Neuroinflammation Within Human COVID-19 Brains

Post by Lina Teichmann

What's the science?

A variety of neurological symptoms have been associated with COVID-19. For example, patients frequently experience loss of smell as well as headaches, fatigue, and memory impairments. This week in Immunity, Schwabenland and colleagues examined the effects of COVID-19 on the brain on a cellular, immunological, and anatomical level.

How did they do it?

Brain tissue of 25 COVID-19 patients was examined post-mortem and compared to brain tissue of three groups of control patients. These patients either (1) died of non-infectious causes which had little or no influence on the brain, or (2) had a history of severe respiratory diseases and were treated with extracorporeal membrane oxygenation, or (3) patients who had multiple sclerosis - an autoimmune disease of the central nervous system. The authors used imaging mass cytometry (IMC), a technique that allows for the spatial mapping and detection of immune populations in the brain. They examined the brain stem as well as the olfactory bulb in a subgroup of the patients as the olfactory bulb is the potential entry site for SARS-CoV-2.

What did they find?

The results showed profound neuroinflammation in the brain tissue of COVID-19 patients with altered brain immune responses and associated neuronal damage, neither of which occurred in the control patient groups. Segmenting the IMC images showed that there were immune cell clusters of innate (non-specific immediate immune response) and adaptive (specific and long-lasting immune response) immune cells in COVID-19 patients that were not present in the brain tissue of the controls. The specific immune activation in COVID-19 brains consisted primarily of CD8 and CD4 T cells around blood vessels and clusters of macrophages and microglial cells that were associated with the disease. The specific characteristics of the immune infiltrate indicated microvascular injury in COVID-19 patients and a damaged blood-brain-barrier. In addition to vascular damage, the results also showed that the immune infiltration in COVID-19 patients was associated with axonal damage. Together, these results elucidate the specific inflammatory patterns of COVID-19 in the brain and indicate that the immune response in the central nervous system is particularly affected by the disease.

What's the impact?

It is essential to understand the effects of SARS-CoV-2 on the body and brain. Schwabenland and colleagues identified neuroinflammatory responses triggered by COVID-19 and highlighted how the immune response is modulated due to the disease. These findings deepen our understanding of COVID-19 and offer new opportunities to develop treatments that could suppress neuroinflammation.

Schwabenland et al. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T cell interactions. Immunity (2021). Access the original scientific publication here.

The US Food and Drug Administration Approves Use of Aducanumab for Alzheimer’s Disease Treatment

Post by Shireen Parimoo

Treatments for Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative illness characterized by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain that lead to widespread neurodegeneration, resulting in dementia and eventual death. AD affects more than 20 million people in the world, and with a growing global aging population, it has become increasingly crucial to develop treatments that can stop or delay the progression of AD symptoms.

Over the decades, several drugs have been developed and tested in randomized clinical trials. The drugs that have previously been approved for treating symptoms of AD help regulate the level of neurotransmitters in the brain. For example, the drug Donepezil helps temporarily mitigate memory-related symptoms by preventing the breakdown of acetylcholine. So far, however, none of these drugs have been effective in preventing the progression of AD or treating the underlying neuropathology. In fact, no new drug has been approved by the United States Food and Drugs Administration (FDA) for AD treatment since 2003.

In The Lancet Neurology, Lon Schneider provides an overview of a novel AD drug – aducanumab – created by the company Biogen. Schneider outlines the mechanism by which the drug targets AD pathology along with the history of its development. Aducanumab is a monoclonal antibody that is markedly different from other AD drug candidates because it directly binds to and clears out Aβ deposits in the brain, thereby targeting the hypothesized neuropathological mechanism underlying AD progression.

Is aducanumab effective?

Early randomized clinical trials showed that aducanumab injections over a year reduced Aβ levels in patients with prodromal or mild AD, though the clinical effects were less conclusive. Following up on these promising results, 1650 patients were enrolled in two separate multi-year phase 3 trials in 2015 to determine the efficacy of aducanumab in reducing the clinical symptoms of AD.

Despite initially promising results, several factors halted further testing of the drug. Firstly, there were issues with uneven participant dropout, missed doses, and poor compliance with the treatment protocol between the placebo and drug groups. Secondly, futility analyses conducted to monitor the interim efficacy of the drug showed mixed results and undesirable side effects like brain swelling. Specifically, differences in clinical symptoms between patients taking aducanumab and placebo only emerged in one of the trials. Moreover, it is unclear whether the differences were due to the drug’s efficacy in improving symptoms or because of worsening symptoms in the placebo group.

Finally, some of the positive results were observed in patients who received high doses of aducanumab, were genetically less at risk for experiencing side effects, and were highly compliant with the treatment protocol. In contrast, the placebo group consisted of more patients who were genetically predisposed to developing side effects and experienced greater clinical decline. Together, these factors posed a challenge to the validity of the findings from the clinical trials.

What’s happening now?

In June 2021, the FDA approved aducanumab under its accelerated approval pathway. This decision came after the FDA advisory committee had initially voted against approving the drug in November 2020. The accelerated approval approach is typically taken when the benefits provided by a drug under consideration outweigh those of existing treatments and are likely to have desirable long-term effects as well.

According to the FDA, their primary reason for approving aducanumab was the reliable dose- and time-dependent reduction in Aβ plaques. It is hoped that in turn, a lower Aβ burden will reduce further clinical decline, even though the evidence for this effect is currently uncertain. The next steps include conducting phase 4 clinical trials to confirm the clinical benefits of aducanumab in AD patients.

Schneider, L. A resurrection of aducanumab for Alzheimer’s disease. Neurology (2020). Access the original scientific publication here.

https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease

Dopamine and Brain Network Dynamics in Schizophrenia

Post by Lincoln Tracy

What's the science?

Working memory allows us to maintain and revise cognitive representations to successfully complete tasks. Dopamine D1 and D2 receptors are responsible for modulating the prefrontal neurons required for working memory in a dual-state manner; D1 receptors maintain cognitive representations while D2 receptors enable flexible shifts between different cognitive states. Evidence suggests that truly functional working memory requires a structured transition through global brain states and reconfiguration of interactions throughout the brain, but it is unclear how the brain guides such transitions and interactions. The network control theory (NCT) has been identified as a promising tool to study such questions. This week in Nature Communications, Braun and colleagues used NCT to study the stability of whole-brain neural states (measured by functional magnetic resonance imaging; fMRI) during a well-established working memory task.

How did they do it?

First, the authors recruited 178 healthy individuals and had them complete an N-back task while undergoing fMRI. The authors were specifically interested in comparing brain states and individual brain activity patterns under a working memory condition (i.e., 2-back) and an attentional control condition (0-back). Using these states, they examined how the brain transitioned between different cognitive states between the two task conditions and how much control energy was required to maintain state stability within a specific task. 

Second, the authors tested the system’s sensitivity to dopaminergic manipulation and whether interfering with D2-related signaling would increase the energy required to switch between the two brain states. A second sample of 16 healthy controls were administered amisulpride, a selective D2 receptor antagonist, before completing the N-back working memory task. 

Finally, the authors examined differences in brain state stability and control state transition ability by recruiting 24 individuals with schizophrenia (a condition involving dopamine dysfunction and working memory deficits) and a matched sample of healthy control participants. The N-back working memory task was completed again during an fMRI scan.

What did they find?

First, the authors found the more cognitively demanding 2-back brain state was less stable than the 0-back control state. The stability of the 2-back state was associated with higher working memory accuracy. Transitioning into the 2-back state from the 0-back required more control energy than transitioning in the opposite direction. The prefrontal and parietal cortices were found to steer the transition between states, while the default mode network was specifically implicated in transitioning to the more cognitively demanding state. Second, they found greater control energy was needed to transition between the N-back task states following amisulpride administration. There was no effect of amisulpride on brain state stability. Finally, they found brain state stability was reduced in individuals with schizophrenia during the 2-back, but not the 0-back, working memory task. Schizophrenic individuals required greater control energy for transitioning between the 0- and 2-back tasks. Together these results suggest schizophrenic individuals have a more diverse brain energy landscape, making the system more challenging to manage appropriately.

What's the impact?

These findings reveal the critical role dopamine signaling plays in steering whole-brain network dynamics (i.e., state stability and switching) during working memory and how this process is altered in schizophrenia. Importantly, this steering is done in a dual-state manner, where D1 and D2 receptors have unique but cooperative functions. Further research and consideration is required to elucidate the specific cognitive processes underlying brain activity and how other patient factors (e.g., schizophrenia severity, medication use, etc.) may influence network dynamics.

Braun et al. Brain network dynamics during working memory are modulated by dopamine and diminished in schizophrenia. Nature Communications (2021).Access the original scientific publication here.