This study was conducted to explore the association between depression in patients with PD with other NMSs, including sleep disorders, cognitive impairment, autonomic dysfunction, hyposexuality, constipation, and hyposmia.
In the past few years, NMS have been thoroughly scrutinized regarding their potential utility as diagnostic and prognostic tools for PD (19). Some recent studies indicate that non-motor dysfunction has a more significant impact on health-related quality of life rather than motor abnormalities due to their high prevalence of more than 20% of patients diagnosed with PD. Also, recent studies reported that almost all PD patients experienced at least one NMS during the disease, showing a pattern of fluctuation. The importance of early diagnosis through NMSs is that by the time patient shows motor symptoms, more than 50% of striatal dopaminergic capacity is diminished (20).
Although the primary pathology in PD is progressive dopaminergic denervation in substantia nigra, other regions and neurotransmitters are also affected. NMSs are associated with neurotransmitters disturbance alongside dopamine deficiency in PD. Therefore, NMSs and their severity might be associated with depression degree in PD patients. The high prevalence of depressive disorders in the early stages of the disease also confirms this hypothesis (21). Depression has also been indicated as a potential essential risk factor for developing PD in the future (22). Different pathophysiologies could lead to depression as a prodromal symptom for PD, such as loss of dopamine and noradrenaline innervation in the limbic system (23), disruption in serotonergic raphe nuclei in sporadic PD, and atrophic regions in cortical gyri and emotion recognition centers in depression-PD patients (24, 25). However, the exact etiology is yet not well understood.
The majority of patients studied in this research were classified as severely depressed, while merely 11.8% of them were mildly depressed and the rest belonged to the moderately depressed group. Our result showed a strong statistical relationship between cognitive impairment in PD patients with their depression severity. Cognitive deficit in PD patients ranges from mild cognitive impairment (MCI) to dementia in the late stages (26) and is suggested to be related to the accumulation of Lewi bodies in cortical regions and cholinergic dysfunction in the cortex (27). Also, one of the early responses to the loss of dopamine in striae is rising the dopamine levels in the prefrontal cortex that could harm cognitive function (28). Other extranigral pathways such as dorsal serotonergic raphe, amygdala, hippocampal formation, limbic thalamic nuclei with prefrontal projections are also simultaneously impaired in cognitive impairment and depression (29). Based on recent studies, the cognitive deficit can also lead to increased depression in patients through deteriorating the quality of life (QOL) (30).
Our work found a significant correlation between depression score (BDI) with sleep quality (PSQ), cognitive performance (MoCA score), and hyposexuality. This is aligned with the above-mentioned former works in this regard. Although longitudinal studies are required to provide further etiological insights. One of the earliest symptoms in PD patients is REM sleep disorders (90%) that can manifest by insomnia, excessive daytime sleep (EDS), REM sleep without atonia, sleep-related breathing disorders such as obstructive sleep apnea, restless leg syndrome, and nocturia (31). Some studies showed that neuronal damage and dysregulation of circadian molecules might lead to these symptoms (32). Also, some works have suggested that interruptions in a-synuclein clearance by the glymphatic system might lead to sleep disorders and therefore fasten the progression of PD. Sleep also plays a significant role in cognitive and memorial functions and might therefore affect QOL in patients (33). Other studies found a significant association between fatigue and EDS with motor symptoms, disease duration, depression, and dopaminergic treatment (34).
The most prevalent NMSs in our research were constipation and hyposexuality, respectively. A statistically significant correlation was found between hyposexuality and patient’s depression severity, but this statistical significance was not found regarding any other NMSs in our research. Autonomic dysfunctions in PD patients consist of a vast spectrum, including cardiovascular, gastrointestinal, and sexual symptoms. Among these symptoms, hyposexuality and constipation are seen in patients frequently (30–50%). Hyposexuality and orgasmic dysfunction are seen in both genders and often neglected because of patients’ embarrassment and clinicians’ focus on more apparent motor symptoms (35). Hyposexuality and sexual disorders are particularly underdiagnosed in societies where sexual tendencies are not openly discussed like Iran (36). The high rates of constipation among depression-PD patients is also concerning since gastroparesis and small intestine bacterial overgrowth can lead to malabsorption of PD medication in patients and, therefore, exacerbate motor symptoms (37). This finding is also in line with the current literature, suggesting an association between severe constipation and depression (38).
As stated above, NMSs are detected earlier in the course of PD. Still, late-stage NMSs such as depression are not proper measures in differentiating stages and phenotypes of disease. This is particularly notable since some studies have suggested that patients with distinct patterns of motor symptoms are prone to more severe NMSs and poorer prognosis (39). Lastly, among all NMSs investigated in this research, BDI was merely found to predict the PSQ score, MoCA, and hyposexuality significantly. In the multivariate regression analysis, MoCA and hyposexuality were the only significant predictors. Therefore, depression is indeed a significant predictor of hyposexuality and cognitive impairment in PD.
Since depression is easier to detect clinically, our findings are significant in regards to the early detection of other NMSs in patients to start and modify their treatment. This could make a considerable difference in QOL in patients. Also, one of the most critical areas in neurodegenerative disease like PD is early diagnosis, since by the time of recognizable motor symptoms, the disease is already advanced. Eventually, NMSs significantly impact the pace of deterioration of symptoms and QOL in PD patients, and their potential utility to diagnose PD earlier (like developing biochemical tests) could be a subject of future related works.