Background

Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (< 65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD.

Methods

We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software.

Results

Our results show significant differences in gene counts of circPSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD = 21, AD = 253, Controls = 23—ADADvsCO: log2FC = 0.794, p = 1.63 × 10–04, ADADvsAD: log2FC = 0.602, p = 8.22 × 10–04). The high gene counts are contributed by two circPSEN1 species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circPSEN1 is involved in several pathways such as axon guidance (p = 3.39 × 10–07), hippo signaling pathway (p = 7.38 × 10–07), lysine degradation (p = 2.48 × 10–05) or Wnt signaling pathway (p = 5.58 × 10–04) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70.

Conclusions

Our findings show the differential expression of circPSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.

[Paper in Acta neuropathologica communications]

We describe a novel system for online prediction of lead seizures from long-term intracranial electroencephalogram (iEEG) recordings for canines with naturally occurring epilepsy. This study adopts new specification of lead seizures, reflecting strong clustering of seizures in observed data. This clustering results in fewer lead seizures (~7 lead seizures per dog), and hence new challenges for online seizure prediction, that are addressed in the proposed system. In particular, the machine learning part of the system is implemented using the group learning method suitable for modeling sparse and noisy seizure data. In addition, several modifications for the proposed system are introduced to cope with the non-stationarity of a noisy iEEG signal. They include: (1) periodic retraining of the SVM classifier using most recent training data; (2) removing samples with noisy labels from training data; and (3) introducing a new adaptive post-processing technique for combining many predictions made for 20 s windows into a single prediction for a 4 h segment. Application of the proposed system requires only two lead seizures for training the initial model, and results in high prediction performance for all four dogs (with mean 0.84 sensitivity, 0.27 time-in-warning, and 0.78 false-positive rate per day). The proposed system achieves accurate prediction of lead seizures during long-term test periods, 3–16 lead seizures during a 169–364 day test period, whereas earlier studies did not differentiate between lead vs. non-lead seizures and used much shorter test periods (~few days long).

[Paper in Brain Science]

Many recent studies on online seizure prediction from iEEG signal describe various prediction algorithms and their prediction performance. In contrast, this paper focuses on proper specification of system parameters, such as prediction period, prediction horizon and data-driven characterization of lead seizures. Whereas prediction performance clearly depends on these system parameters many researchers simply set the values of these parameters in an ad hoc manner. Our paper investigates the effect of these system parameters on online prediction performance, using both synthetic and real-life data sets. Therefore, meaningful comparison of methods/algorithms (for online seizure prediction) should consider proper specification of system parameters.

[Paper in Neural Networks]

We describe new methodology for supervised learning with sparse data, i.e., when the number of input features is (much) larger than the number of training samples (n). Under the proposed approach, all available (d) input features are split into several (t) subsets, effectively resulting in a larger number (t*n) of labeled training samples in lower-dimensional input space (of dimensionality d/t). This (modified) training data is then used to estimate a classifier for making predictions in lower-dimensional space. In this paper, standard SVM is used for training a classifier. During testing (prediction), a group of t predictions made by SVM classifier needs to be combined via intelligent post-processing rules, in order to make a prediction for a test input (in the original d-dimensional space). The novelty of our approach is in the design and empirical validation of these post-processing rules under Group Learning setting. We demonstrate that such post-processing rules effectively reflect general (common-sense) a priori knowledge (about application data). Specifically, we propose two different post-processing schemes and demonstrate their effectiveness for two real-life application domains, i.e., handwritten digit recognition and seizure prediction from iEEG signal. These empirical results show superior performance of the Group Learning approach for sparse data, under both balanced and unbalanced classification settings.

[Paper in 2019 IJCNN]