Chronic or post-coronavirus disease 2019 (COVID-19) syndrome (PCS) refers to symptoms and abnormalities that persist or are present >12 weeks following the onset of acute COVID-19 infection and are not attributable to other diagnoses (1,2). However, the clinical spectrum of post-COVID-19 symptoms in Parkinson's disease (PD) has yet not been fully described, apart from a limited number of small case series (3,4). Previous studies have focused on the chronic worsening of the motor and non-motor symptoms (NMS) in PD following infection with COVID-19 (5-8). These findings need to be carefully interpreted in light of the limitations of the studies, as regards both the methodology and design (small sample, lack of a control group and follow-up).

The main aim of the present study was to compare the long-term incidence of clinical outcomes between patients with PD (PWP) and PCS, and those without PCS at a 6-month follow-up.

A total of 38 PWP exhibiting PCS symptoms were compared with 20 consecutive patients with PD with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but no ongoing symptoms, between May 1, 2020 (the lockdown period) and December 31, 2021 (the post-lockdown period), from the 251 Air Force General Hospital (Athens, Greece) and the Rhodes General Hospital (Rhodes, Greece). The inclusion criteria were as follows: Clinical manifestations of PCS were considered as new-onset following initial recovery from an acute COVID-19 episode by a Delphi consensus. The exclusion criteria were the following: Severe comorbidities. A 6-month period was selected to minimize the effects of PD progression on the changes in clinical features and the recall bias. The following data were collected: Demographics, disease duration, motor and non-motor clinical measures, vaccination status at the baseline timepoints of 0 and 6 months, and the levodopa equivalent daily dose (LEDD). Motor impairment was evaluated with the Unified Parkinson's Disease Rating Scale part ΙΙΙ (UPDRS III) (off phase; i.e., flares of symptoms between regularly scheduled doses of levodopa). NMS were assessed using the Montreal Cognitive Assessment (MoCA) and the Geriatric Depression Scale (GDS). The severity of PD was assessed using the Hoehn and Yahr (HY) scale. The study protocol was approved by health authorities and local independent ethics committees at each participating center (Rhodes General Hospital, no. 199/2020; 251 Air Force General Hospital, no. 251AFH/19-2020), in accordance with the Declaration of Helsinki and the current European Data Protection Regulation. Written informed consent was obtained from all participants.

The demographic and clinical characteristics of the patients at baseline were similar between the PD cases and matched controls (Table I). The most common symptoms reported by the patients with PCS were anosmia/hyposmia and a sore throat (73.7%), followed by dysgeusia and skin rashes (65.8%) (Table II).

No significant associations of age, PD duration, vaccination against COVID-19 and hospitalization due to COVID-19 with PCS symptoms were observed (Table III, Table IV and Table V). However, there was a statistically significant association between the male sex, and pain, headaches and sleep disturbances (P=0.020, P=0.047 and P=0.008, respectively) in patients with PCS (Table VI).

Of note, there was a statistically significant difference in the mean value of LEDD (P=0.039) and in the median UPDRS III score at baseline and 6 months later (P=0.001) in the patients with PD with PCS symptoms (Table VII).

There was no statistically significant difference in demographics or specific scores between the two groups, indicating that no prognostic factor for PCS in PWP could be identified (Table I).

To the best of our knowledge, the present study is the first prospective cross-sectional study describing the effects of PCS on PD motor symptoms and NMS. First, patients with PD with PCS were not older or had a longer disease duration than those without PCS, although males more frequently reported pain, headaches, and sleep disturbances than females. As regards the primary objective of the present study, an aggravation of motor and the new onset of non-motor PD symptoms were observed in the PCS group over the study period.

To date, at least to the best of our knowledge, only two studies have described PCS symptoms in PWP. The most common long-term effects of COVID-19 reported are the deterioration of motor symptoms (52%), increased LEDD (48%), fatigue (41%), cognitive disturbances (22%), and sleep disturbances (22%) (3,4). A severe acute infection (as indicated by a history of hospitalization) is not a prerequisite for the development of persistent post-COVID-19 symptoms in PWP (4). Of note, in the present study, the most frequently reported new symptoms were anosmia/hyposmia and a sore throat (73.7%), followed by dysgeusia and skin rashes, in accordance with previous PCS non-PD cases (9). The present study demonstrated that the LEDD and UPDRS III scores exhibited significant difference at baseline and at 6 months following infection with COVID-19 in PWP with PCS symptoms. The deterioration of motor symptoms may be explained by stress, physical inactivity, pharmacodynamic effects, marked changes in routine and social isolation with a subsequent increase in LEDD. All previous studies (3,4,7-9) were small, lacked a control group, included exacerbated pre-existing symptoms that were previously stable, and recruited only participants infected during the first wave of the pandemic. Although chronic immunological changes may have caused the clinical worsening of PWP after the COVID-19 lockdown, these studies did not adjust for confounders that influence PD motor and non-motor symptoms, such as physical immobility, stress, anxiety, and sleep disturbances during COVID-19 lockdown.

The differentiation between PCS in PD and the general worsening of PD symptoms due to COVID-19 remains challenging. There are several potential mechanisms underlying the aggravation of PD-related neurodegeneration due to SARS-CoV-2 as follows: i) The poor absorption of anti-parkinsonian medications due to drug interaction with cough suppressants for SARS-CoV-2(10); ii) SARS-CoV-2 neurotropism of particularly vulnerable substantia nigra involved in the onset and progression of PD in vitro and human post-mortem studies (11,12); iii) enhanced neurodegeneration due to the persisting neuroinflammation process; SARS-CoV-2-related exosomes, in particular, have the potential to transmit SARS-CoV-2 fragments, transcriptional factors, and inflammatory mediators to brain cells, resulting in prolonged neuroinflammation and α-synuclein aggregation, which may lead to the worsening of PD symptoms. α-synuclein can enhance the SARS-CoV-2-mediated activation of microglia and the NLR family pyrin domain containing 3 inflammasome via the angiotensin converting enzyme 2/NF-κB pathway (13,14). Dopamine or inflammatory marker levels were not assessed in the present study; however, the authors aim to examine these in future studies.

The main limitation of the present study was the small cohort of patients with COVID-19. However, the present study has several strengths: First, the potentially harmful effects of lockdown restrictions on PD motor and non-motor symptoms were excluded. Second, the selection bias was minimized by excluding patients with advanced PD and comorbidities, who are more likely to develop neurological complications.

In conclusion, these novel findings raise critical questions for future analyses. Anosmia in COVID-19 may represent a true viral invasion of the olfactory bulbs (15). This new-onset post-COVID-19 symptom, which often predicts PD-associated clinical and pathological changes (16), may shed light on the possibility of SARS-CoV-2 infection triggering long-term neurodegeneration. Other NMS, such as pain, headaches and sleep disturbances, have been found to be more common in males than in females with PD and PCS, as evidenced in males with PD without PCS (17,18). However, the reason that males are more vulnerable than females to PD and PCS remains to be elucidated.

Moreover, the fact that these new-onset NMS were not associated with the vaccination status in the cohort of wild-type, alpha, and delta variant patients with SARS-CoV-2 suggests a more complex interplay between the immunological response and neurodegeneration. It also remains to be determined whether the current available vaccines against SARS-CoV-2 prevent PWP from PCS.

There is a clear need to distinguish the PCS in PWP from the chronic worsening of PD symptoms due to COVID-19. The diagnostic and treatment tools of PCS are currently insufficient, and numerous clinical trials are warranted to address the hypothesized underlying biological mechanisms, including viral persistence, neuroinflammation and autoimmunity.