A qualitative study of the discrepancy between patient expectations and assessment practices in 5q-adult spinal muscular atrophy in France.

MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs with a critical role in the epigenetic regulation of neuronal development, function, and pathology [, ]. They regulate cellular functions by binding to and inhibiting target genes []. As a single miRNA can bind to several target genes, its expression levels can reflect and regulate multiple (patho)physiological processes []. Thus, they have been investigated for the diagnosis and therapy of neurodegenerative diseases, especially Alzheimer’s Disease (AD) [–]. However, in past studies, neurodegenerative diseases have mostly been dichotomized based on the presence or absence of a diagnosis. Although heuristically useful, this simplification disregards the heterogeneous nature of most such diseases as well as the potential interactions between miRNAs and the brain beyond disease, i.e., both during development and aging []. To further elucidate the role of miRNAs in brain health and neurodegeneration, a detailed understanding of their association with key brain-related phenotypes is needed, coupled with a characterization of their biological functions. Moreover, identifying miRNAs associated with phenotypes typical of neurodegeneration in healthy, younger individuals could aid the development of miRNA biomarkers for the very early detection of neurodegenerative diseases. The hippocampus is essential for long-term memory formation and spatial navigation []. Although diffuse brain atrophy is expected during “healthy” aging, hippocampus-specific atrophy due to accumulation of neuropathology is one of the earliest changes observed in AD and other dementias [–]. Notably, the left hippocampus tends to be smaller than the right [] and this asymmetry increases in dementia [], but there is little evidence for lateralized atrophy in normal aging [, ]. Additionally, a higher genetic risk of AD has been associated with a smaller hippocampus [], which in turn has been associated with future cognitive decline [, ] and worse memory performance, even in non-demented, young individuals [, ]. Thus, the structure and atrophy patterns of the hippocampus in each hemisphere provide granular information on brain health and neurodegeneration. Previous studies have shown that blood-derived miRNA expression is related to brain atrophy in cohorts consisting of neurologic or psychiatric patients [–]. Moreover, we previously showed that some cognition-related miRNAs are cross-sectionally associated with hippocampal volume in the general population []. However, our previous study only examined this association in specific, cognition-related miRNAs. The complete relationship of blood-derived miRNAs with hippocampal structure and atrophy in the general population remains unexplored. This relationship is particularly relevant for miRNAs suggested as biomarkers for the early detection of dementia [], as it would support their involvement in preclinical neuropathology, before the emergence of cognitive symptoms. Here, we aimed to identify blood-derived miRNAs cross-sectionally and longitudinally related to hippocampal volume and left-to-right asymmetry, considering a decrease in hippocampal volume over time as a proxy of hippocampal atrophy. Our analysis was based on data from the population-based Rhineland Study. To determine whether our findings were specific to the hippocampus, we also identified the miRNAs cross-sectionally and longitudinally related to total brain volume. Subsequently, we employed functional genomics to uncover genes and biological pathways regulated by the identified miRNAs. Moreover, we performed genome-wide association studies (GWAS) to detect miRNA expression quantitative trait loci (miR-eQTLs). Lastly, we leveraged these miR-eQTLs to assess potentially causal associations of miRNAs with imaging measures in a Mendelian randomization framework.