Association between third ventricular width assessed by transcranial sonography and plasma homocysteine in Parkinson’s disease with cognitive impairment and their potential to predict conversion to dementia

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative brain disease characterized by damage to nigrostriatal dopaminergic neurons, representing a severe burden to human health (1). In China, with its large and increasingly aging population, there has been an 89.7% increase in the age-standardized incidence and a 167.8% rise in age-standardized prevalence of PD during 1990–2021 (2). Cognitive impairment (CI), which encompasses mild CI (MCI) and dementia, is a highly prevalent and debilitating nonmotor symptom affecting approximately 15–30% of PD patients (3). The incidence of dementia in individuals with PD is 2.5–6 times higher than in age-matched healthy controls (HCs) (4). Moreover, it is estimated that about 50% of PD patients with normal cognition (PD-NC) will develop CI within 6 years (5), and all newly diagnosed MCI cases progress to dementia within 5 years (5). However, current treatments for PD patients with dementia (PDD) such as oral medications (donepezil and rivastigmine), cognitive training, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation combined with virtual reality have yielded less than satisfactory results (6). CI not only significantly impacts functionality and quality of life but also reduces life expectancy and increases mortality (7), placing a considerable toll on patients, families, and the public healthcare system. In 2020, the Lancet Commission suggested that over 40% of dementia cases worldwide could potentially be prevented or delayed, particularly in low- and middle-income countries (8). Therefore, it is crucial for researchers and physicians to identify and predict future dementia in PD patients, considering the variability in timing, characteristics, and pace of cognitive decline within this population.

Neuroimaging is imperative for identifying CI by utilizing positron emission tomography (PET) to assess impaired cholinergic synapses, amyloid, and tau, as well as applying structural magnetic resonance imaging (MRI) to distinguish enlarged vascular gaps and white matter hyperintensity (9,10). These two modalities are time-consuming and costly, and PET induces radiation hazards to the patient. Recent studies have suggested that measuring the width of the third ventricle (V3) using transcranial sonography (TCS) can indirectly indicate cognitive function reproducibly and reliably (11-13). A cross-sectional study verified a correlation between V3 width and CI in PD patients, as well as its’ ability to differentiate PDD from those without (12). A longitudinal study further investigated the predictive value of V3 enlargement in cognitive decline after a median follow-up of 21.5 months in 80 PD-NC (11). However, it remains uncertain whether V3 width can serve as a reliable biomarker for predicting the conversion to dementia in the PD population.

Elevated homocysteine (Hcy) levels resulting from L-dopa treatment, along with potential environmental risk factors such as inadequate vitamin B12 (VitB12) or folate, significantly increase the risk of brain atrophy in PD, especially in older adults and those with PDD. Hcy concentration has been found to be associated with cognitive dysfunction in both community dwellings and established PD patients (14), as well as V3 width (15). However, there is currently a lack of longitudinal research specifying predictive potential of Hcy levels in cognitive conversion in PD, as well as investigating the interaction between Hcy levels and V3 width in cognitive progression. Therefore, this study aimed to examine the association between plasma Hcy levels and V3 width assessed by TCS, and to explore their utility in identifying CI and predicting dementia conversion in patients with PD. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1736/rc).

Methods

Participants and controls

This retrospective study enrolled 257 PD patients [median age, 65 years (range, 26–84 years), 148 males] and 35 age- and sex-matched HC with normal cognition. The sample size was determined based on a previous study (11) and the calculation formula for diagnostic experiments: n = [Z²_1−α/2 × Sen × (1 − Sen)]/(L² × P). Since the prevalence of PD was approximately normally distributed, a two-sided test level of 0.05 was used with Z²_1−α/2 set at 1.96. The diagnostic sensitivity (Sen) of TCS for PD, as reported in the literature (16), was 0.79. The permissible error (L) was set as 0.1, and the prevalence (P) of PD in the Department of Dyskinesia of our research center was estimated to be about 20–25%. Thus, the sample size in the PD group was estimated to be between 130 and 160. To minimize the impact of potential missing values, 257 PD patients who met the inclusion criteria were included from January 2018 to December 2020. All PD participants met the criteria set by the UK Parkinson’s Disease Society Brain Bank (17) or the Consensus Statement of the International Parkinson and Movement Disorder Society (MDS) in 2020 (18).

Individuals were excluded if they had Parkinson syndrome caused by cerebrovascular disease, craniocerebral tumors, trauma, or medications, hydrocephalus, insufficient clinical history, ambiguous V3 results of TCS examination for insufficient temporal bone window, implanted deep brain stimulation (DBS) electrodes, stem cell therapy, pallidotomy, CI occurring before the onset of PD, or PD combined with Alzheimer’s disease (AD). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of Beijing Tiantan Hospital (No. KYSQ 2019-039-01). Each participant provided informed consent.

Clinical and neuropsychological assessment

Age, gender, disease duration, body mass index (BMI), and education level were collected from all participants. Each PD individual underwent a comprehensive set of neurological examinations, including the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III), Hoehn and Yahr (H-Y) staging, Montreal Cognitive Assessment (MoCA), and Mini-Mental State Examination (MMSE). The MoCA and MMSE were utilized to evaluate the global cognitive condition of the participants. The study categorized PD patients into three subgroups based on their cognitive status: 118 PD-NC (MoCA score ≥26), 81 PD patients with MCI (PD-MCI; MoCA score ≥20 and <26), and 58 PDD (MoCA score <20 and MMSE score <26), following the MDS level II criteria for CI in PD and dementia criteria in China (19-21). Notably, to investigate alternation in cognition, two subgroups of patients with PD-NC (n=41) and PD-MCI (n=72) were clinically followed up for an average duration of 31.04±18.84 months.

All neuropsychological evaluations were conducted by two neurologists (L.Z.Y. and H.Y.M.) with over 5 years of experience managing patients with movement disorders. In cases where a consistent diagnosis could not be reached, a senior expert (X.M.W.) with over 10 years of experience in treating patients with movement disorders would make the diagnosis.

TCS examination

One sonographer (F.X.L.), with at least 5 years of expertise in neuroimaging, performed the ultrasound examination. The V3 width was measured by two experienced sonographers (F.N. and S.L.) with over 10 years of experience in neuroimaging, who were unaware of the patient’s clinical diagnosis. The protocol of TCS examination was consistent with our previous study (22). Canon Aplio i900 ultrasound equipment (Canon, Tochigi, Japan), along with the I6SX1 phased array probe operating at a frequency range of 2.0–3.0 MHz, was used for scanning. Scanning setting details included depth at 14–16 cm, dynamic range at 45–55 dB, and adjustment of brightness and gain compensation as needed. In summary, the patient was positioned supine with the temporal window fully exposed. The probe was placed near the temporal window on one side, and parallel to the canthus line. Then, the probe was gradually tilted at an angle of 10–15° towards the head to display the thalamic plane, from which the V3 can be displayed. The V3 is characterized by two parallel hyperechoic lines located between the thalamus on both sides, positioned anteriorly to the pineal gland. For accuracy and reproducibility, the width of V3 was measured from the inner layer of the hyperechogenic ependyma on one side to the inner layer on the other side, as previously described (11) (Figure 1). The measurement was repeated three times to obtain an average value. Interclass correlation coefficient (ICC) was utilized to test interobserver agreement for V3 width calculation.

Figure 1 TCS image depicting the scanning planes at the thalamic level in a patient with PD. TCS image showing the V3 between the hyperechoic lines can be clearly visualized, and the yellow arrow points to the pineal gland, which is easily visible on TCS due to its high echogenicity. PD, Parkinson’s disease; T, thalamus; TCS, transcranial sonography; V3, third ventricle.

Laboratory measurements

A fasting venous blood sample of 5 mL was collected in the morning, and the serum was immediately centrifuged, kept at −80 ℃, and analyzed using an immunoturbidimetric assay. Ferritin, folate, and VitB12 levels were measured using a chemiluminescent assay (e601; Roche, Basel, Switzerland), and Hcy levels were tested by a cyclase assay (Roche AU5800) electrochemiluminescence immunoassay analyzer.

Statistical analysis

The measurement data were presented as mean ± standard deviation or median [interquartile range (IQR)], whereas the discrete variables were expressed as n (%). Differences between groups were compared using one-way analysis of variance (ANOVA) followed by Bonferroni’s corrected post hoc comparisons or unpaired independent t-test (for continuous variables with normal distributions), the Kruskal-Wallis test followed by Dunn’s corrected post hoc comparisons or Mann-Whitney U test (for non-parametric data), or the Chi-squared test (for categorical variables). Spearman correlation analysis and partial correlation analysis were performed to assess the associations between V3 width, plasma Hcy levels, and demographic information. The diagnostic efficacy of biomarkers was compared by utilizing receiver operating characteristic (ROC) curve analysis and identifying the cut-off values derived from maximizing the Youden index. The Cox regression model was utilized to explore the relationship between initial V3 width, plasma Hcy levels, and cognition function in the follow-up data. A P value <0.05 was considered statistically significant. All statistical analyses were performed using the software SPSS 25.0 (IBM Corp., Chicago, IL, USA) and GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA).

Results

The baseline demographic and clinical characteristics of the participants are shown in Table 1, whereas the general information about global PD patients can be found in Table S1. The patient selection flow diagram is available in Figure S1. The ICC for V3 width assessment was 0.90 (range, 0.88–0.93) between the two raters, indicating a high level of interobserver agreement. There were no statistical differences in age, gender, BMI, education level, plasma folate, VitB12, or ferritin across the four groups (all P>0.05); however, there were significant differences in plasma Hcy (adjusted P<0.05) and V3 width (adjusted P<0.001). Compared with the PD-NC and PD-MCI groups, the PDD group had a longer disease duration (all adjusted P<0.05), a greater H-Y stage distribution, and a higher UPDRS-III score (all adjusted P<0.001) (Figure 2A,2B). Additionally, after stratifying the study population by age 60 years, the differences in V3 width among the four groups remained statistically significant (Table 1).

Figure 2 Diagnostic performance of V3 width and plasma Hcy. (A,B) The V3 width (A) and plasma Hcy levels (B) in HC (n=35) and patients with PD-NC (n=118), PD-MCI (n=81), and PDD (n=58). Groups were compared by one-way ANOVA followed by Bonferroni’s post-hoc correction. Boxes show the mean ± standard deviation, and whiskers are the minimum and maximum. Dots are single values. *, P<0.05; **, P<0.001. (C) Spearman partial correlation analysis of H-Y stage, UPDRS-III, MoCA score, Hcy, and the V3 width after adjusting age and disease duration. The correlation coefficient r is shown in the heat map. Line color represents the direction of correlation: red (positive), green (negative), the deeper the color, the stronger the correlation. (D-F) ROC curve analysis exhibited the efficiency of V3 width and plasma Hcy in distinguishing between PDD and those without dementia (D), PD-NC and those with cognitive decline (E), and PD-NC and PD-MCI (F). ANOVA, analysis of variance; AUC, area under the curve; HC, healthy control; H-Y, Hoehn and Yahr; Hcy, homocysteine; MoCA, Montreal Cognitive Assessment; PD, Parkinson’s disease; PD-MCI, Parkinson’s disease with mild cognitive impairment; PD-NC, Parkinson’s disease with normal cognition; PDD, Parkinson’s disease with dementia; ROC, receiver operating characteristic; UPDRS-III, Unified Parkinson’s Disease Rating Scale Part III; V3, third ventricle.

Although the gender distribution was obviously different in plasma Hcy and ferritin, it had no significant differences in other variables (Table S2). Spearman correlation analysis indicated that age and disease duration of all PD participants were significantly correlated with the V3 width, H-Y stage, UPDRS-III score, and MoCA score, and disease duration was also significantly correlated with plasma Hcy level in all participants (Table S3). We included age and disease duration as covariates in the relevant comparative analysis for these reasons.

After adjusting for age and disease duration, the results of Spearman partial correlation analysis showed that plasma Hcy was positively correlated with UPDRS-III, whereas V3 width was positively correlated with H-Y stage and UPDRS-III score. Furthermore, significant correlations between V3 width and MoCA (r=−0.358, P<0.001), plasma Hcy and MoCA (r=−0.187, P=0.013), and V3 width and plasma Hcy (r=0.140, P=0.026) were observed (Figure 2C, Table S4).

ROC curve analysis was utilized to examine the discriminating performance of circulating Hcy and V3 width in cognition dysfunction in PD patients. The results suggested that V3 width yielded a reliable differential diagnosis between PDD and PD without dementia (including both PD-NC and PD-MCI), PD-NC and PD with cognitive decline (including both PD-MCI and PDD), as well as PD-MCI and PD-NC. The area under the curve (AUC) values for V3 width were 0.767 [95% confidence interval (CI): 0.694–0.839], 0.735 (95% CI: 0.674–0.796), and 0.683 (95% CI: 0.606–0.761) for the respective comparisons. In contrast, the AUC values for plasma Hcy were 0.628 (95% CI: 0.543–0.712), 0.657 (95% CI: 0.590–0.723), and 0.664 (95% CI: 0.585–0.743) for the same comparisons (Figure 2D-2F).

To investigate the predictive value of V3 width for the conversion from normal cognition to MCI conversion and from MCI to dementia in PD, a total of 41 PD-NC patients and 72 PD-MCI patients were followed over an average period of 31.04±18.84 months. The PD-NC group cases were followed for a mean duration of 32.41±22.29 months, whereas those with MCI were followed up for 30.25±16.68 months. In terms of PD-NC patients, 23 (56.1%) progressed to MCI and 1 (2.4%) developed PDD. Some 23.6% of PD-MCI patients progressed to PDD. Tables S5-S7 provide detailed demographic and clinical information for PD patients with follow-up and those without, as well as information on cognitive stability and progression during the follow-up period. PD-MCI patients with a V3 width ≥6.55 mm at baseline had a significantly higher risk for developing PDD compared to those with a V3 width <6.55 mm (hazard ratio =4.085; 95% CI: 1.922–8.682; P<0.001; Sen 77.8%; specificity 90.7%). Furthermore, the PD-NC patients had a nearly two-fold increased risk of converting to MCI if their baseline V3 width was ≥5.75 mm, with a Sen of 62.5% and specificity of 100% (Table 2). Notably, baseline plasma Hcy level was not a significant predictor of cognitive changes during long-term follow-up according to the Cox regression analysis.

Discussion

The main findings of our study revealed that PDD and PD-MCI exhibited higher levels of plasma Hcy concentration and a wider V3 width compared to PD-NC patients and the HC group. Both plasma Hcy levels and V3 width showed a significant negative correlation with MoCA scores in PD patients. Additionally, there was a slight positive correlation between plasma Hcy levels and V3 width in PD patients. The measurement of V3 width using TCS has potential to distinguish between PDD, PD-MCI, and PD-NC. It may also serve as an independent neuroimaging biomarker for predicting cognitive decline and the progression from MCI to dementia in PD.

The degree of parkinsonism was associated with the extent of atrophy in the V3 region, as evaluated through structural MRI. This study observed a negative relationship between the width of V3, assessed by TCS, and the MoCA score, which indicates the severity of cognitive dysfunction in PD. TCS is a cost-effective and reliable alternative to MRI for evaluating the width of V3 in patients with metallic foreign objects or those experiencing claustrophobia. A previous study determined that the thresholds for V3 width measured by TCS, indicating the likelihood of diagnosing PDD, were 6.0 mm for individuals under the age of 70 years and 7.5 mm for those over the age of 70 years in the German population (12). Another study conducted in Central China concluded that a V3 width of 4.75 mm has moderate ability to diagnose PD patients with CI with a Sen of 62.7% and a specificity of 75.6% (11). Our ongoing research in North China has identified an optimal cutoff of 5.75 mm for PD-MCI and 6.55 mm for PDD. These variations in cutoff values may be attributed to differences in age, gender, and disease duration, which were identified as distinct risk predictors for cognitive decline in PD (8,23,24). The V3 width measured by TCS can offer valuable insights into the natural aging process and brain atrophy in dementia. Consistent with previous studies (11,12), a positive correlation between age and V3 width was observed. Other factors such as geographic and ethnic differences in the research population, as well as screening tests used for cognitive function assessment (e.g., MMSE and MoCA), could potentially account for the observed variations in threshold values. Although TCS has limitations in assessing overall brain atrophy due to its restricted resolution, V3 width remains an easily recognizable structure with a discrimination rate of up to 96%, even in cases with a suboptimal temporal bone window (12).

The pathomorphological correlations of cognitive deficits in PD is heterogeneous, with current knowledge of the pathogenesis of cognitive dysfunction in PD primarily based on influential studies by Braak and colleagues (25,26). They proposed a pattern of Lewy pathology spreading from the rostral to caudal areas of the brain, involving the alpha-synuclein. However, one third of cases in earlier stage 3 of PD show dementia even in the absence of Lewy bodies in the cortex (27). Growing evidence has demonstrated deficits in the cholinergic, dopaminergic, and noradrenergic systems in various regions (which can be detected using molecular imaging techniques), including the lateral geniculate nucleus, hippocampus, caudate nucleus, cingulum, and lateral cortical territories, all of which play a role in driving CI across different domains (28). When the supply of cerebral blood flow is insufficient, both intracranial perfusion and cerebral blood volume are reduced, which further disrupts neurovascular coupling and leads to cognitive decline (29). Despite this complexity, it has been suggested that the widening of V3 width may be an independent risk factor for cognitive progression in PD, regardless of the underlying pathological diversity of CI (12).

Cerebrospinal fluid and plasma levels of β-amyloid and neurofilament light are biological markers of cognitive function in neurodegenerative diseases (30,31). However, some patients may find it uncomfortable to undergo a lumbar puncture to obtain a cerebrospinal fluid sample, and plasma concentrations of these two indicators are not routinely available. Instead, recent studies suggest that elevated plasma Hcy, a marker that can be easily measured in daily tests, is correlated with cognitive deficits in various central nervous system disorders and neurodegenerative diseases (32-34). Possible mechanisms involve Hcy promoting oxidative stress, increasing the release of inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and mediating neuronal apoptosis through energy consumption and DNA damage, resulting in death of neuronal cells and brain atrophy (35). It is worth nothing that although Hcy levels are strongly correlated with folate and VitB12, which are coenzymes for methionine and Hcy metabolism, no significant differences were observed in folate and VitB12 levels among the four groups studied. This lack of difference may be due to the routine use of dopamine therapy in patients with PD, which causes an increase in circulating Hcy concentration (36).

Spearman correlation analysis demonstrated a significant relationship among age, disease duration, V3 width, and Hcy level. After adjusting for age and disease duration as covariates, Spearman’s partial correlation analysis further supported the connection between V3 width and Hcy concentration in PD, consistent with previous studies by Fu et al. and Sapkota et al. (15,37). As mentioned before, elevated Hcy levels affect brain volume through a variety of mechanisms, ultimately influencing cognitive function. The dilation of V3 width is associated with cerebral atrophy and enlargement of the periventricular space, providing insight into the positive correlation observed between V3 width and plasma Hcy concentration. In addition to the enlargement of V3, research has shown that increased Hcy levels in PD were associated with cognitive performance and structural damage, such as frontal cortical thinning, and microstructural damage in both frontal and posterior-cortical regions (38). Notably, patients with postural instability gait difficulty phenotype of PD typically exhibit significant cognitive dysfunction and elevated Hcy levels (39). However, the correlation between V3 enlargement and PD subtypes warrants further investigation.

To further investigate the predictive power of baseline V3 width and Hcy level on cognition progression in PD, a follow-up was conducted on 113 patients. The results of the Cox regression model showed that the initial width of V3 significantly predicted the transition from normal cognition to MCI, and from MCI to dementia. PD-MCI patients with a V3 width greater than 6.55 mm had a four-fold increased risk of developing dementia compared to those with a V3 width lower than 6.55 mm. Setting a cutoff value of 5.75 mm for the V3 width resulted in lower Sen (62.5% vs. 77.7%) but higher specificity (100% vs. 90.6%) in detecting cognitive decline. These findings align with the research conducted by Gao et al. (11). However, our study found that the initial Hcy level was not a reliable predictor of cognition shifts. Unlike Sleeman et al.’s study (40), which focused on newly diagnosed PD-NC, our study included patients at various disease stages and receiving treatment, potentially impacting Hcy levels. This approach reflects the clinical reality, as not all patients presenting to the clinic have newly identified and untreated PD. Although both V3 dilation and high Hcy levels are linked to cognitive decline in PD, V3 and age are positively correlated with cerebral atrophy, which is challenging to reverse once present. An enlarged V3 exhibits reduced responsiveness to medication. In contrast, as mentioned before, Hcy levels are influenced by several factors, such as dietary deficiencies in VitB12 and folate, as well as daily oral administration of L-dopa in patients with PD. Consequently, plasma Hcy levels may fluctuate. This variability may help to explain why the V3 is more useful in predicting dementia transition whereas plasma Hcy levels are not.

Some limitations need to be addressed. Firstly, in the present study, we applied MoCA and MMSE to evaluate the cognitive status of the participants. However, we did not delve into a detailed analysis of the correlation between the certain domains of MoCA/MMSE and V3 width and Hcy levels. Consequently, we were unable to conduct a comprehensive analysis of the specific cognitive aspects affected by V3 dilation and elevated Hcy concentration. Secondly, due to the irregularity in follow-up durations and the limited observation period of some individuals (which may not have been sufficient to adequately track cognitive changes in PD patients), we were unable to carry out a Kaplan-Meier curve analysis based on cognitive ability or consistently monitor changes in V3 widths and Hcy levels over time. However, these areas could be a direction for future research. Additionally, due to limitations in sample size and the necessity for subsequent follow-up, we did not conduct age stratification when evaluating the predictive performance of V3 width on CI. Given that the V3 width varies between younger and older individuals, it is essential to stratify the V3 width by age in future studies to more accurately assess its predictive value for PDD across different age groups. Moreover, it is important to highlight that there was a significant overlap between the groups, and although the ROC curves showed moderate accuracy, the Spearman correlations, although statistically different, were quite modest (ranging from 0.1 to 0.4). Larger cohort studies in the future, incorporation of wider range of TCS parameters and biomarkers, along with the combination of various subtypes of PD, will enhance our exploration of their impact on CI in PD.

Conclusions

The study revealed a correlation between V3 dilation measured through TCS, elevated plasma Hcy levels, and the severity of cognitive decline in PD patients. The baseline width of the V3 was identified as a promising neuroimaging biomarker with the potential to predict cognition dysfunction and the conversion from mild MCI to dementia in PD.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1736/rc

Funding: This study was supported by the National Natural Science Foundation of China (No. 82271995), the Sichuan Science and Technology Program (No. 2025ZNSFSC1753), and the Luzhou Science and Technology Program (No. 2024JYJ047).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1736/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Ethics Committee of Beijing Tiantan Hospital (No. KYSQ 2019-039-01). Each participant provided informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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