Brief Report

GHM Open. 2024; 4(1):32-36.
DOI: 10.35772/ghmo.2024.01003

The potential association between COVID-19 and Parkinson's diseaselike symptoms
Taketomo Maruki1, Shinichiro Morioka1, Satoshi Kutsuna2,*, Yasuyoshi Kimura3, Hideki Mochizuki3, Norio Ohmagari1
1

Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan;
Department of Infection Control, Osaka University Graduate School of Medicine/Faculty of Medicine, Japan;
3
Department of Neurology, Osaka University Graduate School of Medicine/Faculty of Medicine, Japan.
2

Abstract: Although the initial triggers of Parkinson's disease (PD) remain largely unknown, viral infections have been
implicated in some cases. In this study, we investigated the neurological sequelae and explored the potential association
between post COVID-19 conditions and the development of Parkinson's disease-like symptoms by conducting aquestionnaire survey on patients with COVID-19. We surveyed patients who had recovered from COVID-19 andvisited the outpatient service of the institution from February 2020 to November 2021. Demographic and clinicaldata and data regarding the presence and duration of post COVID-19 conditions were obtained. The most common
symptom was insomnia, experienced by 141 participants (27.9%). Bradykinesia was the next most common symptom,
experienced by 66 participants (13.1%). Moreover, 18 (3.6%) participants reported persistence for > 180 days. Notably,
the median duration of bradykinesia was 90 days. The proportions of patients with dysbasia, resting tremor, notpreviously noted constipation, and somniloquy were 9.1%, 5.0%, 4.8%, and 2.8%, respectively. Few participants had
any of these symptoms lasting for more than 180 days. None of the participants was first diagnosed with PD, otherneurological diseases, or dementia after COVID-19. Longitudinal follow-up surveys are needed to better understand therelationship between COVID-19 and PD.
Keywords: Parkinson's disease (PD), neurological Sequelae, post COVID-19 Conditions

Introduction

process is associated with a characteristic prodrome (9).
Although the initial triggers of PD are largely unknown,
viral infections have been implicated in some cases (10).
Notably, patients developed clinical parkinsonism a few
weeks after contracting COVID-19 (11-13).
One of the well-known sequelae of COVID-19
is dysosmia, which is an early symptom in the onsetof PD (14). We hypothesized that COVID-19 might
trigger the onset of PD. In this study, we investigated
the neurological sequelae and the potential association
between post COVID-19 conditions and developmentof Parkinson's disease-like symptoms by conducting aquestionnaire survey on patients with COVID-19.

The Coronavirus disease 2019 (COVID-19) pandemic,
caused by the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), has spread worldwide
since early 2020 (1). Approximately 10–20% of people
experience various mid- and long-term effects after
recovering from COVID-19 (2). Notably, the sequelae
of COVID-19 are known as post COVID-19 conditions.
Frequent symptoms of post COVID-19 conditions
include fatigue, cough, and dysosmia; however, multiple
symptoms often overlap and persist (3-6). Furthermore,post COVID-19 is known to affect neurological andmotor functions, and myalgic encephalomyelitis/
chronic fatigue syndrome occurs in the nervous systemafter recovery from COVID-19 (7). A recent study
demonstrated that SARS-CoV-2 infection may lead tocognitive decline and brain atrophy including olfactory
pathways (8), further highlighting the association
between COVID-19 and neurodegenerative disorders.
Parkinson's disease (PD), a progressive neurodegenerative
disorder, is characterized by a range of motor and nonmotor symptoms. Importantly, years or even decades
before the onset of the typical motor symptoms, the PD

Patients and Methods
This study was designed as a single-center, crosssectional survey in which a self-reported, online, or
paper-based questionnaire was sent to eligible patients in
February 2022 without reminders (4). Participation in thissurvey was voluntary, but not anonymous. Participants
who recovered from COVID-19 were requested tocomplete and return the questionnaire. Informed
consent was obtained through a consent checkbox,(32)

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either online or via a paper-based questionnaire. The
study was reviewed and approved by the institutional
ethics committee, specifically the Ethics Committeeof National Center for Global Health and Medicine(NCGM) (NCGM-S-004406-00). Furthermore, the study
was conducted in accordance with the principles of the
Declaration of Helsinki.
Patients who recovered from COVID-19 andvisited the outpatient service of the institution between
February 2020 and November 2021 to undergo a predonation screening test for COVID-19 convalescentplasmapheresis were recruited (15). Most participants
had received acute-phase treatment for COVID-19 inother hospitals. Furthermore, all participants in this study
were Japanese, as the screening test was specificallydesigned for Japanese patients.
We developed a questionnaire based on findings
from our previous study on prolonged- and late-onset
symptoms of COVID-19 and comprehensive discussions
among the authors. Moreover, we attempted to minimize
the number of questions required to maximize theresponse rate. Five nonmedical employees of NCGM
were included in the pilot study and provided feedbackon the items' content, clarity, and format and whether thesurvey questions were self-explanatory. Minor revisions
were made in response to the feedback.
Patient characteristics were investigated, including
information regarding the acute phase of COVID-19
and the presence and duration of symptoms related
to COVID-19. Disease severity was categorized asfollows: mild, requiring no oxygen therapy; moderate,necessitating oxygen therapy but not mechanicalventilation; and severe, involving mechanical ventilation
with or without extracorporeal membrane oxygenation.
Post-acute phase symptoms related to PD included
insomnia, somniloquy (Rapid eye movement sleep
behavior disorder [RBD] like symptoms), resting
tremors, bradykinesia, dysbasia, and not previously
noted constipation. This information was obtained using
an online/paper-based questionnaire, as it was difficult toobtain this information from medical records, given thatmany participants in this study were treated for the acutephase of COVID-19 at other hospitals.
Patient characteristics, the presence of pneumonia,
disease severity, and treatments administered during
the acute phase of COVID-19 were described using themedian and interquartile range for continuous variables
and as absolute values (n) accompanied by percentages(%) for categorical variables.
The proportions of patients with prolonged
symptoms, those with symptoms lasting for at least 30
days within 180 days of symptom onset, and those withsymptoms lasting beyond 180 days were described.

were diagnosed with COVID-19 between February2020 and December 2021. The median number ofdays (interquartile range) from COVID-19 diagnosis
to completion of the questionnaire survey was 392(243–473 days). Moreover, the median age of theparticipants was 48 years, and 59.6% were women.
Notably, all participants were Japanese. In terms of
disease severity, 393 (77.8%), 58 (11.5%), and 5 (1.0%)
participants had mild, moderate, and severe disease,respectively. Furthermore, 59 (11.7%) patients received
corticosteroids, and 57 (11.3%) received antivirals. A
total of 237 (46.9%) participants had no underlying
medical conditions. Only one participant reported anunderlying neurological disease (Table 1).
The most common symptom was insomnia,
experienced by 141 participants (27.9%). However,none of the participants reported that it persisted
for more than 180 days, with a median duration of
insomnia of 45 days. Bradykinesia was the next mostcommon symptom, experienced by 66 participants(13.1%). Additionally, 18 (3.6%) patients reported
persistence for > 180 days; the median duration ofbradykinesia was 90 days. The proportions of patients

Table 1. Demographic and clinical characteristics of theparticipants (n = 505)
Characteristics
Age, median (IQR), years
Female sex, n (%)

48.0 (42.0, 55.0)301 (59.6)

Ethnicity, n (%)
Japanese

505 (100)

Timing of the interview
Days since symptom diagnosis of
COVID-19, median (IQR)

Results and Discussion
A total of 505 responses were obtained. All patients

(33)

Value

392 (243, 473)

Individual comorbidity, n (%)
No underlying medical conditions
Hypertension
Bronchial asthma
Dyslipidemia
Diabetes
Malignancy
Connective tissue disease
Chronic kidney disease
Immunodeficiency
Neurological disease237 (46.9)
70 (14.9)
69 (14.7)
59 (12.6)
19 (4.1)
13 (2.6)
4 (0.8)3 (0.6)2 (0.4)1 (0.2)Highest severity during clinical course of
COVID-19
Mild
Moderate
SevereUnknown

393 (77.8)
58 (11.5)5 (1.0)49 (9.7)

Pharmacological treatments
Antiviral
Corticosteroids
Casirivimab/ imdevimab
Sotrovimab

57 (11.3)
59 (11.7)
4 (0.8)4 (0.8)

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with dysbasia, resting tremor, not previously noted
constipation, and somniloquy were 9.1%, 5.0%, 4.8%,
and 2.8%, respectively. Notably, few participants had
any of these symptoms lasting for more than 180 days.
Finally, none of the participants was first diagnosed
with PD, other neurological diseases, or dementia after
COVID-19 (Table 2).
Direct tissue damage by SARS-CoV-2 infection,
constitutive inflammatory responses including
autoimmunity, and psychiatric impairment havebeen suggested as underlying etiologies of long
COVID-19 (16). Furthermore, it has already beenreported that COVID-19 exacerbates motor function
and neurological deficits in existing patients with
PD and causes new symptoms (17). Specifically, it isthought that the insufficient response to dopaminergic
drugs after infection altered transport of dopaminergic
drugs through the blood-brain barrier (BBB) after
systemic infection, and altered dopamine metabolism
and receptor signaling are due to the response toproinflammatory cytokines (18). Another possibility
is that extracerebral inflammatory processes canexacerbate pre-existing neuroinflammatory processes(19). Moreover, COVID-19 may indirectly influence
symptoms in PD through factors such as substantialchanges in routine life, social isolation, stress, anxiety,and prolonged immobility (20). However, the causal
relationship between COVID-19 and the onset of PD
and the mechanism by which COVID-19 triggers
neurodegeneration remain determined (18). Importantly,
studies on the risk of developing PD have shown thatpatients with viral or bacterial infections have a 20%
higher risk of developing PD than controls do (21), and
COVID-19 may be involved in developing PD.
S A R S - C o V- 2 e n t e r s t h e b r a i n t h r o u g h t h eolfactory bulb, axonal transport from peripheral
nerves, and hematogenous pathways through the BBB(22). Post-infection, immune-mediated processes
play an important role in the development of PD(23). Interestingly, 13.1% of the participants in thisstudy reported bradykinesia, and 3.6% reported that
their symptoms persisted for more than 180 days.
Bradykinesia emerged as a distinct long-term sequela,

in contrast to other items in the study, which few
participants reported as persisting beyond 180 days.
While the direct relationship between bradykinesia
and early symptoms of PD remains unclear, suchmanifestation may be a transient symptom of disuse
and muscle weakness linked to COVID-19. Notably,
all participants who reported dysbasia improved within
the 180-day timeframe. Therefore, bradykinesia isconsidered a significant symptom of post-COVID-19,
and continued follow-up is recommended.
Olfactory dysfunction is an early and sensitivemarker of the preclinical phase of PD (14). α-synuclein
pathology in PD is thought to originate from enteric or
peripheral autonomic nervous system, or brain regions
such as olfactory bulb and amygdala (24). In a priorstudy, 57.8% of COVID-19 patients reported olfactory
disturbances; notably, 20.1% of these persisted forseveral months, and 10.3% continued for more than ayear. Although olfactory disturbances are a frequent
sequela of COVID-19, none of the patients in thisstudy developed PD after contracting COVID-19. One
reason is that this study's median period from onset toinvestigation was as short as 392 days, which was notlong enough to lead to PD onset. Notably, previous
studies examining the association between viral
infections and the development of PD have reported
that a period of 5–10 years after infection is associatedwith the development of PD (25).
This study had some limitations. First, there may
be recall bias because the questionnaire survey was
conducted on subjects who had been infected with
COVID-19 for some time. Second, the participants may
have reported resting tremors that they confused with
COVID-19 chills. Third, difficulties in walking andmovement may be caused by disuse after contracting
COVID-19. Fourth, the period from the onset of
COVID-19 to the investigation was short, and the timeto the onset of PD may have been too short. COVID-19
is a disease with rising prevalence globally. It should
also be noted that the questionnaire survey used in thisstudy, which asked about subjective symptoms, is nota diagnostic criterion for PD on its own. The Japanese
Ministry of Health, Labour and Welfare defines

Table 2. Number of participants with post-acute COVID-19 symptoms and the persistence of symptoms
Number of patients with thesymptom (%)
Insomnia
Bradykinesia
Dysbasia
Rest tremor
Not previously noted constipation
Somniloquy
First diagnosed with Parkinson's
disease or other neurologicaldisease or dementia

Number ofpatients with thesymptom (%)

Lasting less than
30 days (%)

Lasting at least 30
days within 180 days
since the onset (%)

Lasting more than
180 days (%)

Duration ofsymptoms in days
(median, IQR)

141 (27.9)
66 (13.1)
46 (9.1)
25 (5.0)
24 (4.8)
14 (2.8)
0 (0.0)115 (22.8)
22 (4.4)
40 (7.9)22 (4.4)
17 (3.4)
10 (2.0)-

10 (2.0)
21 (4.2)
4 (0.8)2 (0.4)4 (0.8)1 (0.2)-0 (0)18 (3.6)
0 (0)
0 (0)
1 (0.2)0 (0)-45 (10,255)
90 (30,255)
90 (14,240)
30 (9, 90)
30 (14,270)
7 (7, 180)-

(34)

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diagnostic criteria include the presence of parkinsonism,
absence of specific abnormalities on the head computed
tomography or magnetic resonance imaging, absenceof exposure to drugs or toxic substances that cause
parkinsonism, and improvement of parkinsonism with
antiparkinsonian drugs (26). Dopamine transporter
positron emission tomography (PET) data or dopamine
receptor PET data, and a more commonly used toolsuch as the unified parkinson's disease rating scale isalso useful for diagnosis. Therefore, it is necessary to
conduct a follow-up survey to determine whether thenumber of patients with PD will increase.

8.
9.
10.

11.

12.

Conclusion
In this study, none of the patients developed PD after
COVID-19 infection. Long-term follow-up with morepatients may clarify the relationship between COVID-19
and PD. Therefore, longitudinal follow-up surveys are
warranted to better understand the relationship between
COVID-19 and PD.

13.

14.

Funding: This work was supported by the Emerging/Reemerging Infectious Diseases Project of Japan and theJapan Agency for Medical Research and Development(AMED; 20HA1006 and 20fk0108416h0001).

15.
16.

Conflict of Interest: The authors have no conflicts ofinterest to disclose.

17.

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E-mail: kutsuna@hp-infect.med.osaka-u.ac.jp(36)