Can SARS-CoV-2 Infection Lead To Neurodegeneration And Parkinson’s Disease? Part 2

3.2. SARS-CoV-2 Neuropathology

In general, neuropathological hallmarks of COVID-19 autopsy cases are diffuse edema, gliosis with activation of microglia and astrocytes, ischemic lesions, intracranial bleeds, arteriosclerosis, hypoxic-ischemic injury, encephalitis/meningitis, and diffuse inflammation [34,35]. 

Because diffuse edema may cause a series of physical symptoms, including fatigue, shallow breathing, headache, dizziness, etc., people often ignore its impact on memory. Some studies have found that symptoms of edema often lead to poor memory in people because it affects brain function and blood circulation.

First, we need to understand what diffuse edema is. It is a condition caused by excess fluid in the body. It can be caused by cardiovascular disease, kidney problems, liver disease, or certain medications. Symptoms of diffuse edema include general edema, swelling of hands and ankles, abdominal edema, etc.

Research shows that edema symptoms can cause a series of reactions in people's brains, leading to a decline in cognitive abilities and memory. For example, symptoms of edema may cause ischemia and hypoxemia in the brain, which can lead to the death of nerve cells in the brain and subsequently affect people's cognitive functions. At the same time, edema symptoms will also cause a large amount of fluid to accumulate in the human body, which will affect the balance of salts, hormones, and other substances, further affecting people's cognitive ability and memory.

However, incorporating positive thoughts can help us improve the negative effects of diffuse edema, thereby improving our memory. For example, we can improve edema symptoms through a healthy lifestyle, such as a reasonable diet and moderate exercise. In addition, some techniques to regulate emotions, such as deep breathing, yoga, and meditation, can also help us reduce the symptoms of edema and thereby improve memory.

In addition, we can also improve memory through some cognitive training, such as reading, learning new things, playing intellectual games, etc. These exercises can help us improve our thinking and concentration, thereby improving the negative effects of edema symptoms.

Diffuse edema does affect people's memory, but we can overcome its effects with positive thinking and lifestyle. Through these efforts, we can maintain a healthy body and sharp memory, improve our quality of life, and make us more fulfilled and happy. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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Patients suffering from severe COVID-19 showed a reduction in the number of neurons and an elevation in the number of activated microglial cells and astrocytes, as well as higher levels of proinflammatory cytokines measured by qPCR [36]. Matching the hypothesis of hematogenous invasion into the brain, Paniz-Mondolfi et al. detected the virus in capillary endothelium and neurons in frontal lobe tissue from a patient with COVID-19 [11,37]. 

The virus was not observed in glial cells in vivo [11]. Another group similarly found SARS-CoV-2 to favor CNS endothelial cells with the ACE2-receptor expressed in smooth muscle cells of blood vessels [38]. 

Small vessel disease was identified in five out of nine COVID-19 autopsy cases; however, SARS-CoV-2 was only detected in one case using immunohistochemistry [39]. Detection of SARS-CoV-2 in the brain using PCR was equally difficult; the highest viral load was documented in the olfactory bulb, while SARS-CoV-2 PCR was repeatedly negative in the substantia nigra [30,34,40]. 

Viral presence is, however, rarely detected in viral encephalitis in general (e.g., in herpesvirus-, arbovirus- or enterovirus-induced encephalitis) [6]. The brains of COVID-19 autopsy cases showed microglial activation in the olfactory bulb, frontal cortex, hippocampus, and most prominently in the brainstem, whereas lymphocytes did not appear to be activated [39]. 

Interestingly, patients with a history of delirium during COVID-19 demonstrated more microglial activation in the hippocampus [39]. Patients with and without sepsis could not be distinguished neuropathologically, contradicting the common hypothesis that neuropathology develops secondary to a cytokine storm during septic disease [39].

3.3. SARS-CoV-2 Neuroinflammation/Biomarkers

Apart from the direct influence of SARS-CoV-2 on the brain by invasion into the CNS, secondary effects on cerebral functions due to systemic alterations in the course of the disease are widely discussed. 

Investigations of brain tissue, biofluids, and the systemic reaction showed a (neuro-)inflammatory response triggered by COVID-19. Multiple cytokines were found to be elevated in the blood during acute COVID-19, while increased levels of pro-inflammatory markers were not detected in the cerebrospinal fluid (CSF) [41]. Serum levels of IL-4, IL-10, IL-6 and IL1β were elevated in COVID-19 patients [33,42,43]. IL-1- and IL-6 are known to trigger neuroinflammation [9]. 

SARS-CoV-2 antibodies were frequently detected in the CSF of COVID-19 patients, although this does not prove intrathecal antibody production [41,44,45]. The detection of the virus via PCR from CSF was impossible in most cases [41,44,45]. 

Only a few authors described sporadic positive results in SARS-CoV-2 PCR from CSF in patients with severe cerebral symptoms [46–48]. 

Analysis of markers indicating CNS lesions revealed elevated levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in plasma of patients with moderate to severe COVID-19 [17,49]. Additionally, three of eight patients with severe COVID-19 had signs of a disrupted blood-brain barrier, one had a specific intrathecal antibody synthesis and four were positive for 14-3-3 in the CSF [44]. 

The data on CSF pleocytosis are controversial so far. A case series of 15 patients and a review summarizing CSF white blood cell counts of 409 COVID-19 patients with neurological symptoms observed frequent pleocytosis (defined as >5 cells/µL) in 36% of 15 and 17% of 409 cases [30,50]. 

On the other hand, a case series of 13 patients with COVID-19 and encephalopathy or seizures reported CSF pleocytosis in only one case, similar to a study with 18 patients with COVID-19 and neurological complications that discovered pleocytosis in four cases and reported all four to be likely due to blood contamination [51,52]. 

Sun et al. investigated the cargo of neuronal-enriched extracellular vesicles and interestingly found elevated NfL, amyloid-β, neurogranin, tau, and phosphorylated tau in COVID-19 patients implicating possible neurodegenerative processes [42]. 

Take home messages of Chapter 1 (Section 3): 1. It is likely that SARS-CoV-2 can be neurotropic since this was shown for other human coronaviruses (HCov-OC43, Hcov-229E, SARS-CoV, MERS-Cov) in the past. 2. 

There are three possible routes of SARS-CoV-2 neuroinvasion: The transneuronal route via the olfactory nerve, the hematogenous route via vascular endothelium or a permeable blood-brain barrier, and the "Trojan-horse-mechanism" by infiltration of immune cells and subsequent invasion into the CNS via diapedesis. 3. Neuropathologically, SARS-CoV-2 leads to microglial activation in distinct CNS areas. 4. SARS-CoV-2 triggers a neuroinflammatory response with increased serum levels of several cytokines (e.g., IL-1, IL-6) and elevated markers such as NfL and GFAP in the CSF indicating CNS lesions.

4. Chapter 2

Viral Infection and Neurodegeneration

Besides the COVID-19 pandemic, there is broad (epidemiological) evidence linking other viral infections to neurodegenerative diseases, especially PD and AD, which will be reviewed in the following chapters. 

The idea, that viral infections can promote neurodegeneration first developed with encephalitis lethargica after the Spanish flu epidemic at the beginning of the 20th century [53]. Since then, a connection between infections and neurodegenerative diseases has been assumed repeatedly. A meta-analysis of 287,773 PD patients and 7,102,901 controls revealed that individuals with reported infections in the past had an elevated risk for PD (odds ratio, 1.20) [54]. 

This effect was foremost attributable to bacterial infections [54]. In line with this, a more recent study found a "higher infectious burden" defined by the existence of more antibodies against different viruses and bacteria in the blood of PD patients [55]. More specifically, PD risk was shown to be elevated after VZV infection (adjusted hazard ratio, 1.17) and PD patients were more often seropositive for EBV [56,57]. 

HCV is a well-established risk factor for PD as is HSV-1 infection for the development of AD [58–61]. Influenza viruses were brought into context with PD since encephalitis lethargica had a Parkinsonian phenotype, and an influenza virus was proposed as the infectious agent of the Spanish flu [53]. 

Furthermore, H1N1 infection led to persistent microglial activation as a sign of chronic neuroinflammation in wild-type mice [62]. H5N1 accordingly led to microglial activation and α-synuclein aggregation in mice resulting in the loss of dopaminergic neurons in the substantia nigra, which is recognized as the pathological hallmark of PD [63]. Furthermore, the influenza A virus was detected postmortem in the substantia nigra of PD patients [64]. 

A recent case-control study using data from the Danish National Patient Registry revealed that an influenza diagnosis was associated with the development of PD up to ten years later (odds ratio 1.73) [65]. 

Thus, a strong association between influenza viruses and PD is suspected but needs to be further elucidated. Japanese encephalitis virus causes a parkinsonian phenotype during acute disease, but even persistent parkinsonism with MRI lesions in the substantia nigra was observed three to five years after viral infection [66]. West Nile virus can also induce parkinsonism during acute infection. 

In postmortem studies, elevated α-synuclein levels were detected in patients infected with West Nile virus [57,67,68]. An interesting hypothesis about the function of α-synuclein was developed in an α-synuclein-knockout mouse model after West Nile infection [67]. 

The absence of α-synuclein in this model led to disastrous disease progression, suggesting a protective role of α-synuclein against viral infection [57,67]. It was postulated that α-synuclein entraps viral particles as a cellular defense mechanism, which persists after the infection leading to its pathological aggregation and subsequent neurotoxic effects. 

The same mechanism was proposed for β-amyloid, which can entrap HSV-1 and inhibit its viral replication and entry in vitro and in vivo [69,70]. HSV-1 infection was implicated as a disease risk factor foremost in AD but also in PD in different in vitro and in vivo investigations [71,72]. A 2.56-fold increased risk of developing dementia was reported in a retrospective cohort study with 8362 patients with acute HSV-1 or HSV-2 infections [60]. 

A phase 2 study investigating whether valaciclovir can slow the progression of AD in patients with HSV-1 is currently ongoing (clinicaltrials.gov NCT03282916) [70].

There are different studies suggesting the involvement of the adaptive immune system in the development of neurodegeneration. Genome-wide association studies have found an association of specific major histocompatibility complex II gene alleles with PD and T-cells of PD patients were shown to react to α-synuclein epitopes [73]. 

Another group showed that Th17-T-cells contribute to PD pathogenesis in a cell culture model of PD using induced pluripotent stem cells (iPSCs) [74]. Recently, T-cells were found to be adjacent to Lewy bodies and dopaminergic neurons in the brains of Lewy-body-dementia patients and stimulation of CD4+ T-cells with a phosphorylated α-synuclein epitope resulted in increased IL-17 production as a sign of a Th17-response [75]. 

Take home messages of Chapter 2 (Section 4): 1. Multiple epidemiological studies link different (viral) infections to PD, as individuals with certain infections have an elevated risk for PD. 

2. The protein α-synuclein might physiologically act as an infection defense mechanism, entrapping viral particles, which could lead to its pathological aggregation and subsequent neurotoxic PD effects. 

3. The involvement of the adaptive immune system in the development of neurodegenerative diseases has been increasingly implicated supporting the hypothesis that infections, and thus activation of the immune system can trigger neurodegenerative cascades.

5. Chapter 3

5.1. General Implications of SARS-CoV-2 in Neurodegeneration

The previously discussed mechanisms of viral neurotropism and neuroinflammation raise the question of whether long-term neurodegeneration has to be expected after COVID-19 disease. 

SARS-CoV-2 and potentially pathogenic proteins involved in neurodegeneration have been linked by different studies. It was observed that the spike protein receptor binding domain binds to heparin and heparin-binding proteins including amyloid-β, α-synuclein, tau, prion, and TDP-43, which may initiate the pathological aggregation of these proteins resulting in neurodegeneration [76,77]. 

The same mechanism is described for HSV-1, which catalyzes the aggregation of amyloid-β in vitro and in vivo and is a well-established risk factor for AD [76,78]. Recently, it was demonstrated that viral particles (including SARSCoV-2 spike protein) facilitate the spreading of protopathic seeds by altering intercellular cargo transfer [79]. Viruses use different strategies to take control over host cellular functions, such as interfering with autophagy and mitochondrial or lysosomal functions, which are implicated in the development of neurodegenerative disease as well [80]. 

SARS-CoV-2 alters autophagy and mitochondrial and lysosomal functions in infected lung cells [81]. Furthermore, viral changes in proteostasis of the host cell can lead to accelerated "aging" of the infected tissue, which may then boost neurodegenerative processes that are common in senescent cells [80]. 

Ferrosenescence is an iron-mediated premature aging process of cells that results in an iron-induced disruption of DNA repair and, thus, in neurodegeneration [82]. An interesting aspect of viral capabilities is the induction of ferrosenescence in host cells to facilitate viral replication [82]. These data support the notion that SARS-CoV-2 infections can induce alterations promoting neurodegenerative cascades.

5.2. COVID-19 and Possible Mechanisms Connected to Parkinson's Disease

Several links between COVID-19 and the development of PD are elaborated in this section. 

In 1985, it was observed that infection of mice with the mouse hepatitis virus (that has been identified as a murine analog of the human Coronaviridae) resulted in mild encephalitis and the deposition of viral antigens mostly in the nucleus subthalamic and the substantia nigra [83]. 

This led to subsequent gliosis in those regions, suggesting a link between the virus and PD/postencephalitic parkinsonism [83]. Antibodies against Coronaviridae were found to be elevated in the CSF of PD patients compared to controls as early as 1992 [84]. Thus far, three case reports of PD onset in timely correlation to COVID-19 disease have been reported; however, a clear causal link could not be established [85]. 

Two cases of patients developing COVID-19-associated encephalitis with progressive atypical parkinsonism and FDG-PET alterations reminiscent of postencephalitic parkinsonism were published recently [86]. Several mechanisms by which COVID-19 might contribute to the development of PD were previously reviewed and discussed: Vascular insults in the nigrostriatal system could lead to subsequent parkinsonism [87]. 

Furthermore, the cytokine storm associated with severe COVID-19 triggers neuroinflammation and, subsequently, neurodegeneration [33,87]. Systemic levels of IL-6 are elevated in COVID-19, and a small prospective observational study revealed that a higher level of IL-6 was associated with an increased risk of developing PD [88].

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