Childhood dementia encompasses a heterogeneous group of >100 rare and ultra-rare neurogenetic disorders characterised by progressive neurocognitive decline. With therapy available for only <5 % of childhood dementias, identification of biomarkers to interrogate and link shared biological pathways are important for the development of disease-modifying therapies. This study aimed to utilise an untargeted mass spectrometric approach to identify CSF-based biomarkers associated with childhood dementias.
This was a retrospective cross-sectional study that included children with childhood dementia (n = 11) and controls (n = 14) recruited at Sydney Children’s Hospital Network, NSW, Australia between June 2022-Oct 2023. Cerebrospinal fluids were depleted of high-abundant proteins using human 14 (Hu14) column (4.6 x 100 mm, Agilent, United States) followed by in-solution trypsin digestion. Depleted and bound fractions were analysed using liquid chromatography–mass spectrometry (LS-MS/MS) methodology via a Q-Exactive Plus mass spectrometer. Bioinformatic analyses incorporated variance stabilizing normalization and removal of unwanted variation.
This study revealed 25 proteins (downregulated = 19, upregulated = 6, log fold change > 0.5) that were significantly dysregulated in the CSF of patients with childhood dementias. Downregulated proteins included Gelsolin, Amyloid beta precursor like protein 2. and neuroendocrine protein 7B2. Upregulated proteins included subtypes of Apolipoproteins. Gene Ontology (GO) and pathway analysis have identified these proteins in adult-onset dementias (including Alzheimer’s and Parkinsons disease), where their dysregulation is implicated in axonogenesis, neuron apoptotic processes, and extracellular matrix organization pathways.
Our study reinforces the concept that childhood and adult dementias may share common pathogenic pathways. High-throughput proteomics can be leveraged to identify CSF-based protein signatures involved in the complex interplay between neurodevelopment and neurodegeneration. Further research is required to validate these biomarkers and expand our understanding of the underlying pathophysiology of childhood dementia but also drive us toward effective therapeutic strategies.