor. We removed five items, as they did not fit the model. High internal consistency was demonstrated. Test–retest reliability showed that the majority of items (87.9%) had substantial-to-almost perfect κ values. Conclusion The Amsterdam IADL Questionnaire (Amsterdam IADL questionnaire is a registered trademark of Alzheimer Center VU University Medical Center, Amsterdam, The Netherlands) is a 70-item informant-based computerized questionnaire aimed at detecting early dementia and early-onset dementia. Initial results show that this questionnaire is a promising new tool.
  Pieter Jelle Visser , Stephanie Vos , Ineke van Rossum and Philip Scheltens
  Two sets of research criteria for Alzheimer‘s disease are now available: those published by an International Working Group in 2007, and the recommendations published by the National Institute on Aging and the Alzheimer‘s Association (NIA–AA) in 2011. They both provide guidelines for the diagnosis of asymptomatic and symptomatic Alzheimer‘s disease. The coexistence of two sets of criteria for the same disorder raises the question of which set of criteria should be preferred. A comparison of the criteria revealed differences in approach, terminology, and use of cognitive markers and biomarkers. Most persons who meet the International Working Group criteria will also meet the NIA–AA criteria and vice versa. However, the NIA–AA criteria allow for a subclassification of persons based on biomarker results within each diagnostic category. Further research is needed to validate the criteria. Modifications are likely to be made before the criteria can be used in daily practice.
  Petra E. Spies , Jurgen A.H.R. Claassen , Petronella G.M. Peer , Marinus A. Blankenstein , Charlotte E. Teunissen , Philip Scheltens , Wiesje M. van der Flier , Marcel G.M. Olde Rikkert and Marcel M. Verbeek
  Background We aimed to develop a prediction model based on cerebrospinal fluid (CSF) biomarkers, that would yield a single estimate representing the probability that dementia in a memory clinic patient is due to Alzheimer‘s disease (AD). Methods All patients suspected of dementia in whom the CSF biomarkers had been analyzed were selected from a memory clinic database. Clinical diagnosis was AD (n = 272) or non-AD (n = 289). The prediction model was developed with logistic regression analysis and included CSF amyloid β42, CSF phosphorylated tau181, and sex. Validation was performed on an independent data set from another memory clinic, containing 334 AD and 157 non-AD patients. Results The prediction model estimated the probability that AD is present as follows: p(AD) = 1/(1 + e – [–0.3315 + score]), where score is calculated from –1.9486 × ln(amyloid β42) + 2.7915 × ln(phosphorylated tau181) + 0.9178 × sex (male = 0, female = 1). When applied to the validation data set, the discriminative ability of the model was very good (area under the receiver operating characteristic curve: 0.85). The agreement between the probability of AD predicted by the model and the observed frequency of AD diagnoses was very good after taking into account the difference in AD prevalence between the two memory clinics. Conclusions We developed a prediction model that can accurately predict the probability of AD in a memory clinic population suspected of dementia based on CSF amyloid β42, CSF phosphorylated tau181, and sex.
  Esther L.G.E. Koedam , Annelies E. van der Vlies , Wiesje M. van der Flier , Nicolaas A. Verwey , Ted Koene , Philip Scheltens , Marinus A. Blankenstein and Yolande A.L. Pijnenburg
  Objective In this study we investigated the relationships between cerebrospinal fluid (CSF) biomarkers (tau and amyloid-β1-42 [Aβ1-42]) and cognition or behavior in patients with frontotemporal dementia (the behavioral variant, bvFTD). Methods We included 58 patients with bvFTD. All patients underwent a neuropsychological assessment and lumbar puncture. Relationships between CSF biomarkers and cognition or behavior were assessed with linear regression analysis. Results After correction for age, sex, and education, CSF tau levels were found to be negatively related to the Visual Association Test (standardized β = −0.3, P < .05), whereas CSF Aβ1-42 levels were found to be positively related to the Mini-Mental State Examination (β = 0.3, P < .05), the frontal assessment battery (β = 0.5, P < .05), and digit span backwards test (β = 0.3, P = .01). We did not find relations between CSF biomarkers and behavior (measured by the neuropsychiatric inventory). After excluding all patients with a CSF biomarker profile often seen in Alzheimer‘s disease (high levels of tau and low levels of Aβ1-42), we still found relations between CSF Aβ1-42 levels and Visual Association Test object naming (β = 0.4, P < .05), as well as between CSF Aβ1-42 levels and the frontal assessment battery (β = 0.5, P < .05, but there was no relation between CSF tau and cognition. Conclusion Low CSF Aβ1-42 levels are associated with worse general cognitive function and worse executive function in patients with bvFTD. Our results provide circumstantial evidence for a pathophysiological role of Aβ1-42 in bvFTD.
  Wesley Jongbloed , Maartje I. Kester , Wiesje M. van der Flier , Robert Veerhuis , Philip Scheltens , Marinus A. Blankenstein and Charlotte E. Teunissen
  Background Multiplex assays such as xMAP have been proposed for the assessment of Alzheimer‘s disease (AD) biomarkers amyloid β 42 (Aβ42), tau (Tau), and phosphorylated tau (pTau) in cerebrospinal fluid (CSF). Here, we compared the traditional enzyme-linked immunosorbent assay (ELISA) and xMAP with respect to their: (1) absolute biomarker concentration, (2) ability to distinguish AD from nondemented subjects, (3) ability to monitor AD longitudinally, and (4) ability to predict progression from mild cognitive impairment (MCI) to AD. Methods We selected 68 AD, 62 MCI, and 24 nondemented subjects, performed clinical examinations, and obtained CSF at baseline and 2 years later. Aβ42, Tau, and pTau were measured with both ELISA and xMAP. Results Biomarker levels differed considerably between the two assays, and the differences were concentration dependent. No differences were observed in ability to distinguish nondemented subjects from AD patients between ELISA (area under curve of 0.84 for Aβ42, 0.79 for Tau, and 0.75 for pTau) and xMAP (area under curve of 0.82 for Aβ42, 0.75 for Tau, and 0.73 for pTau), all P < .05. Increased Aβ42 levels of AD patients at follow-up compared with baseline were detected with ELISA, whereas increased Tau levels for nondemented subjects and MCI patients were only detected with xMAP. The hazard ratios for progression from MCI to AD did not differ between the assays. Conclusion Both ELISA and multiplex assays can be used to measure AD biomarker levels in CSF to support clinical diagnosis and predict progression from MCI to AD with similar accuracy. Importantly, the assays‘ output in absolute biomarker concentrations is remarkably different, and this discrepancy cannot be reconciled with simple correction factors.
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