Roadmap to Alzheimer's Biomarkers in the ClinicClinical validity of medial temporal atrophy as a biomarker for Alzheimer's disease in the context of a structured 5-phase development framework
Graphical abstract
Introduction
Biomarker assessment at the time of clinical dementia is important for differential diagnosis and thereby also for prognosis and potential treatment. New clinical criteria have introduced the use of biomarkers for the diagnosis of Alzheimer's disease (Dubois et al., 2007, Dubois et al., 2014, Jack et al., 2011a, McKhann et al., 2011). These criteria also recommend the use of biomarkers for the diagnosis of Alzheimer's disease in nondemented subjects with mild cognitive impairment (MCI) (Albert et al., 2011). Early diagnosis offers an opportunity for early intervention, improved guidance for caregivers and more accurate prognosis.
Several biomarkers for Alzheimer's disease have been developed; however, there is insufficient systematically addressed evidence to implement them for a diagnosis of Alzheimer's disease at the MCI stage in routine clinical practice (Frisoni et al., 2011). To overcome a similar problem in the field of oncology, Pepe et al., (2001), suggested to systematize the investigation of cancer biomarkers based on a framework borrowed from drug development. A similar approach may boost the adoption of Alzheimer's disease biomarkers in clinical practice. An effort has recently been launched to adapt the oncology framework to suit the current goal of diagnosis of Alzheimer's disease at the MCI stage, as described in the accompanying summarizing article (Frisoni et al., 2017; Boccardi et al., 2017). The present study fulfills a specific part of this wider plan: the analysis of the available evidence for medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) in the context of this framework. The other studies from this effort assessed within the common framework of the following biomarkers are as follows: episodic memory assessment (Cerami et al., 2017), cerebrospinal fluid measures (Mattsson et al., 2017), amyloid positron emission tomography (PET) (Chiotis et al., 2017), [18F]fluorodeoxyglucose-PET (Garibotto et al., 2017), and [123I]-Ioflupane and [123I]-metaiodobenzylguanidine imaging (Sonni et al., 2017).
In a research setting, there are 3 methods commonly used to assess atrophy of the medial temporal lobe: visual rating, manual volumetry, and automated volumetry. In visual rating, atrophy is assessed on an ordinal scale. The most widely adopted visual rating scale in research, used in more than 100 publications, is the 5-point Scheltens scale which was developed over 20 years ago (Scheltens et al., 1992). MTA is visually assessed on coronal images taking into account the width of the choroid fissure, width of temporal horn, and height of hippocampus. Although visual rating scales can be broadly applied to a range of imaging acquisition methods and performed by a trained radiologist, it is still only sparsely adopted in clinical practice (Gardeniers et al., 2015). In manual volumetry, hippocampal atrophy is quantified by drawing multiple regions of interest by an experienced rater on adjacent coronal MRI slices, typically 1- to 3-mm thick. This requires trained raters and is time consuming. Several automated methods, which estimate volumes of structures by means of a computer algorithm, have been developed. Most of these algorithms involve an automated segmentation and classification of hippocampal tissue. Volume is then calculated as the sum of all voxels classified as hippocampal tissue. These techniques require specialist software and expertise and are also time consuming, and results can vary across scanners and acquisition protocols. Manual and automated volumetry is currently only used in research settings and not yet implemented for clinical use.
In this article, we will review evidence for the maturity of visual rating of MTA (vMTA) and hippocampal volume (HCV) as biomarkers for Alzheimer's disease at the MCI stage, where evidence is interpreted under the light of an adapted version of the oncology framework (Frisoni et al., 2017; Pepe et al., 2001).
Section snippets
Methods
This review was performed with reference to the oncology framework (Pepe et al., 2001), which was adapted to the field of dementia, specifically to the aim of performing the diagnosis of sporadic Alzheimer's disease at the MCI stage (Frisoni et al., 2017). The lexicon of this framework is extensively described by Frisoni et al., (2017), and is summarized in this section. Only sporadic, not familial Alzheimer's disease, is considered. The standard reference for diagnosis was Alzheimer's disease
Phase 1—pilot studies
The aim of phase 1 studies is to find leads for potential biomarkers based on pathological findings.
Alzheimer's disease is characterized by extracellular amyloid beta depositions and intraneuronal or extraneuronal neurofibrillary changes, eventually leading to neuronal destruction. Autopsy studies have shown that these changes already start many years before the onset of clinical symptoms with early and prominent neurofibrillary tangles in medial temporal lobe structures (Braak and Braak, 1991,
Conclusions and future perspectives
In this article, we reviewed the evidence for MTA as a biomarker for prediction of Alzheimer's disease at the MCI stage. We performed this review in the context of a wider effort, aiming to accelerate the use of Alzheimer's disease biomarkers at the predementia stage, where differentiating Alzheimer's disease from normal aging and other causes of cognitive impairment is of huge clinical and societal relevance. The effort has borrowed a biomarker validation framework developed for oncology
Disclosure statement
Drs. Ten Kate and Lovblad have nothing to disclose. Dr. Barkhof has received consulting fees or honoraria from Novartis, Roche, Serono, Bayer-Schering, Biogen-IDEC, Genzyme, TEVA, and Jansen Alzheimer Immunotherapy. Dr. Visser reports nonfinancial support from GE Healthcare, outside the submitted work. Dr. Frisoni has served in advisory boards for Roche, Lilly, BMS, Bayer, Lundbeck, Elan, Astra Zeneca, Pfizer, Taurx, Wyeth, GE, and Baxter. In the last 2 years, he received speaker honoraria from
Acknowledgements
The Geneva Task Force for the Roadmap of Alzheimer's Biomarkers includes the participants to a workshop held in Geneva on December 8–9, 2014. The PI of the Geneva Roadmap effort is Giovanni B Frisoni, with Bengt Winblad and Clifford R Jack Jr as co-PIs. The task force includes experts in biomarker development from the oncology community; experts on diagnostic Alzheimer's disease biomarkers from Switzerland and Europe; representatives of pertinent scientific societies (Federation of European
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