The Cognitive Impairment At Acute Stage After Intracerebral Hemorrhage

Background: We determined the frequency and factors of cognitive impairment at acute stage and investigate the prognostic effect of the cognitive function at acute stage on the delayed cognitive impairment after acute intracerebral hemorrhage (ICH). Methods: A total of 208 patients with acute ICH were enrolled from January 2017 to February 2019. Cognitive function was assessed during the acute stage and follow-up after ICH using Montreal Cognitive Assessment (MoCA) score. The signicant acute stage and delayed cognitive impairment was dened as a MoCA score <20 within 1 week after hospital admission and during follow-up respectively. Results: During a mean 20 (IQC 17-23) months follow-up, 185 patients with follow-up cognitive function data. There are 89 (42.8%) and 86 (46.5%) patients had acute stage and delayed signicant cognitive impairment respectively. The older age, large baseline hematoma volume, more severe ICH, and low level of education were signicant associated with signicant cognitive impairment at acute stage (all P(cid:0) 0.009). In the multivariable logistic regression model, the low acute phase MoCA score (odds ratio [OR] 0.59; 95% condence interval [CI] 0.48-0.71; P(cid:0)0.001) was the only one independent factor associated with delayed signicant cognitive impairment after ICH. Conclusions: Near half of patients have signicant cognitive impairment at acute stage after ICH, which is more frequent in the elderly, those with large baseline hematoma volume, and more severe initial neurological decit. The acute phase MoCA score was independent increased the risk of delayed cognitive impairment.


Introduction
Intracerebral hemorrhage (ICH) is well recognized as a serious type of stroke with high risk of premature mortality and morbidity [1,2]. Post-stroke cognitive impairment is common in the survivors and is reported to associated with poor prognosis [3][4][5].
The rate of cognitive impairment or dementia after ICH was higher than those with ischemic stroke [5][6][7][8][9][10][11][12]. A recently meta-analysis of 11 studies shown the prevalence of cognitive impairment ranged from 14 to 88% after ICH for different de nition and follow-up period [10]. And most of these studies was focus on the long-term cognitive impairment after ICH. However, data on early cognitive impairment, especially at acute stage, after ICH is limited [11,12]. A more recently study of 141 ICH patients indicated 75.2% patients had cognitive impairment during 2 weeks after ICH onset [11]. Meanwhile, the characteristics and the factors of cognitive impairment at acute stage after ICH were unclear. Additional, whether the cognitive function at acute stage will affecting the long-term cognitive impairment after ICH was not investigated.
Herein, in this study, we assess the frequency and factors of cognitive impairment at acute stage after ICH. Moreover, we investigate the predict effect of cognitive function at acute stage on the long-term cognitive impairment after ICH.

Study participants
We prospectively identi ed acute ICH patients from the Second A liated Hospital of Soochow University in China from January 2017 to February 2019. Brie y, patients with computerized tomography (CT) con rmed ICH from onset to admission were potentially eligible for the study. After excluding patients with trauma, brain tumor, hemorrhagic transformation of ischemic stroke, and vascular cerebral malformations, a total of 372 potentially eligible participants were enrolled. Additional exclusion criteria were as follows: 1) time from onset to admission over 5 days (n=8); 2) Pre-existent cognitive impairment, Demographic characteristics, lifestyle risk factors, medical history, clinical laboratory tests were collected at the time of enrollment. Trained neurologists assessed the baseline stroke severity using the National Institutes of Health Stroke Scale (NIHSS). Baseline imaging data including hematoma volume, hematoma location, intraventricular extension was assessed by two neuroradiologists who were blinded to the clinical data according to baseline head CT scan. And the hematoma volume was assessed using the formula ABC/2 method [14]. Using a standard mercury sphygmomanometer, blood pressure (BP) measurements were performed in the supine position for admission. Blood samples were collected at hospital admission or within 24 hours after hospital admission.

Cognitive function assessment and outcomes
The median follow-up was 20 (interquartile ranges [IQC] 17-23) months. The cognitive function was assessment using Montreal Cognitive Assessment (MoCA) score at acute phase (within 1 week after hospital admission) and follow-up by trained staff. The signi cant cognitive impairment at acute stage was de ned as a MoCA score <20 within 1 week after hospital admission. And the delayed signi cant cognitive impairment was de ned as a MoCA score <20 during the follow-up [15,16].

Statistical analysis
Baseline characteristics of patients were summarized by means and SD for normally distributed variables, medians and interquartile ranges (IQR) for skewed continuous variable, and numbers (%) for categorical variables. Between-group comparisons were made using independent Student's t test was performed for continuous variables with a normal distribution. Wilcoxon rank-sum test was used for those with skewed distributions and chi-square tests for categorical variables.
Crude and multivariable logistic regression was used to determine the factors association with acute stage and delayed signi cant cognitive impairment. All the variables with p < 0.2 in the univariate analysis were included in multivariable analyses. To assess the effect of cognitive function at acute stage on the delayed signi cant cognitive impairment, two multivariable logistic regression models were used, including and not including cognitive function at acute stage in the model. Data are reported as odds ratios (ORs) with 95% con dence interval (CIs). C-statistics (areas under receiver operating characteristic [ROC] curves) was used to assess the discriminatory ability of acute phase cognitive function on the delayed cognitive impairment. Pearson correlation was used to investigate the association between acute phase cognitive function and delayed function.
All P values were 2-tailed, and a signi cance level of 0.05 was used. All analyses were conducted using the SPSS version 17.0 statistical software (SPSS Inc., Chicago, IL, USA).

Results
Complete data on cognitive function data were available for 208 acute ICH patients (148 men and 60 women). The mean age of the participants was 60.5 ± 13.6 years (range from 26 to 92 years). During a mean follow-up time point of 20 (interquartile ranges [IQC] 17-23) months, we identi ed 23 deaths from all causes and 185 patients with follow-up cognitive function data. There are 89 (42.8%) and 86 (46.5%) patients had acute stage and delayed signi cant cognitive impairment respectively, whose MoCA score <20. The table 1 shown the baseline characteristics of acute ICH patients with and without signi cant cognitive impairment at acute stage. Compare to patients without signi cant cognitive impairment at acute stage, those with acute stage signi cant cognitive impairment were more likely to be older and female, with low baseline diastolic BP. Patients with acute stage signi cant cognitive impairment were also had severity stroke (high NIHSS score) and large hematoma volume. Compare to patients without delayed signi cant cognitive impairment, those with delayed signi cant cognitive impairment were more likely to be older and female, with low baseline diastolic BP, higher baseline NIHSS score and large hematoma volume. Moreover, patients with delayed signi cant cognitive impairment have a higher odd of early cognitive impairment (Supplementary Table 1

Discussion
In present study of 208 ICH patients observed the cognitive impairment in the acute phase after ICH and its predictor effect on the long-term cognitive function. We found all the patients with one or more cognitive domains impairment and nearly 50% patients with signi cant cognitive impairment in the rst week after hospital admission among ICH patients and the independent factors associated with cognitive impairment in acute phase was older age, large baseline hematoma volume, more severe ICH, and low level of education. Moreover, the cognitive function in the acute phase was strongly independent associated with delay cognitive impairment after ICH.
Most of these studies were focus on the long-term cognitive impairment after ICH. Data of cognitive impairment at acute phase after ICH were limited [11,12,17]. Recently, a study from China found 106 patients with cognitive impairment de ned by MoCA score <26 in the rst two weeks among 141 acute ICH patients [11]. Nakase, et al study demonstrated nearly 20% of patients with new cognitive impairment at hospital discharge among 306 ICH patients according to the criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [17]. Another studies from UK of 187 ICH patients noted 84% and 65% patients with at least one or in two or more cognitive domain impairment at the 12 days after ICH [12]. In our studies, we found all the patients have one or more cognitive domain impairment and 42.8% patients with signi cant cognitive impairment de ned with MoCA score <26 in the rst week after hospital admission. Our nding was consisted with other studies that there was a high rate of cognitive impairment in the acute phase among ICH [11,12,17]. The different rate of cognitive impairment at acute phase may due to the criteria of cognitive impairment, the assess time of cognitive function, the race and sample size.
In our study, the memory recall, visuospatial and executive function, attention and orientation were the most common domain impairment at acute stage. Our nding was consisted with Banerjee, et al study that de cits in non-verbal IQ, information processing speed and executive functions were common in the rst two weeks after ICH [12]. The features of cognitive domain impairment at acute stage after ICH needs further studies with large patients to con rm.
The factors associated with cognitive impairment at acute phase were not well studied. The study by Nakase, et al shown the baseline white blood cell (WBC) count, C-reactive protein (CRP) and NIHSS score were higher among patients with cognitive impairment [17]. Another study from China indicated dominant-hemisphere hemorrhage, admission systolic BP, abnormal red blood cell (RBC), high mean corpuscular volume (MCV) was independent with the cognitive impairment at early stage [11]. In our study, we found older age, large baseline hematoma volume, more severe ICH, and low level of education were the factors associated with cognitive impairment. While, no signi cant association between the serum biomarkers and cognitive impairment were found in our study. The different ndings partly relate to the difference in the important baseline characteristics such as hematoma volume, NIHSS score, the different confounders in the model.
Whether the cognitive function in the acute phase was affect the delayed cognitive impairment was uncertain. The data from a recently study indicated 64% patients have cognitive impairment in the rst two weeks were still with cognitive impairment during 6 months follow-up [11]. In our study, we noted older age, large baseline hematoma volume, high baseline NIHSS score, labor location and low level of education were signi cant associated with delayed signi cant cognitive impairment after ICH if the acute phase MoCA score was not in the model, which was consisted with previous studies ndings [5][6][7][8][9]18].
After the acute phase MoCA score add in the model, we found the acute phase MoCA score was the only one independent factor predicts the delayed signi cant cognitive impairment after ICH. Moreover, the signi cant relationship between MoCA score at acute phase and during follow-up was seen suggest we should pay more addition to the cognitive impairment in the acute phase.
The strengths of this study including a long-term follow-up and investigate the association between cognitive impairment at acute phase and in the long-term follow-up. However, the study has several limitations. Firstly, the number of patients was small and from one hospital. Secondly, a signi cant proportion of patients were excluded for loss of follow-up, which may also contribute to selection bias. Thirdly, the cerebral small-vessel disease (CSVD) on MRI scan was reported to associated with cognitive domain impairment after ICH [8], we were unable to evaluate the prognostic effect of CSVD on the cognitive impairment due to lack of relevant data.

Conclusions
In summary, our study has shown each patient had one or more cognitive domains impairment and half of the patients with signi cant cognitive impairment in the rst week after hospital admission in patients with acute ICH. The cognitive function in the acute phase was signi cantly increased the risk of delay cognitive impairment after ICH. Our ndings suggest should assess the cognitive function in the acute phase among ICH patients.

Declarations Acknowledgements
We thank the study participants and their relatives and the clinical staff for their support and contribution to this study.
Authors' contributions SJY, HH, and YJC contributed to the concept and rationale for the study. SJY and CG were responsible for the rst draft; SJY and JYW contributed statistical analyses. CG, WZ, JPX, and JL performed the data collection; HH and YJC for the rst revision; All authors read and approved the nal manuscript.

Availability of data and materials
All data generated or analyzed during this study are included in this published article. Some or all data or models generated or used during the study are available from the corresponding author by request.

Ethics approval and consent to participate
We obey the principles of the 1983 Declaration of Helsinki and this study was approved by the Ethics Committee of the Second A liated Hospital of Soochow University. Informed consent was obtained from all participants. All methods were performed in accordance with the relevant guidelines and regulations     MoCA, Montreal Cognitive Assessment; ICH, intracerebral hemorrhage; WBC, white blood cell; CRP, Creactive protein; OR, odds ratio. Figure 1 The correlation between acute phase MoCA score and follow-up MoCA score after ICH.