Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. EADI. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

Deciphering the genetic landscape of Alzheimer disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer Disease BioBank (EADB) consortium a discovery meta-analysis of genome-wide association studies (GWAS) based on a new large case-control study and previous GWAS (in total 39,106 clinically diagnosed cases, 46,828 proxy-AD cases and 401,577 controls) with the most promising signals followed-up in independent samples (18,063 cases and 23,207 controls). In addition to 34 known AD loci, we report here the genome-wide significant association of 31 new loci with the risk of AD. Pathway-enrichment analyses strongly indicated the involvement of gene sets related to amyloid and Tau, but also highlighted microglia, in which increased gene expression corresponds to more significant AD risk. In addition, we successfully prioritized candidate genes in the majority of our new loci, with nine being primarily expressed in microglia. Finally, we observed that a polygenic risk score generated from this new genetic landscape was strongly associated with the risk of progression from mild cognitive impairment (MCI) to dementia (4,609 MCI cases of whom 1,532 converted to dementia), independently of age and the APOE e4 allele.

This paper presents a novel computer-aided diagnosis (CAD) technique for the early diagnosis of the Alzheimer's disease (AD) based on nonnegative matrix factorization (NMF) and support vector machines (SVM) with bounds of confidence. The CAD tool is designed for the study and classification of functional brain images. For this purpose, two different brain image databases are selected: a single photon emission computed tomography (SPECT) database and positron emission tomography (PET) images, both of them containing data for both Alzheimer's disease (AD) patients and healthy controls as a reference. These databases are analyzed by applying the Fisher discriminant ratio (FDR) and nonnegative matrix factorization (NMF) for feature selection and extraction of the most relevant features. The resulting NMF-transformed sets of data, which contain a reduced number of features, are classified by means of a SVM-based classifier with bounds of confidence for decision. The proposed NMF-SVM method yields up to 91% classification accuracy with high sensitivity and specificity rates (upper than 90%). This NMF-SVM CAD tool becomes an accurate method for SPECT and PET AD image classification.

Covariance matrix estimation arises in multivariate problems including multivariate normal sampling models and regression models where random effects are jointly modeled, e.g. random-intercept, random-slope models. A Bayesian analysis of these problems requires a prior on the covariance matrix. Here we compare an inverse Wishart, scaled inverse Wishart, hierarchical inverse Wishart, and a separation strategy as possible priors for the covariance matrix. We evaluate these priors through a simulation study and application to a real data set. Generally all priors work well with the exception of the inverse Wishart when the true variance is small relative to prior mean. In this case, the posterior for the variance is biased toward larger values and the correlation is biased toward zero. This bias persists even for large sample sizes and therefore caution should be used when using the inverse Wishart prior.

Plantar fasciopathy is very prevalent, affecting one in ten people in their lifetime.Around 90% of cases will resolve within 12 months with conservative treatment.Gastrocnemius tightness has been associated with dorsiflexion stiffness of the ankle and plantar fascia injury.The use of eccentric calf stretching with additional stretches for the fascia is possibly the non-operative treatment of choice for chronic plantar fasciopathy.Medial open release of approximately the medial third of the fascia and release of the first branch of the lateral plantar nerve has been the most accepted surgical treatment for years.Isolated proximal medial gastrocnemius release has been reported for refractory plantar fasciopathy with excellent results and none of the complications of plantar fasciotomy.Cite this article: EFORT Open Rev 2018;3:485-493. DOI: 10.1302/2058-5241.3.170080.

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