In this study, the performance of the ANT was assessed for the first time among HIV-negative patients with early forms of NS, patients without NS, and healthy controls. Patients with early forms of NS exhibited poorer performance in orienting and alerting function than those without NS and less efficient orienting function than healthy controls. However, no difference was observed in executive function among the groups, which suggests a selective impairment of attention function in HIV-negative patients with early forms of NS.
Late-stage NS usually progresses to paralytic dementia, which leads to severe cognitive decline and neuropsychiatric symptoms, thus prompting clinicians to assess cognitive function in these patients. Cognitive impairment, including inattention; disorientation to time and place[14, 20]; and impairments in language, memory recall, and visuospatial and frontal executive functions[5], have been commonly reported in patients with late-stage NS. In contrast, the diagnosis of early forms of NS is more likely to be missed because clinical symptoms and manifestations are either absent or nonspecific. The MMSE is routinely employed to evaluate the attention and executive functions in patients with late-stage NS. Whether attentional impairment occurs in patients with early forms of NS without detectable cognitive decline is yet to be elucidated. Thus, objective and effective assessment using specific rating scales is necessary. The ANT is an effective tool for assessing attention network efficiency of alerting, orienting, and executive functions and is widely used in other diseases, including Alzheimer’s disease, posterior circulation ischemia and HIV-associated cognitive disorder [21–23]. This study highlights the benefit of the ANT in distinguishing cognitive impairment among patients with early forms of NS.
This study showed that HIV-negative patients with early forms of NS exhibited significantly shorter RTs than those without NS and healthy controls in tasks engaging the orienting network. This result indicates that after receiving target stimuli or locating targets, patients with early forms of NS exhibit less efficient orienting attention functions. Contrary to this result, patients with early forms of NS showed equal response delay under incongruent and congruent target conditions compared with healthy controls and those without NS. This finding suggests that patients with early forms of NS exhibit equally efficient executive attention function. Moreover, a significant difference in alerting function was observed between the NS and non-NS groups but not healthy controls. Age has been shown to be associated with alterations in alerting function [9, 24], and has been identified as a risk factor for HIV-negative patients with NS in our previous study[25]; thus, we further employed MANOVA with Bonferroni post-hoc test to determine whether patients with NS still displayed less efficient orienting and alerting attention functions. The findings indicated that early forms of NS may be associated with a specific structural impairment of the brain networks related to localization or alerting function rather than executive function. Posner et al. proposed that attentional networks comprise three networks related to anatomical locations: alerting, which is driven by the neurotransmitter norepinephrine around the thalamus, frontal cortex, and parietal cortex; orienting, which is driven by the neurotransmitter acetylcholine around the parietal and frontal lobes, temporoparietal junction, pulvinar, and superior colliculus; and executive function, which is driven by dopamine around the anterior cingulate and lateral prefrontal cortex[26] Notably, cognitive decline associated with NS improved after donepezil therapy, which can increase cholinergic activity [27]. This result confirmed the key role of acetylcholine in cognitive decline related to NS.
The relationship between cognitive decline and cranial imaging abnormalities was determined in patients with NS [5, 12]. Patients with NS presenting with ischemic stroke who had higher burden of cerebral small vessel disease presented with reduced cognitive function accompanied by progressive brain damage [12]. Gao et al. reported that cerebral atrophy mainly located in the anterior brain and abnormal signals distributed in various regions of the brain mainly in the frontal and temporal lobe in patients with general paresis, who had cognitive domains of delayed recall, visuospatial/executive and language ability damaged, the temporal lobe might be the first brain region to be damaged in general paresis [13]. The perfusion abnormalities in the frontal, insular, and posterior cingulate regions in a pilot single photon emission computed tomography (SPECT) study among HIV-negative patients with NS indicated potential associations between regional structure and cognitive deficits [28]. Our study alluded that patients with early forms of NS presented with MRI abnormalities in the parietal lobes and/or frontal lobes and/or the temporoparietal junction, which are correlated with the orienting or/and alerting function. Intracranial T. pallidum-related inflammation and the immunological process might be related to neural network impairment, thereby resulting in lobe function abnormalities, mild cognitive decline, and dementia. MRI abnormalities in the frontal lobes or parietal lobes or the temporoparietal junction pertaining to orienting and alerting network impairment indicated a priority change in the neural structures associated with them.
This study has several limitations. First, it focused on early forms of NS, participants were recruited from a single center, and the sample size was limited. These factors might have led to selection bias. Second, although limited functional neuroimaging studies have used SPECT or PECT/CT to adequately explore the association of cerebral perfusion with metabolic abnormalities and cognitive decline in these patients, most of them have reported variable results. Further attentional assessment at additional time points, such as after antisyphilis therapy, could be performed to better estimate the post-treatment cognitive development, which is warranted in future studies.