Biology subjects

Michael, B. D.

Publications and source records attributed to Michael, B. D..

3 recordsLinked to original sources

bioRxiv2026

Regional Similarity to Sex-Typical Young Adult Brain Architecture is a Longitudinal Correlate of Neuroinflammation and Depression in Later Adulthood

Lifespan trajectories of psychiatric and neurodegenerative risk show robust overlap and marked sex differences. Nonetheless, their neurobiological underpinnings are still poorly understood. One potential culprit is the predominant categorical definition of sex, which overlooks the tapestry of sex-dependent and sex-independent features recently shown to typify each human brain. Shifting from a holistic, dichotomous approach to regionally specific, continuous assessments of sex differences in brain function could help identify individualized therapeutic targets for both psychiatric and neurological conditions. To probe the psychiatric and neurological relevance of functional alignment with sex-typical brain architecture, we analyzed longitudinal neuroimaging and clinical data from a healthy aging cohort (N = 353, aged 36-87 years). We identified complementary patterns of deviance from sex-typical brain architecture along the canonical sensorimotor-to-association axis, which overlapped areas enriched in microglial genes and genes regulating sex steroid metabolism. The two connectivity patterns differentiated longitudinally between psychiatric symptoms and neurodegeneration as a function sex and age: one connectivity pattern related to more severe future depression in younger women, whereas the second related to later neurodegeneration (higher GFAP and pT217 blood concentration) and poorer fluid cognition (inhibition, episodic memory, processing speed, working memory) in older men. The aforementioned effects showed some context-specificity, as they involved connectivity patterns characterized during awake rest and cognitive control, but not associative memory performance. Taken together, our findings attest to the value of integrating regionally specific, continuous assessments of sex differences in brain function with inflammation-relevant biomarkers in order to support precision medicine approaches across the life course.

neuroscience↗

bioRxiv2025

Cytokines of the Interleukin-1 superfamily and Interleukin-6 are associated with neuroinflammation and brain injury in Herpes Simplex Virus Encephalitis

Herpes simplex virus (HSV) is the leading cause of encephalitis, with high rates of morbidity and mortality. Dysregulated immune responses have been associated with poor outcomes in small series, driving interest in immunotherapies. However, the key mediators of neuropathology, their cellular sources, and responsiveness to corticosteroid treatment remain unknown. We present findings from an RCT of dexamethasone in 55 adults with HSV encephalitis, alongside a representative murine model. Clinical severity and adverse outcomes were associated with neuroglial injury biomarkers (GFAP, tau, UCH-L1), increased cerebral oedema on MRI, and higher IL-1RA, IL-18, and IL-6. These mediators were more abundant in matched CSF than serum, and were not reduced by dexamethasone. In the model, neurons, astrocytes and microglia robustly expressed IL-1 and IL-6, supporting their CNS origin. These findings identify IL-1 and IL-6 signalling as key drivers of immunopathology in HSV encephalitis and potential therapeutic targets to mitigate neuroinflammation and improve outcomes. FundingNational Institute for Health and Care Research (grant number 12/205/28).

neuroscience↗

bioRxiv2021

Viral neuroinvasion and neurotropism without neuronal damage in the hACE2 mouse model of COVID-19

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, also after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally orientated regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.

pathology↗