Can SARS-CoV-2 Infection Lead To Neurodegeneration And Parkinson’s Disease? Part 3

Another possible mechanism of inducing PD would be viral neurotropism resulting in direct neuronal damage in strategic areas. IPSC-derived midbrain dopaminergic neurons were shown to be submissive to SARS-CoV-2 infection, which triggered an inflammatory response and subsequently cellular senescence in vitro [89]. 

Cellular senescence is one of the inevitable life processes of human beings. As we age, our bodies and brains gradually age. However, one of the biggest concerns is whether memory is lost as cells age.

Although age does have an impact on memory, it does not mean that cell aging will directly lead to amnesia. Memory is related to both brain structure and function, as well as factors such as environment, lifestyle, and personal preferences.

A study of long-lived people showed that their memory is better than that of the average person. This is because many people in the longevity group have developed good living habits, maintained a positive attitude, and at the same time experienced more life experiences and learning experiences, which have had a positive impact on the maintenance of memory.

In addition, ordinary people can also use a series of methods to delay the impact of cell aging on memory. Here are some ways to do it:

1. Exercise your body and brain: Moderate physical exercise and mental training can stimulate brain vitality and blood circulation, and slow down the rate of cell aging and cognitive decline.

2. Stay positive: Staying positive, realizing your potential, and accepting new experiences and challenges can keep your brain's neurotransmitters and functions more active.

3. Maintain a healthy diet and sleep: A nutritionally balanced, light, and healthy diet and adequate sleep are very important to maintain the stability and functional health of the brain.

4. Social activities: Communicating, communicating, and sharing experiences and life insights with others can promote brain vitality and improve people's emotional state, thus having a positive impact on the maintenance of memory.

In general, although cell aging is inevitable, we can delay its impact on memory through active lifestyle, mentality, diet, and social activities, to have a healthier and more active life in the long journey of life. Life status. It can be seen that we need to improve memory. Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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RNA-sequencing analysis of the ventral midbrain tissue of COVID-19 patients revealed a comparable phenotype of inflamed neurons and identified low levels of SARS-CoV-2 transcripts [89]. These data underline that there may be a special susceptibility to SARS-CoV-2 of particularly vulnerable midbrain regions involved in the development of PD. 

The general susceptibility of central nervous structures to SARS-CoV-2 was shown by Ramani et al., who infected brain organoids and observed viral entry, especially in neurons. The infection induced an altered distribution and hyperphosphorylation of tau and subsequent neuronal death [90]. A link between NF-κB and PD was previously established because NF-κB was increased in the substantia nigra of MPTP-treated mice [91]. 

MPTP treatment is a common animal model of PD as the neurotoxin leads to nigrostriatal degeneration and loss of dopaminergic neurons [91,92]. Suppressing NF-κB in this model led to the prevention of the degeneration of dopaminergic neurons [91]. In an in vitro model of dopaminergic neurons, treatment with 6-OHDA led to NF-κB activation, caspase activation, and apoptotic death that was prevented by inhibition of NF-κB [93]. 

NF-κB is activated by SARS-CoV-2 via pattern recognition receptors, which might be a neurodegenerative trigger [93]. Other interesting aspects are the shared implications for the angiotensin–aldosterone system in COVID-19 and PD. 

Angiotensinogen is produced by astrocytes as part of a local independent renin-angiotensin system (RAS) [94,95]. Its pathological overactivation (that also results from the degeneration of dopaminergic neurons) led to oxidative stress and inflammation, whereas its inhibition was considered a treatment option in several neurodegenerative diseases including PD and AD [96,97]. 

SARS-CoV-2 uses the ACE2- receptor as an entryway into host cells and, therefore, intervenes with the RAS as well [10]. A previously observed connection between the H1N1 influenza virus and α-synuclein aggregation could potentially be relevant for SARS-CoV-2, too. H1N1 led to the aggregation of endogenous α-synuclein in LUHMES cells [98]. 

As a reason for the pathological αsynuclein aggregation following H1N1 infection, an impairment of the autophagosome of infected LUHMES-cells was proposed [98]. Interestingly, α-synuclein aggregates were also seen in the olfactory bulb after intranasal instillation of H1N1 [98]. Early symptoms of PD are olfactory and vegetative dysfunction including obstipation as well as the prodromal syndrome REM sleep behavior disorder (RBD). 

Olfactory dysfunction is a very common early symptom of COVID-19, and the olfactory route is discussed as one way of viral entry into the CNS [21,26]. Therefore, it seems plausible that COVID-19 might influence the pathogenesis of PD as SARS-CoV-2 can take a route of spreading that was described for the developing neuropathology in PD [99,100]. 

Polysomnographic investigations in 11 patients four months after initial infection with SARS-CoV-2 revealed episodes of REM sleep without atonia in 4 patients, which is a characteristic (prodromal) sign of RBD [101]. 

Another interesting aspect is that the development of PD is linked to the gut microbiome and its dysbiosis [102]. SARS-CoV-2 causes an imbalance of the gut microbiome (dysbiosis) and intestinal inflammation indicated by elevated fecal calprotectin in COVID-19-associated diarrhea, which proposes a possible link to PD [103,104]. SARS-CoV-2 RNA was detected in the feces of about 50% of patients with COVID-19, supporting the hypothesis of intestinal infection [105]. 

Molecular investigations have established links between COVID-19 and PD focusing on protein interactions. In all, 44 proteins in the CNS implicated in PD were found to interact with 24 host proteins from the lung that interact with SARS-CoV-2 viral proteins [106]. The two most promising interaction candidates were Rab7a and NUP62 [106]. Rab7a is a lysosomal protein reducing the proportion of cells with α-synuclein particles as well as the toxicity of α-synuclein, whereas NUP62 is involved in autophagosome formation [106]. 

The comparison of transcriptomic modulations induced by SARS-CoV-2 and PD also revealed significant overlap in several pathways [107]. On the other hand, a protective role of α-synuclein against COVID-19 was proposed since α-synuclein, like β-amyloid, is upregulated in the face of viral infections and can restrict viral replication acting as a defense mechanism in the brain [108]. 

This leads to the speculation that PD patients with higher α-synuclein levels in the brain might have some protection against SARS-CoV-2 infection [109]. Before the COVID-19 pandemic, a Japanese retrospective cohort study showed that hospitalized PD patients were less likely than other patients to die from pneumonia [109]. 

If the viral infection leads to an upregulation of α-synuclein as a defense mechanism, it may induce prolonged inflammation and neuronal death triggering the development of PD in the long run as was shown earlier for West Nile virus infections [87]. 

Interestingly, a hypothetical connection between COVID-19 and atypical parkinsonism can be established as well, although data on this topic are rare so far. It was demonstrated that atypical Parkinson's syndromes such as multisystem atrophy and progressive supranuclear palsy are associated with microglial activation as a sign of neuroinflammation and that the microglial activation contributes to the progression of neurodegeneration [110–112]. 

Recently, it was shown that microglial activation can be visualized by PET imaging, which might function as a biomarker for tauopathies [113,114]. Microglial activation and neuroinflammation are seen in COVID-19 as described in Chapter 1, creating a link between atypical parkinsonism and COVID-19 [39].

5.3. Alzheimer's Disease, Cognitive Deficits and COVID-19

There is cumulating evidence demonstrating a close connection between cognitive disturbances and COVID-19. A prospective longitudinal study revealed that cognitive decline measured by the Montreal Cognitive Assessment (MOCA) was apparent in 21% of mild COVID-19 patients vs. 2% of seronegative individuals [115]. Another study found pathological MOCA results in 18 of 26 COVID-19 patients and also FDG-PET abnormalities (frontoparietal hypometabolism) in 10 patients matching the clinical deficit [45]. 

Cognitive decline was not only observed during acute infection but there are also reports of persistent cognitive impairment after recovering from COVID-19, as MOCA abnormalities were detected in a group of post-COVID-19 patients [116]. Another study confirmed that cognitive deficits persisted in 70% of COVID-19 patients for at least 1 month after hospital discharge [116,117]. Similarly, 46 of 57 recovering COVID-19 patients (81%) had signs of cognitive impairment [13,118]. 

Interestingly, persisting memory and concentration deficits were found after SARS-Cov-1 and MERS infections in 15–20% of cases [119]. Another interesting study used transcranial magnetic stimulation to investigate recovered COVID-19 patients who suffered from severe disease with ICU stay and neurological complications reporting fatigue and showing abnormal scores in the frontal assessment battery during the subacute phase [120]. 

The transcranial magnetic stimulation in these patients revealed severe impairment of GABAergic intracortical circuits while glutamatergic transmission was intact [120]. GABAergic impairments are usually common in frontotemporal dementia and executive dysfunction [120,121]. However, it has to be noted that cognitive impairment is a common problem after suffering from acute respiratory distress syndrome (ARDS), which can have multiple reasons other than COVID-19 [116,122–124]. After ARDS, cognitive disturbances persisted in long-term follow-ups in about 10% of cases [116,122]. 

Other studies found cognitive deficits and psychiatric disorders (mainly depression and anxiety) in up to 60% of ARDS survivors after 12 months [125]. Dementia was found to be one of the strongest risk factors for COVID-19 and is associated with higher mortality [126–130]. Patients with dementia have difficulties in following hygiene rules, mask requirements, behavioral instructions, and distancing rules due to cognitive deficits [124,131]. 

Dementia patients frequently live in nursing homes where a higher risk for infection with the virus is present in many areas [124]. COVID-19 disease in dementia patients often appeared atypical presenting foremost with delirium/confusion and few infectious symptoms [129,132]. Confusion and mood and behavioral disturbances persisted in 19.2% of survivors [129]. An analysis of the network-based relationship for the gene/protein sets between virus and host factors as well as different neurological diseases in an interactome network model showed a proximity between COVID-19 and cognitive decline as well as AD and PD [13]. 

Postmortem studies demonstrated that ACE2 expression was increased in the brains of AD patients. Especially in severe dementia, ACE2 expression was elevated, which could lead to a higher susceptibility to COVID-19 [123,124,133]. Ischemic white matter damage occurs early in AD contributing to the progression of dementia. COVID-19 can induce vascular lesions due to hypercoagulability and can be expected to accelerate disease progression in AD patients [123,134]. 

It was hypothesized that amyloid-β, the protein implicated in AD development, is an antimicrobial peptide involved in fighting cerebral SARS-CoV-2 infection as previously described for α-synuclein in PD [123,135]. It could be speculated that amyloid-β is upregulated as a defense mechanism during infection leading to an overactivation with pathological deposition of amyloid-β in the long run [123,135]. 

Apoε4, an established risk factor for AD, was also recognized as a prominent risk factor for COVID-19, potentially linking the two pathophysiologies [136]. COVID-19 severity could be statistically predicted by the Apoε4 genotype [136]. In human iPSCs models with the Apoε4 genotype, neurons, and astrocytes were more susceptible to SARS-CoV-2 infection than non-Apoε4 cells and brain organoids [12]. 

Another point of overlap is IL-6, which was shown to be elevated in COVID-19 and was also considered a biomarker with prognostic value in AD [49,123,137]. SARS-CoV-2 is likely to disturb autonomic functions in vagal regulation centers in the brainstem [127]. In AD, autonomic functions are impaired as well, since higher cardiac sympathetic function and lower parasympathetic function are reported in patients [127]. 

Therefore, noninvasive (auricular) vagal nerve stimulation is discussed as a therapeutic strategy for AD as well as severe COVID-19, since downregulation of inflammatory pathways (reduction of IL-6 levels) is expected as a result [127]. Supporting this theory, trans auricular vagal nerve stimulation was able to reduce cognitive dysfunction in a preclinical murine model of AD [138]. 

AD leads to alterations in calcium homeostasis in the brain; RNA viruses use the same mechanism to facilitate viral replication [124]. Therefore, viral replication might be easier in the brain of AD patients where calcium homeostasis is already abnormal [124]. There is an association between AD and diabetes type II, which elevates the risk of developing AD [139]. 

AD and diabetes type II were both found to be strong risk factors for COVID-19 endangering those patient groups particularly and proposing a mechanistic link between these diseases that could explain an overlapping pathophysiology [139]. Take home messages of Chapter 3 (Section 5):

1. Viruses have different strategies to take control over host cellular functions, for example, impairing autophagy and mitochondrial or lysosomal properties, whose dysfunction has been implicated in neurodegenerative diseases.

2. Neuroinflammatory alterations due to COVID-19 such as elevated IL-6 levels or activation of NF-κB might trigger/accelerate the development of PD.

3. Direct CNS invasion by SARS-CoV-2 might also lead to the induction of neurodegenerative cascades in strategic areas.
4. COVID-19 can lead to acute and persisting cognitive deficits, although some of those might be due to ARDS.

5. Dementia and Apoε4 genotype are strong risk factors for COVID-19 and its associated mortality.

6. Chapter 4

Parkinson's Disease and COVID-19: Effects on PD Symptoms, Psychological and Social Aspects The impact of the pandemic on aspects of daily life was massive for the entire world population, and patients with chronic diseases in need of regular care were especially affected. An extensive analysis of worldwide studies (210,419 participants total) showed that acute care for neurological disorders, in general, was disrupted due to the pandemic in 47.1% of cases [140]. 

The impact on PD patients was differentially described, as specific problems occurred with pandemic-associated restrictions. Psychological issues as well as aspects regarding care and supply of medication were found to be most burdensome in this cohort [140]. COVID-19 can alter the pharmacodynamics of levodopa also due to diarrhea, which is a common symptom of COVID-19 [141]. This leads to motor fluctuations in infected PD patients [141]. PD patients suffering from COVID-19 often develop a post-COVID syndrome (85.2%) consisting of worsened motor functions, increased daily levodopa dose requirement, fatigue, loss of concentration, and sleep disturbances [142]. 

However, subjective worsening of motor and non-motor symptoms of uninfected PD patients during the time of the pandemic was also recorded in different studies [143,144]. New behavioral symptoms were observed in 26% of PD patients in an Italian cross-sectional study [144]. PD patients reported feeling lonely and deprived of support and communication with their physicians [143]. 

It was hypothesized that dopamine-dependent adaptation is a requirement for successful coping; thus, PD patients are cognitively less flexible and can have more difficulties adapting to new environments [145,146]. Therefore, the pandemic may lead to a relevant amount of stress in PD patients who are forced to adapt to a new environment quickly. 

Psychological stress was shown to worsen PD symptoms as well as the efficacy of dopaminergic medication especially on the tremor [145,147]. This could be an explanation for symptom exacerbation in PD patients during the pandemic. It was found that 103 PD patients reported four main problems in the first Italian lockdown: 1. fear of contracting corona, 2. reduction of physical activity, 3. not being able to access support services and clinics, and 4. reduction of socialization [148]. There was an objective reduction of physical activity, measured by a smartphone application, as most PD patients failed to meet 30 min of activity per day [149]. 

This was aggravated further in 44% during confinement [149]. It is well known that physical activity and training an important treatment strategies in PD to maintain motor functions and independence, so the deprivation of physical activity during a lockdown can be suspected to lead to symptom progression and loss of independence [149]. Moreover, 66% of PD patients in a large cohort at Columbia University reported mood and sleep disturbances in the face of the pandemic; depression and insomnia were the most frequently reported psychiatric symptoms in multiple other studies as well [150–154]. 

A Chinese study revealed that PD patients had more sleep disturbances and anxiety than healthy controls and that these symptoms were independently associated with an exacerbation of other PD symptoms [154]. Sleep problems were also associated with a poorer quality of life [153]. Mindfulness-based interventions were shown to reduce depression and anxiety, improve motor function, and strengthen resilience [145]. As this can be accomplished virtually, it appears to be a useful treatment strategy now and for the future [145]. The hours of caregiving increased dramatically during the pandemic. 

Care was mostly provided by family members [155,156]. Caregiver burden was increased during the COVID-19 era [144]. Interestingly, Montanaro et al. and others showed that anxiety and depression were frequent in both PD patients and their caregivers [157,158]. Depression was observed in 35% of PD patients and 21.7% of caregivers; 39% of PD patients and 40% of caregivers suffered from anxiety [158]. 

Therefore, caregivers should receive more support, particularly during this pandemic to cope with their burden and the neuropsychiatric symptoms of their relatives [159]. However, COVID-19 does not only have an impact on PD symptoms; it was also discussed that pre-existing PD can elevate the risk of mortality or case fatality when an infection with SARS-CoV-2 occurs. The data on this topic are controversial (subsumed in Table 1).

A detailed review by Fearon et al. summed up that COVID-19 mortality is probably not increased in PD patients who tended to experience less dyspnea during the infection, were completely asymptomatic more often, and were less likely to require hospitalization [141,160,165–167]. The duration of ICU stays/hospitalization and ventilation did also not differ in PD and non-PD COVID-19 patients in a large analysis of German inpatients [165]. An Italian study compared COVID-19 patients with PD to COVID-19 patients without PD and found no difference in mortality (5.7% of PD COVID-19 patients died vs. 7.6% of non-PD COVID-19 patients) [160]. 

This trend could be supported by the hypothesis that amantadine and entacapone might have protective value against COVID-19, which was suggested by different studies [172–174]. However, a systematic review of a total of 1061 PD patients with confirmed COVID-19 showed a higher hospitalization rate, case fatality, and mortality for these patients than that for non-PD COVID-19 patients [175]. 

A limitation of this study was the missing age matching, which is likely to influence the result, as age is one of the most established risk factors for case fatality and mortality of COVID-19 [175,176]. An American study compared 78,355 non-PD COVID-19 patients to 694 COVID-19 patients with PD and found increased mortality even after adjusting and matching to age and sex [169]. 

A multicentric German study showed that the prevalence and mortality of COVID-19 were higher in PD than in non-PD inpatients [168]. These data are inconclusive, and a definite suggestion on whether PD patients are more at risk for a (severe) COVID-19 infection cannot be made at this point. It should be noted that PD patients who suffer from COVID-19 infection are likely to present with atypical symptoms such as mood changes, fatigue, joint pain, flushing, and exacerbation of PD symptoms, which can complicate the diagnosis of SARS-CoV-2 infection [177]. 

Take home messages of Chapter 4 (Section 6): 1. Post-COVID-syndrome, altered pharmacodynamics of levodopa, and worsening of motor symptoms are common in PD patients with COVID-19. 2. Even uninfected PD patients often suffer from subjective worsening of motor and non-motor symptoms, reduced physical activity, as well as increased stress, anxiety, and depression. 3. Whether PD elevates the risk of COVID-19 mortality is not clear yet, since data on this topic is inconclusive.

7. Concluding Remarks

The overview presented in this review underlines that COVID-19 has a cerebral/ neurological impact. Whether SARS-CoV-2 can enter the CNS and impose direct neuronal damage or whether neurological symptoms are rather due to secondary effects cannot be differentiated with certainty. The influence of the infection on neurodegenerative diseases is also not clear yet, but various pathophysiological theories exist linking COVID-19 to neurodegeneration and making it appear likely that the pandemic can have an (accelerating) influence on neurodegenerative diseases such as AD and PD. 

The same was proposed for other viral infections in the past, though a clear triggering/accelerating influence of viral infections on neurodegeneration could only be demonstrated for a few viruses such as HCV and HIV so far. Monitoring recovered COVID-19 patients especially patients with neurodegenerative diseases and COVID-19 will hopefully answer some of these questions in the future. Such a prospective investigation also withholds the potential to learn more about the neurodegenerative pathophysiology and develop new strategies for disease-modifying treatments.

Author Contributions: Conceptualization: L.K.; writing-original draft preparation: L.K.; writing- review and editing: F.W., G.U.H. and M.K.H.; visualization: M.K.H. All authors have read and agreed to the published version of the manuscript.

Funding: L.K. was supported by PRACTIS-Clinician Scientist Program of Hannover Medical School, funded by the German Research Foundation (DFG, ME 3696/3-1). Otherwise, the research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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