Recent advances in the pathology of prodromal non-motor symptoms olfactory deficit and depression in Parkinson’s disease: clues to early diagnosis and effective treatment

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by movement dysfunction due to selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. Non-motor symptoms of PD (e.g., sensory dysfunction, sleep disturbance, constipation, neuropsychiatric symptoms) precede motor symptoms, appear at all stages, and impact the quality of life, but they frequently go unrecognized and remain untreated. Even when identified, traditional dopamine replacement therapies have little effect. We discuss here the pathology of two PD-associated non-motor symptoms: olfactory dysfunction and depression. Olfactory dysfunction is one of the earliest non-motor symptoms in PD and predates the onset of motor symptoms. It is accompanied by early deposition of Lewy pathology and neurotransmitter alterations. Because of the correlation between olfactory dysfunction and an increased risk of progression to PD, olfactory testing can potentially be a specific diagnostic marker of PD in the prodromal stage. Depression is a prevalent PD-associated symptom and is often associated with reduced quality of life. Although the pathophysiology of depression in PD is unclear, studies suggest a causal relationship with abnormal neurotransmission and abnormal adult neurogenesis. Here, we summarize recent progress in the pathology of the non-motor symptoms of PD, aiming to provide better guidance for its effective management.

Introduction

Parkinson’s disease (PD) is a progressive neurological disorder characterized by motor dysfunction that affects 10 million people globally, and this number is expected to double by 2030 (Dorsey et al. 2007). Many non-motor PD symptoms, including loss of smell, sleep disorders, depression, and constipation, can precede motor symptoms by several years. Dopamine replacement strategies are widely used for symptomatic therapy for PD as they improve key motor symptoms including bradykinesia, rigidity, and tremor. However, non-motor symptoms usually do not respond to motor deficits-targeting dopamine replacement therapy (Ray Chaudhuri et al. 2018; Deuel and Seeberger 2020). Leaving non-motor symptoms untreated can lead to a poor disease prognosis and a negative effect on the quality of life of patients with PD (Sauerbier et al. 2016). Although dopaminergic pathology is the cardinal feature in the brains of patients with PD, a more diffuse pathology might be associated with non-motor symptoms as well; the cholinergic glutamatergic, noradrenergic, and serotonergic systems (Brandão et al. 2020). Therefore, understanding the pathology of PD’s non-motor symptoms and ensuring an early and accurate diagnosis and an appropriate therapeutic approach in the PD prodromal stage remains a major and challenging goal for PD treatment. Using neuropathological PD findings as gold standard, the accuracy for a PD clinical diagnosis was only 26% in untreated or not clearly medication-responsive subjects, and 53% in early PD patients (< 5 year’s duration) responsive to medication (Adler et al. 2014).

The olfactory deficit shows high prevalence in patients with PD, early and easy diagnosis, and persistence throughout the disease course. Olfactory dysfunction has a prevalence > 90% in patients with PD and is a potential preclinical biomarker and a cardinal prodromal symptom that may precede neuropathology (Bohnen et al. 2008b; Shill et al. 2021). Although a correlation between olfactory dysfunction and neurodegenerative disorders has been increasingly recognized (Bahuleyan and Singh 2012), the underlying mechanism is not completely understood.

Depression is a nonspecific symptom, but the most common psychiatric symptom in PD, occurring in over one-third of cases. Depression may be present throughout all PD stages. For instance, at disease onset, up to 40% of patients with PD experience depression, whereas in the advanced stage, up to 70% of patients will have presented with depressive symptoms (Aarsland et al. 2009). Additional research has shown that the average onset of depressive symptom was 17.6 years earlier than the average age at PD diagnosis (Seritan et al. 2019). If PD onset could be recognized early, disease progression could be slowed by initiating appropriate neuroprotective treatment at the most effective stage. Depression could be one of the effective clinical markers of prodromal PD (Hustad and Aasly 2020), but the pathophysiology of depression in PD remains poorly understood. In the present review, we summarize the current progress in two pathological features of PD–olfactory deficits and depression–to provide crucial insights into the requirements of early diagnosis and clearer recommendations for PD treatment.

Olfactory dysfunction

Hyposmia is one of the characteristic non-motor signs of early PD, which may occur early, before the onset of motor disorders (Fig. 1). Clinical and experimental evidence suggest pathological changes in the olfactory bulb (OB), such as formation of pathological protein aggregates and changes in neurotransmitter signaling, at relatively early stages of PD, suggesting that olfaction may be vulnerable from early stages of PD progression (Table 1) (Rey et al. 2018). Olfactory dysfunction is correlated with disease progression and cognitive decline in PD (Domellöf et al. 2017; Cecchini et al. 2019). Furthermore, the effective levodopa dose is higher in patients with PD with hyposmia than in patients with normosmia (He et al. 2020). Therefore, detection of olfactory impairment could be useful for accurate PD diagnosis in the prodromal stage and for predicting disease progression risk.

Fig. 1

Timeline of Parkinson’s disease

Table 1 Pathological features of olfactory deficits with PD model

Olfactory ability and olfactory atrophy in PD

Patients with PD are often unaware of their olfactory deficit before testing. Less than 25% of patients with olfactory disturbance seem to realize their problem prior to diagnosis (Schmidt et al. 2020). Some patients with PD misestimate their own olfactory function as better than their actual odor identification ability (Leonhardt et al. 2019). Olfactory disturbance negatively affects the quality of life, by impacting the enjoyment of food, mood, and social interaction (Frasnelli and Hummel 2005; Vassilaki et al. 2017). Olfactory function is typically measured in a clinical setting by odor discrimination, odor identification, and odor detection threshold tasks (Fullard et al. 2017). The most frequently used and well-characterized method for olfaction assessment is odor identification by the University of Pennsylvania Smell identification Test (UPSIT), which includes 40 microencapsulated odorous substances presented in a “scratch ‘n’ sniff” booklet (Doty et al. 1984). Other olfactory performance clinical tests, such as odor detection threshold tests (e.g., Smell Threshold Test or Connecticut Chemosensory Clinical Research Center Test), can be used in combination with the UPSIT (Fullard et al. 2017). The UPSIT scores of PD were strongly correlated with various motor and non-motor symptoms, such as anxiety, depression and sleep disturbances, as well as with the degree of nigrostriatal dopaminergic cell loss, indicating that olfactory assessment using UPSIT could be a potential diagnostic tool for predicting disease progression. (Roos et al. 2019). In a few cases, olfactory deficits have also been reported in patients with familial PD (Liu et al.

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Acknowledgements

This research was supported by GRRC program of Gyeonggi Province (GRRC-CHA2017-A01, Analysis of Regional Specialized Resources and Operation of Regional Research Service Center), and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1I1A1A01074592, NRF-2019R1I1A1A01063630) and the Ministry of Science and ICT (NRF-2018R1A2B6004008).

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1. College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do, 11160, Republic of Korea

   Yeo** Bang & Hyun ** Choi

2. College of Pharmacy, Woosuk University, Wanju, Jeollabuk-do, 55338, Republic of Korea

   Juhee Lim

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Correspondence to Hyun ** Choi.

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Bang, Y., Lim, J. & Choi, H.J. Recent advances in the pathology of prodromal non-motor symptoms olfactory deficit and depression in Parkinson’s disease: clues to early diagnosis and effective treatment. Arch. Pharm. Res. 44, 588–604 (2021). https://doi.org/10.1007/s12272-021-01337-3

• Received: 10 March 2021

• Accepted: 01 June 2021

• Published: 19 June 2021

• Issue Date: June 2021

• DOI: https://doi.org/10.1007/s12272-021-01337-3

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