Aducanumab, a human monoclonal antibody, was approved in June of 2021 as the first disease-modifying treatment for Alzheimer’s disease by the United States Food and Drug Administration (U.S. FDA). A substantial proportion of patients with Alzheimer’s disease live in low- and middle-income countries (LMICs), and the debilitating effects of this disease exerts burdens on patients and caregivers in addition to the significant economic strains many nations bear. While the advantages of a disease-modifying therapy are clear in delaying the progression of disease to improve patient outcomes, aducanumab’s approval by the U.S. FDA was met with controversy for a plethora of reasons. This paper will provide precursory insights into aducanumab’s role, appropriateness, and cost-effectiveness in low- and middle-income countries. We extend some of the controversies associated with aducanumab, including the contradicting evidence from the two trials (EMERGE and ENGAGE) and the resources required to deliver the treatment safely and effectively to patients, among other key considerations.

Neurodegenerative diseases (ND) are a form of non-communicable disease that have placed immense social and financial burdens on society. The number of people affected by ND is an ongoing trend due to the global issue of an ageing population. Hence, more effort should be made to treat ND, so alternative options like natural components are considered. Tocotrienol (T3) is a form of vitamin E that possesses many beneficial properties, such as antioxidant, anti-cancer and anti-inflammatory properties. In recent years, many clinical studies revolving around diseases such as neurodegenerative diseases, cardiovascular diseases and osteoporosis appear to suggest that T3 supplementation can be effective in alleviating the symptoms of these diseases. Given that T3 has multiple health benefits and is a potential therapeutic agent for ND, it is important to understand the mechanism through which T3 exerts the beneficial works. One such pathway is the NF-κB signalling pathway, which is closely associated with neuroinflammation and neurodegenerative diseases. Understanding the mechanism of how T3 affects this pathway could be crucial to demonstrate the efficacy of T3 in the management of ND.

Infectious diseases caused by fungi, viruses, or bacteria can have a profound impact on human cognition. This can be due to either direct spread to the central nervous system (CNS) or indirect neuroinflammation. Ultimately causing neuronal damage and even neurodegeneration. Deteriorations in cognition, such as poor encoding and attention deficits, have been reported secondary to infectious diseases. Preclinical studies have identified the underlying mechanisms of these infection-related cognitive effects, such as through blood-brain barrier (BBB) disruption and M1 microglial polarization. These mechanisms are spearheaded by inflammatory markers that are released/initiated by the pathogens over the course of the infection. Among them, the high mobility group box 1 (HMGB1) protein is a common biomarker implicated across several infection-related cognitive deficits. Understanding these effects and mechanisms is crucial for the development of strategies to prevent and treat infection-related cognitive impairment. This review will thus consolidate and elucidate the current knowledge on the potential role of HMGB1 as a therapeutic target for infection-related cognitive impairments. This review will not only advance scientific understanding but also have significant clinical and public health implications, especially considering recent global health challenges. Based on the selected articles, extracellular HMGB1, as opposed to intracellular HMGB1, acts as damage-associated molecular patterns (DAMPs) or alarmins when released in the peripheries secondary to inflammasome activation. Due to their low molecular weight, they then enter the CNS through routes such as retrograde transport along the afferent nerves, or simple diffusion across the impaired BBB. This results in further disruption of the brain microenvironment due to the dysregulation of other regulatory pathways. The outcome is structural neuronal changes and cognitive impairment. Given its key role in neuroinflammation, HMGB1 holds promise as both a biomarker for diagnostic detection and a potential therapeutic target candidate for preventing infection-related cognitive impairment.

Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Huntington’s Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.

Neurotrauma plays a significant role in secondary injuries by intensifying the neuroinflammatory response in the brain. High Mobility Group Box-1 (HMGB1) protein is a crucial neuroinflammatory mediator involved in this process. Numerous studies have hypothesized about the underlying pathophysiology of HMGB1 and its role in cognition, but a definitive link has yet to be established. Elevated levels of HMGB1 in the hippocampus and serum have been associated with declines in cognitive performance, particularly in spatial memory and learning. This review also found that inhibiting HMGB1 can improve cognitive deficits following neurotrauma. Interestingly, HMGB1 levels are linked to the modulation of neuroplasticity and may offer neuroprotective effects in the later stages of neurotraumatic events. Consequently, administering HMGB1 during the acute phase may help reduce neuroinflammatory effects that lead to cognitive deficits in the later stages of neurotrauma. However, further research is needed to understand the time-dependent regulation of HMGB1 and the clinical implications of treatments targeting HMGB1 after neurotrauma.