Live brain biopsy during CSF shunt surgery for precision diagnostics and multi-omic research

Diagnostic testing and neurosurgical management involving CSF shunting in patients with idiopathic normal pressure hydrocephalus (iNPH) offers a unique, ethically sustainable opportunity to study the aging human brain. The common co-occurrence of neurodegenerative pathologies such as amyloid-β plaques and neurofibrillary tau tangles (NFT) provides a valuable window for research into the Alzheimer's disease-related mechanisms. Interindividual variability among iNPH patients enables investigation and validation of biomarkers and molecular mechanisms, opening possibilities for new treatments. In vitro techniques and culturing methods for living brain tissue expand the utility of samples for electrophysiological studies, drug testing, and examining genetic risk variants. Careful sectioning and processing are essential for high-quality samples with intact cells for functional analysis. A rigorous pipeline is also needed for preserving samples for transcriptomic, proteomic, and structural analyses, with emphasis on RNA integrity and tissue architecture for single-cell sequencing and spatial analysis. Here, we review the use of small cortical brain biopsies in neurodegenerative diseases research and diagnostics. Furthermore, we share our team's experience in acquiring and preserving living brain samples during iNPH CSF shunt surgeries, along with our protocols for resection, use, and preservation of biopsies for preclinical research. We highlight the potential of living human tissue for neuroscience, early neurodegenerative disease diagnosis, and targeted therapies.