Parkinson’s disease (PD) is a representative neurodegenerative disorder with motor symptoms that include tremor, bradykinesia, rigidity, and/or gait disturbance [1]. Dopaminergic degeneration in the substantia nigra is known to be a key pathologic burden associated with such motor symptoms in patients with PD [2]. In addition, non-motor symptoms (NMSs) are strongly suspected to be related to non-dopaminergic degenerations of the noradrenergic, serotonergic, and cholinergic systems as well as dopaminergic degeneration beyond the substantia nigra [3]. Not only motor symptoms, but also NMSs can significantly impact the quality of life of patients with PD. Therefore, studying these motor and non-motor symptoms is necessary to deepen our understanding of the pathophysiology of PD and to better treat patients with PD.

It has been widely reported that some important NMSs, which include sleep disorders, loss of smell, depression, and constipation, could be present before development of the motor symptoms of PD [4]. Such NMSs not only provide pathophysiological evidence of disease progression, but also help clinicians diagnose PD easier or earlier in real clinical settings. Besides, clinicians have occasionally seen patients with PD complaining of dizziness at very early stages or even at a de novo state [5, 6]. A previous study reported that dizziness could precede diagnosis by about five years, and that it could be regarded as a potential NMS in the prodromal stage of PD [7]. Interestingly, another report recently documented that dizziness in patients with PD might not be associated with orthostatic hypotension [5], inferring that dizziness is not directly linked to cardiovascular dysfunction or orthostatic hypotension. However, the clinical differences between patients with de novo PD who complain of dizziness, and those who do not, have yet to be well understood. Therefore, the aim of this study was to investigate the clinical characteristics and the relevance of dizziness in drug naïve patients with de novo PD, focusing on the very early stages while excluding the adverse effects of dopaminergic medications, which might induce dizziness or orthostatic hypotension.

If a patient with PD is experiencing dizziness, a comprehensive evaluation to determine the underlying cause is crucial. Treatment will depend on the specific cause identified. In our daily clinical practice, we occasionally encounter patients, even those with de novo PD, who complain of dizziness, which appears to be non-specific. Based on these clinical experiences, we hypothesized that dizziness could be one of the non-motor symptoms in PD, like constipation or depression. Specifically, we aimed to clarify the frequency and clinical presentation of dizziness in patients with PD in the de novo state.

Up to 30% of the elderly occasionally feel dizzy in their daily lives, while up to about 46~68% of patients with PD feel dizzy [6, 18]. However, the prevalence of dizziness should be interpreted with caution since many previous studies were conducted on patients with a med-on state [6, 18, 19], implying that a significant number of parkinsonian patients might show drug-induced adverse effects including dizziness, not a symptom of the disease itself. Our study investigated the presence of dizziness and its characteristics only in the drug naïve state of patients with de novo PD. As a result, we found that about 42% of patients with de novo PD had dizziness. By excluding adverse effects of taking anti-parkinsonian drugs, we could uncover the clinical impact of dizziness on other motor or non-motor symptoms in patients with PD itself, especially during very early stages of the disease.

Dizziness is a general term that could be distinguished into four categories according to its presumed etiologies [17]. In the current study, we showed that the types of dizziness in patients with de novo PD were diverse. The most common type of dizziness in patients with de novo PD was presyncope or orthostatic dizziness (38%). All other types of dizziness accounted for 62% (36% with lightheadedness or non-specific type, 18% with disequilibrium or feeling unbalanced, and 8% with vertiginous type). Of note, we figured out that dizziness was not associated with orthostatic hypotension (Table 1). In line with our results, Park et al. [19] also showed that about half of PD patient with dizziness did not have an orthostatic hypotension. Moreover, Klanbut et al. [20] demonstrated that orthostatic hypotension in some patients with PD was asymptomatic. On the other hand, Park and Kang recently showed that vestibular dysfunction might be involved in the pathogenesis of dizziness in PD [5]. Collectively, we could suspect that dizziness itself is not directly linked to orthostatic dizziness in patients with PD. It seems that the underlying mechanism of dizziness in PD can be multidimensional, rather than due to a single reason. Accordingly, the precise mechanisms for the relationship between dizziness and PD remain to be further elucidated.

Intriguingly, our study revealed that dizziness was significantly linked to women with de novo PD than to men with this disorder (Tables 1,2). It is currently unclear if women complain more of dizziness because they are women since it is generally accepted that dizziness tends to increase with age, and is reported higher in women [21, 22]. Besides, there is another possibility of there being other reasons for why women with PD complain of more dizziness. Some sex differences in motor symptoms and non-motor symptoms including depression and pain have been investigated in subjects with PD [23, 24]. The mechanism of sex-specific differences in PD is known to be associated with various players including hormonal, neuroendocrinal, genetic, and biochemical/molecular factors [25]. However, to the best of our knowledge, such a sex difference for dizziness in PD has yet to be evaluated. Further studies are required to address this issue.

Notably, we found that the presence of dizziness in patients with de novo PD was significantly related to not only lower scores of MoCA-K, but also higher scores of SCOPA-AUT (specifically, cardiovascular dysautonomia). Recent evidence has demonstrated that dizziness in older adults might be an important risk factor of cognitive impairment or dementia [26]. Moreover, in line with our findings, Lee and colleagues [27] have reported that dizziness in the elderly with parkinsonism including PD, normal pressure hydrocephalus, and multiple system atrophy is significantly associated with both cognitive impairment and postural instability. Accordingly, they supposed that postural instability might be a crucial factor of dizziness [27]. However, our results did not reveal any association between dizziness and postural instability probably because our study population was limited to those with a de novo state of PD, implying that most participants had little problem of postural instability. Postural instability significantly contributes to the disease progression of PD. Therefore, it is reasonable to infer that another important determinant of dizziness in patients with de novo PD may exist beyond postural instability. Further, a recent review has illustrated a possible linkage between cognitive dysfunctions and cardiovascular dysautonomia [28]. Moreover, another review has suggested that orthostatic hypotension-induced cerebral hypoperfusion might cause cognitive decline in patients with PD [29]. Collectively, we could deduce that dizziness in patients with de novo PD might be regarded as an indicative symptom for cardiovascular dysautonomia as well as cognitive impairment.

The SCOPA-AUT questionnaire consists of 25 items that assess various aspects of autonomic dysfunction, including cardiovascular function, gastrointestinal function, and urinary function. The cardiovascular domain of the SCOPA-AUT questionnaire comprises three items related to orthostatic dizziness [16]. However, dizziness itself was not identical to orthostatic dizziness, since dizziness in patients with PD could be presented as being of various types [6, 17], which have already been described. Moreover, the investigation of the characteristics of subjective dizziness and the SCOPA-AUT scale was separately conducted in the current study. Our study primarily focused on examining the clinical correlation between subjective complaints of dizziness and motor/non-motor symptoms in patients with de novo PD. Further follow-up studies are needed to investigate the association between cardiovascular dysfunction or orthostatic dizziness and clinical features of patients with de novo PD.

This study has several shortcomings. First, this was a retrospective study with a relatively small sample size. Novertheless, we could draw meaningful conclusions through the multivariable logistic regression analyses. However, caution should be exercised in extrapolating the findings of this study, and further larger-scale prospective studies are necessary. Second, it is important to note that the SCOPA-AUT questionnaire is an indirect method of assessing autonomic dysfunction, although the SCOPA-AUT questionnaire is a validated and reliable tool for evaluating autonomic dysfunction in patients with PD. Therefore, additional tests and evaluations may be necessary for a complete assessment of the relationship between dizziness and autonomic dysfunction in patients with de novo PD. Third, as this study is a retrospective study, we only investigated the medical history and could not perform a thorough evaluation of all medications. Therefore, we could not investigate the association between various medications, including alpha-blockers, diuretics, and calcium channel blockers, which can cause orthostatic hypotension. In addition, this study conducted various surveys on symptoms such as dizziness and autonomic abnormalities to obtain clinical information, so it may include recall bias from the participants.

In conclusion, we found that a considerable number of patients with de novo PD complained of dizziness and that their characteristics of dizziness varied. Such dizziness was more prevalent in women than in men, and was significantly associated with cognitive decline and cardiovascular dysautonomia. Thus, clinicians should monitor these clinical symptoms in patients with PD who complain of dizziness and provide appropriate management early.

PD, Parkinson’s disease; BMI, body mass index; UPDRS-III, Unified Parkinson’s Disease Rating Scale part III; PIGD, postural instability and gait disorder; TD, tremor-dominant; MoCA-K, Korean version of Montreal Cognitive Assessment; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; PFS, Parkinson’s Disease Fatigue Scale; SCOPA-AUT, Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction; GI, gastrointestinal; CV, cardiovascular.

The data underlying this article will be shared on reasonable request to the corresponding author.

KYK designed the research study. JY, ROK, and EJL performed the research. KYK, JY, ROK, and EJL analyzed the data. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

All procedures were performed in accordance with ethical standards of the institution and/or the national research committee as well as with the 1964 Helsinki Declaration and its subsequent amendments. This study was retrospective and was approved with waiver of individual informed consent by the ethics committee of our Institutional Review Board (IRB No. 2022-12-003).

We thank all staffs in our department of Neurology for their kind and enthusiastic support.

This study was supported by Soonchunhyang University Research Fund.

The authors declare no conflict of interest.