*4.1. Sources of Neuroinflammation*

The mechanisms involved in neuroinflammation by biomolecular or cellular pathways are alike in aging and metabolic diseases such as depression, dementia, diabetes, and hypertension, as well as cerebral insult conditions such as stroke, and contribute silently to neuroinflammation. In elderly groups of patients, the mechanism of inflammation has been strongly associated with the pathogenesis of dementia and functional impairment [89]. Local and systemic inflammation in CNS significantly contributes to the development of small cerebral vessel diseases such as vascular dementia, which is mainly hypothesized as microvascular changes that cause a state of chronic hyper perfusion and lead to the death of oligodendrocytes and consecutively cause the destruction of myelin fibers, which increases inflammation in the affected brain region [90,91].

Other markers of inflammation such as C-reactive protein (CRP) can help with the prediction of clinical and subclinical atherosclerosis and play a major role in the identification of brain hemorrhage and conditions of stroke. Various other metabolic disorders such as diabetes [92], obesity, and hypertension also lead to dysfunction of the adipose tissue and induce low-grade inflammation, thereby worsening neuroinflammation in patients with a history of stroke [93]. Another factor that induces the synthesis of proinflammatory cytokines is aging processes. The inflammation triggered due to aging in the brain manifests chronic activation of parenchymal and perivascular macrophages and increases expression of microglial cells, thereby increasing the number of astrocytes. This chronic activation and signaling of pro-inflammatory cytokines increases the vulnerability of the patient to psychiatric disorders [94].

Females that are obese are mainly observed to have elevated concentrations of interleukin-6, CRP, and adipokines [95]. All these pro-inflammatory cytokines contribute positively to manifesting symptoms of depression and anxiety. Upon surgical removal of fat tissues, an alleviation in anxiety was noted. Further metabolic diseases such as hypertension and obesity accompanied with older age groups pose as a prevalent risk factor in the initiation of cognitive dysfunction, including depression, dementia, and other neurodegenerative disorders [96].

The biological mechanism responsible for depression is still lucid, and patients are administered conventional anti-depressant therapy for the correction of the disease; however, it has been noted that neuroinflammation suppresses the beneficial effects of the therapy in one-third of patients, leading to resistance in treatment [97]. The putative mechanism that links inflammation and neurodegeneration includes elevated pro-inflammatory cytokines, mainly IL-6 or IL-8 [98], oxidative stress, higher glutamate, and uncoupling of endothelial nitric oxide synthase. In severe psychiatric illnesses such as major depressive disorder, evidence of neurovascular dysfunction was determined to be indirectly associated with increased concentrations of inflammatory cytokines in the periphery [99].

Hyperactivated immune response results in an inflammatory cytokine rush and poses problems to the central nervous system [100]. Immune responses are generally triggered upon exposure to certain infectious agents such as viruses, bacteria, or any other associated pathogens [101]. A pathogen can enter the CNS through two different hypothetical pathways, including hematogenous dissemination, through which the pathogen gains direct access to the brain via the blood–brain barrier, and neuronal retrograde dissemination [102,103]. Different pathogens interact in distinct ways and lead to the activation of macrophages and further stimulation of inflammatory cytokines and neuroinflammation.
