Introduction

Syphilis is prevalent worldwide, with 10.6 million new cases reported annually by the WHO, and the incidence of General paresis of the insane (GPI) has been rising in recent years.1 The skin lesions of syphilis patients, as well as their secretions and blood contain syphilis spirochetes, and uninfected people can be infected by small breaks in the skin or mucous membranes during sexual contact with a syphilis patient, and very rarely through blood transfusions or other means of transmission. It is called the great imitator because of the numerous clinical symptoms it displays, including cognitive impairment, motor dysfunction, and neuropsychiatric symptoms.2

“Neurosyphilis” refers to central nervous system (CNS) infection caused by Treponema pallidum subspecies T. pallidum,3,4 and patients may present with CNS manifestations at any time during the course of syphilis. CNS involvement in syphilis patients is classified into four syndromes: syphilitic meningitis, meningovascular syphilis, parenchymatous neurosyphilis, and gummatous neurosyphilis.5 GPI is a late-onset parenchymal neurosyphilis that can cause progressive dementia.6 However, it can be cured with appropriate antibiotics. Advanced lesions in GPI can become irreversible due to neuron loss and permanent axon damage. Patient prognosis during treatment can be predicted by assessing the presence of brain atrophy, particularly in the medial temporal lobe, as detected by magnetic resonance imaging (MRI).7 But early diagnosis and treatment are crucial. In patients with GPI, neuroimaging abnormalities may provide more reliable information than laboratory results, as false negatives and false positives are inevitable in laboratory assessment of syphilis.8 Because the CNS manifestations of neurosyphilis are diverse and nonspecific, accurate diagnosis remains problematic.

Voxel-based morphometry (VBM) is based on MRI, which provides detailed anatomical images of the brain. The basic concept of VBM is to analyze differences in the local composition of brain tissues (such as gray matter, white matter, and cerebrospinal fluid) at the voxel level. A voxel is a three-dimensional unit of volume, similar to a pixel in a two-dimensional image, but it represents a volume element in a three-dimensional space. By comparing the distribution and density of voxels representing different tissue types between groups of individuals - such as patients with a neurological disorder and healthy controls, it is possible to identify regions of the brain that may have undergone structural changes due to disease, development, or other factors. The technique has been applied to many different disorders, including neurodegenerative diseases, movement disorders, epilepsy, multiple sclerosis, and schizophrenia.9–13 It helps to understand the changes occurring in the brain associated with these disorders and elucidates the relationship between these brain changes and the characteristic clinical features.

In a quantitative study of gray matter volume in patients with neurosyphilis, Zi-Ning Lu et al14 analyzed the gray matter (GM) microstructure of patients with early-stage neurosyphilis using VBM. The results showed regional reductions in GM volume in the left frontal cortex and bilateral temporal/occipital cortex in patients with neurosyphilis, which may be associated with cognitive impairment and intracranial infection, and may be useful for understanding the underlying neural characteristic of neurosyphilis. While many studies have reported clinical and neuroimaging findings in HIV-negative patients with neurosyphilis, little attention has been paid to quantitative brain gray matter volume (GMV) characteristics about GPI. Here, we present our findings in eighteen HIV-negative patients with GPI and discuss the potential value of GM alterations in the diagnosis of GPI. In the present study, we evaluated GM alterations in HIV-negative patients with GPI and controls using VBM analysis.

Materials and Methods Participants

A total of 18 patients with GPI were enrolled from March 2018 to September 2019. The diagnosis of GPI was based on serological tests and cerebrospinal fluid analysis. HIV antibodies were negative in all patients. Treponema pallidum particle asset (TPPA) or rapid plasma reagent (RPR) test results were positive in all patients, and syphilis toluidine red unheated serum test (TRUST) results were also positive. Patients with other potential causes, such as hypertension, diabetes, and related neurological symptoms and signs, were excluded.

Age-, sex-, and education-matched healthy volunteers were included as controls. All control participants had a Mini-Mental State Examination (MMSE) score of 27 or higher. The inclusion criteria for the control participants were as follows: (1) no cognitive impairment or neurological symptoms and no history of systemic, mental, or neurological diseases; (2) no positive signs on physical examination of the nervous system; and (3) no abnormal signs on brain MRI.

The study was approved by the ethics committees of our hospital, and all participants provided written informed consent.

MRI Scan Parameters

Participants underwent MRI scanning using a 3.0 T MRI system (Discovery 750w GE Healthcare) with the following sequences: T1W and T2W axial imaging, T1W sagittal imaging, fast fluid attenuated inversion recovery (FLAIR), and T1-weighted 3D axial IR-prepped FSPGR (BRAVO) sequences. The resulting slices were 1.0 mm thick and were contiguous. The in-plane spatial resolution of the coronal slices was 0.5×0.5×1 mm/pixel. The field of view was 256 mm × 256 mm, and the matrix size was 512×512. The flip angle was 15°, the TR was 7.472 ms, the TE was 2.796 ms, and the TI was 450 ms.

VBM Analyses

MR images were analyzed using FreeSurfer v5.0.9, a set of automated tools. FreeSurfer enables automatic reconstruction of the cortical surface using T1-weighted MR images. The analysis process involves several key steps, including removal of non-brain tissue, automated Talairach transformation, segmentation of subcortical and cortical matter, intensity correction, and delineation of gray/white/pial boundaries. Once cortical models are generated, deformable procedures such as cortical inflation, registration to a spherical atlas, and parcellation of the cerebral cortex into gyral and sulcal units are applied. After initial processing by FreeSurfer, all MRI scans were meticulously examined slice by slice to ensure accurate registration of gray and white matter voxels. Any errors found were corrected, and the scans were reprocessed and subjected to a second visual inspection.

Statistical Analyses

All the statistical analyses were performed using the Statistical Package for the Social Sciences version 25 (SPSS 25) to identify the significant vertex clusters. Differences in GMV were evaluated by two-sample t-tests with age and sex as covariates. The statistical significance of group differences was set at p < 0.01 with correction for false discovery rate (FDR). Pearson’s correlation analysis was used to examine the relationship between the GMV of each brain atlas and the MMSE score in the GPI group. The significance level was set at p < 0.05.

Results Clinical Data

All patients included in the study were male, ranging in age from 21 to 68 years (mean: 49.2 years). The duration of the disease ranged from 3 months to 7 years. Among the GPI patients, 15 had elevated cerebrospinal fluid white blood cell (CSF-WBC) counts and cerebrospinal fluid total protein (TP) levels. In all patients, memory loss and mood abnormalities were the main manifestations (Figure 1). The control group consisted of 24 men aged 28 to 67 years (mean age: 52.1 years). Table 1 shows the general clinical data and laboratory test results of the 18 GPI patients and 24 normal controls.

Table 1 Demographics, Laboratory Test Results, and Neuropsychological Test Results of the Participants

Figure 1 Clinical symptoms and signs of HIV-negative GPI patients (n=18).

GMV Comparison

Compared to the normal control group, the GPI group showed a decrease in GM volume in multiple regions, including the bilateral frontal cortices (superior frontal gyrus, middle frontal gyrus, orbital gyrus), bilateral temporal/occipital cortices (superior temporal, bilateral inferior temporal, bilateral parahippocampal, bilateral cingulate, left precentral, left fusiform, left posterior superior temporal sulcus, left lateral occipital, right middle temporal, right precuneus, right insular, right medioventral occipital), and right parietal cortices (right superior parietal, right inferior parietal) (p<0.01, FDR corrected). In addition, there was an increase in GMV in the bilateral basal ganglia, right hippocampus, and bilateral thalamus (p<0.01, FDR corrected) (Figure 2, Tables 2 and 3).

Table 2 GMV Differences Between Patients with GPI and Healthy Controls

Table 3 Differences in Deep GMVs (Mean ± SD)

Figure 2 GMV alterations in GPI group compared with normal controls. Red‒yellow and blue-light blue color maps indicate GM atrophy and expansion, respectively, in GPI patients compared with normal controls.

Correlations Between GM Volumes and MMSE Scores

In the GPI group, the GM volumes of the right rostral hippocampus (r = −0.524, p = 0.026), bilateral dorsal caudate nucleus (r = −0.604, p = 0.008; r = −0.685, p = 0.002), and right rostral temporal thalamus (r = −0.560, p = 0.016) showed significant negative correlations with the MMSE scores (Figure 3A–D). However, there were no significant correlations between GMV and MMSE scores in other brain regions.

Figure 3 Correlations between neuroimaging data and neuropsychiatric metrics in patients with GPI. (A) GMV in the right rostral hippocampus (rHipp_R) was negatively correlated with the MMSE score. (B) GMV in the left dorsal caudate nucleus (dCa_L) was negatively correlated with the MMSE score. (C) GMV in the right dorsal caudate nucleus (dCa_R) was negatively correlated with the MMSE score. (D) GMV in the right rostral temporal thalamus (rTtha_R) was negatively correlated with the MMSE score.

Discussion

VBM is a voxel-based method for studying the morphology of brain structures.15,16 This method reflects the differences in the corresponding anatomical structure by calculating the density change of a certain voxel in unit volume. VBM is a measurement method that can automatically, comprehensively, and objectively analyze changes in the whole brain microstructure.17 In this study, we evaluated changes in the gray matter of GPI patients using VBM analysis.

Untreated paralytic dementia can occur in all stages of syphilis.18 In our study, the clinical findings included memory deterioration (11 [61%] of 18), abnormal emotions (11 [61%] of 18), speech disorders (5 [28%] of 18), hallucinations (4 [22%] of 18), gait instability (4 [22%] of 18), dizziness (3 [17%] of 18), and numbness of the extremities (2 [11%] of 18). The study by Yingxin et al showed that high CSF protein levels were an important marker for the diagnosis of neurosyphilis.19 Similarly, the 18 GPI patients in our study had elevated CSF protein levels and elevated CSF WBC counts.

In this study, compared with healthy controls, HIV-negative GPI patients exhibited reduced gray matter volume in multiple brain regions, particularly in the bilateral frontal, temporal and occipital lobes. Previous research has shown that MRI scans of HIV-negative individuals with neurosyphilis show brain atrophy in the frontal, temporal, and medial temporal lobes,7,20 which is consistent with the findings of this study. The potential mechanism involves the direct invasion of Treponema pallidum into nerve tissue, leading to widespread brain atrophy, degeneration, neuronal loss, glial cell proliferation, and cortical atrophy. Damage to the frontal lobes may be associated with the development of psychiatric symptoms, dementia, and dysarthria.18,20 The superior and middle frontal gyri are implicated in motor activity, working memory, and cognitive control.21,22 Clinical evidence indicates that the superior temporal gyrus plays a crucial role in language production, interpretation, and self-monitoring and is believed to be the neurological foundation for language-related psychotic symptoms in patients.23 The inferior temporal gyrus is associated with vision, language, and emotion. These findings suggest that the frontal and temporal cortices are essential for memory, cognition, and language and that a decrease in gray matter volume in the frontal and temporal lobes may contribute to the neuropathology of memory loss, mood changes, and speech confusion in patients with GPI. Bilateral frontal or temporal lobe atrophy may reflect cortical destruction and loss of neurons in these areas.24 Chenhui Mao et al suggest that25 although temporal lobe involvement is clearly neurosyphilis, later spread to the entire brain is inevitable, and symptoms of frontal lobe involvement may appear earlier. Another study showed that initial infection causes the mesial temporal T2-weighted hyperintensity, with no treatment, may disappear at a later stage when the tissues undergo irreversible atrophy.26 In addition, Pesaresi I et al found that cortical hypointensity on susceptibility-weighted imaging was mostly distributed in the frontal and temporal lobes, which may be related to iron deposits within activated microglia in GPI patients.27 Severe medial temporal lobe atrophy is associated with severe cognitive impairment and adverse cognitive outcomes in GPI patients.28 The exact cause of this atrophy in the medial temporal lobe remains unclear, but it may be due to widespread dysfunction of the cerebral cortex, which connects with other brain regions, such as the frontal, temporal, and parietal lobes. When atrophy affects the medial temporal lobe, including the hippocampus, the prognosis for the patient’s social functioning may be unfavorable even with appropriate treatment.7,29 Neurosyphilis is a great mimicker and it has been reported that neurosyphilis can mimic early-onset Alzheimer ‘s disease with bilateral hippocampal atrophy.30 The parahippocampal gyrus and thalamus are integral components of the limbic system and are crucial for memory and emotion regulation. Additionally, the cingulate cortex, precuneus, and thalamus play roles in attention, motivation, emotion, and memory processing.31,32 Limbic frontal networks, such as the dorsolateral prefrontal cortex, orbitofrontal cortex, and cingulate cortex, are involved in emotional and affective functions.31–33 Therefore, the decrease in GMV in the bilateral parahippocampal and cingulate gyri may lead to alterations in memory and mood among patients with GPI.

The hippocampus, a crucial component of the septal area-hippocampus-limbic cholinergic circuit, plays a significant role in human learning and memory. This region receives and processes background information, such as temporal and spatial information, from the hippocampal gyrus.34,35 Dysfunction of this region may underlie memory loss in patients with GPI.30,36 The caudate nucleus is essential for controlling gait and walking speed. A larger volume of the caudate nucleus may indicate an increase in neurons or glial cells, potentially leading to impaired motor control and unstable walking in patients with GPI.37

A reduction in GMV was observed in some occipital and parietal cortices, including the left lateral occipital cortex, right medioventral occipital cortex, superior parietal lobule, and inferior parietal lobule. Reduced gray matter volume in the parietal and occipital lobes in patients with GPI has rarely been reported in previous studies. This new finding suggests that VBM analysis may be more sensitive than conventional MRI for detecting these changes.

The MMSE is a tool used to assess the severity of cognitive impairment. Negative correlations were found between the gray matter volume indices of the right rostral hippocampus (r = −0.524, p = 0.026), bilateral dorsal caudate nucleus (r = −0.604, p = 0.008; r = −0.685, p = 0.002), and right rostral temporal thalamus (r = −0.560, p = 0.002; P = 0.016) and MMSE scores in the GPI group. This finding suggests that as GMV increases in these areas, the neuropsychological symptoms of GPI patients worsen. The basal ganglia is a complex system of nerve nuclei located deep within the brain and connected to the cerebral cortex, thalamus, and brainstem. This region plays a role in higher cognitive functions such as memory, emotion, motor processes, and reward learning. Our findings of increased GMV in the right rostral hippocampus, bilateral dorsal caudate nucleus and the right rostral temporal thalamus have not been previously reported in the literature. Several factors should be considered to explain the regionally increased GMV found in the present study. First, T. pallidum enters the deep tissues by crossing endothelial cell junctions,38 which then causes meningeal inflammation, increases the permeability of the blood-brain barrier, and causes widespread cerebral congestion, marked microvascular proliferation, and increased blood flow. Some components of cytotoxic and interstitial edema, inflammation, meningeal vasculitis, or microglial hypertrophy may also be present.39,40 Then, for brain regions at different stages of pathologic change, there may be brain regions with increased or decreased GMV. Second, alterations in GMV may be associated with changes in dendritic, synaptic and neuronal density, as well as increased afferentation in certain regions.41 Third, some studies have reported that inflammatory and immune mechanisms may be related to brain structures that directly affect neuronal proliferation, migration, differentiation, and apoptosis. Finally, the relatively small sample size of this study and the fact that the patients were all men may be statistically biased, and larger studies are needed to confirm these findings.42 Further studies are needed to confirm the potential mechanisms of the exact GMV changes in patients with GPI.

Traditional psychiatric diagnosis has been overly reliant on either self-reported measures or clinical rating scales. Whereas VBM is an objective and scientific measurement technique. It may be possible to somewhat objectively quantify the reduction or increase of the frontal, temporal, and basal ganglia GMV in neuropsychiatric complications of syphilis. The combination of epidemiologic history, clinical presentation, positive serologic test for syphilis spirochetes in serum, routine cerebrospinal fluid examination and clinical rating scales may provide some assistance in the clinical diagnosis of GPI. Additionally, the basic treatment for neuropsychiatric symptoms is penicillin G, VBM may be able to evaluate the early detection of the disease, monitor disease progression, and assess treatment response. If it is to be used more routinely in the diagnosis of neuropsychiatric complications of syphilis, in-depth longitudinal studies involving larger sample sizes should be conducted.

This study has several limitations that should be considered. First, the study included only male syphilis patients. Therefore, it is unclear whether there are any differences in GMV between male and female syphilis patients, as this has not been addressed in the literature. Future studies should continue to explore whether these findings are applicable to female patients and how they affect the progression and manifestation of GPI. Second, the sample size of this study was relatively small, and more prospective studies with larger sample sizes should be conducted to confirm the results of this study. Finally, the study could not explain the observed increase in subcortical gray matter volume in the GPI group.

Conclusion

HIV-negative individuals with GPI showed different gray matter alterations in the cerebral cortex and subcortical structures. The reduction in gray matter volume in GPI patients predominantly affected the bilateral frontal, temporal, limbic, and basal ganglia regions, which may correlate with symptoms such as memory loss, affective disturbances, and motor dysfunction. In addition, the increased gray matter volume in regions such as the right rostral hippocampus, bilateral dorsal caudate nucleus, and right caudal temporal thalamus in GPI patients may be related to neuropsychological symptoms, although further validation in larger studies is needed. VBM has certain value in evaluating GMV in patients with GPI. However, the underlying mechanisms of the observed changes in GMV need to be further investigated.

Abbreviations

GMV, Gray matter volume; HIV, Human immunodeficiency; GPI, General paresis of the insane; VBM, Voxel-based morphometry; 3D T1WI, 3D T1-weighted imaging; TPPA, Treponema pallidum particle asset; RPR, Rapid plasma reagent; TRUST, Toluidine red unheated serum test; MMSE, Mini-Mental State Examination; FLAIR, Fast fluid attenuated inversion recovery; FDR, false discovery rate; CSF-WBC, cerebrospinal fluid white blood cell; TP, total protein.

Data Sharing Statement

The datasets used during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

All procedures of this study were performed in accordance with the Declaration of Helsinki and were approved by Ethics Committee of Beijing Ditan Hospital (approval no. 2020‑024). All participants gave written informed consent prior to taking part in this study.

Acknowledgments

An unauthorized version of the Chinese MMSE was used by the study team without permission, however this has now been rectified with PAR. The MMSE is a copyrighted instrument and may not be used or reproduced in whole or in part, in any form or language, or by any means without written permission of PAR (www.parinc.com).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest in this work.

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