GRAPHICAL ABSTRACT

INTRODUCTION

Cognitive impairment is among the most debilitating nonmotor symptoms in Parkinson’s disease (PD) [1], substantially compromising functional independence and patients’ quality of life [2]. The progression of cognitive decline reflects a complex interplay between nonmodifiable factors, such as age and genetic predisposition, and modifiable factors, such as mood disorders, sleep disturbances, and metabolic health [3]. Early identification of modifiable risk factors is essential, as it provides a strategic window for targeted therapeutic and lifestyle interventions. By proactively addressing these factors, clinicians might help attenuate the trajectory of cognitive deterioration observed in patients with PD.

Depression and anxiety are among the most prevalent nonmotor symptoms in patients with PD and are increasingly being recognized as critical contributors to decreased quality of life and more complex clinical management [4]. These neuropsychiatric disturbances can impair cognitive performance, particularly in the executive and mnemonic domains, through multifactorial neurobiological mechanisms [5,6]. The underlying pathophysiology involves synergistic dysfunction of the dopaminergic, serotonergic, and noradrenergic systems, disrupting the functional integrity of frontostriatal and limbic circuits [7,8]. Furthermore, chronic mood dysfunction may reduce cognitive reserve and exacerbate neuroinflammatory processes, accelerating the progression from mild cognitive impairment to dementia [9,10].

Although the association between neuropsychiatric symptoms and specific cognitive deficits in PD is well documented [11,12], few studies have concurrently evaluated the independent and combined effects of depression and anxiety—both potentially modifiable factors—on cognitive performance. Accordingly, the aim of this study was to characterize neuropsychological differences among patients with early-stage PD stratified by depression and anxiety status.

MATERIALS & METHODS

Study participants

A total of 149 patients with PD were consecutively enrolled from the Movement Disorders Clinic at Chonnam National University Hospital between January 2022 and December 2024. All participants underwent clinical evaluation by a movement disorder specialist (S.M. Choi) to confirm the diagnosis according to the Movement Disorder Society (MDS) clinical diagnostic criteria [13]. Eligibility was limited to patients in early to middle stages of PD (Hoehn and Yahr [H-Y] stages 1–3) [14] with a symptom duration of ≤5 years. Individuals with atypical or secondary parkinsonism, poor dopaminergic response, dementia, significant brain MRI abnormalities, or severe systemic comorbidities were excluded.

This study was approved by the Institutional Review Board of Chonnam National University Hospital (IRB No.: CNUH-2026-087) and data were retrieved from the institutional parkinsonism registry. All participants provided written informed consent, and the study protocol adhered to the principles of the Declaration of Helsinki.

Clinical evaluation

All participants underwent a comprehensive neurological evaluation, including anthropometric measurements (height and weight). Clinical history, including symptom duration and years of formal education, was systematically documented. Parkinsonian symptom severity was assessed using the H-Y stage [14] and the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III [15]. Global cognitive function was assessed using the Korean version of the Mini-Mental State Examination (K-MMSE) [16]. Depressive and anxious symptoms were assessed using the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI), respectively [17,18]. While these scales are widely validated for screening purposes in patients with PD, they represent a measure of symptom severity rather than a formal psychiatric diagnosis. Participants were stratified into subgroups on the basis of threshold scores of a BDI ≥14 and a BAI ≥8. These specific cutoff points were chosen on the basis of previous validation studies in patients with PD to ensure high sensitivity in detecting even mild neuropsychiatric symptoms [17,18].

All participants completed the Seoul Neuropsychological Screening Battery to obtain detailed cognitive profiles [19]. This comprehensive instrument provides standardized assessments across five core domains: attention, language, visuospatial function, memory, and executive function. The battery was administered by trained examiners in strict accordance with the standardized manual, and the resulting scores were used for domain-specific analyses.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics, version 29.0 (IBM Corp.). Initial intergroup comparisons of clinical and cognitive variables—stratified by the presence of depression or anxiety—were conducted using independent-samples t-tests and chi-square tests. To account for baseline differences, analyses of covariance (ANCOVAs) were subsequently performed for the cognitive assessments. Prior to performing ANCOVA, several assumptions were tested to ensure the validity of the model. The Shapiro–Wilk test was used to assess the normality of the data distribution, and Levene’s test was performed to confirm the homogeneity of variance. Additionally, the variance inflation factor (VIF) was calculated to evaluate potential multicollinearity between covariates, such as the H-Y stage and MDS-UPDRS motor score. The VIF for these motor severity markers was 1.07, far below the standard threshold of 5, indicating no significant multicollinearity and confirming the robustness of the model. Additionally, we performed group comparisons for medication status (de novo vs. medicated), levodopa equivalent daily dose (LEDD), and the use of anticholinergics to evaluate potential pharmacological confounders. In the depression model, the covariates included the duration of formal education and H-Y stage, whereas in the anxiety model, education and MDS-UPDRS motor scores were included. For comparisons involving both comorbidities, education, H-Y stage, and MDS-UPDRS motor scores were included as covariates. To address the risk of type I errors arising from multiple comparisons across various cognitive domains, we applied the Bonferroni correction. Both unadjusted and Bonferroni-corrected p values are reported to provide a comprehensive evaluation of the findings. Effect sizes for ANCOVA were calculated using partial eta-squared (η²), with values of 0.01, 0.06, and 0.14 considered small, medium, and large effects, respectively. Statistical significance was defined as p<0.05.

RESULTS

The demographic and clinical characteristics of the participants are summarized in Table 1. There were no significant differences between the groups with respect to age, sex distribution, symptom duration, body mass index, or K-MMSE score. However, certain clinical variables differed significantly. Compared with their respective counterparts, both the depression group and the anxiety group had fewer years of formal education (p=0.007 and p=0.033, respectively). In terms of disease severity, the depression group had higher H-Y stage scores than the nondepression group (p=0.038), whereas the anxiety group had higher MDS-UPDRS motor scores than the nonanxiety group (p=0.003). With respect to medication status at the time of assessment, the majority of the study population (n=108, 72.4%) were de novo patients. As summarized in Table 1, there were no significant intergroup differences in the frequency of de novo status, LEDD, or the use of anticholinergic agents.

The results of the neuropsychological tests according to depression status are presented in Table 2. According to the unadjusted analysis, the depression group performed significantly worse across multiple domains, including language (Korean version-Boston Naming Test), visuospatial function (Rey Complex Figure Test [RCFT]), verbal memory (Seoul Verbal Learning Test [SVLT] recognition), visual memory (RCFT immediate and delayed recall), and executive function(phonemic generative naming, Color Stroop test, and digit symbol coding). After adjustment for the duration of formal education and H-Y stage using ANCOVA, most differences were no longer significant. Notably, only the SVLT recognition score remained significantly lower in the depression group (p=0.009). However, this difference did not persist after the stringent Bonferroni correction was applied for multiple comparisons (adjusted p>0.05).

Table 3 presents the neuropsychological test performance according to anxiety status. In the unadjusted analysis, the anxiety group had lower scores across multiple domains, including visuospatial function (RCFT), verbal memory (SVLT delayed recall), visual memory (RCFT immediate and delayed recall), and executive function (phonemic generative naming, Color Stroop test, Digit Symbol Coding, Trail Making Test [TMT]-A, TMT-B). After adjusting for the duration of formal education and MDS-UPDRS motor scores, significant differences persisted in visual memory (RCFT immediate recall, p=0.006) and frontal executive function (Color Stroop test, p=0.016). Notably, the anxiety-related impairments in RCFT immediate recall and the Color Stroop test were robust enough to maintain significance under the Bonferroni-corrected threshold (p<0.05 after adjustment).

When patients with both depression and anxiety were compared with those without either condition (Table 4), the comorbid group was characterized by significantly fewer years of education (p=0.007) and greater clinical severity, as evidenced by higher H-Y stages (p=0.031) and MDS-UPDRS motor scores (p=0.011). There were no significant intergroup differences in the frequency of de novo status, LEDD, or the use of anticholinergic agents (Table 4). Compared with asymptomatic patients, those with comorbid depression and anxiety presented significantly lower scores across most cognitive domains, including language, visuospatial function, verbal and visual memory, and executive functions (Table 5). However, after adjusting for confounding factors, many of these differences were attenuated and lost statistical significance. Notably, impairments in RCFT immediate and delayed recall, as well as the Color Stroop test, remained robustly significant (p<0.05). Crucially, the deficits in RCFT immediate recall (p=0.002), RCFT delayed recall (p=0.025), and the Color Stroop test (p=0.010) remained robustly significant even after rigorous correction for multiple testing, highlighting the substantial combined impact of comorbid affective symptoms on these specific cognitive markers.

DISCUSSION

This study in patients with early PD yielded several key findings: 1) both depression and anxiety were associated with lower educational attainment and greater clinical severity; 2) depression was notably associated with a trend toward lower verbal memory recognition, although this effect did not survive rigorous multiple testing correction; 3) anxiety independently affected immediate visual recall and inhibitory executive control; and 4) comorbid depression and anxiety were associated with broader and more extensive impairments in visual memory—including both immediate and delayed recall—and frontal executive function, even after stringent Bonferroni adjustment.

Depression was initially associated with impaired verbal memory, which is consistent with the findings of previous literature [20]. Although some studies have reported deficits in other cognitive domains, such as executive function, attention, and processing speed, these differences did not remain significant after adjustments were made for confounding variables [11]. In our cohort, while SVLT recognition scores were significantly lower in the depression group after covariate adjustment (p=0.009), these findings were attenuated after Bonferroni correction. These findings suggest that while verbal memory recognition may be a sensitive indicator of depressive symptoms in patients with PD, its independent effect size might be relatively modest when individuals are subjected to conservative statistical thresholds. The neural substrates of verbal memory recognition are mediated primarily by the medial temporal lobe system, particularly the hippocampus and perirhinal cortex, which subserve in terms of recollection and familiarity, respectively [21,22]. Furthermore, effective recognition depends on the functional integrity of the prefrontal–hippocampal circuit for strategic information monitoring and the limbic–prefrontal network [23]. Both pathways are frequently disrupted in patients with depression [5]. Neuroimaging and pathological studies of patients with PD and comorbid depression corroborate significant structural and functional abnormalities within these circuits [7,24,25], providing a plausible mechanistic explanation for the potential recognition deficits observed in our cohort [24,26].

The anxiety group exhibited independent deficits in immediate visual recall and inhibitory executive control, as measured by the RCFT and Color Stroop test. Crucially, these impairments remained statistically significant even after the Bonferroni correction, highlighting their robustness as cognitive markers of anxiety in patients with early PD. Although previous research suggests that anxiety may affect multiple cognitive domains, including working memory, executive function, memory, and language [27], our findings indicate that these deficits were specifically localized to visual memory and inhibitory executive control. Both the strategic organization of complex figures in the RCFT and the resolution of cognitive interference in the Stroop test require sustained attention and working memory capacity [28,29], which are critically dependent on fronto-striatal and frontoparietal circuits [30]. Anxiety has been associated with functional impairments in these neural systems, which leads to diminished cognitive efficiency [6]. Consistent with these observations, neuroimaging studies in patients with PD and comorbid anxiety have similarly revealed reduced functional and structural connectivity within the frontostriatal and frontoparietal networks [8,31]. These connectivity disruptions may account for the selective deficits in inhibitory control and visual memory observed in our anxiety group, as these functions rely heavily on the coordinated recruitment of these neural circuits.

Depression and anxiety are closely linked to cognitive performance, with overlapping pathogenetic mechanisms that can accelerate neurocognitive decline [32]. Although the coexistence of both conditions is clinically expected to produce greater cognitive impairment than either condition alone [32,33], empirical evidence regarding their combined effects in early PD remains limited. In this study, depression and anxiety were independently associated with deficits in verbal recognition and visual and executive function, respectively, whereas their comorbidity resulted in broader and more pervasive impairments across visual memory and frontal executive domains. Specifically, although the depression-only group initially had lower verbal recognition scores, this difference was no longer observed in the comorbid group. This discrepancy likely stems from the relatively weak association between depression and verbal recognition memory—as evidenced by its failure to survive multiple testing correction in the depression-only model—and may have been further attenuated in the comorbid group by the predominant impact of anxiety-related deficits and the increased stringency of statistical adjustments. Notably, the comorbid group showed the most pervasive and statistically stable executive and visuospatial deficits, surviving the most stringent statistical adjustments. This globalized pattern likely reflects widespread dysregulation of fronto-striatal-limbic networks, in which the combined affective burden overwhelms cognitive compensatory capacity in patients with early PD. Given that these neuropsychiatric symptoms can be mitigated through interventions such as group cognitive–behavioral therapy, our findings underscore the importance of early screening and targeted management [34,35]. Identifying comorbid depression and anxiety as clinical indicators may facilitate timely treatments that are potentially linked to a better cognitive trajectory in patients with PD.

Some limitations should be acknowledged. First, the cross-sectional design precludes any causal inferences or conclusions regarding longitudinal cognitive decline, and longitudinal studies are needed to elucidate the temporal dynamics between mood disorders and cognitive trajectories in patients with PD. Second, as a single-center study, the generalizability of the findings may be limited by potential selection bias associated with a tertiary referral population. Third, the mood assessment relied on self-report questionnaires (BDI and BAI) rather than structured clinical interviews (e.g., Diagnostic and Statistical Manual of Mental Disorders, 5th Edition-based interviews), which are the gold standard for psychiatric diagnosis. Although these scales exhibit high sensitivity and are well established for assessing symptom burden in Parkinson’s research, the lack of clinical interviews may limit the diagnostic precision and potentially lead to an overestimation or underestimation of the prevalence of clinical depression and anxiety disorders. Fourth, pharmacological confounders were not fully controlled. Specifically, detailed information regarding the use of antidepressants and hypnotics was not available, precluding their inclusion as covariates in the analysis. However, it is noteworthy that more than 70% of our participants were de novo patients, and LEDD and anticholinergic use did not significantly differ among the subgroups. Fifth, we did not formally assess apathy, which frequently overlaps with depression in PD but has independent effects on cognitive domains, particularly executive function. The absence of this distinction may limit our understanding of the specific contribution of depressive symptoms versus apathy. Finally, other potentially confounding factors, such as subclinical vascular burden (e.g., white matter hyperintensities) and sleep disturbances, were not quantitatively incorporated into our models. Future longitudinal studies with multidimensional assessments are necessary to disentangle these complex interactions.

In conclusion, depression and anxiety have distinct yet additive detrimental effects on cognition in early-stage PD. While depression is strongly associated with verbal memory recognition deficits, anxiety independently and robustly compromises visual recall and inhibitory executive control. Comorbid depression and anxiety induce broader and more statistically resilient cognitive deficits, particularly in visual memory and frontal executive function. These findings underscore the importance of routine early screening for neuropsychiatric symptoms in patients with PD, as timely intervention may be linked to preserving cognitive function and potentially delaying progression toward dementia.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This research was supported by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2024-00361688).

Acknowledgments

We thank all participants to take their time and be part of this study.

Author Contributions

Conceptualization: Hak-Loh Lee, Seong-Min Choi. Data curation: Hak-Loh Lee, Seong-Min Choi. Formal analysis: Hak-Loh Lee, Seong-Min Choi, Soo Hyun Cho. Funding acquisition: Seong-Min Choi, Byeong C. Kim. Investigation: Hak-Loh Lee, Seong-Min Choi, Byeong C. Kim. Methodology: Hak-Loh Lee, Seong-Min Choi, Soo Hyun Cho. Project administration: Seong-Min Choi, Byeong C. Kim. Resources: Hak-Loh Lee, Soo Hyun Cho. Software: Hak-Loh Lee, Soo Hyun Cho. Supervision: Seong-Min Choi, Byeong C. Kim. Validation: Seong-Min Choi, Byeong C. Kim. Visualization: Hak-Loh Lee, Soo Hyun Cho. Writing—original draft: Hak-Loh Lee, Seong-Min Choi. Writing—review & editing: Seong-Min Choi, Byeong C. Kim.

REFERENCES

• 1. Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers 2021;7:47.ArticlePubMedPDF
• 2. Dhar SS, Jeenger J, Singroha V, Sharma M, Mathur DM. Psychiatric morbidity, cognitive dysfunction and quality of life in drug-naive patients with Parkinson’s disease: a comparative study. Ind Psychiatry J 2019;28:13–18.ArticlePubMedPMC
• 3. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 2020;396:413–446.ArticlePubMedPMC
• 4. Pachana NA, Egan SJ, Laidlaw K, Dissanayaka N, Byrne GJ, Brockman S, et al. Clinical issues in the treatment of anxiety and depression in older adults with Parkinson’s disease. Mov Disord 2013;28:1930–1934.ArticlePubMed
• 5. Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci 2011;12:467–477.ArticlePubMedPDF
• 6. Sylvester CM, Corbetta M, Raichle ME, Rodebaugh TL, Schlaggar BL, Sheline YI, et al. Functional network dysfunction in anxiety and anxiety disorders. Trends Neurosci 2012;35:527–535.ArticlePubMedPMC
• 7. Lou Y, Huang P, Li D, Cen Z, Wang B, Gao J, et al. Altered brain network centrality in depressed Parkinson’s disease patients. Mov Disord 2015;30:1777–1784.ArticlePubMedPDF
• 8. Oosterwijk CS, Vriend C, Berendse HW, van der Werf YD, van den Heuvel OA. Anxiety in Parkinson’s disease is associated with reduced structural covariance of the striatum. J Affect Disord 2018;240:113–120.ArticlePubMed
• 9. Hu M, Shu X, Wu X, Chen F, Hu H, Zhang J, et al. Neuropsychiatric symptoms as prognostic makers for the elderly with mild cognitive impairment: a meta-analysis. J Affect Disord 2020;271:185–192.ArticlePubMed
• 10. Sun L, Li W, Qiu Q, Hu Y, Yang Z, Xiao S, et al. Anxiety adds the risk of cognitive progression and is associated with axon/synapse degeneration among cognitively unimpaired older adults. EBioMedicine 2023;94:104703.ArticlePubMedPMC
• 11. Costa A, Peppe A, Carlesimo GA, Pasqualetti P, Caltagirone C. Major and minor depression in Parkinson’s disease: a neuropsychological investigation. Eur J Neurol 2006;13:972–980.ArticlePubMed
• 12. Reynolds GO, Hanna KK, Neargarder S, Cronin-Golomb A. The relation of anxiety and cognition in Parkinson’s disease. Neuropsychology 2017;31:596–604.ArticlePubMedPMC
• 13. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015;30:1591–1601.ArticlePubMed
• 14. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427–442.ArticlePubMed
• 15. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008;23:2129–2170.PubMed
• 16. Kang Y, Na DL, Hahn S. [A validity study on the Korean Mini-Mental State Examination (K-MMSE) in dementia patients]. J Korean Neurol Assoc 1997;15:300–308.Korean.
• 17. Schrag A, Barone P, Brown RG, Leentjens AF, McDonald WM, Starkstein S, et al. Depression rating scales in Parkinson’s disease: critique and recommendations. Mov Disord 2007;22:1077–1092.ArticlePubMedPMC
• 18. Schrag A, Taddei RN. Depression and anxiety in Parkinson’s disease. Int Rev Neurobiol 2017;133:623–655.ArticlePubMed
• 19. Ryu HJ, Yang DW. The Seoul Neuropsychological Screening Battery (SNSB) for comprehensive neuropsychological assessment. Dement Neurocogn Disord 2023;22:1–15.ArticlePubMedPMCPDF
• 20. Malak ALSB, Vasconcellos LF, Pereira JS, Greca DV, Cruz M, Alves HVD, et al. Symptoms of depression in patients with mild cognitive impairment in Parkinson’s disease. Dement Neuropsychol 2017;11:145–153.ArticlePubMedPMC
• 21. Eichenbaum H, Yonelinas AP, Ranganath C. The medial temporal lobe and recognition memory. Annu Rev Neurosci 2007;30:123–52.ArticlePubMed
• 22. Brown MW, Aggleton JP. Recognition memory: what are the roles of the perirhinal cortex and hippocampus? Nat Rev Neurosci 2001;2:51–61.ArticlePubMedPDF
• 23. Blumenfeld RS, Ranganath C. Prefrontal cortex and long-term memory encoding: an integrative review of findings from neuropsychology and neuroimaging. Neuroscientist 2007;13:280–291.ArticlePubMedPDF
• 24. Yuan J, Liu Y, Liao H, Tan C, Cai S, Shen Q, et al. Alterations in cortical volume and complexity in Parkinson’s disease with depression. CNS Neurosci Ther 2024;30:e14582. ArticlePubMedPMCPDF
• 25. Goto M, Kamagata K, Hatano T, Hattori N, Abe O, Aoki S, et al. Depressive symptoms in Parkinson’s disease are related to decreased left hippocampal volume: correlation with the 15-item shortened version of the Geriatric Depression Scale. Acta Radiol 2018;59:341–345.ArticlePubMedPDF
• 26. Das T, Hwang JJ, Poston KL. Episodic recognition memory and the hippocampus in Parkinson’s disease: a review. Cortex 2019;113:191–209.ArticlePubMed
• 27. Ehgoetz Martens KA, Silveira CRA, Intzandt BN, Almeida QJ. State anxiety predicts cognitive performance in patients with Parkinson’s disease. Neuropsychology 2018;32:950–957.ArticlePubMed
• 28. Shin MS, Park SY, Park SR, Seol SH, Kwon JS. Clinical and empirical applications of the Rey-Osterrieth Complex Figure Test. Nat Protoc 2006;1:892–899.ArticlePubMedPDF
• 29. Kane MJ, Engle RW. Working-memory capacity and the control of attention: the contributions of goal neglect, response competition, and task set to Stroop interference. J Exp Psychol Gen 2003;132:47–70.Article
• 30. D’Esposito M, Postle BR. The cognitive neuroscience of working memory. Annu Rev Psychol 2015;66:115–142.ArticlePubMed
• 31. Perepezko K, Naaz F, Wagandt C, Dissanayaka NN, Mari Z, Nanavati J, et al. Anxiety in Parkinson’s disease: a systematic review of neuroimaging studies. J Neuropsychiatry Clin Neurosci 2021;33:280–294.ArticlePubMed
• 32. Botto R, Callai N, Cermelli A, Causarano L, Rainero I. Anxiety and depression in Alzheimer’s disease: a systematic review of pathogenetic mechanisms and relation to cognitive decline. Neurol Sci 2022;43:4107–4124.ArticlePubMedPMCPDF
• 33. Orgeta V, Leung P, Del-Pino-Casado R, Qazi A, Orrell M, Spector AE, et al. Psychological treatments for depression and anxiety in dementia and mild cognitive impairment. Cochrane Database Syst Rev 2022;4:CD009125.ArticlePubMedPMC
• 34. Rezazadeh Yazd SA, Gashtil S, Moradpoor M, Pishdar S, Nabian P, Kazemi Z, et al. Reducing depression and anxiety symptoms in patients with Parkinson’s disease: the effectiveness of group cognitive behavioral therapy. Parkinsonism Relat Disord 2023;112:105456.ArticlePubMed
• 35. Chen JC, Tseng TY, Fuh JL, Cheng YH, Lin DW, Chiang HL. The effects of biofeedback therapy on anxiety and depression in Parkinson’s disease: a pilot study. J Mov Disord 2025;18:360–364.ArticlePubMedPMCPDF

Figure & Data

References

Citations

Citations to this article as recorded by  

Comments on this article