Bascunana, P. | Search bioRxiv

bioRxiv2026

Predictive value of brain 18F-FDG PET neuroimaging in a mouse model of sudden death

Sudden unexpected death (SUD) is a major cause of mortality in neurological disorders, with poorly understood mechanisms and no reliable biomarkers. Brain-heart axis dysfunction has been implicated in SUD pathogenesis. Using the FUSdelta14 mouse model, we tested whether cerebral glucometabolism, assessed by 18F-FDG PET, reflects autonomic dysregulation and predicts SUD vulnerability. 18F-FDG PET/CT and ECG were acquired at 10 weeks of age (FUSdelta14/delta14 n=12, FUS+/delta14 n=14, FUS+/+ n=12). Heart rate variability was analyzed in time and frequency domains, brain uptake via volume of interest and voxel-wise approaches, and correlations assessed by Pearson's analysis. A classification-tree model tested SUD predictability within the FUSdelta14/delta14 group. Female FUSdelta14/delta14 mice showed reduced 18-FFDG uptake in basal forebrain septum, left amygdala, and brainstem, with increased uptake in hypothalamus and right midbrain, alongside cardiac size, metabolic and heart rate variability alterations. 50% experienced SUD; in this subgroup, PET showed cortical hypometabolism (insular, entorhinal) and hypermetabolism in hypothalamus, amygdala, septum, and brainstem. Although brainstem uptake was able to singlehandedly predict SUD in this particular FUSdelta14/delta14 group (AUC=0.787), cross-validation also highlighted cortical metabolism as a relevant feature (UsageRate=0.38 and 0.44, respectively). 18F-FDG PET identifies region-specific metabolic signatures of brain-heart axis dysfunction linked to SUD, supporting its potential as a non-invasive biomarker for risk stratification.

neuroscience↗

bioRxiv2023

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43.

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of [~]50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.

neuroscience↗