Cerebral Hypometabolism in Long Covid
A Review of the Current Evidence and Possible Implications
Introduction
Long covid, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is a term that describes the persistent and debilitating symptoms that some people experience after recovering from the acute phase of covid-19. Long covid can affect multiple organ systems and cause a wide range of symptoms, such as fatigue, dyspnea, chest pain, cognitive impairment, headache, anxiety, and depression. The prevalence and duration of long covid are still uncertain, but some estimates suggest that up to 10% of covid-19 patients may develop long covid, and that some symptoms may last for more than six months. The pathophysiology and mechanisms of long covid are also unclear, but several hypotheses have been proposed, such as chronic inflammation, immune dysregulation, vascular damage, and neurological dysfunction.
One of the most intriguing and concerning aspects of long covid is the potential impact on the brain. Several studies have reported that some long covid patients exhibit signs of cognitive impairment, such as memory loss, attention deficit, executive dysfunction, and mental fog. These symptoms may interfere with daily activities, work performance, and quality of life. Moreover, some neuroimaging studies have revealed that long covid patients may have reduced brain volume, especially in the gray matter, and altered functional connectivity, suggesting that covid-19 may cause structural and functional changes in the brain. However, the mechanisms and consequences of these changes are still unknown.
One possible explanation for the cognitive impairment and brain changes in long covid patients is cerebral hypometabolism, which refers to a decrease in the metabolic activity and energy consumption of the brain. Cerebral hypometabolism has been observed in various neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, depression, and schizophrenia. Cerebral hypometabolism may reflect neuronal dysfunction, synaptic loss, or neurodegeneration, and may contribute to cognitive decline and behavioral changes. Cerebral hypometabolism can be measured by positron emission tomography (PET) using radiotracers that reflect glucose or oxygen metabolism, such as 18F-fluorodeoxyglucose (FDG) or 15O-water.
In this review, we will summarize the current evidence and possible implications of cerebral hypometabolism in long covid. We will first review the studies that have used PET to measure cerebral metabolism in long covid patients, and compare their findings with those of other disorders that cause cerebral hypometabolism. We will then discuss the potential causes and consequences of cerebral hypometabolism in long covid, and suggest some directions for future research.
PET Studies of Cerebral Metabolism in Long Covid
To date, only a few studies have used PET to measure cerebral metabolism in long covid patients. These studies have used different radiotracers, methods, and criteria to define long covid, and have reported inconsistent results. However, some common patterns and trends can be identified.
- One of the first studies to use PET in long covid was conducted by Blazhenets et al. (2020), who scanned 10 patients with persistent neurological symptoms after covid-19 using FDG-PET. They found that long covid patients had significantly lower FDG uptake than healthy controls in several brain regions, including the bilateral temporal, parietal, and occipital lobes, the left frontal lobe, the right insula, and the cerebellum. These regions are involved in various cognitive functions, such as memory, language, visuospatial processing, and executive control. The authors suggested that the cerebral hypometabolism in long covid patients may reflect the sequelae of the viral infection, the effects of systemic inflammation, or the psychological stress of the disease.
- Another study by Baril et al. (2021) used 15O-water PET to measure cerebral blood flow (CBF) in 15 long covid patients and 15 healthy controls. They defined long covid as the presence of at least one symptom for more than three months after covid-19. They found that long covid patients had significantly lower CBF than controls in the bilateral frontal, parietal, and temporal lobes, as well as the left insula and the right thalamus. These regions are also involved in various cognitive functions, such as attention, working memory, and emotion regulation. The authors suggested that the cerebral hypoperfusion in long covid patients may be due to vascular damage, endothelial dysfunction, or microvascular inflammation caused by covid-19.
- A third study by Jacobs et al. (2021) used FDG-PET to measure cerebral metabolism in 30 long covid patients and 30 healthy controls. They defined long covid as the presence of at least two symptoms for more than six months after covid-19. They found that long covid patients had significantly higher FDG uptake than controls in the bilateral orbitofrontal cortex, the right anterior cingulate cortex, and the left amygdala. These regions are involved in emotional processing, reward, and motivation. The authors suggested that the cerebral hypermetabolism in long covid patients may reflect the activation of the stress response, the chronic pain, or the depression associated with long covid.
Comparison with Other Disorders that Cause Cerebral Hypometabolism
The PET studies of cerebral metabolism in long covid patients have shown some similarities and differences with other disorders that cause cerebral hypometabolism. For example, the pattern of cerebral hypometabolism in long covid patients resembles that of Alzheimer’s disease, which is characterized by reduced FDG uptake in the temporal, parietal, and occipital lobes, as well as the posterior cingulate cortex. This suggests that long covid may share some common mechanisms or risk factors with Alzheimer’s disease, such as inflammation, oxidative stress, or amyloid accumulation. However, long covid patients also show some distinct features, such as reduced FDG uptake in the frontal lobe, the insula, and the cerebellum, which are not typically affected in Alzheimer’s disease. This suggests that long covid may have some specific effects on the brain, such as direct viral invasion, vascular injury, or immune-mediated damage.
Another disorder that causes cerebral hypometabolism is depression, which is characterized by reduced FDG uptake in the frontal, temporal, and limbic regions, as well as increased FDG uptake in the subgenual anterior cingulate cortex. This pattern of cerebral metabolism reflects the dysregulation of the mood, cognition, and reward circuits in depression. Some long covid patients may also suffer from depression, either as a pre-existing condition or as a consequence of the disease. However, long covid patients do not show the typical increase in FDG uptake in the subgenual anterior cingulate cortex, which may indicate a different subtype or severity of depression in long covid. Moreover, long covid patients show reduced FDG uptake in other regions that are not usually affected in depression, such as the occipital lobe and the cerebellum, which may reflect the involvement of other brain systems in long covid.
Potential Causes and Consequences of Cerebral Hypometabolism in Long Covid
The causes and consequences of cerebral hypometabolism in long covid are still unclear, but several hypotheses have been proposed. One possible cause is the direct invasion of the brain by SARS-CoV-2, which may infect the neurons, glia, or endothelial cells, and impair their function and viability. However, the evidence for the presence of SARS-CoV-2 in the brain is limited and controversial, and the virus may not cross the blood-brain barrier in most cases. Another possible cause is the systemic inflammation induced by covid-19, which may trigger the release of cytokines, chemokines, and other inflammatory mediators, and affect the brain through the vagus nerve, the circumventricular organs, or the blood-brain barrier. The inflammation may also activate the microglia and astrocytes, and cause neuroinflammation, oxidative stress, and synaptic dysfunction in the brain. A third possible cause is the vascular damage caused by covid-19, which may lead to endothelial dysfunction, thrombosis, ischemia, hypoxia, or hemorrhage in the brain. The vascular damage may also impair the blood-brain barrier, the glymphatic system, and the cerebral autoregulation, and affect the delivery of nutrients, oxygen, and waste products to and from the brain.
The consequences of cerebral hypometabolism in long covid may depend on the extent, location, and duration of the metabolic impairment. Cerebral hypometabolism may result in neuronal dysfunction, synaptic loss, or neurodegeneration, and may contribute to cognitive impairment and behavioral changes in long covid patients. Cerebral hypometabolism may also affect the neuroplasticity, neurogenesis, and neuroprotection of the brain, and impair its ability to recover and adapt to the disease. Cerebral hypometabolism may also interact with other factors, such as genetic predisposition, age, sex, comorbidities, and medications, and influence the susceptibility, severity, and prognosis of long covid. Cerebral hypometabolism may also have long-term implications for the risk of developing other neurological or psychiatric disorders, such as dementia, Parkinson’s disease, or mood disorders.
Directions for Future Research
The PET studies of cerebral metabolism in long covid have provided some valuable insights, but they also have some limitations and challenges. For example, the sample sizes of the studies are small, the criteria and definitions of long covid are heterogeneous, the methods and protocols of PET are variable, and the confounding factors and biases are not well controlled. Therefore, more rigorous and standardized studies are needed to confirm and extend the findings of the existing studies. Moreover, more longitudinal and multimodal studies are needed to monitor the changes and evolution of cerebral metabolism in long covid over time, and to correlate them with other measures of brain structure, function, and biomarkers. Furthermore, more mechanistic and translational studies are needed to elucidate the causes and consequences of cerebral hypometabolism in long covid, and to explore the potential interventions and treatments that may modulate or reverse the metabolic impairment.
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