Correlation Between Cognitive Impairment And Neuroimaging And Inflammatory Markers In Patients With Subcortical Ischemic Vascular Disease

Vascular cognitive impairment(VCI)is caused by or associated with vascular factors. It forms a spectrum that includes vascular cognitive impairment no dementia(VCIND), vascular dementia(VaD)and mixed AD/VaD. As the condition is preventable to a large extent, it is important to identify patients at early stage of cognitive impairment and to treat appropriately. However, progress in VCI research has been hindered by lack of unified and satisfactory diagnostic criteria for the condition. Research emphasis of VCI gradually turned to the relatively homogeneous subcortical ischemic vascular disease(SIVD).SIVD is regarded as the most common subgroup of vascular cognitive impairment related to cerebral small vessel disease(SVD). It is characterised by extensive cerebral white matter lesions (WML) and lacunar infarcts in deep grey and white matter structures. SIVD is thought to be responsible for a certain pattern of cognitive impairment with predominant executive dysfunction. However, the relationship between SIVD and cognition is unclear, in part because of methodological inconsistencies across studies. In some studies, cognitive assessment has included mainly or exclusively global measures, which lack sensitivity to detect subtle cognitive changes.WML is showed as"white matter hyperintensities (WMH)"on T2 and fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) sequence. Some studies showed that WML might result in cognitive symptoms. Although conventional MRI methods, such as quantitative and semiquantitative visual rating scales, have been widely adopted in previous SIVD studies, the cognitive relevance of these measures is still equivocal. It could not reflect the damage occurred and progression of SIVD in the high signal white matter lesions. Diffusion tensor imaging (DTI) is a non-invasive water diffusion technique and can be used for quantitatively measuring the degree and directionality of the displacement distribution of water molecules. DTI detects microstructural alterations in white matter by measuring the directionality of molecular diffusion (fractional anisotropy, FA) and the average motion of water molecules (mean diffusivity, MD). Studies in SIVD have shown that DTI is a more reliable and sensitive technique for the early detection of cognitive impairment compared with conventional MRI. However the underlying pathological basis for these DTI changes remains uncertain. 1H magnetic resonance spectroscopy (1H-MRS) is a valuable tool for the assessment of several biochemical compounds in the brain in vivo, such as N-acetylaspartate (NAA), myoinositol (mI), Choline (Cho) and Creatine (Cr). Previous studies in patients with SVD have shown reductions in NAA and choline in lesions and normal appearing white matter, compared with controls.There were few reports considering the relationship among MRS, DTI and cognitive impairment of SIVD. Combining MRS with DTI may provide valuable information about the pathophysiological changes underlying DTI abnormalities and help us to better understand the SIVD process.It has been proposed that the pathogenesis of SIVD related to cerebral small vessel disease caused by various mechanisms. Inflammation plays an important role in the pathogenesis of SIVD. Inflammatory cytokines are elevated in the CSF and plasma of individuals with subcortical vascular dementia. The examination of inflammatory markers in relation to VaD might be benefit to early treatment. Recent work has demonstrated that VaD and AD share a common neuropathological hallmark: microglial activation associated with increased CD40/CD40L pathway signaling. There was still no report on potential relationship between CD40/CD40L and cognitive impairment in SIVD patients.In this study we applied neuropsychological tests, conventional MRI scanning, DTI, 1H-MRS techniques and inflammatory markers to estimate neuropsychological profile and white matter characteristics of imaging in patients with SIVD. Moreover, the relationship between WML and cognitive function impairment was also investigated. It could be possible to gain reliable data which is benefit to early diagnosis and treatment of cognitive impairtment in SIVD.Part 1: Contributions of white matter lesions to cognitive impairment in patients with subcortical ischemic vascular diseaseObjectives : To describe the cognitive profile of patients with subcortical vascular cognitive impairment by using a set of cognitive measures. To investigate the nature of white matter lesions and its correlation to the cognitive function in patients with SIVD.Methods: Extensive neuropsychological tests including MMSE and covering 5 cognitive domains were performed on 53 patients with SIVD diagnosed according to the MRI criteria of Erkinjuntti and 25 normal elderly controls (NC) matched in age and gender. Global cognitive status was assessed with the Mini-Mental Status Examination (MMSE) and montreal cognitive assessment (MoCA). Memory functions were evaluated with the delayed word recall tests of MMSE and MoCA, word recall and word recornition of ADAS-cog with learning trial. Executive function was assessed with stroop colour words test (CWT) and trail making test (TMT). The visuospatial function was evaluated with block design test (BDT) and clock drawing test (CDT). Moreover, the digit span test (DST) and verbal fluency test (VFT) with animal category were used in evaluating attention and language function respectively. The patients were divided into VaD and VCIND group. Age, sex, educational level and history were recorded. Age-related white matter change rating scale, which is a visual rating scale developed by Wahlund, was used to qualitative measure and locate the WML. Finally, correlation analysis and hierarchical multiple regression analysis were used to examine the relationship between general cognitive function and WML.Results: (1) The overall level of cognitive performance in these tests was significant inferior in VaD subjects as compared to NC subjects (P<0.05). VCIND group was worse than that of the normal elders in the tests including MMSE, MoCA, BDT, TMT, CWTb, CWTc and DST backwards (P<0.05). Between VaD and VCIND groups, significant differences were found in the same fields (P<0.05). Compared with VCIND patients, VaD subjects showed decline on the memory, executive function, visuospatial and attention function.(2)The mean WML rating scores in VaD patients and VCIND patients were(12.73±3.35)and(10.44±3.23), respectively, higher than that of NC group (P﹤0.05), which was (2.00±2.18). The study groups differed significantly from each other (P<0.05). As to each regions, the scores of frontal area, parieto-occipital area, temporal area and basal ganglia area inVaD patients were remarkedly increased than that of NC group (P<0.05), but no difference was noted at infratentorial area. Compared with controls, patients with VCIND had increased scores in frontal area and parieto-occipital area (P<0.05). A significant difference between VaD group and VCIND group was observed in frontal area and temporal area (P<0.05).(3)Correlation analysis revealed that the score of total WML was negatively correlated with MMSE, MoCA, BDT, CDT, DST and VFT scores significantly after controlling for the effects of age, gender and educational attainment (P<0.01). Positive correlations were observed between WML and word recall, word recognition (P<0.05) and TMT, CWT (P<0.01) respectively. In the hierarchical multiple regression analysis, the score of total WML explained 13.6-42.0% of the variance in each cognitive field (P<0.01).Conclusions(:1)SIVD is related to comprehensive cognitive impairment, specifically contributed to the deterioration of executive, visuospatial and attention function. Language and memory impairment were affected slightly. The predominant impairments in patients with VCIND are executive, visuospatial and attention deficits, while in patients with VaD suffered from the progressive cognitive impairment and overall cognitive decline. (2) WML located at frontal area and parieto-occipital area was serious.The cognitive function impairment in SIVD patients could be associated with the degree of WML. (3) The score of total WML could explains 13.6-42.0% of the variance in each cognitive field independently. Extension of WML may have distinct impact on the executive and visuospatial dysfunction.Part 2: Evaluation of microstructural white matter lesions in patients with subcortical vascular cognitive impairment using diffusion tensor imagingObjective: To investigate the microstructural white matter lesions and its correlation with the cognitive function in patients with VaD and VCIND by using diffusion tensor imaging (DTI) technique.Methods:17 patients with VaD, 16 patients with VCIND, and 18 normal elderly controls (NC) matched in age and gender were recruited. DTI images were acquired, and fractional anisotropy (FA), mean diffusivity (MD) of normal-appearing white matter (NAWM) in splenium of the corpus callosum, frontal, parietal, temporal, occipital lobes, periventricular area and white matter lesions in periventricular area were determined. These diffusion measurements were compared across the 3 groups, and significant differences were further performed for correlation with tests of comprehensive cognitive function.Results:(1) Compared with controls, patients with VaD had reduced FA in the bilaterial frontal lobes, bilaterial temporal lobes, bilaterial parietal lobes, splenium of the corpus callosum, left periventricular area and right periventricular WML (P﹤0.05). Additional areas showing increased MD were the left parietal lobe, splenium of the corpus callosum, bilaterial periventricular areas and bilaterial periventricular WML(P﹤0.05). Compared with NC group, VCIND patients demonstrated decreased FA value in the bilaterial frontal lobes,bilaterial parietal lobes, right periventricular WML(P﹤0.05)and increased MD in right periventricular WML(P﹤0.05). Patients with VaD had higher MD in the bilateral periventricular NAWM and WML and lower FA in bilateral temporal lobes, splenium of the corpus callosum than VCIND patients(P﹤0.05). (2) After adjusting for age, gender and education, a correlation analysis of the MD and FA of each ROI with cognitive impairment in five fields was performed in all subjects. FA values in bilateral parietal lobes, left temporal lobe, splenium of the corpus callosum, left periventricular NAWM, right periventricular WML and MD values in the left parietal lobe, splenium of the corpus callosum, bilateral periventricular NAWM and WML correlated with global cognitive function (MoCA score) (P<0.05). FA values in bilateral frontal lobes, bilateral parietal lobes, splenium of the corpus callosum, left periventricular NAWM, right periventricular WML and MD values in the left parietal lobe, splenium of the corpus callosum, bilateral periventricular NAWM and WML were found to be statistically correlated with executive measures (P<0.05). FA values in bilateral parietal lobe, splenium of the corpus callosum, right periventricular WML and MD values in the right parietal lobe, splenium of the corpus callosum, bilateral periventricular NAWM and WML correlated with visuospatial function (P<0.05). FA values in splenium of the corpus callosum, bilateral periventricular NAWM and right periventricular WML and MD values in the left parietal lobe, bilateral periventricular NAWM and WML were found to be statistically correlated with attention tes(tP﹤0.05). (3) Multiple linear regression analysis of NAWM with cognition was done for the five neuropsychological measures with significant univariate correlations. MMSE score correlated with diffusivity in left periventricular normal-appearing white matter (P=0.023). FA value in right parietal lobe NAWM positive correlated with MoCA and BDT(P﹤0.05). FA value in left frontal lobe positive correlated with TMT(P=0.014). DST score negative correlated with diffusivity in right periventricular NAWM(P=0.012).Conclusions:(1) The select microstructural white matter lesions in NAWM of SIVD patients could be showed by DTI. These lesions are major presented in the frontal lobe, parietal lobe and periventricular regions. (2) FA and MD values changes in normal appearing white matter correlated significantly with cognitive performance. Microstructural white matter impairment might be important to comprehensive cognitive decline in SIVD patients. (3) DTI is a more reliable and sensitive technique for the early detection of cognitive impairment in SIVD patients. (4)DTI measures may be useful for monitoring disease progression and may serve as surrogate markers for intervention trials in SIVD.Part 3: Evaluation of the lesions in left thalamus and left paraventricular white matter region in patients with subcortical vascular congnitive impairment using 1H magnetic resonance spectroscopy and diffusion tensor imagingObjective : To investigate the lesions of left thalamus and left paraventricular white matter region and the correlation with cognition in patients with SIVD compared with healthy controls by using 1H magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI). Methods: 14 patients with VaD, 14 patients with VCIND, and 12 gender and age matched normal controls (NC) were recruited. All subjects underwent clinical examination, neuropsychological assessment. The quantitative analysis of N-acetylaspartate (NAA), myoinositol (mI), Choline (Cho) and Creatine (Cr) resonance signals in region of interests (ROI) located in the left thalamus and left paraventricular white matter region were measured. Ratios of NAA/ Cr, mI/ Cr and Cho/ Cr were calculated in three groups. At the same time, conventional MRI and DTI scanning were received, fractional anisotropy (FA) and mean diffusivity (MD) values of white matter in the same bilateral regions were measured respectively. In addition, the relationship was described between the MRS, DTI ratios and cognitive impairment reflected in MMSE, MoCA and TMT of all subjects.Results:(1) The NAA/Cr ratio showed a gradual decrease in the SIVD patients in the left thalamus and left paraventricular white matter region compared with control(sP﹤0.05). No significant difference between VaD and VCIND groups was observed in NAA/ Cr ratio(P﹥0.05). There was no statistically differences in the other ratios among three groups(P﹥0.05). (2) Compared with controls, patients with VaD had significantly reduced FA in the left paraventricular white matter region and increased MD in the bilateral thalamus and paraventricular area(P﹤0.05). VCIND patients demonstrated increased MD value in the left thalamus and left paraventricular white matter compared with NC group(P﹤0.05). No significant difference between VaD and VCIND patients was observed (P﹥0.05). (3) After controlling for age-related, no correlation was found between NAA/Cr, mI/Cr, Cho/Cr value and DTI parameters in the ROI(P﹥0.05). (4) A significant positive correlation was observed between TMTb time and Cho/Cr(P=0.001)and also MD value in the left thalamus (P<0.05). A statistically positive correlation was found between NAA/Cr and MoCA score in the left paraventricular region(P=0.019). MD values in bilateral paraventricular white matter areas were negatively correlated with MoCA score and positively correlated with TMT(P<0.05). FA value in the left paraventricular white matter area was positively correlated with MoCA score and negatively correlated with TMTb time(P<0.05).Conclusions:(1) It is suggested that axonal loss or dysfunction in the left paraventricular white matter and microstructural white matter lesions were important process in SIVD patients. (2) The characteristic axonal loss or dysfunction and diffusion abnormalities in thalamus could be found in early SIVD patients. Combining 1H-MRS with DTI alterations could provide the valuable informations about potential lesions of thalamus in patients with SIVD. (3) The change of Cho/Cr value in the left thalamus was correlated with executive function and NAA/Cr value in the left paraventricular white matter might be important to global cognitive function. (4) The MD values in the paraventricular white matter and thalamus were correlated with cognitive impairment, especially executive dysfunction in patients with SIVD.Part 4: Clinical significance of serum inflammatory markers in patients with subcortical ischemic vascular diseaseObjective:To evaluate the levels of soluble CD40 ligand (sCD40L), interleukin-6 (IL-6)and high sensitivity c-reactive protein (hsCRP)in the serum of Patients with SIVD and the correlation with cognition and white matter lesions (WML).Methods:19 patients with VaD, 20 patients with VCIND and 15 gender and age matched normal controls (NC) were recruited. All subjects were underwent clinical examination, neuropsychological assessment and conventional MRI. The serum levels of sCD40L, IL-6, hsCRP were detected by enzyme linked immunosorbent assay (ELISA) and fixedtime nephelometry methods in all subjects, respectively. In addition, the relationship was described among these inflammatory factors and WML, cognitive impairment in patients with SIVD.Results:(1) A statistically increase of sCD40L serum level of SIVD patients versus healthy controls was detected ( P<0.05). No significant difference between VaD and VCIND groups was observed (P﹥0.05). (2) Compared with controls, patients with SIVD had elevated IL-6 serum levels ( P<0.05). There was no statistically difference in the VaD and VCIND patients (P﹥0.05). (3) The serum hsCRP expression was increased in VaD patients compared with the other groups(P<0.05). (4) There was no statistically correlation between the serum levels of sCD40L, IL-6, hsCRP and MMSE, MoCA, WML scores. (5) Slight positive correlation among sCD40L, IL-6, hsCRP was observed (P<0.01).Conclusions:(1) Increased serum levels of sCD40L, IL-6, hsCRP in patients with SIVD might indicate that inflammatory processes may be activated in SIVD. (2) Enhanced serum levels of sCD40L, IL-6, hsCRP could not imply the association with the severity of cognitive impairment and WML in SIVD patients. (3) The inflammatory markers including sCD40L, IL-6, hsCRP maybe promote the pathological changes of SIVD in common.