Preoperative symptoms of depression, anxiety, and cognitive impairment in glioma patients: A cerebral perfusion CT study

Abstract Purpose Glioma patients have varying degrees of psychiatric symptoms, which severely affect the quality of life of patients and their families. The present study investigated the correlation between preoperative psychiatric symptoms and local cerebral perfusion parameters of in glioma patients. Patients and methods The depression, anxiety, and cognitive impairment (CI) scores of 39 patients were assessed separately, and all of the patients underwent a preoperative perfusion computed tomography scan. Results This study found that: (1) The incidence of preoperative symptoms of depression, anxiety, and CI was 46.15%, 48.72%, and 25.64%, respectively. (2) Cerebral blood volume (CBV) (lesion‐sided [LS] occipital lobe white matter [WM] and parietal lobe WM and normal‐sided temporal lobe WM), permeability surface (PS) (LS temporal lobe gray matter [GM] and parietal lobe WM) in the depression group were significantly decreased (p < .05). (3) CBV (LS occipital lobe WM), cerebral blood flow (LS parietal lobe GM, centrum ovale and frontal lobe WM and normal‐sided frontal lobe WM, temporal lobe WM and parietal lobe WM), and mean transition time (MTT) (normal‐sided frontal lobe WM and temporal lobe WM) in the anxiety group were significantly increased (p < .05). (4) CBV (LS temporal lobe GM), MTT (LS anterior limb of internal capsule), and PS (LS thalamus) in the CI group were significantly increased (p < .05). Conclusion This study showed that glioma patients had different levels of psychological distress in glioma patients before surgery, which may be related to the changes in brain perfusion caused by the tumor.


INTRODUCTION
Clinicians often focus on the symptoms of intracranial hypertension and neurological function, such as headache, epilepsy, and hemiparesis in glioma patients, but the psychological symptoms, such as depression, anxiety, and cognitive impairment (CI), were easily ignored (Aldape et al., 2019;Lapointe et al., 2018;Rooney et al., 2014). Previous studies have shown that glioma patients suffer from varying degrees of depression (15%-50%), anxiety (30%-63%), and CI (29%-90%), which can seriously affect the patients' quality of life and survival time (D'Angelo et al., 2008;Rooney et al., 2014;van Loon et al., 2015;Zwinkels et al. 2016). In addition, the onset of psychiatric symptoms may be the initial trigger for clinical presentation in several cases of the glioblastoma multiforme (Leo et al., 2020). Previous studies have suggested that symptom manifestation is likely to be influenced by tumor location and size, tumor-induced increases in intracranial pressure, functional disturbances in transmission and connectivity of neural pathways caused by gray and/or white matter (GM/WM) compression, and redistribution of cerebral blood flow (CBF) caused by vascular compression (Silvani et al., 2011). However, the pathophysiological mechanism remains unclear.
Studies have shown that abnormalities in brain structure and function caused by changes in CBF perfusion may be a major cause of psychiatric symptoms. In the study of primary depression, Taylor et al. (2013) proposed the "vascular depression hypothesis," which links underlying vascular risk factors to adverse effects on brain function that influence the development of depression. Meanwhile, some studies have found reduced perfusion in different brain regions in patients with mild CI or Alzheimer's disease (Binnewijzend et al., 2013;Dai et al., 2009;Lou et al., 2016). In Alzheimer's disease and Parkinson's disease, some studies have shown that positron emission tomographycomputed tomography (CT) can detect brain metabolism decline and correlate the severity of psychiatric symptoms with metabolic changes (Carey et al., 2021;Henderson et al., 2020;Wolinsky et al., 2018).
The changes in cerebral perfusion caused by various factors appear to play an important role in the development of psychiatric symptoms. Meanwhile, tumor formation and growth are accompanied by abnormal biological metabolism and angiogenesis, leading to obvious changes in blood flow in tumors, peritumoral brain regions, and even non-lesional lateral brain regions (Boele et al., 2015;Fan et al., 2019;Mugge et al., 2020). Whether abnormalities in CBF play an important role in glioma-associated psychological distress is a matter for further study.
In the present study, we investigated tumor perfusion and its relationship with perfusion in the normal brain regions using perfusion computed tomography (PCT). Second, the relationship between perfusion parameters of brain regions and psychiatric symptoms was investigated.

Subjects
We reviewed the records of 57 consecutive patients who underwent Exclusion criteria were as follows: (1) patients with recurrent glioma; (2) previous brain biopsy or surgery; (3) unable to participate in the psychiatric assessment; (4) had a medical history or family history of psychological distress. Finally, 39 cases were included (Figure 1

PCT protocol
The method of the PCT protocol was based on our previous study (Wang et al., 2021). First, all patients underwent a non-contrastenhanced CT scan on the Philips Brilliance 256-slice spiral CT scanner after the patients had undergone an iodine anaphylaxis test and the result was negative. Second, the contrast agent (iobitridol, 350 mgI/mL) was administered rapidly (6 mL/s) via an elbow intravenous bolus injection at the elbow using an automatic injector (2 mL/kg). Third, normal saline (30 mL) was injected at the same rate. After a delay of 5 s, scanning was performed with the following parameters: 80 kV, 100 mA s, 0.4 s/cycle, 4.1 s interval, 13 cycles in total, 5 mm slice thickness, 512 × 512 matrix, 54.4 s contrast agent tracking time, and 12.8 cm coverage. Finally, the reconstructed dynamic images were transferred to the workstation for processing in the Philips Extended Brilliance Workstation using CT brain perfusion software.

Selection of regions of interest (ROIs)
The

PCT data processing and analysis
Two experienced radiologists, blinded to the results of the psychiatric assessment, were responsible for measuring perfusion parameters.

Neuropsychological assessment
Depression was assessed using the 17-item Hamilton Depression Rating Scale, with scores ≥7 indicating symptoms of depression (Hamilton, 1960). Anxiety was assessed using the Hamilton Anxiety Scale, with scores >7 indicating symptoms of anxiety (Hamilton, 1959). CI was assessed using the Mini Mental State Examination, with the symptoms of CI were defined as ≤24 points for junior high school education and above, ≤20 points for primary school education, and ≤17 points for illiteracy, respectively (Folstein et al., 1975). All interviews were scored by a clinically experienced psychiatrist.

Statistical analyses
SPSS 22.0 statistical software was used for statistical analysis. The number of count data cases (percentage) was expressed, and the measurement data were expressed as mean ± standard deviation (x ± s).
Measurement data were analyzed by independent samples t-test, and count data were analyzed by chi-squared test or rank-sum test. Pearson's correlation analysis was used for correlation analysis. p ≤ .05 was considered statistically significant.
There were 9 (23.1%) patients in whom all the neuropsychological evaluations were normal (Figure 2). There were no significant differences in terms of age, sex, education level, marital status, operative Karnofsky Performance Status, tumor grade, location, and side in the clinical characteristics between depression and non-depression groups (Table   S1), anxiety and non-anxiety groups (Table S2), and CI and CN groups (Table S3).

Comparisons of perfusion parameters between depression group and non-depression group
CBV (occipital lobe WM and parietal lobe WM of LS and temporal lobe WM of NLS), PS (temporal lobe GM and parietal lobe WM of LS) in depression group were statistically different compared with that of non-depression group (Table 2, Figure 3).

3.3
Comparisons of perfusion parameters between anxiety group and non-anxiety group CBV (occipital lobe WM of LS), CBF (parietal lobe GM, centrum ovale and frontal lobe WM of LS and frontal lobe WM, temporal lobe WM and parietal lobe WM of NLS), and MTT (frontal lobe WM and temporal lobe WM of NLS) in anxiety group were statistically different compared with that of non-anxiety group (Table 3, Figure 4).

Comparisons of perfusion parameters between CI group and CN group
CBV (temporal lobe GM of LS), MTT (anterior limb of internal capsule of LS), and PS (thalamus of LS) in CI group were statistically different compared with that of CN group (Table 4, Figure 5).  Previous studies shown that the posterior cingulate and the inferolateral parietal lobes in the posterior regions of the default mode network dysfunction, one of the pathophysiological mechanisms of depression, were associated with episodic memory retrieval . In addition, the parietal cortex was one of the commonly identified brain regions of emotional regulation in anxiety disorders using functional MRI, associated with sensory information, with topdown response-related information to facilitate flexible, goal-directed behavior. Meanwhile, prefrontoparietal neural circuits were important in the pathogenesis of anxiety disorders (Wang et al., 2018). Karim et al. (2017) found that severe worry was significantly associated with increased CBF in several neocortical regulatory regions. In our study, the ROIs with significantly different blood flow perfusion changes mainly involved the brain regions, which related to the emotional regulation and cognitive function of the default mode network, affective network, and visual cortical areas (Zeng et al., 2012). The results of our study showed that MMT values in the anterior limb of the internal capsule were significantly increased between the CI group and the CN group, which was consistent with dementia patients (Amen et al., 2017). Previous studies have almost unanimously concluded that

TA B L E 3
The difference in perfusion parameters between the anxiety group and the non-anxiety group  the CBF decreases in patients with dementia. Streitparth et al. (2008) found a significant decrease in occipital and temporal CBV values and a significant decrease in CBF values with increasing degree of dementia in the frontal lobe, basal ganglia, and the occipital region, which contradicted to our study in which we found increased values of CBV in the temporal GM. Thus, we suggested that the preoperative psychiatric symptoms in patients with glioma may be related to changes in the perfusion of related brain regions, which may lead to impaired function of fibrous bundles.

ROIs
There were some differences in the ROIs of depression group, anxiety group, and CI group. Depression group and CI group mainly involved LS, whereas anxiety group involved bilateral ROIs. A previous study showed that increased anxiety was clearly associated with increased CBF, because anxiety increases the sensitivity of CBF to changes in PCO 2 (Van den Bergh et al., 2013). Therefore, we hypothesized that anxiety may be caused by diffuse changes in cerebral perfusion, which could be caused by increased neuronal activity. In addition, the perfusion parameters, including CBV, CBF, MTT, and TTP, represented the cerebral hemodynamics, whereas PS represented the integrity of the blood-brain barrier (BBB). Both abnormalities could cause abnormal WM function, which caused the psycho-cognitive symptoms (Onishi et al., 2018). Our results showed that the possible mechanism of the depression group and the CI group could be both the changes in cerebral perfusion and BBB, whereas the anxiety group could be only the changes in cerebral perfusion.
With the development of noninvasive cerebral perfusion imaging technology, the different characteristics of tumor perfusion have been used in diagnosis, differential diagnosis, classification, prediction of molecular pathological mutations, monitoring of tumor recurrence, and prediction of generation time in glioma (Karegowda et al., 2017;Onishi et al., 2018;Wang et al., 2021;Zhang et al., 2017

Clinical implications
To our knowledge, this study was the first to analyze the perfusion parameters and preoperative symptoms of depression, anxiety, and CI in patients with glioma. The results of our study were as follows: (1) patients with glioma could have preoperative symptoms of depression, anxiety, and CI; (2)

Study limitations
Our study had several limitations. First, the samples of this study were relatively small because relatively few patients had PCT scan, which may lead to a possible bias. Second, the hemodynamic parameters were obtained by drawing different ROIs of the brain, so the local occupying effect of the tumor cannot be completely excluded. Third, the subregions in different brain regions could not be analyzed due to the low resolution of PCT. Future studies should replicate this study in larger samples using other advanced neuroimaging techniques to provide additional data on the factors involved in the pathogenesis of psycho-cognitive symptoms in the patients with glioma.

CONCLUSION
In conclusion, preoperative symptoms of depression, anxiety, and CI may be present in some glioma patients and may be closely related to the brain perfusion parameters.

AUTHOR CONTRIBUTIONS
Ke Wang and Wanrui Fu designed the study and wrote the article, Shenjie Li analyzed the image data, Lizhen Chen and Wei Xiang collected the materials, Yajie Gan conducted the psychiatric evaluation, and Ligang Chen and Jie Zhou cared for the patients and revised the report.

ACKNOWLEDGMENTS
We would like to thank the patients who agreed to participate in the research. This study was supported by Sichuan Science and Technology Program (2022YFS0630).

CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflict of interests related to this work.

DATA AVAILABILITY STATEMENT
The data supporting the results of this study are available upon request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.