Tag: brain fog

The Potential Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Post-COVID-19 Condition: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog

Abstract:

Post-COVID-19 condition (commonly known as Long COVID) is a heterogeneous clinical condition in which Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and brain fog stand out among the different clinical symptoms and syndromes. Cerebral metabolic alterations and neuroendocrine disorders seem to constitute an important part of the pathophysiology of Post-COVID-19 condition (PCC).

Given the substantial lack of specific drugs and effective therapeutic strategies, hypothalamic phospholipid liposomes, which have been on the market for several years as adjuvant therapy for cerebral metabolic alterations resulting from neuroendocrine disorders, might represent a potential option in an overall therapeutic strategy that aims to control PCC-associated symptoms and syndromes. Their pharmacological mechanisms and clinical effects strongly support their potential effectiveness in PCC. Our initial clinical experience seems to corroborate this rationale. Further controlled clinical research is warranted in order to verify this hypothesis.

Source: Menichetti F. The Potential Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Post-COVID-19 Condition: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog. J Clin Med. 2023 Aug 23;12(17):5478. doi: 10.3390/jcm12175478. PMID: 37685544; PMCID: PMC10488182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10488182/ (Full text)

Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization

Abstract:

Post-COVID cognitive deficits, including ‘brain fog’, are clinically complex, with both objective and subjective components. They are common and debilitating, and can affect the ability to work, yet their biological underpinnings remain unknown.

In this prospective cohort study of 1,837 adults hospitalized with COVID-19, we identified two distinct biomarker profiles measured during the acute admission, which predict cognitive outcomes 6 and 12 months after COVID-19.

A first profile links elevated fibrinogen relative to C-reactive protein with both objective and subjective cognitive deficits. A second profile links elevated D-dimer relative to C-reactive protein with subjective cognitive deficits and occupational impact. This second profile was mediated by fatigue and shortness of breath. Neither profile was significantly mediated by depression or anxiety.

Results were robust across secondary analyses. They were replicated, and their specificity to COVID-19 tested, in a large-scale electronic health records dataset. These findings provide insights into the heterogeneous biology of post-COVID cognitive deficits.

Source: Taquet, M., Skorniewska, Z., Hampshire, A. et al. Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization. Nat Med (2023). https://doi.org/10.1038/s41591-023-02525-y https://www.nature.com/articles/s41591-023-02525-y (Full text)

Treatment of Brain Fog of Long COVID Syndrome: A Hypothesis

Abstract:

The emergence of the SARS-CoV-2 (COVID-19) virus has exacted a significant toll on the global population in terms of fatalities, health consequences, and economics. As of February 2023, there have been almost 800 million confirmed cases of the disorder reported to the WHO [1], although the actual case-positive rate is estimated to be much higher.

While many cases recover, the mortality rate associated with the illness is about 1% (based on the WHO data). Most patients experience the illness as a mild to moderate disorder and recover without significant sequelae. However, as the COVID-19 pandemic has continued, there has emerged a significant group of COVID-19 survivors who experience persistent symptoms beyond the acute course of the illness.

As many as one in eight patients report persistent symptoms 90 to 150 days after the initial infection [2]. These so-called Long COVID or post-COVID syndrome patients are mostly drawn from those who were hospitalised for the disorder, but both non-hospitalised and vaccinated subjects may also experience the syndrome [3]. While an agreed definition of Long COVID is yet to be settled, a multiplicity of symptoms affecting most major organ systems has been reported in patients.

Common Long COVID symptoms include fatigue, dyspnoea, headaches, myalgia, anosmia, dysgeusia, cognitive symptoms, and mental disorders such as depression and anxiety [4]. It is estimated that approximately a third of patients with Long COVID exhibit either fatigue, cognitive impairment, or both up to 12 weeks after a confirmed diagnosis of COVID-19 [5].

Source: Norman TR. Treatment of Brain Fog of Long COVID Syndrome: A Hypothesis. Psychiatry International. 2023; 4(3):242-245. https://doi.org/10.3390/psychiatryint4030024 https://www.mdpi.com/2673-5318/4/3/24 (Full text)

Long COVID, POTS, CFS and MTHFR: Linked by Biochemistry and Nutrition

Abstract:

The recent pandemic has energized research spotlighting chronic fatigue disorders. The similarities between Long COVID (LC) and Chronic Fatigue Syndrome (CFS), often accompanied by postural orthostatic tachycardia syndrome (POTS) are striking.

Furthermore, the majority afflicted with LC and CFS may be those with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, present in the majority of Americans and characterized by hypomethylation. Elevated homocysteine (Hcy) and depressed B9 and B12 may be links. Speculation about an association between these laboratory analytes and MTHFR abnormalities has been previously reported (Regland et al., 2015).

The absence of a blood-brain barrier (BBB) in CNS circumventricular organs (CVOs) that control autonomic and neuroendocrine functions, problematic in LC, CFS, POTS, and MTHFR, is provocative. Diffusion of CNS Hcy is associated with brain fog, cognitive impairment, and dementia. This provides a distinct link between MTHFR variants and the fog of LC, CFS, and POTS.

Small intestine bacterial overgrowth (SIBO), present in about 17% of Americans, is linked to POTS, mast cell activation syndrome (MCAS), and Ehlers Danlos syndrome (EDS). All exhibit histamine intolerance and female predominance. This may be due to hypomethylation and/or intestinal diamine oxidase (DAO) deficiency.

Metabolism of monoamines and histamine requires methylation. Specific CNS nuclei in CVOs may also provide insight to the POTS paradox. The similar gut microbiomes of LC/CFS (and vitamin D deficiency) may via CVOs trigger an imbalance in glutamate/GABA neurotransmission that translates to neuroendocrine and baroreflex dysfunction. Homozygosity for the MTHFR 677T allele can facilitate hypermethylation via an alternative “rescue” riboflavin pathway triggered by significant Hcy increase.

Hypermethylation predominates in Long Covid. The primary problem in these syndromes is compromised mitochondrial function due to oxidative stress induced by an antioxidant shortfall.

Victims are also frequently deficient in 25(OH)D3 (the storage form of vitamin D), magnesium, and B vitamins, consumed by the persistent chronic inflammatory state. Estrogen increases histamine, norepinephrine, and bradykinin (BKN), which may in part explain the brain fog and its predilection for females.

Source: Patrick W Chambers. Long COVID, POTS, CFS and MTHFR: Linked by Biochemistry and Nutrition. Journal of Orthomolecular Medicine. 38. https://www.researchgate.net/publication/373073968_Long_Covid_POTS_CFS_and_MTHFR_Linked_by_Biochemistry_and_Nutrition#fullTextFileContent (Full text)

Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19

Abstract:

The coronavirus disease 2019 (COVID-19) remains an epidemic worldwide. Most patients suffer residual symptoms, the so-called “Long COVID,” which includes respiratory and neuropsychiatric symptoms. Brain Fog, one of the symptoms of Long COVID, is a major public health issue because it can impair patients’ quality of life even after recovery from the disease. However, neither the pathogenesis nor the treatment of this condition remains unknown.

We focused on serum ferritin levels in this study and collected information on the onset of Brain Fog through questionnaires and found that high ferritin levels during hospitalization were associated with the occurrence of Brain Fog. In addition, we excluded confounders as far as possible using propensity score analyses and found that ferritin was independently associated with Brain Fog in most of the models. We conducted phase analysis and evaluated the interaction of each phase with ferritin levels and Brain Fog.

We found a positive correlation between serum ferritin levels during hospitalization and Brain Fog after COVID-19. High ferritin levels in patients with Brain Fog may reflect the contribution of chronic inflammation in the development of Brain Fog. This study provides a novel insight into the pathogenic mechanism of Brain Fog after COVID-19.

Source: Ishikura T, Nakano T, Kitano T, Tokuda T, Sumi-Akamaru H, Naka T. Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19. Sci Rep. 2023 Aug 11;13(1):13095. doi: 10.1038/s41598-023-40011-0. PMID: 37567939; PMCID: PMC10421912. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421912/ (Full text)

Neuropsychological measures of post-COVID-19 cognitive status

Abstract:

Background: COVID-19 may result in persistent symptoms in the post-acute phase, including cognitive and neurological ones. The aim of this study is to investigate the cognitive and neurological features of patients with a confirmed diagnosis of COVID-19 evaluated in the post-acute phase through a direct neuropsychological evaluation.

Methods: Individuals recovering from COVID-19 were assessed in an out-patient practice with a complete neurological evaluation and neuropsychological tests (Mini-Mental State Examination; Rey Auditory Verbal Test, Multiple Feature Target Cancellation Test, Trial Making Test, Digit Span Forward and Backward, and Frontal Assessment Battery). Pre- and post-COVID-19 global and mental health status was assessed along with the history of the acute phase of infection. Post-COVID-19 cognitive status was modeled by combining persistent self-reported COVID-related cognitive symptoms and pathologic neuropsychological tests.

Results: A total of 406 individuals (average age 54.5 ± 15.1 years, 45.1% women) were assessed on average at 97.8 ± 48.0 days since symptom onset. Persistent self-reported neurological symptoms were found in the areas of sleep (32%), attention (31%), and memory (22%). The MMSE mean score was 28.6. In total, 84 subjects (20.7%) achieved pathologic neuropsychological test results. A high prevalence of failed tests was found in digit span backward (18.7%), trail making (26.6%), and frontal assessment battery (10.9%). Cognitive status was associated with a number of factors including cardiovascular disease history, persistent fatigue, female sex, age, anxiety, and mental health stress.

Conclusion: COVID-19 is capable of eliciting persistent measurable neurocognitive alterations particularly relevant in the areas of attention and working memory. These neurocognitive disorders have been associated with some potentially treatable factors and others that may stratify risk at an early stage.

Source: Lauria A, Carfì A, Benvenuto F, Bramato G, Ciciarello F, Rocchi S, Rota E, Salerno A, Stella L, Tritto M, Di Paola A, Pais C, Tosato M, Janiri D, Sani G, Lo Monaco R, Pagano FC, Fantoni M, Bernabei R, Landi F, Bizzarro A; Gemelli Against COVID-19 Post-acute Care Group. Neuropsychological measures of post-COVID-19 cognitive status. Front Psychol. 2023 Jul 10;14:1136667. doi: 10.3389/fpsyg.2023.1136667. PMID: 37492442; PMCID: PMC10363721. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10363721/ (Full text)

Long COVID, the Brain, Nerves, and Cognitive Function

Abstract:

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms.
Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies.
This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored.
Source: Reiss AB, Greene C, Dayaramani C, Rauchman SH, Stecker MM, De Leon J, Pinkhasov A. Long COVID, the Brain, Nerves, and Cognitive Function. Neurology International. 2023; 15(3):821-841. https://doi.org/10.3390/neurolint15030052 https://www.mdpi.com/2035-8377/15/3/52 (Full text)

Chronic inflammation, neuroglia dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome

Highlights:

  • Plasmalogens (Pls) are lipids containing a vinyl-ether bond in their glycerol backbone
  • Pls have antioxidant properties and are important for curved membrane assemblies
  • Post-COVID-19 symptoms are highly prevalent and share several features with ME/CFS
  • Pls depletion is a shared biological hallmark of ME/CFS and acute COVID-19 syndrome
  • Pls replacement is a promising tool against neuroinflammation in these two conditions

Abstract:

After five waves of COVID-19 outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties (“brain fog”), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions.

Of great interest, recent evidence revealed a significant reduction of plasmalogens contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms.

Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.

Source: Chaves AM, Braniff O, Angelova A, Deng Y, Tremblay MÈ. Chronic inflammation, neuroglia dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome. Brain Res Bull. 2023 Jul 7:110702. doi: 10.1016/j.brainresbull.2023.110702. Epub ahead of print. PMID: 37423295. https://www.sciencedirect.com/science/article/pii/S0361923023001272?via%3Dihub (Full text)

The Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Long Covid: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog

Abstract:

Long Covid is a heterogeneous clinical condition in which Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and brain fog stand out among the different clinical symptoms and syndromes. The cerebral metabolic alterations and neuroendocrine disorders seem to constitute an important part of Long Covid.

Given the substantial lack of drugs and effective therapeutic strategies, hypothalamic phospholipid liposomes which have been on the market for several years as adjuvant therapy of cerebral metabolic alterations resulting from neuroendocrine disorders, can be taken into consideration in an overall therapeutic strategy that aims to control the Long Covid associated symptoms and syndromes. Their pharmacological mechanisms and clinical effects strongly support their usefulness in Long Covid. Our initial clinical experience corroborates this rationale. Further research is imperative in order to obtain robust clinical evidence.

Source: Menichetti, F. The Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Long Covid: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog. Preprints.org 2023, 2023070005. https://doi.org/10.20944/preprints202307.0005.v1 https://www.preprints.org/manuscript/202307.0005/v1 (Full text available as PDF file)

Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID

Abstract:

Sustained cognitive deficits are a common and debilitating feature of “long COVID”, but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function.
KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID.
Source: Fesharaki Zadeh A, Arnsten AFT, Wang M. Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID. Neurology International. 2023; 15(2):725-742. https://doi.org/10.3390/neurolint15020045 https://www.mdpi.com/2035-8377/15/2/45 (Full text)