A 6-month longitudinal study on worsening of Parkinson’s disease during the COVID-19 pandemic

Further studies are required to investigate the impact of the COVID-19 pandemic on Parkinson’s disease (PD) progression. This study investigated the motor and non-motor progression of people with PD (PWP) at 6 months during the COVID-19 pandemic compared with that during the pre-pandemic period. Patients were recruited from Ain Shams University Hospitals, Cairo, in the period between April 2019 and December 2020. Fifty patients were included, of whom 17 and 33 patients were followed for 6 months before and during the pandemic, respectively. All patients were assessed at baseline and at 6 months using the MDS-UPDRS, Schwab and England scale (S&E), Hoehn and Yahr scale (H&Y), Berg Balance Scale, Timed Up and Go test (TUG), International Physical Activity Questionnaire, New Freezing of Gait Questionnaire, Non-Motor Symptoms Scale, and Beck Depression Inventory (BDI). Both groups were matched in age, gender, and disease characteristics. Patients followed during the pandemic showed more significant worsening of the total, part I and motor part of MDS-UPDRS, and balance scores (p < 0.001) than those followed during the pre-COVID-19 period. Gait (TUG), balance, and physical activity worsening were significantly correlated with baseline BDI, gait and balance scores, total and part I MDS-UPDRS scores, H&Y, and S&E OFF scores. Gait deterioration (TUG) was correlated with baseline physical activity (r = −0.510, p = 0.002). PWP showed worsening of motor and non-motor symptoms during the COVID-19 pandemic at the 6-month follow-up. Worsening of gait, balance, and physical activity was correlated with baseline motor and physical activity OFF scores.


INTRODUCTION
Since the outbreak of the coronavirus disease 2019 (COVID- 19) pandemic, individuals with Parkinson's disease (PD) have been considered a vulnerable group to the effects of the COVID-19 pandemic, directly by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and indirectly by pandemicrelated restrictions, chronic stress, anxiety, physical inactivity, and compromised medical care. These effects included worsening of motor symptoms, higher mortality in advanced PD, worse anxiety and depression, impaired physical activity, and disruption of patients' care [1][2][3] . Several recent studies have linked reduced physical activity and exercise to motor worsening during the pandemic, implying the significance of maintaining patients' activity during restrictions 4,5 .
Moreover, it has been proposed that the COVID-19 pandemic may be followed by a higher incidence of neurodegenerative diseases; however, the evidence is insufficient to confirm that COVID-19 may trigger or accelerate neurodegeneration 6 . However, the impact of the COVID-19 pandemic and related measures on disease progression has not been explored. A recent retrospective study has reported a worsening of motor symptoms with a significant increase in motor disease progression during pandemicrelated restrictions compared with that during the pre-pandemic period. The assessment was limited to ON-state and motor aspects 7 . Therefore, longitudinal studies are warranted to investigate the possibility of altered progression of motor and non-motor aspects of PD during the pandemic.
Accordingly, the current longitudinal study investigated the short-term motor and non-motor progression and related determinants of a cohort of people with PD (PWP) during the COVID-19 pandemic compared with the progression during the pre-pandemic period of another matched cohort.

RESULTS
Fifty patients were included, of whom 17 and 33 patients were followed for 6 months before and during the pandemic, respectively. Both groups were matched for demographic and clinical characteristics except for longer disease duration (p = 0.007) and lower rigidity ON scores (p = 0.01) for patients followed during the pandemic (Table 1). Physical activity ((International Physical Activity Questionnaire [IPAQ]) was nonsignificantly lower in patients during the pandemic. All patients did not report symptoms suggestive of COVID-19 infection. Cronbach's alpha coefficient of the questionnaires ranged from 0.75 to 0.98, indicating a satisfactory internal consistency.
Disease progression before and during the COVID-19 pandemic Patients followed before the pandemic showed a moderately significant progression at 6 months of MDS-UPDRS-I (Non-Motor Aspects of Experiences of Daily Living [nM-EDL]) (p = 0.044) and OFF-state motor scores (p = 0.047). The Schwab and England Activities of Daily Living scale (S&E) OFF-and ON-state scores showed a significant progression (p = 0.04 and 0.011, respectively) although not H&Y. Postural Instability and Gait Disorder (PIGD) ON and OFF-states, axial OFF-state, and New Freezing of Gait Questionnaire (NFOG-Q) OFF-state scores showed a moderately significant progression. The total non-motor symptoms scale (NMSS) and IPAQ showed significant worsening (p < 0.001)  Table 2).
Compared with the patients followed before the pandemic, those followed during the pandemic had greater significant worsening of the total and motor MDS-UPDRS OFF-and ON-state scores, MDS-UPDRS part I (p < 0.001), rigidity OFF (p = 0.04) and ON-state scores (p < 0.001), bradykinesia ON-state scores (p < 0.001), BBS OFF-and ON-state scores (p < 0.001) (significant after Bonferroni correction), axial OFF-state scores, and TUG (p = 0.01, non-significant after Bonferroni correction). Levodopa equivalent daily dosage (LEDD), MMSE, NMSS, IPAQ, and PDQ showed similar changes in both groups ( Table 2).
Correlations of disease progression during the pandemic During the pandemic, the worsening of motor severity (H&Y) was correlated with disease duration (r = 0.500, p = 0.003), whereas motor complications (part IV) were directly correlated with baseline cognition (p = 0.02) and S&E (p = 0.03) and inversely correlated with depression and total and motor MDS-UPDRS scores (p = 0.04) (non-significant after Bonferroni correction); conversely, total and other MDS-UPDRS progression did not show significant correlations (Table 3).
On comparison between the two groups regarding the assessment scale scores after 6 months, significant worsening was noted in MDS-UPDRS-I in the patients followed during the COVID-19 period (p = 0.003) (Supplementary Table 3).

DISCUSSION
Several cross-sectional studies have constantly described the worsening of motor and non-motor symptoms during the COVID-19 pandemic. However, its impact on disease progression was not adequately investigated. Distinctively, this longitudinal study explored disease progression during the pandemic and showed worsening of motor and non-motor symptoms over a 6-month follow-up during the pandemic compared with that during the pre-pandemic period. Gait, balance, and physical activity worsening were correlated with baseline motor and physical activity scores. The current study showed the possibility of deleterious effects of pandemic lockdown on disease progression in PWP.
The current findings are consistent with those of previous cross-sectional studies. An Indian study showed worsening of motor symptoms, especially bradykinesia in 69.2% of cases during the COVID-19 pandemic, followed by tremor, rigidity, and gait freezing 8 . Additionally, PWP reported worsening in mental health, quality of life, and physical inactivity during this pandemic 5 . These indirect effects of COVID-19 are more confirmed and may be more common and more harmful than the direct effects of viral infections 1,9,10 . The worsening of motor and non-motor symptoms has been attributed to stress, physical inactivity, pharmacodynamic effects, dramatic changes in routine, and social isolation 11,12 . The impact of stress on PD progression has been previously investigated and proven to negatively affect the course of the disease 1,2,4 .
Conversely, the impact on disease progression is not well investigated. However, a recent study by Ineichen et al. has reported increased motor disease progression during pandemic-related restrictions compared with that before the COVID-19 pandemic, which is consistent with the current study 7 . Similar to symptom worsening, more deterioration during the pandemic could be explained by stress, physical inactivity, and social isolation.
PWP are more vulnerable to recent stressors, which is attributed to more dopamine depletion and consequently reduced coping mechanisms for stress 13 . Moreover, chronic stress may induce oxidative damage to the cell membrane, as well as inflammatory and regulatory T-cell dysfunction, leading to a possible increase in midbrain dopaminergic neuron loss and motor symptom worsening 14 . Additionally, chronic stress accelerates dopaminergic cell loss in animal PD models and exacerbates the neuropathological changes 15 . The accompanying microglial activation and oxidative stress may mechanistically justify the stress-induced neurodegeneration in PD 16 .
Remarkably, gait (TUG), balance, and physical activity were markedly worsened during the pandemic, which was related to baseline motor and physical activity scores. Consistently, a recent study, which assessed 12 patients before and 2 months after lockdown, has shown moderate gait, falls, and balance worsening although not freezing of gait, despite being contacted by a multidisciplinary team 17 .
Approximately 29% of patients with PD are less physically active than the normal population, which are predicated by disease severity, gait, and impairment of activities of daily living 18 . Increased physical activity and exercise have a positive effect on motor and non-motor symptoms and probably PD disease progression 19 . Moreover, exercise may improve the progression of PD manifestations and enhance motor and cognitive circuitrelated neuroplasticity [20][21][22] .
Despite there being no reported cases of SARS-CoV-2 infection, its direct effect on disease progression due to subclinical infection could not be totally excluded. An Italian study reported motor and non-motor deterioration that was attributed to infection and drug pharmacodynamic-related mechanisms. A quarter of patients with PD and COVID-19 had mild symptoms and recovered without treatment 23 .
SARS-CoV-2-related neurodegenerations, especially nigrostriatal degenerations, have been proposed owing to the possibility of neuro-invasion via the olfactory bulb, Angiotensin-Converting Enzyme 2 (ACE2) receptor expression by dopaminergic neurons, associated inflammatory and vascular changes that overlap with PD pathogenesis, and progression in addition to reported cases of SARS-CoV-2-related parkinsonism with dopamine transporter imaging abnormalities 1,24 . However, the impact of COVID-19 on neurodegeneration, including the development or increased progression of PD, has not yet been confirmed.
The strengths of the current study include the comprehensive assessment in the OFF and ON states and follow-up of patients with mild-to-moderate PD before and during the pandemic, with a comprehensive assessment of motor and non-motor symptoms and matched baseline characteristics of patients in both groups.
The current study has some limitations. The small number and short follow-up period, as well as the lack of confirmation or exclusion of SARS-CoV-2 infection using laboratory tests during assessments, are considered its limitations. Furthermore, our cohort included patients with mild-to-moderate PD who should be considered in the interpretation of our findings.
This study confirms the impact of the COVID-19 pandemic on the motor and non-motor symptoms of PD and demonstrates another possible effect, which is the short-term worsening of disease progression, implying the significance of managing related factors, including anxiety, chronic stress, and physical inactivity, and considering this effect in interpreting longitudinal studies during the pandemic.

METHODS
This is a retrospective analysis of the data from our longitudinal study (PDPRO-EGY, clinicalTrial.gov, NCT04062279) that investigated the progression of Egyptian patients with PD. Patients were recruited from the movement disorders outpatient clinic of Ain Shams University Hospitals (Cairo, Egypt) in the period between April 2019 and December 2020. Patients with PD who were diagnosed using the International Parkinson and Movement Disorders Society (MDS) diagnostic criteria 25 and completed both baseline and 6-month follow-up assessments before or during the pandemic period were included and compared. Patients who completed baseline and follow-up assessments during the pandemic were included as the "one group" (from March to December 2020), whereas those who completed the follow-up before March 2020 (before lockdown procedures in Egypt) were included as the "control group." Patients excluded include patients with atypical or acquired parkinsonism, those who did not complete the follow-up assessment, those who were assessed in the pre-pandemic (baseline) and during the pandemic A. Shalash et al. Table 3. Correlations between disease progression during the COVID-19 pandemic and baseline characteristics.  A. Shalash et al.
(6-month follow-up) periods, and those who underwent functional brain surgery (before or during the follow-up period).

Sampling and sample size
The sample size was calculated using an online calculator (https:// www.calculator.net/sample-size-calculator.html), where for a 95% confidence level and a margin of error 5, the minimal sample size was estimated to be 16 patients for each group.

Ethical considerations
All participants provided written informed consent. The study was approved by the ethical committee of the Faculty of Medicine of Ain Shams University according to the Declaration of Helsinki.

Data collection
All patients were evaluated at baseline and at 6-month follow-up using the total and different parts of the

Statistical analysis
Data analysis was performed using IBM SPSS software package version 25.0 (IBM Corp., Armonk, NY). Qualitative data were described as frequencies and percentages and compared using the chi-square test, whereas quantitative data were presented as medians and interquartile ranges or means ± standard deviations and compared using either the Mann-Whitney U test or Student's t test according to the distribution of the data, respectively. The Wilcoxon signed-rank test was used to compare baseline and follow-up data within each group. The Spearman correlation coefficient was used to evaluate the correlation between different variables. The significance was set at p < 0.05. Bonferroni correction was performed for the multiple comparisons and correlations, and an adjusted p-value was used. Cronbach's α coefficient was used as a measure of the internal consistency of used questionnaires.