Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy

Abstract

The incidence of dementia is increasing at an alarming rate, and has become a major public health concern. Alzheimer disease (AD) is the most common form of dementia and is characterized by progressive cognitive impairment. In addition to classical neuropathological features such as amyloid plaques and neurofibrillary tangles (NFT), accumulation of activated immune cells has been documented in the AD brain, suggesting a contribution of neuroinflammation in the pathogenesis of AD. Besides cognitive deterioration, non-cognitive symptoms, such as agitation, aggression, depression and psychosis, are often observed in demented patients, including those with AD, and these neuropsychological symptoms place a heavy burden on caregivers. These symptoms often exhibit sudden onset and tend to fluctuate over time, and in many cases, they are triggered by an infection in peripheral organs, suggesting that inflammation plays an important role in the pathogenesis of these non-cognitive symptoms. However, there is no mechanistic explanation for the relationship between inflammation and neuropsychiatric symptoms. Observations from experimental mouse models indicate that alteration of brain blood vessels, especially blood-brain barrier (BBB) dysfunction, may contribute to the relationship. The current review summarizes the results from recent studies on the relationship between inflammation and AD, while focusing on cerebrovascular alterations, which might provide an insight into the pathogenesis of cognitive/non-cognitive symptoms in AD patients and suggest a basis for the development of new therapeutic treatments for these conditions.

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

“…Thus, it is possible that the CNS abnormalities observed in ME/CFS patients can be explained, at least in part, by the ability of leptin and resistin to cross and/or disrupt the bloodbrain barrier (46). Moreover, systemic inflammation, such as that found in our patients, has been invoked as a mechanism for neuroinflammation in other neurodegenerative disease models (47)(48)(49). In animal models, systemic administration of LPS alone has been shown to result in neuroinflammation (45,50).…”

The neuropathology and cerebrovascular mechanisms of dementia

“…These studies have led to the observation that such 'neurovascular inflammation' is mediated by the peripheral systemic immune response, and that the two immune systems may work synergistically, thus influencing AD neuropathology and cognition. 101 Although significant neurovascular inflammation has been reported, its role and contributions to the AD brain remains unclear.…”

“…A growing body of literature links active inflammatory responses to AD neuropathology. 101 Epidemiologic data suggest that neuroinflammation serves as an independent predictor of early death in AD. 102 Microglia, the resident macrophage of the brain, have been shown to associate with A plaques in AD.…”

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

“…[1][2][3][4] Neuroinflammation is considered to play an important role in a variety of neuropathologies, such as Alzheimer's disease, Parkinson's disease and traumatic brain injury. [5][6][7] P2X 7 receptor antagonists have been developed as potential pharmaceuticals for the treatment of various diseases including neuroinflammation. [8][9][10] We are interested in biomedical imaging to detect and quantify neuroinflammation, with positron emission tomography (PET) offering the best opportunity for success with development and validation of suitable targeted radioligands.…”