The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the “sentinels” of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in physiologic brain aging and Alzheimer’s disease (AD). A systematic literature search of all published articles about microglial senescence in human healthy aging and AD was performed, searching for PubMed and Scopus online databases. Among 1947 articles screened, a total of 289 articles were assessed for full-text eligibility. Microglial transcriptomic, phenotypic, and neuropathological profiles were analyzed comprising healthy aging and AD. Our review highlights that studies on animal models only partially clarify what happens in humans. Human and mice microglia are hugely heterogeneous. Like a two-sided coin, microglia can be protective or harmful, depending on the context. Brain health depends upon a balance between the actions and reactions of microglia maintaining brain homeostasis in cooperation with other cell types (especially astrocytes and oligodendrocytes). During aging, accumulating oxidative stress and mitochondrial dysfunction weaken microglia leading to dystrophic/senescent, otherwise over-reactive, phenotype-enhancing neurodegenerative phenomena. Microglia are crucial for managing Aβ, pTAU, and damaged synapses, being pivotal in AD pathogenesis.

Alzheimer’s disease (AD) is one of the most common neurodegenerative pathologies. Its incidence is in dramatic growth in Western societies and there is a need of both biomarkers to support the clinical diagnosis and drugs for the treatment of AD. The diagnostic criteria of AD are based on clinical data. However, it is necessary to develop biomarkers considering the neuropathology of AD. The A_2A receptor, a G-protein coupled member of the P1 family of adenosine receptors, has different functions crucial for neurodegeneration. Its activation in the hippocampal region regulates synaptic plasticity and in particular glutamate release, NMDA receptor activation and calcium influx. Additionally, it exerts effects in neuroinflammation, regulating the secretion of pro-inflammatory cytokines. In AD patients, its expression is increased in the hippocampus/entorhinal cortex more than in the frontal cortex, a phenomenon not observed in age-matched control brains, indicating an association with AD pathology. It is upregulated in peripheral blood cells of patients affected by AD, thus reflecting its increase at central neuronal level. This review offers an overview on the main AD biomarkers and the potential role of A_2A adenosine receptor as a new marker and therapeutic target.

Variants of cerebral amyloid angiopathy (CAA) have been increasingly reported. Iatrogenic CAA (iCAA) is a subtype arising in patients with a history of neurosurgery. Current etiopathogenetic hypotheses focus on previous exposure to contaminated materials, such as cadaveric dura, followed by a prion-like mechanism. CAA-related inflammation (CAA-ri) represents the inflammatory variant of CAA, usually with a good response to immunosuppressive therapy. To date, the association between iCAA and CAA-ri has not been clarified yet. This study reports cases of iCAA evolving into CAA-ri, emphasizing the clinical and radiologic overlaps between these conditions. This retrospective observational study included patients with clinical and radiologic features of CAA-ri and a history of neurosurgical intervention, observed at 2 Italian neurologic centers. Patients were identified from CAA databases and screened for neurosurgical history before 1990. Eligible cases met diagnostic criteria for CAA-ri. Clinical data were anonymized and included surgical details, evidence of amyloid-β in the CNS (amyloid-PET, CSF biomarkers, genetic screening), and CAA-ri features (symptoms, imaging findings, treatment, and outcomes). We identified 6 patients with iCAA who developed clinical and instrumental features of CAA-ri during their follow-up. The mean age at neurosurgery was 17.2 years (range: <1-43) while the onset of CAA-ri occurred at 61.8 years (range: 48-79), with an average latency of 44.7 years (range: 36-59). Despite immunosuppressive treatment, 2 patients experienced a rapid decline in their clinical condition and deceased within a few months from CAA-ri onset. This study increases awareness about the potential occurrence of CAA-ri in patients with iCAA, confirming its aggressive nature and highlighting the importance of neuroinflammation in the pathogenesis of the disease. In these patients, CAA-ri seems to be associated with a severe clinical course and a poor response to steroid treatment, often resulting in a fatal outcome in the short term.

INPLASY2024100082 Investigating Neuropathological Correlates of Hyperactive and Psychotic Symptoms in Dementia: A Systematic Review Keywords: neuropathology, BPSD, neuropsychiatric symptoms, psycho…