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Parkinson’s Disease, SARS-CoV-2, and Frailty: History
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Contributor: Sara Palermo ,
Mario Stanziano
, Anna Nigri , Cristina Civilotti , Alessia Celeghin

Literature has long established the association between aging and frailty, with emerging evidence pointing to a relationship between frailty and SARS-CoV-2 contagion. The possible neurological consequences of SARS-CoV-2 infection, associated with physical and cognitive frailty, could lead to a worsening of Parkinson’s disease (PD) in infected patients or—more rarely—to an increase in the Parkinsonian symptomatology. A possible link between those clinical pictures could be identified in vitamin D deficiency, while the whole process would appear to be associated with alterations in the microbiota–intestine–brain axis that fall within the α-Synuclein Origin site and Connectome (SOC) model, and allow for the identification of a body-first PD and a brain-first PD. The model of care for this condition must consider intrinsic and extrinsic variables so that care by a multidisciplinary team can be successfully predicted. 

  • Parkinson’s disease
  • COVID-19
  • frailty
  • hypovitaminosis D

1. COVID-19 and Parkinson’s Disease: “Is There an Unexpected Relationship?”

There is evidence that the COVID-19 virus can cause damage to the brain cells, potentially triggering a neurodegenerative process [1][2]. On average, the loss or reduction of the sense of smell has been reported in three out of four people infected with SARS-CoV-2 [2]. Angiotensin-converting enzyme 2 (ACE2) dysregulation is implicated in the entry of SARS-CoV-2 into human host cells. Olfactory neurons are supported by ACE2 receptor-positive sustentacular cells. Salt ions in the mucus are delicately balanced by these cells, and if this balance is upset, neuronal signals to the brain may cease, which can lead to olfaction perturbation. These cells also provide metabolic and physical support to the finger-like cilia that line the olfactory neurons responsible for odors detection [3].
There is no doubt that an ACE2 imbalance contributes to the core pathologies of PD and COVID-19, including aberrant inflammatory responses, oxidative stress, mitochondrial dysfunction and dysregulation of the immune system. Moreover, alpha-synuclein-induced dopaminergic degeneration, gut–brain axis dysregulation, blood–brain axis disruption, autonomic dysfunction, anxiety, depression and hyposmia are all associated with ACE2 dysregulation in PD [4]. It is precisely the loss of smell that could be a new way of detecting the risk of developing Parkinson’s disease at an early stage, as it occurs in 90% of people who contract the disease and are still in the preclinical/early phase, which is about a decade before the appearance of motor symptoms [5]. Considering that the opportunity to adopt neuroprotective therapies that achieve the desired effect is lost by waiting until the onset of the motor phase of Parkinson’s disease, this event could open up the adoption of integrated treatments earlier than the standard period.
Research investigating possible relationships between COVID-19 infection and PD has yielded mixed results [6]. What is known is that Parkinson’s disease patients do not have a higher risk of becoming infected [7] but, once infected, an increased risk of more serious infection is possible [6]. More recently, it has been shown that the aggregate prevalence of COVID-19 infection in PD cases is 5%, in addition to hospitalization and mortality rates of 49% and 12% [8]. Older and more chronic PD patients appear to be particularly susceptible to infection, with a significantly higher mortality rate (40%) and with a particular risk of death for those undergoing advanced therapies, such as deep brain stimulation or levodopa infusion therapy [9]. Individuals with PD-MCI were more likely to experience PD-specific rather than cognitive symptoms after quarantine [10], and in PD COVID-19-confined patients, the cognitive and behavioral functions deteriorated more rapidly than in subjects without motor impairment [10]. Moreover, the infection induced significant worsening of motor performance, motor disability, and daily living experiences, including increased fatigue [10][11]. Although many PD patients present with typical COVID-19 symptoms, some atypical PD patients present with an isolated worsening of the Parkinsonian symptoms, requiring increased dopamine replacement therapy and presenting worse outcomes [6]. The worsening of the PD symptomatology, including gait dysfunction and risk of falls, may be attributed to the reduced mobility, stress, anxiety and isolation during the pandemic, which could have negative consequences; however, SARS-CoV-2 infection has also been linked to secondary neurodegeneration or may have an effect on dopaminergic neurotransmission [12].
The mechanism that might compromise the nigrostriatal dopaminergic nervous systems during COVID-19 is unclear [13][14]. A susceptible genetic make-up might make patients vulnerable to immunologically mediated mitochondrial damage and neuronal oxidative stress [13][14]. Another hypothesis could be that the virus causes inflammation through microglial activation, contributing to protein aggregation and neurodegeneration [15]. Indeed, the exosomal cargo of the SARS-CoV-2 virus may be capable of promoting neurodegenerative and neuroinflammatory cascades in the brain as it travels from the periphery to the brain. This cascade may lead to the development of Parkinsonism and Parkinson’s disease [16]. Finally, the multiple stroke hypothesis favors the combination of toxic stress and inhibition of neuroprotective responses leading to neuronal death [17]. Immune activation in the olfactory system could therefore lead to α-synuclein misfolding and the development of Parkinson’s disease [18][19]. This mechanism is supported by post-mortem studies, which show increased levels of pro-inflammatory cytokines (such as tumor necrosis factor [20] and interleukins IL1 and IL6 [21]). In addition, patients with Parkinson’s disease have an elevated CSF antibody response to seasonal coronaviruses, compared to healthy controls of the same age [22].

Neuroimaging Evidence

The brain inflammation and damage to neuronal circuits seen in patients who died from COVID-19 are similar to those seen in Alzheimer’s and Parkinson’s patients [23]. Extensive cellular perturbations have been observed, predicting how choroid plexus barrier cells perceive and transmit peripheral inflammation in the brain and showing how peripheral T-cells infiltrate the parenchyma [23]. In addition, genes related to cognition, schizophrenia and depression would be more frequently activated in the brains of COVID-19 patients [23].
Reports of neuroimaging data of patients who developed Parkinsonism have followed one another over time. Mendez-Guerrero and colleagues [24] reported a case in which DaT-SPECT confirmed a bilateral decrease in presynaptic dopamine uptake that asymmetrically involved both putamen regions. Cohen and collaborators [25] confirmed this type of alteration in another patient. PET scanning showed a decrease in 18F-FDOPA uptake in both putamen regions, more evident on the left side [25]. This was also found in a non-postencephalitic case [26], for which a decreased dopamine transporter density on the left putamen (even if more evident in the mid-putamen) was clearly traceable.
Morassi and colleagues [27] found that the FDG-PET/CT results resembled those observed in post-encephalitic Parkinsonism, with cortical hypo-metabolism associated with hyper-metabolism in the brain stem, mesial temporal lobes and basal ganglia. Moreover, hypermetabolic brain areas correlated with brain regions showing increased cortical thickness, suggesting their involvement during the inflammatory process [27].

2. Physiological Aging: From Frailty to Susceptibility to Neurodegenerative Diseases and Viral Infection

Older adults are more prone to frailty and disease onset due to an impaired crosstalk between the innate and the adaptive arms of the immune system and to inflammaging [28][29][30].
In addition to immunosenescence and inflammaging, a number of mechanisms contribute to COVID-19 infection risk and severity, such as a cytokine storm and a reduced gut microbiota diversity, which causes frail elderly to have a weak immune system [31]. Importantly, a change in the gut microbiota is better indicated by frailty than chronological age [32].
The increase in inflammatory cytokines is related with sarcopenia and muscle weakness, possibly due to prolonged immobility during hospitalization or confinement during lockdown. In addition, a common feature of infectious diseases is a decrease in calorie and nutritional intake, which can, again, negatively impact the health of muscles, bones and joints [33][34]. Eventually, this clinical picture can lead to a decline in multiple systems’ function [35], with a disrupted homeostasis, accelerated aging and age-related diseases [36].
The neurotrophic properties of the virus and the infection-induced sustained pro-inflammatory state facilitate neurodegenerative processes through increased beta-amyloid deposition and microglia activation [37][38][39][40], leading to Alzheimer’s and Parkinson’s disease, which are the two most common pathological manifestations. Indeed, a systemic inflammatory status and increased oxidative processes could explain the impact of pneumonia on cognition. In addition, pneumonia-related hypoxia is also linked to neurodegeneration and cerebrovascular injury, which predispose individuals to cognitive impairment and major neurocognitive disorders [41]. As a result, frail older adults are more likely to suffer adverse outcomes and death from SARS-CoV-2 infection [31] and experience a less effective COVID-19 vaccination constellated with more side effects [28][31].
The incidence rates of physical-cognitive decline and frailty increase with the aging population and with the presence of neurodegenerative diseases. Affecting more than 1% of the population over the age of 60 and 5% of people over the age of 85, PD is closely linked to both aging and frailty [42]. Precisely, the association between weight loss (one of the clinical biomarkers of frailty according to Fried’s biomedical model), poor nutritional status, motor complications and PD progression is a frequent yet under-recognized complication in Parkinson’s disease [43][44]. Ahmed and coauthors [45] found that one-third of patients with optimally treated PD met the criteria for frailty, a prevalence five-fold higher than expected in a comparable elderly population; moreover, the number of diagnostic components positive for frailty increased with the severity of PD. Indeed, an association between frailty and PD disease duration, motor impairment, postural instability/gait difficulty and total daily levodopa dose was observed [46]. Moreover, frailty appears to be associated with a mild behavioral impairment, with potential effects on impulse dyscontrol [47], which has previously been associated with executive-metacognitive dysfunction in Parkinson’s disease [48][49]

3. A Further Hint: Vitamin D

3.1. Vitamin D, SARS-CoV-2 Infection Risk and Severity

The hypothesis of the role of vitamin D in the susceptibility to SARS-CoV-2 infection stems from the observation of the high prevalence of hypocalcemia (50%) among hospitalized patients during the Ebola (2016) and SARS (2003) epidemics [50]. Up to 80% of COVID-19 patients hospitalized in Italy during the first wave of the pandemic reported a reduction of the quantity of calcium in laboratory exams ([Ca2+] < 1.18 mmol/L). Free calcium is required for virus–cell interactions (via the spike protein and ACE2), viral replication and the inflammatory response to the infection. The association between vitamin D status and infection risk could therefore be, at least in part, consequent to the deregulation of (phospho)calcium homeostasis [51]. The fact that calcium is critical in the infection process is also demonstrated by the fact that the pharmacological blockade of L-type calcium channels slows the rate of replication of porcine deltacoronavirus [52]. Moreover, an increased risk of SARS-CoV-2 infection, with an OR of 1.43 (95% CI of 1.00–2.05), was found in association with deficient values of vitamin D (25(OH)D) (vitamin D deficiency is defined as less than 20 ng/mL (50 nmol/L), while insufficiency corresponds to 21–29 ng/mL (52.2–72.5 nmol/L)) [53].
Furthermore, comorbidities and aging are involved. Therefore, it is impossible to determine whether micronutrient deficiency contributes to the SARS-CoV-2 infection risk or, rather, reflects (or is consequent to) a pathophysiological condition that itself increases the infection risk. Chronic hypovitaminosis D may, however, predispose to comorbidities and thus indirectly influence disease severity: for example, advanced age and obesity are associated with vitamin D deficiency and a more severe COVID-19 course [54]. Despite the fact that lower levels of vitamin D appear to be associated with more severe COVID-19 symptoms and an increased risk of hospitalization, the association with other clinical outcomes—such as mechanical ventilation, intensive care unit admissions and mortality—is unclear [55].

3.2. Vitamin D: Common Element in the Continuun between Aging, Frailty and Parkinson’s Disease

In the human body, vitamin D is produced endogenously when the skin is exposed to sunlight, whereas exogenous sources include certain natural foods and supplements. The vitamin D intake in Europe is generally low, between 2 and 3 g per day [56]. It has been found that there is a north–south gradient in the 25(OH)D status, with more-northern countries (Sweden and Finland) having higher percentage values than southern countries (Spain and Italy) [57]. Hypovitaminosis D is particularly prevalent in the elderly population, particularly among institutionalized and community-dwelling elderly [9][58], as well as among those over 80 [59]. Lower levels of vitamin D are associated with reduced sun exposure and reduced skin synthesis capacity, leading to lower levels of cholecalciferol [60]. In addition, renal function efficiency decreases with aging, resulting in a reduction in the activity of the 1-hydroxylase enzyme that converts 25(OH)D into calcitriol, whose levels in the elderly are inversely related to serum creatinine levels and glomerular filtration rates [61]. A reduction in the level of the VDR receptor (specific for 25(OH)D) within the skeletal muscle system of the elderly and the progressive decline of intestinal mucosal sensitivity to calcitriol may also contribute to vitamin D deficiency [60].
Many geriatric pathological conditions, including bone fragility and fractures, sarcopenia, neoplasms, cardiovascular disease and depression, are related to hypovitaminosis D [60]. The picture described is consistent with the frailty syndrome. There is no doubt that vitamin D has a role to play in frailty, as both animal models and large population-based studies have shown that low serum vitamin D levels are associated with a higher risk of frailty in humans [62]. Based on a meta-analysis [63], the OR of frailty for the lowest versus the highest level of vitamin D can reach 1.27 (95% CI = 1.17–1.38, I2 = 59%), with a low vitamin D level significantly associated with the frailty risk in women. Indeed, postmenopausal women are prone to sarcopenia, which could result in functional impairment, disability, and fractures [64]. Subsequent quantitative analyses confirmed significant differences when comparing frail and pre-frail subjects [65]. Additionally, 25(OH)D concentrations were significantly associated with lower gait speed and impairment in the Timed Up and Go test, two measures of physical performance associated with frailty in the elderly [66]. Finally, a significant relationship was observed between physical frailty and serum vitamin D concentration in predicting cognitive frailty [67].
The role played by hypovitaminosis D in PD patients compared to a control group was ascertained over two decades ago [68]. Studies found a high prevalence of hypovitaminosis D in Parkinson’s disease individuals [69][70], elucidating the inverse association between blood 25-hydroxyvitamin D concentrations and the incidence of PD [71]. This is due to a deterioration in the gastrointestinal function, which is significantly more prevalent in people with “early PD” [69][72]. Hypovitaminosis D appears to be associated with disease severity and progression, but not with PD onset age or illness duration. Furthermore, reduced vitamin D levels in PD patients have been linked to a higher risk of falling. Less is known regarding vitamin D impact on the cognitive function and other nonmotor symptoms [68][73].

This entry is adapted from the peer-reviewed paper 10.3390/brainsci13040528

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