Lacunar infarction with leukoaraiosis may aggravate cognitive dysfunction★

Dejin Sun, Xueqin Zhang, Penju Liu, Jiechun Chen, Jinxia Cao, Aixia Zhuang,Qinghong Zeng, Shouqin Feng, Yi Zhang, Jiandong Jiang

1Department of Neurology, Lianyungang Second People’s Hospital (Lianyungang Hospital of Bengbu Medical College), Lianyungang 222023,Jiangsu Province, China

2Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China

3Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100730, China

4Neurophysiological Room, Lianyungang Second People’s Hospital (Lianyungang Hospital of Bengbu Medical College), Lianyungang 222023,Jiangsu Province, China

5Department of Radiology, Lianyungang Second People’s Hospital (Lianyungang Hospital of Bengbu Medical College), Lianyungang 222023,Jiangsu Province, China

INTRODUCTION

Risk factors for cerebrovascular disease,including hypertension, diabetes mellitus,hyperlipidemia, myocardial infarction, atrial fibrillation, peripheral artery disease, stroke and transient ischemic attack, a long history of smoking and heavy drinking, may trigger lacunar infarction (LI) andleukoaraiosis (LA),which are linked to age-related white matter changes[1].LI, a type of stroke to which elderly individuals are susceptible, contributes to the development of vascular dementia.LI-induced LA and vascular cognitive impairment have been the subjects of much research interest[1-6].

Qualitative studies have shown that cognitive functions decline in patients exhibiting LA, and LA has been found to aggravate cognitive impairment in patients with LI[7-10].However, quantitative and semi-quantitative studies of LA are rare, preventing firm conclusions about the condition and its effects.We propose that white matter changes may lead to impairments in cognitive function.As such, the current study sought to evaluate the cognitive function of LI patients using the P300 component of the event-related potential evoked by a two-tone auditory stimulus(ERP 2t-P300) and neuropsychological testing, to obtain a visual semi-quantitative score of the accompanying LA on the age-related white matter changes scale(ARWMC)[11], in a broader attempt to elucidate the influence of LA on the cognitive function of LI patients.

RESULTS

Quantitative analysis of subjects

A total of 134 patients with LI that were hospitalized in the Department of Neurology,Lianyungang Second People’s Hospital(Lianyungang Hospital of Bengbu Medical College), China from July 2008 to July 2010, were involved in this study.There were no drop-outs during the experiment,so all 134 patients were included in the final analysis.

Diagnostic criteria

Subcortical white matter lesions were assessed as mild, moderate and severe according to the criteria of Priceet al[12].Patients were divided into three equal groups (mild, moderate and severe)(scoring 0 to peak) based on the brain MRI results of the ARWMCs score.LA-typical imaging changes in LI patients are shown in Figure 1.

General subject information

The 134 patients included 69 males and 65 females,aged 52-84 years, with an education duration ranging from 0-18 years.Fifty patients had a history of smoking,42 had a history of drinking, 105 suffered from hypertension,33 suffered from coronary heart disease, and 36 had experienced stroke.Low-density lipoprotein levels ranged from 1.9-4.4 mmol/L, and National Institute of Health Stroke Scale (NIHSS)[13]scores ranged from 0-16 points.We collected complete data sets for all 134 LI cases, and LA scores ranged from 0-22 points.Among the patients,the mild group (n=41) exhibited scores between 0-4 points, accounting for 30.6% of all cases; the moderate group (n=48) exhibited scores between 5-9 points, accounting for 35.8% of the sample; the severe group (n=45) exhibited scores between 10-22 points, accounting for 33.6% of the sample.The mean ages of LI patients in the mild, moderate and severe groups were 68.8±6.2,72.1±6.1 and 74.6±5.6 years, respectively, with significant differences between groups (P< 0.05).There was no significant difference in gender, level of education,NIHSS score, smoking history or drinking history among the three groups (P> 0.05; Table 1).

Neuropsychological test of mild, moderate and severe LI patient groups

Mild, moderate and severe groups of patients were selected using Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), clock drawing test (CDT), verbal fluency test (VFT), digit span test (DST)and Stroop color word test (CWT).The scale scores exhibited a decline.MMSE and DST scores in the severe group significantly decreased compared with mild and moderate groups (P< 0.05), there was no significant difference between the mild and moderate groups (P>0.05).MoCA, CDT, VFT scores gradually decreased,while CWT scores gradually increased with the severity of LI (mild, moderate and severe) (P< 0.05; Table 2).

Neuroelectrophysiological P300 test in LI patients

Among the 134 patients, 18 cases failed to complete the ERP 2t-P300 test because they were uncooperative or cannot tolerate the procedure, and 13 patients either failed to exhibit P300 waveforms or exhibited ambiguous waveforms that could not be confirmed as P300 waves.The remaining 103 cases (39 mild, 38 moderate and 26 severe)exhibited P300 waves that were appropriate for analysis.There were significant differences in P300 latency between each pair of groups (P< 0.05); Pz8.0 and Cz8.0 amplitude in the moderate and severe groups was significantly lower than in the mild group; Cz2.0 amplitude in the severe group was significantly lower than that in the mild and moderate groups (P< 0.05; Table 3).

Table 1 Comparison of age, sex, education level and risk factors for stroke in lacunar infarction patients

Table 2 Neuropsychological test results (scores) in lacunar infarction patients

Table 3 Event-related potential P300 latency (ms)and amplitude (μV)in lacunar infarction patients

Covariance analysis of age and cognitive function in LI patients

Taking the age of LI patients as a covariate, cognitive function scores on the MMSE, MoCA and electrophysiology Cz2.0 Lat and Pz2.0 Lat were submitted to a regression analysis.The results revealed that age was a covariance of cognitive function.Covariance analysis showed significant differences in the MMSE (F=21.35,P=0.000), MoCA (F=25.09,P=0.000), Cz2.0 Lat (F=9.649,P=0.002) and Pz2.0 Lat (F=8.866,P=0.004)among the three groups.

Correlation analysis of cognitive function and LA score in LI patients

A correlation and multiple regression analysis on neuropsychological and neuroelectrophysiological score with LA score revealed that LA scores were negatively correlated with MMSE, VFT, MoCA, CDT, DST scores and P300 Cz2.0, Pz2.0, Cz8 .0, Pz8.0 amplitude, and positively correlated with CWT and P300 Cz2.0, Pz2.0, Cz8.0,Pz8.0 latency (Table 4).

DISCUSSION

A previous prophase study in our research group adopted a reliable measure, the ARWMCs[14-15], for conducting visual semi-quantitative analysis of LA,and evaluated cognitive function with the MMSE and MoCA scales.The results revealed that LA aggravated cognitive impairment in ischemic stroke patients[16].In the current study, neuropsychological and neurophysiological tests indicated aggravation of cognitive impairment in LI patients with LA.Previous qualitative studies have reported that LA leads to vascular cognitive impairment[17-22].The current study utilized a neuropsychological test scales because LA patients are mainly characterized by functional impairments of executive control, according to the neuropsychological test program for evaluating vascular cognitive impairment issued by the U.S.National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network[23].

Table 4 Correlation and regression analysis on leukoaraiosis score and cognitive function in lacunar infarction patients

The present findings indicated that higher ARWMCs scores were associated with more severe LA and lower cognitive function scores in neuropsychological tests(MMSE, MoCA).In addition, correlation analysis revealed a negative correlation between the extent of white matter lesions and cognitive neuropsychological scores.We speculate that more serious LA indicates more serious damage to the network of nerve fibers, and more severe overall cognitive impairment.In this study, the average MMSE score was 26.3 points in the mild group.Since the normal level in the Chinese population is 26 points, cognitive function was within the normal range in this group.However, the average MoCA score was 24.6 points (compared with the normal level in the Chinese population of 26 points), so cognitive impairment was clearly defined by this measure[24].In addition, the MoCA score exhibited significant differences between each pair among the mild, moderate and severe groups, while no significant difference in MMSE score was observed between the mild and moderate groups.These experimental findings indicate that the MoCA scale is more sensitive than the MMSE scale for recognizingexecutive function and visual spatial skills.This finding is in accordance with previous reports[3-7,25].

The present findings revealed that more severe LA was associated with lower CDT scores.The CDT is designed to evaluate executive and control functions, including identifying, organizing, planning and implementation,as well as visual-spatial and spatial encoding functioning[26].Gourovitchet al[27]proposed that the interruption of prefrontal cortex-subcortical loops in the left hemisphere leads to a decline in executive and control functions, as well as visual-spatial functions.According to Kimet al[28], CDT scores in patients with periventricular white matter lesions were significantly decreased compared with patients exhibiting deep white matter lesions, and that excitation dysfunction was more severe.At the same time, DST scores exhibited significant differences in the severe group compared with the mild and moderate groups.DST scores exhibited the opposite pattern to scores in the MoCA 5-minute delayed memory test, indicating that transient memory is the main feature of working memory.A number of studies have reported that LA with a semi-oval-shaped center in the frontal cortex of the dominant hemisphere tends to cause severe memory impairments compared with LA in the prefrontal lobe of the non-dominant hemisphere[29].The time taken to perform the CWT was found to be significantly prolonged with increasing illness severity.Functional MRI studies of patients after the Stroop test have reported prominent prefrontal and cingulate gyrus activity, and that both areas contribute to executive control effects[30-31].In accordance with these previous reports, the current study also demonstrated significant differences in VFT scores between any two of the mild, moderate and severe groups.Lamaret al[32]reported that the decrease of VFT score was a hallmark of damage to the integrity of association fibers in the left temporal lobe.

The present study revealed that LA score was negatively correlated with DST scores, indicating that LA aggravated transient memory impairment.No significant difference was found between the moderate and mild groups, suggesting that transient memory dysfunction was slight in patients with mild to moderate LA.The age of LI patients in the mild, moderate and severe groups showed an increasing trend.The leukoaraiosis and disability study reported that age is an important factor for the LA progression[22].The large-sample long-term CIVIC study (n=1 347) reported similar findings[33].In the current study, the correlation analysis and comparison of covariance analysis between age and cognitive function suggested that differences in cognitive function still existed among mild, moderate and severe groups.As such,we propose that elderly patients with ischemic cerebrovascular disease are likely to show enhanced deficits in cognitive function.

In the current study, the average MMSE score in the mild group was 26.22±3.18 (within the normal range) while the latency of the P300 was prolonged, exhibiting a similar pattern to the MoCA scale scores.Thus, the latency of the P300 was considered an auxiliary indicator for screening mild VCI.Podemskiet al[34]utilized the P300 to evaluate cognitive function in patients with LA,and found that ERP P300 latency was consistent with neuropsychological test results, so the P300 can be independently used to evaluate cognitive function.Oishiet al[35]reported that more prolonged P300 latency in patients with LA was associated with more severe LA lesions.The present study also found a significant declining trend in patients with mild, moderate and severe LI.Podemskiet al[34]also measured the P300 to evaluate cognitive function, reporting that amplitude was not a sensitive index.However, this may have been due to the small sample size of the study.In summary, the present findings indicate that LI induces vascular cognitive impairment, and that patients with LA are more likely to exhibit cognitive impairment.

SUBJECTS AND METHODS

Design

A single-center, prospective, cohort study.

Time and setting

Experiments were conducted from July 2008 to July 2010 in Department of Neurology, the Second People’s Hospital in Lianyungang (Lianyungang Hospital of Bengbu Medical College), China.

Subjects

A total of 134 LI patients were selected from July 2008 to July 2010 in Department of Neurology, Lianyungang Second People’s Hospital (Lianyungang Hospital of Bengbu Medical College), China.

Inclusion criteria

LI diagnostic criteria accorded with the classification criteria developed by the Fourth National Cerebrovascular Disease Conference of China; aged 45-85 years; 14 days after onset.

Exclusion criteria

Cases with clear diagnosis of brain metastases, cardiac infarction, and LA induced by multiple sclerosis and poisoning, rather than ischemic vascular disease; cases with LI in key organs and lobe infarction-induced severe cognitive dysfunction, greatly influencing cognitive function assessment; cases involving consciousness disorder,head trauma, drug abuse, drug dependence, mental disorders, serious systemic and chronic diseases that affect cognitive function; cases with serious aphasia,hearing disorders, dysarthria, vision loss and other cognitive functions interfering with assessment; cases with serious depression and anxiety (Hamilton Depression Rating Scale score > 7 points; Hamilton Anxiety Scale score > 7 points); uncooperative cases.All enrolled patients underwent a cranial MRI examination and visual semi-quantitative scoring for LA.The patients’ NIHSS score, age, gender, education level and risk factors for stroke such as hypertension and hyperlipidemia were recorded.NIHSS score in all patients was evaluated by a trained associate chiefly neurologist, with the same test environment and language.Experimental protocols were in accordance with theAdministrative Regulations on Medical Institution,issued by the State Council of the People’s Republic of China[36].All subjects and/or their relatives were informed of the method of examination prior to the enrollment, and gave full cooperation and written informed consent.

Methods

Neuroimaging examination in LI patients

All LI patients underwent head scanning with a 1.5 T MRI scanner (GE, Fairfield City, Connecticut, USA), with T1,T2 and T2 flair sequences.LA semi-quantitative scores were obtained using the ARWMCs.The brain was divided into ten regions, namely bilateral frontal, parietal-occipital, temporal subcortex, basal ganglia and infratentorial white matter.LA severity was graded as 0-3 levels, and LA score ranged 0-22 points[35].LA assessment was conducted by a trained neurologist and a radiologist who were blinded to the assessment.

Assessment of cognitive function in LI patients

Cognitive function was evaluated with a combination of neuropsychological testing scales and ERP measurement.

Neuro-electrophysiological ERP test: The latency and amplitude were recorded with ERP 2t-P300 using Nicolet Viking IV (D type) evoked potentials (Nicolet, Sandiego,CA, USA) in a shielding chamber.Electrodes were placed according to the international 10/20 method, such that recording electrodes were placed on the central point (Cz) and vertex point (Pz), while reference electrodes were placed on the mastoid process, and a ground electrode was placed on the frontal pole (FPz).Patients were presented with binaural sound at a comfortable volume.Acoustic stimulation was presented as a pure tone, 20 ms duration, stimulation frequency once per second.A 0.75 kHz tone was the fixed high-probability non-target stimulus, accounting for 80%of the total stimulus presentations; the remaining 20% of the stimuli were 2.0 kHz pure tones and 8.0 kHz pure tone low-probability target stimuli.Patients were required to count low-probability target stimuli for two tests.During the testing process the patients were instructed to remain awake, focused, and relaxed with their eyes closed.Each case was first pre-tested, to ensure they fully understood the process and requirements.The whole process was interpreted by a physician from the neurophysiological room who was blinded to the patients’group.

Neuropsychological tests: All LI patients were tested on the MMSE, MoCA, CDT, VFT, DST and Stroop CWT scale.The MMSE and MoCA (Beijing version)[37]were used as tests of overall cognitive function.Patients who had received less than 12 years of education were graded as the MoCA original points plus 1 point for correction.Executive control and visual-spatial function were tested using the 5-point CDT scale, in which the patients were required to draw a circle of approximately 10 cm diameter (a clock dial) on paper with a pen,marking a 1-12 o’clock scale and the position of an hour-hand and a minute-hand set at 11: 10.Language function was tested using the VFT, in which patients were required to name as many animals as possible within 1 minute, scored on a 5-point scale.Memory and attention function was tested with the DST, in which patients were required to repeat a set of numbers with a progressively increasing number of ciphers, in the normal order and reverse order respectively.The final DST score was calculated by the addition of the highest number of ciphers in the normal order and reverse order.Information processing speed was tested with Part A of the CWT(Chinese version).In this test, patients were required to quickly and correctly read 50 Chinese characters representing colors (yellow, red, blue and green), which were randomly arranged.The results were expressed as the time taken to complete the task.The testing procedures were blindly performed by a trained neuropsychological physician using uniform instructions, tools and testing environments.

Statistical analysis

Statistical analysis was conducted with SPSS 11.5 software (SPSS, Chicago, IL, USA).Normally distributed data were expressed as mean±SD.Mean values were compared using one-way analysis of variance.When the results indicated significant differences (P< 0.05), the means were compared using the least significant difference-tmethod.Non-normally distributed data were compared with a rank test.Count data were represented as the number of cases, and compared with the chi-square test.Correlation analysis between neuropsychological and electrophysiological test results with the LA score was conducted using Pearson multiple correlation and regression analyses.A value ofP< 0.05 was considered to indicate statistically significant differences, using two-tailed tests.

Author contributions:Dejin Sun, Xueqin Zhang and Jiandong Jiang had full access to all data and conducted tests of data integrity and data analysis.Penju Liu, Jiechun Chen, Jinxia Cao,Aixia Zhuang, Qinghong Zeng, Shouqin Feng, and Yi Zhang were involved in data collection.Dejin Sun, Penju Liu and Jinxia Cao participated in data analysis and interpretation.Xueqin Zhang and Jiandong Jiang participated in study design, study supervision, and manuscript development.

Conflicts of interest:None declared.

Ethical approval:Experiments were approved by the Medical Ethics Committee of the Second People’s Hospital of Lianyungang (Lianyungang Hospital of Bengbu Medical College),China.

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