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Advanced age represents one of the major risk factors for Parkinson’s Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson’s Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson’s Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson’s Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson’s Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson’s Disease patients, and healthy siblings of Parkinson’s Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson’s Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson’s Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson’s Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson’s Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson’s Disease.

The genetic component of many common traits is associated with the gene expression and several variants act as expression quantitative loci, regulating the gene expression in a tissue specific manner. In this work, we applied tissue-specific cis-eQTL gene expression prediction models on the genotype of 808 samples including controls, subjects with mild cognitive impairment, and patients with Alzheimer's Disease. We then dissected the imputed transcriptomic profiles by means of different unsupervised and supervised machine learning approaches to identify potential biological associations. Our analysis suggests that unsupervised and supervised methods can provide complementary information, which can be integrated for a better characterization of the underlying biological system. In particular, a variational autoencoder representation of the transcriptomic profiles, followed by a support vector machine classification, has been used for tissue-specific gene prioritizations. Interestingly, the achieved gene prioritizations can be efficiently integrated as a feature selection step for improving the accuracy of deep learning classifier networks. The identified gene-tissue information suggests a potential role for inflammatory and regulatory processes in gut-brain axis related tissues. In line with the expected low heritability that can be apportioned to eQTL variants, we were able to achieve only relatively low prediction capability with deep learning classification models. However, our analysis revealed that the classification power strongly depends on the network structure, with recurrent neural networks being the best performing network class. Interestingly, cross-tissue analysis suggests a potentially greater role of models trained in brain tissues also by considering dementia-related endophenotypes. Overall, the present analysis suggests that the combination of supervised and unsupervised machine learning techniques can be used for the evaluation of high dimensional omics data.

Introduction Recent developments in artificial intelligence (AI) and neuroimaging offer new opportunities for improving diagnosis and prognosis of dementia. To synthesise the available literature, we performed a systematic review. Methods We systematically reviewed primary research publications up to January 2021, using AI for neuroimaging to predict diagnosis and/or prognosis in cognitive neurodegenerative diseases. After initial screening, data from each study was extracted, including: demographic information, AI methods, neuroimaging features, and results. Results We found 2709 reports, with 252 eligible papers remaining following screening. Most studies relied on the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset (n=178) with no other individual dataset used more than 5 times. Algorithmic classifiers, such as support vector machine (SVM), were the most commonly used AI method (47%) followed by discriminative (32%) and generative (11%) classifiers. Structural MRI was used in 71% of studies with a wide range of accuracies for the diagnosis of neurodegenerative diseases and predicting prognosis. Lower accuracy was found in studies using a multi-class classifier or an external cohort as the validation group. There was improvement in accuracy when neuroimaging modalities were combined, e.g. PET and structural MRI. Only 17 papers studied non-Alzheimers disease dementias. Conclusion The use of AI with neuroimaging for diagnosis and prognosis in dementia is a rapidly emerging field. We make a number of recommendations addressing the definition of key clinical questions, heterogeneity of AI methods, and the availability of appropriate and representative data. We anticipate that addressing these issues will enable the field to move towards meaningful clinical translation.

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