Pisa syndrome (PS) is a rare postural deformity characterized by persistent lateral trunk flexion, appearing or worsening while sitting, standing, or walking, and can be improved or completely mitigated by supine positioning and passive mobilization (Doherty et al., 2011). PS was first used to describe a secondary trunk muscle tone disorder after treatment with antipsychotic drugs (Ekbom et al., 1972). Subsequently, PS was widely used for patients in Alzheimer’s disease (Woo et al., 2020), Parkinson’s disease (PD) (Castrioto et al., 2014), secondary parkinsonism (Marsili et al., 2019; Su et al., 2022), and other neurological disorders (Marchione et al., 2014; Pandey, 2014).

Postural control relies on the interactive network involving the cortex, basal ganglia, and brainstem, integrating motor (trunk muscles), sensory (visual, vestibular, and proprioceptive), and cognitive functions (Barone et al., 2016; Tinazzi et al., 2016). The development of PS is multifactorial, involving potential central and peripheral mechanisms that vary across different underlying diseases (Doherty et al., 2011). Current evidences (Tinazzi et al., 2016) suggest that dysfunction of the nigrostriatal pathway, impaired sensory information processing, cognitive deficits, and altered somatosensory orientation perception contribute to the pathophysiology of PS.

Studies have demonstrated that PS is significantly associated with alterations in executive function, attention, language, visuospatial perception, and visuospatial processing in PD patients (Amboni et al., 2013; Vitale et al., 2016; Artusi et al., 2019; Liu et al., 2019a). Cognitive impairment, a common clinical feature in both dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), exhibits overlapping affected cognitive domains (Walker et al., 2019). However, compared to PDD, DLB patients present more pronounced deficits in attention, executive function, visuospatial processing, language, and nonverbal memory, with visuospatial and perceptual impairments often manifesting at earlier stages (Smirnov et al., 2020). These findings highlight the need to explore the potential relationship between domain-specific cognitive dysfunction and postural abnormalities in DLB. Additionally, neuropsychiatric symptoms (NPS) differ between PD patients with and without PS (Vitale et al., 2016). Research by Tinazzi et al. (2015) suggests that NPS may influence PS development in PD. The Diagnostic and Treatment Guidelines for DLB recognize diverse NPS as supportive clinical features, which are recognized high-risk factors for dementia progression and may precede overt cognitive decline (McKeith et al., 2017; Guo et al., 2023; Kang et al., 2023).

Beyond the motor impairment, PS profoundly impacts patients’ daily functioning and quality of life (QoL) (Tinazzi et al., 2016). The postural deformity can lead to difficulties with balance and gait, significantly increasing the risk of falls and consequent injuries (Tinazzi et al., 2016; Gonzalez et al., 2023). It can also cause chronic back pain and reduce mobility, further limiting patients’ independence in activities of daily living. This increased dependency, coupled with the visible deformity, contributes to social stigma and isolation. Consequently, the management of PS places a substantial additional burden on caregivers, who must provide physical assistance, ensure safety to prevent falls, and cope with the psychological distress of their care recipients.

Building on prior evidence, this cross-sectional study aims to compare cognitive profiles and neuropsychiatric symptom variations between DLB patients with and without PS. The findings may provide clinical insights for improving postural stability, preventing falls, enhancing daily living capacity and QoL, and reducing caregiver burden.

The demographic and clinical features of DLB patients with and without PS are summarized in Table 1. Among the 218 DLB patients, 35 patients (19 males, 54.3%) presented with PS at the time of evaluation. Patients with PS had a significantly longer disease duration (56.46 ± 35.68 vs. 69.31 ± 33.29, p = 0.016) and presented with higher scores of ADL (39.60 ± 16.20 vs. 48.06 ± 15.54, p = 0.002) and prevalent of familial history of dementia (40.0% vs. 20.8%, p = 0.014). No significant difference was found for sex, mean age of onset, education level, marriage, caregiver, smoking, alcohol consumption, diabetes mellitus, hypertension, heart disease, stroke, and HAMD scores between the two groups.

Comparisons of cognitive assessment results between DLB patients with and without PS are presented in Figure 1. The global cognitive evaluation did not show a significant difference between the two groups, with a MoCA score of 8.00 ± 5.30 for PS + vs. 9.96 ± 6.09 for patients without PS (p = 0.113). However, the PS + group showed a significantly worse performance in visuospatial/executive abilities (1.43 ± 1.29 vs. 0.86 ± 0.91, p = 0.013) and attention (2.83 ± 1.81 vs. 1.97 ± 1.32, p = 0.012) in the subscores of MoCA. As well, patients with PS presented with lower scores of CDT (1.38 ± 1.17 vs. 0.83 ± 0.92, p = 0.007). No significant differences were observed in the other cognitive domains evaluated. In addition, a higher proportion of patients with PS were in the moderate and severe dementia groups than in the mild and MCI groups, compared to individuals without PS (82.9% vs. 17.1%, p = 0.019).

Figure 2 shows the incidence and scores of neuropsychiatric symptoms between DLB patients with and without PS. Comparative analysis revealed that DLB patients with PS had a significantly higher prevalence and severity of specific neuropsychiatric symptoms. Notably, they exhibited a greater frequency of delusions (57.1% vs. 32.8%; p = 0.006), hallucinations (80.0% vs. 54.1%; p = 0.004), and aberrant motor behaviors (45.7% vs. 21.9%; p = 0.020) compared to patients without PS. Concordantly, the NPI total score was significantly elevated in the PS group (29.69 ± 21.50 vs. 20.66 ± 17.97; p = 0.008), with notably higher composite scores for delusions (2.37 ± 2.76 vs. 1.44 ± 2.67; p = 0.008), hallucinations (4.23 ± 3.23 vs. 1.99 ± 2.56; p < 0.001), and aberrant motor behaviors (1.74 ± 2.44 vs. 1.02 ± 2.41; p = 0.006). No significant differences were observed in the other neuropsychiatric manifestations evaluated.

Comparison of caregiver distress score between DLB patients with and without PS are showed in Table 2. The PS group demonstrated significantly higher scores on the ZBI score compared to the group without PS (26.52 ± 17.74 vs. 18.04 ± 18.69, p = 0.023). Caregivers of patients with DLB complicated by PS exhibited significantly greater distress severity compared to those caring for patients without PS (p = 0.011). Notably, within neuropsychiatric symptoms subdomains, caregivers in the DLB + PS group presented heightened care distress associated with delusion (p = 0.030), hallucination (p < 0.001), anxiety (p = 0.020), aberrant motor behavior (p = 0.001), and sleep disturbance (p = 0.009) when contrasted with the group without PS.

This study represents the first investigation into the correlations between PS and cognitive deficits, neuropsychiatric manifestations, and caregiver burden in patients with DLB. The findings demonstrate that DLB patients with PS exhibit poorer performance in specific cognitive domains (e.g., attention, visuospatial and executive functions) and higher incidence/severity scores of certain NPS (e.g., delusions, hallucinations, aberrant motor behavior). Furthermore, delusions, hallucinations, aberrant motor behavior, anxiety, and sleep disturbances in patients with PS impose greater distress on caregivers and are associated with an overall increased caregiver burden.

Postural control is maintained through the integration of motor, sensory, and cognitive functions (Borel and Alescio-Lautier, 2014). Postural control deficits are linked to cognitive impairment in PD patients (Amboni et al., 2013). Abnormal subjective visual perception in PD patients with PS may contribute to postural deformities (Di Matteo et al., 2011). Functional deficits in vertical perception in PS patients are associated with impaired integration of visual, vestibular, and somatosensory information (Scocco et al., 2014; Huh et al., 2018), which is not only a hallmark of PS but also a risk factor for its development (Huh et al., 2018).

Given the shared neuropathological features and the overlap in motor and cognitive profiles between DLB and PD, it is plausible that similar mechanisms underpin postural control deficits in both conditions (Vitale et al., 2016; Gonzalez et al., 2023). Retrospective studies (Liu et al., 2019a, b) have identified significant executive dysfunction in PD patients with PS. In advanced PD stages, PS correlates with impairments in attention, language, and visuoperceptual functions (Vitale et al., 2016; Artusi et al., 2019). Vitale et al. (2016) revealed a significant association between PS and altered attention and visuoperceptual functions in PD patients, suggesting that PS pathogenesis may involve abnormalities in the frontostriatal system and posterior cortical functions. Artusi et al. (2022) similarly demonstrated that poorer visuospatial performance and vestibular tone imbalance are significantly correlated with PS.

These findings in PD are particularly relevant to DLB, which is characterized by more pronounced and earlier deficits in attention, executive function, and visuospatial abilities compared to PDD (McKeith et al., 2017; Smirnov et al., 2020). The poorer visuospatial/executive performance and attention deficits observed in patients with PS support the potential role of visuospatial and attentional impairments in PS pathogenesis, possibly mediated by distorted perception of trunk positioning. The severity of trunk misperception in PS patients correlates with the degree of visuospatial deficits (Artusi et al., 2019; Artusi et al., 2023). Additionally, the inferior language performance in PS patients, particularly in processing nouns with perceptual/sensory content, may relate to posterior temporal lobe dysfunction (Palermo et al., 2021). Although our study did not identify significant language deficits in DLB patients with PS—possibly due to the limitations of the global cognitive assessment used—the findings of Artusi et al. (2019) in PD patients with PS suggest that language dysfunction, potentially related to posterior temporal lobe dysfunction, could be a domain worthy of future investigation in DLB populations with this postural syndrome. A higher proportion of moderate-to-severe dementia in patients with PS suggests that progressive cognitive decline may impair awareness of postural abnormalities, exacerbating PS severity.

Our study highlights that DLB patients with PS exhibit more severe NPS and greater impairment in activities of daily living, as evidenced by their significantly higher ADL scores. QoL in DLB is influenced by multiple factors (Roberts et al., 2017), including progressive cognitive decline that disrupts social/occupational functioning and ADL (Mirza et al., 2022; Guo et al., 2023). Ye et al. (2017) reported significantly reduced QoL in PD with PS patients, though some studies (Tinazzi et al., 2015) argue that PS itself may not be the primary determinant, with disease duration and other factors playing contributory roles. NPS in DLB are strongly associated with QoL deterioration (Mirza et al., 2022; Guo et al., 2023; Kang et al., 2023). Patients with PS typically have longer disease duration, more severe dementia, and more pronounced motor impairments, all of which may amplify neuropsychiatric manifestations and QoL decline.

Differences in NPS exist between PD patients with and without PS. Tinazzi et al. (2016) elucidated the clinical and pathophysiological mechanisms by which NPS may influence PS development in PD. Al-Wardat et al. (2023) proposed that chronic musculoskeletal pain in PD patients with PS, varying in intensity, differentially impacts NPS. Asymmetric basal ganglia output, abnormal proprioceptive integration, antipsychotic medication use, and cognitive dysfunction may collectively modulate the incidence and severity of NPS in PD patients (Barone et al., 2016; Tinazzi et al., 2016). Although direct evidence in DLB is scarce, the high prevalence and severity of NPS in DLB, coupled with shared pathophysiological substrates, suggest that the interplay between NPS and postural control observed in PD is highly likely to be present and potentially even more pronounced in DLB. Our findings of significantly more severe delusions, hallucinations, and aberrant motor behavior in DLB patients with PS provide direct clinical evidence for this intricate relationship.

DLB patients demonstrate higher NPS prevalence than other dementias (Aarsland, 2020; Schwertner et al., 2022), with these symptoms serving as both prodromal markers and risk factors for disease progression (Hamilton et al., 2021; Guo et al., 2023; Kang et al., 2023). Vivid visual and auditory hallucinations in DLB are linked to atrophy in parieto-occipital regions (McKeith et al., 2017), while delusions, anxiety, aberrant motor behavior, and sleep disturbance are also common (Elefante et al., 2021). Pennington et al.’s comparison of cognitive and NPS profiles between PD and DLB patients provides insights into NPS differences between patients with and without PS (Pennington et al., 2021). The concordance between higher incidence/severity of delusions, hallucinations, and aberrant motor behavior in patients with PS suggests that frequent and severe NPS exacerbates patient and caregiver distress, amplifying caregiver burden.

The frequency of NPS and the severity of psychiatric manifestations in patients with DLB may be closely associated with the degree of dementia or serve as early warning signs of disease progression (Kawada, 2019; Kim et al., 2021). These symptoms significantly impair caregivers’ quality of life, sleep, and mental health, exacerbating caregiver distress and caregiving burden (Kang and Hur, 2021; Rigby et al., 2021). NPS such as anxiety, apathy, depression, and cognitive decline or dementia are primary contributors to caregiver burden in PD patients (Rigby et al., 2021). Al-Wardat et al. (2023) and Tinazzi et al. (2016) demonstrated that axial postural abnormalities and dorsal pain in PD patients can exacerbate preexisting NPS in those with PS, rendering these symptoms more challenging to manage.

In our study, patients with PS exhibited more severe caregiver distress and a higher overall caregiving burden, particularly due to symptoms such as delusion, hallucinations, anxiety, aberrant motor behavior, and sleep disturbance. These findings suggest that PS and NPS synergistically interact, compounding caregiver distress and burden, while profoundly impacting caregivers’ QoL and mental health. Such comorbidities are highly prevalent among individuals with PD (Elefante et al., 2021). For caregivers of DLB patients with PS, who often contend with a double burden of severe NPS and disabling postural disorder, the heightened distress levels we observed underscore an urgent need for targeted support. This may provide critical insights for refining caregiving strategies and priorities, ultimately alleviating burden and improving the overall caregiving experience.

Our findings highlight the necessity for an integrated management strategy in DLB patients with PS. Clinically, the specific deficits in attention and visuospatial function call for tailored cognitive rehabilitation, while the severe neuropsychiatric burden requires careful symptom management and proactive caregiver support to alleviate the documented increase in distress and burden. Future research should prioritize longitudinal studies to establish causality, investigate the underlying neurobiological mechanisms, and develop targeted interventions aimed at mitigating PS progression and improving patient and caregiver outcomes.

This study has several limitations that should be acknowledged. Firstly, the findings are derived from a cross-sectional design, we are unable to determine whether such cognitive profile and neuropsychological changes are causative or consequential to the postural abnormality. Additionally, as no specific inclusion or exclusion criteria were applied based on dementia severity, the patient group was consequently relatively heterogeneous in terms of disease stage, which may confound the interpretation of our findings and hinder their generalizability. Secondly, although this is a multicenter study of DLB combined with PS, all participants were recruited from dementia clinics, potentially introducing selection bias. Therefore, our results require further validation through studies with larger sample sizes and multiple follow-up assessments. Finally, when we evaluate the impact of cognitive function and neuropsychological factors, we need to further apply more specific scales to re-evaluate and verify. For example, by Benton Judgment of Line Orientation (BJLOT) for visuo-spatial abilities, by Semantic Verbal Fluency (SVF) and Phonemic Verbal Fluency (PVF) for language, by Digit Cancellation Test (DCT) and Trail Making Test A (TMT A) for attention, etc.

In conclusion, our study delineates a distinct clinical phenotype associated with PS in patients with DLB. This phenotype is distinguished by severe impairments in attention and visuospatial/executive functions, coupled with a heightened severity of NPS, most notably delusions, hallucinations, and aberrant motor behavior. These specific cognitive profiles call for targeted rehabilitation strategies, while the pronounced neuropsychiatric burden necessitates integrated and carefully calibrated management in clinical implications. Most importantly, the significantly elevated caregiver burden underscores the critical need for robust support systems. Addressing this complex comorbidity through a multifaceted approach is paramount to improving patient outcomes, enhancing quality of life, and alleviating the profound distress experienced by caregivers.