Neuroinflammation describes the immune response within the central nervous system, which includes the brain and spinal cord. This process is the body’s way of protecting neural tissue from injury, infection, or disease. While an acute inflammatory response is rapid and typically resolves after the threat is cleared, a different, more damaging form of immune activity can take hold. This persistent, low-grade immune reaction is known as smoldering neuroinflammation. This chronic state of immune activation is now understood to be a significant factor driving the progression of various neurological disorders.
Defining Smoldering Neuroinflammation
Smoldering neuroinflammation is characterized by a sustained, persistent activation of the brain’s immune system. Unlike acute inflammation, this slow-burning process operates at a chronic, low level, often too subtle to be detected by conventional clinical means.
This low-level activity causes gradual, sustained damage to neurons and supporting cells over years. This represents a fundamental shift from a protective immune response to a neurotoxic one, resulting in the continuous, slow loss of neural tissue and the accumulation of neurological disability.
The distinction between acute and smoldering activity is important because many current therapies successfully control the acute, relapsing forms of inflammation. However, the smoldering process often continues unchecked within the central nervous system, driving disease progression even in the absence of new lesions or visible relapses. This maintains an environment hostile to neuronal health and repair.
The Cellular Drivers of Chronic Brain Inflammation
The persistence of smoldering neuroinflammation is maintained primarily by the brain’s resident immune cells. Microglia are the central players, acting as the primary immune surveillance within the central nervous system. In a smoldering state, these cells become chronically “primed” or activated, shifting their function from protective to harmful.
Once primed, microglia release a variety of damaging molecules, including pro-inflammatory cytokines such as Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6). This sustained release of inflammatory mediators creates a toxic microenvironment that contributes directly to neuronal dysfunction and loss.
Astrocytes also contribute to the smoldering process by reacting to signals released by microglia. These cells become “reactive,” leading to the formation of glial scars that inhibit neural repair. The detrimental crosstalk between these two cell types perpetuates the low-grade inflammatory cycle.
Neurological Conditions Linked to Smoldering Activity
Smoldering activity is increasingly recognized as a major driver of disability in a range of neurodegenerative disorders. In Multiple Sclerosis (MS), this chronic inflammation is believed to be responsible for the progression independent of relapse activity (PIRA). Patients experience worsening disability even without acute relapses visible on a standard MRI. This persistent activity contributes to the atrophy of both gray and white matter in the brain.
In Alzheimer’s Disease (AD), the accumulation of abnormal proteins triggers the brain’s immune response. The prolonged activation of microglia and astrocytes around these protein aggregates is a form of smoldering neuroinflammation that exacerbates the disease. The chronic immune response fails to clear the toxic proteins and instead contributes to the progressive loss of synapses and neurons.
Similarly, in Parkinson’s Disease (PD), the misfolded protein alpha-synuclein aggregates, which form Lewy bodies, stimulate a chronic inflammatory reaction in specific brain regions, particularly the substantia nigra. The sustained release of inflammatory chemicals in this area leads to the degeneration of dopamine-producing neurons, a hallmark of the disease.
Identifying and Monitoring Smoldering Inflammation
Detecting smoldering inflammation presents a challenge because it often occurs in areas of the brain that appear normal on conventional magnetic resonance imaging (MRI). Researchers are turning to advanced neuroimaging techniques to visualize the activated immune cells directly.
Positron Emission Tomography (PET) scans use specialized radioactive tracers that bind to the translocator protein (TSPO), which is highly expressed on activated microglia. Measuring TSPO binding, or the “glial activity load,” provides a quantitative measure of chronic immune activation. For example, a specialized tracer called F-18 PBR 06 has been used to detect this persistent inflammation in individuals with MS. In addition to imaging, researchers are exploring fluid biomarkers, such as specific proteins found in cerebrospinal fluid or blood, that can indicate ongoing chronic immune activity.