Path integration changes as a cognitive biomarker for vascular cognitive impairment? A pilot study

Objective To explore changes and clinical significances of serum cystatin (Cys) C levels in patients with vascular cognitive impairment (VCI) after acute stroke, in order to provide evidence for early diagnosis and treatment of patients with VCI. Methods From December 2012 to December 2013, a total of 120 cases of acute stroke patients who were treated in Department of Neurology and Neurosurgery, Dongying People's Hospital were included in this study, as study group. According to whether the patients complicated VCI or not after stroke, study group were divided into VCI subgroup (n=60) and non-VCI subgroup (n=60). And at the same period, a total of 60 cases of elderly health examination who were over 50 years old and without complaints of cognitive dysfunction were included in control group (n=60). Systematic evaluations of VCI patients' cognitive function were evaluated by mini-mental state examination (MMSE) scale, and severity of VCI was divided according to results of MMSE score. Levels of serum Cys C in three group were detected with immunoturbidimetry by automatic biochemical analyzer, and relationship between serum Cys C levels and VCI severity was analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Dongying People's Hospital. Informed consent was obtained from all participants. Results There were no significant differences in gender, age, years of education, high blood pressure, diabetes and other socio-demographic data among VCI subgroup, non-VCI subgroup and control group (P>0.05). Level of serum Cys C in VCI subgroup was (1.68±0.46) mg/L, which was higher than (0.88±0.42) mg/L of non-VCI subgroup and (0.83±0.32) mg/L of control group, and difference among three group was statistically significant (F=12.99, P<0.05). In VCI subgroup, there was statistical difference of levels of serum Cys C in patients with different VCI degrees (F=7.98, P<0.05). There were 19 cases of severe VCI patients with MMSE score ≤13 whose serum levels of Cys C were (1.92±0.36) mg/L. There were 23 cases of moderate VCI patients with MMSE score of ≥14-20 whose serum levels of Cys C were (1.33±0.41) mg/L. There were 18 cases of mild VCI patients with MMSE score of ≥21-24 whose levels of Cys C were (1.09±0.28) mg/L. There was statistical difference among above three groups (F=7.98, P<0.05). The higher levels of serum Cys C in VCI patients after acute stroke were, the more serious the degree of their VCI. The results of bivariate Spearmen correlation coefficient analysis showed that there was a negative correlation between levels of Cys C and MMSE scores in VCI patients (r=-0.421, P=0.039). Conclusions Levels of Cys C in VCI patients after acute stroke were related to their development of VCI. Levels of serum Cys C could be one of biomarkers in peripheral blood as an early diagnosis of VCI, to provide biological evidence for early diagnosis and treatment of VCI. Key words: Stroke; Cognition disorders; Diagnosis; Cystatin C

This study examined the diagnostic value of the total MoCA score and its subscores in differentiating Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), and vascular dementia (VaD). A total of 241 patients (AD=110, FTD=90, DLB=28, and VaD=13) and 59 healthy persons, who were referred to a dementia clinic with memory impairment in Firoozgar Hospital, were included in this study. MoCA tests were performed in all patients and normal persons. By using the receiver operating characteristic (ROC) curve and measuring the area under the curve (AUC) for the total MoCA score in each group, AUC was 0.616, 0.681, 0.6117, and 0.583 for differentiating AD, FTD, DLB, and VaD patients, respectively. Among the groups, just the VaD group showed no significant usefulness in using the total MoCA score to differentiate it. To compare MoCA subscores, AD patients had higher scores in digit span, literal fluency, and abstraction but lower delayed recall scores compared with FTD patients. The total MoCA score and its subscores could not differentiate people with different types of dementia in the setting of screening.

Objetive: The study aimed to describe the prevalence and severity of neuropsychiatric symptoms in patients with Alzheimer’s disease (AD) and vascular dementia (VaD). Patients and methods: We prospectively studied 65 patients with dementia, 37 met the criteria of NINCDS-ADRDA for probable AD and 28 the clinical and radiological criteria of NINDS-AIREN for VaD. Among VaD patients, 22 met the radiological criteria for subcortical VaD. The Minimental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were used to evaluate cognitive and neuropsychiatric symptoms. All patients underwent a neuroimaging study (CT scan and/or MRI). Patients were not treated with antidementia or psychotropic drugs. Results: Age, gender, educational level and MMSE scores did not differ between patients (p &gt;0.05). The total prevalence of neuropsychiatric symptoms was similar in both groups (AD 94.6% vs. VaD 96.4%, p= 0.727). Sleep disturbances (35.1% vs. 3.6%, p =0.002) and appetite changes (37.8% vs. 14.3%, p = 0.032) were more prevalent in AD patients than in VaD patients who met the NINDS-AIREN criteria. Sleep disturbances (35.1% vs. 4.5%, p =0.008), appetite changes (37.8% vs. 13.6%, p = 0.047) and aberrant motor behaviour (24.3% vs. 0%, p =0.012) were more prevalent in AD patients than in subcortical VaD. The total scores for sleep disturbance, appetite changes and aberrant motor behaviour were higher in AD patients (p &lt; 0.05). Conclusions: There were no significant differences between AD and VaD patients, except that sleep disturbances, appetite changes and aberrant motor behaviour that were more prevalent and severe in AD.

To investigate the plasma levels of endogenous hydrogen sulfide (H2S), a gasotransmitter, and homocysteine (Hcy) in patients with Alzheimer's disease (AD), vascular dementia (VD), and cerebrovascular disease (CVD) and their role in the pathogenesis of AD and VD. 31 AD patients, 28 VD patients, 20 CVD patients , and 23 normal controls (NC group) underwent examination of plasma concentrations of H2S and Hcy, mini mental state examination (MMSE), activity of daily living scale (ADL), Hachinski ischemic score (HIS) , and Hamilton's depression scale (HRSD). The severity of AD and VD was evaluated according to the global deterioration scale (GDS). (1) The plasma H2S levels of the AD, VD, and CVD patients were (34 +/- 7), (36 +/- 5), and (37 +/- 7) micromol/L respectively, all significantly lower than that of the NC group [(45 +/- 7) micromol/L, all P < 0.01]. However, there were no significant differences in the plasma H2S level among the AD, VD, and CVD patients (all P > 0.05). The plasma H2S concentration was negatively correlated the severity of AD. (2) The plasma Hcy levels of the AD, VD, and CVD patients were (14.0 +/- 3.0), (16.0 +/- 6.1), and (14.4 +/- 4.9) micromol/L respectively, all significantly higher than that of the NC group [(9.8 +/- 2.5) micromol/L, P < 0.01). However, there was no significant difference in the plasma Hcy level among these 3 groups (all P > 0.05). The plasma Hcy concentration was positively correlated with the severity of AD or VD. H2S and Hcy are both involved in the pathogenesis of AD, VD, and CVD, and its alteration in level may be associated with the severity of AD and VD.

Amyloid beta(40) (Abeta(40)) is the most abundant Abeta peptide in the brain. The cerebrospinal fluid (CSF) level of Abeta(40) might therefore be considered to most closely reflect the total Abeta load in the brain. Both in Alzheimer's disease (AD) and in normal aging the Abeta load in the brain has a large inter-individual variability. Relating Abeta(42) to Abeta(40) levels might consequently provide a more valid measure for reflecting the change in Abeta metabolism in dementia patients than the CSF Abeta(42) concentrations alone. This measure may also improve differential diagnosis between AD and other dementia syndromes, such as vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). To investigate the diagnostic value of the CSF Abeta(42)/Abeta(40) ratio in differentiating AD from controls, VaD, DLB and FTD. We analysed the CSF Abeta(42)/Abeta(40) ratio, phosphorylated tau(181) and total tau in 69 patients with AD, 26 patients with VaD, 16 patients with DLB, 27 patients with FTD, and 47 controls. Mean Abeta(40) levels were 2850 pg/ml in VaD and 2830 pg/ml in DLB patients, both significantly lower than in AD patients (3698 pg/ml; p<0.01). Abeta(40) levels in AD patients were not significantly different from those in controls (4035 pg/ml; p=0.384). The Abeta(42)/Abeta(40) ratio was significantly lower in AD patients than in all other groups (p <0.001, ANCOVA). Differentiating AD from VaD, DLB and non-AD dementia improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) concentrations alone (p<0.01) The Abeta(42)/Abeta(40) ratio performed equally well as the combination of Abeta(42), phosphorylated tau(181) and total tau in differentiating AD from FTD and non-AD dementia. The diagnostic performance of the latter combination was not improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) alone. The CSF Abeta42/Abeta40 ratio improves differentiation of AD patients from VaD, DLB and non-AD dementia patients, when compared to Abeta42 alone, and is a more easily interpretable alternative to the combination of Abeta42, p-tau and t-tau when differentiating AD from either FTD or non-AD dementia.

P01-502 - Follow-up study on plasma and cerebrospinal fluid levels of B amyloids and tau proteins in patients with alzheimer's disease

Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14% of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45%) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55% of its origin is still unknown.

ObjectivesThe genetic background of vascular cognitive impairment (VCI) is poorly understood compared to other dementia disorders. The aim of the study was to investigate the genetic background of VCI in a well‐characterized Finnish cohort.Materials & MethodsWhole‐exome sequencing (WES) was applied in 45 Finnish VCI patients. Copy‐number variant (CNV) analysis using a SNP array was performed in 80 VCI patients. This study also examined the prevalence of variants at the miR‐29 binding site of COL4A1 in 73 Finnish VCI patients.ResultsIn 40% (18/45) of the cases, WES detected possibly causative variants in genes associated with cerebral small vessel disease (CSVD) or other neurological or stroke‐related disorders. These variants included HTRA1:c.847G>A p.(Gly283Arg), TREX1:c.1079A>G, p.(Tyr360Cys), COLGALT1:c.1411C>T, p.(Arg471Trp), PRNP: c.713C>T, p.(Pro238Leu), and MTHFR:c.1061G>C, p.(Gly354Ala). Additionally, screening of variants in the 3′UTR of COL4A1 gene in a sub‐cohort of 73 VCI patients identified a novel variant c.*36T>A. CNV analysis showed that pathogenic CNVs are uncommon in VCI.ConclusionsThese data support pathogenic roles of variants in HTRA1, TREX1 and in the 3′UTR of COL4A1 in CSVD and VCI, and suggest that vascular pathogenic mechanisms are linked to neurodegeneration, expanding the understanding of the genetic background of VCI.

Immune dysregulation has been observed in the brain and blood of patients with Alzheimer's disease (AD). However, a convenient assay to evaluate peripheral immune dysregulation in AD has not been developed, partly due to the inconsistent observations from different studies. We hypothesized that peripheral immune dysregulation may only exist in a subpopulation of AD patients; therefore it may be valuable to identify this subpopulation with a convenient assay. Along this line, we selected 14 candidate genes based on our analysis of microarray data on peripheral blood of AD and other diseases. We used RT-qPCR to examine the expression of these 14 genes in a cohort of 288 subjects, including 74 patients with AD, 64 patients with mild cognitive impairment (MCI), 51 patients with vascular dementia (VaD), and 99 elderly controls with no cognitive dysfunction/impairment. Seven of these 14 genes displayed significant difference in group comparison. Switching from group comparison to individualized evaluation revealed more in-depth information. First, there existed a wide dynamic range for the expression of these immune genes in peripheral blood even within the control group. Second, for the vast majority of the patients (AD, VaD, and MCI patients), the expression of these genes fell within the dynamic range of the control group. Third, a small portion of outliers were observed in the patient groups, more so in the VaD group than that in the AD or MCI groups. This is our first attempt to conduct personalized evaluation of peripheral immune dysregulation in AD and VaD. These findings may be applicable to the identification of peripheral immune dysregulation in AD and VaD patients which may lead to tailored treatment toward those patients.

Hypertension is considered a risk factor for stroke and dementia. Ambulatory blood pressure monitoring (ABPM) is a useful tool in the diagnosis and treatment of hypertension. This study aimed to evaluate blood pressure using ABPM, in 30 Alzheimer's disease (AD) patients and 30 vascular dementia (VaD) patients in comparison with 30 healthy controls. BP was recorded every 15min from 6 AM to 10 PM, and every 30min from 10 PM to 6 AM. Mean systolic (SBP) and diastolic (DBP) blood pressure during daytime, nighttime, diurnal index, pulse pressure, and heart rate were extracted from the ABPM recordings.VaD patients presented higher SBP values compared to AD patients and healthy controls. DBP values in the AD group were the lowest, while VaD patients presented the highest DBP values, including day and nighttime. Mean arterial pressure values were also the highest in the VaD group, while AD patients had similar values with the control group. The VaD patients presented the lowest systolic diurnal index compared to AD patients and controls. The mean pulse pressure and nighttime pulse pressure values were higher in both groups of dementia patients when compared with the control group. Increased SBP, pulse pressure, and alteration in the circadian pattern with the highest incidence of the non-dipper and reverse dipper patterns were found in patients with dementia when compared with the healthy elderly. Also, decreased values of DBP were found in AD patients, especially during the night period.

Vascular factors increase the risks of developing Alzheimer's disease (AD) and they contribute to AD pathology. Since amyloid beta (Aβ) deposits can be observed in both diseases, there is an overlap which impedes a clear discrimination and difficult clinical diagnosis. In the present study, we compared cerebrospinal fluid (CSF) profiles of neurodegenerative and inflammatory biomarkers in a patient cohort of controls (n = 50), AD (n = 65) and vascular dementia (VaD) (n = 31) cases. Main results were validated in a second cohort composed of AD (n = 26), rapidly progressive AD (rpAD) (n = 15), VaD (n = 21), and cognitively unimpaired patients with vascular encephalopathy (VE) (n = 25) cases. In the study, cohort significant differences were detected in tau, p-tau, and Aβ1-42 (Aβ42) levels between AD and VaD patients, but not for the neuron-specific enolase (NSE), S100B protein, 14-3-3 and YKL-40. Differential tau, p-tau, and Aβ42 levels between AD and VaD were confirmed in the validation cohort, which additionally showed no differences between AD and rpAD, nor between VaD and VE. The evaluation of the biomarker performance in discrimination between AD and VaD patients revealed that the best diagnostic accuracy could be obtained when tau, p-tau, and Aβ42 were combined in form of Aβ42/p-tau (AUC 0.84–0.90, sensitivity 77–81%, specificity 80–93%) and (tau × p-tau)/Aβ42 ratio (AUC 0.83–0.87, sensitivity 73–81%, specificity 78–87%). Altogether, our studies provided neurodegenerative biomarker profiles in two cohorts of AD and VaD patients favoring the combination of CSF biomarker to differentiate between diseases.

Purpose: To determine the differential diagnosis of Alzheimer’s disease (AD) and vascular dementia (VaD) using visual rating scales. Material and Methods: 119 brain Magnetic Resonance Imaging (MRI) examinations of patients diagnosed ei- ther with AD (n=85) or VaD (n=34) were assessed. Double blinded visual evaluation was performed by two neu- roradiologists. Final clinical diagnosis was set by a be- havioural neurologist. The following rating scales were valued: Pasquier rating scale (GCA), Fazekas Scale assess- ing both periventricular (PV) and white matter (WM) lesions. Posterior Cortical Atrophy (PCA) and scales re- garding specific cortical regions: dorso-frontal (DF), or bito-frontal (OF), anterior-cingulate (AC), basal ganglia (BG), anterior-temporal (AT), insula, lateral-temporal (LT), entorhinal (ERC), perirhinal (PRC), anterior-fusi- form cortex (AFC), anterior-hippocampus (AHIP) and posterior-hippocampus (PHIP). Both Left (L) and Right (R) hemispheres were examined. Results: The indicators with the highest value of area under the curve (AUC) were Fazekas-WM (AUC: 0.906), Fazekas-PV (AUC: 0.894), R-ERC (AUC: 0.858) and L-ERC (AUC: 0.820). Best sensitivity for distinguishing VaD from AD was achieved by PCA (91%), R-ERC (91%), Fazekas-WM (89%) and L-ERC (87%). Highest specificity was achieved by Fazekas-WM (97%), R-PHIP (91%), L-PHIP (91%), R-AC

Vascular cognitive impairment(VCI) ranks as the second most prevalent type of dementia.Increasing evidence has shown that inflammation and multi-faceted neuro-immune interactions integrate systemic and central inflammatory pathways, thereby inducing vascular tissue injury and contributing to the development of vascular cognitive impairment (VCI).V-type immunoglobulin-like suppressor of T cell activation (VISTA) is an Negative checkpoint regulators(NCR) that is associated with CNS homeostasis, interactions with peripheral immunity and CNS inflammation.The primary objective of this study was to seek the correlation between VISTA and VCI in patients with cardiovascular risk factors.Our secondary objective was to explore the potential of VISTA as a biomarker for VCI. We enrolled individuals with cardiovascular risk factors in this cross-sectional study research and categorized them into two groups: without cognitive impairment (control) and with cognitive impairment (VCI). VISTA expression in peripheral blood mononuclear cells (PBMCs) was analyzed using relative quantitative polymerase chain reaction. VISTA expression was identified in monocyte subsets using flow cytometry. We use Enzyme linked immunosorbent assay to detect inflammatory factors in serum. In PBMC in patients with VCI, the expression of VSIR was significantly reduced. In contrast to controls, fasting glucose, fibrosis, and the levels of interleukin 6 (IL-6) in VCI patients were noticeably higher, and uric acid levels were significantly lower. Vsir mRNA expression in PBMCs correlated negatively with IL-6 levels, Trail Making Test B scores, and Hachinski scores and positively with Boston Naming Test scores. In intermediate monocytes, flow cytometry showed reduced Vsir expression, which was connected with VCI. The percentage of intermediate monocytes, uric acid, and the VISTA mean fluorescence intensity on intermediate monocytes were shown to be independent factors to VCI by multivariate logistic regression analysis. Decreased VISTA promotes the occurrence of VCI in patients with cardiovascular risk factors by promoting monocytes toward the proinflammatory intermediate monocyte subset. VISTA may serve as a potential biomarker for distinguishing VCI in individuals with cardiovascular risk factors.

The aim of this study was to investigate whether there is a difference between Alzheimer disease (AD) dementia and pure vascular dementia (VaD) in relation to nitrosative stress levels. We determined serum nitric oxide (NO), oxidized low-density lipoproteins (ox-LDL), and 3-nitrotyrosine levels (3-NT) in healthy elderly individuals (controls, n=15, mean age=73.4+/-7.9 y), AD patients (n=30; mean age=71.2+/-12.7 y) and VaD patients (n=20; mean age=75.2+/-7.5 y). Patients were under anticholinesterase drug therapy. Our results showed that serum NO and ox-LDL levels in AD patients group were significantly higher than in both controls (P<0.001 and P<0.001) and VaD patients (P<0.01 and P<0.001). However, no significant differences in plasma NO and ox-LDL levels were found between VaD and controls. Our study did not reveal significant differences in plasma 3-NT values of dementia patients when compared with controls. There was a significant negative correlation between Mini-Mental State Examination score and serum NO levels in dementia patients (r=-0.349, P<0.01). Serum NO levels were also positively correlated with serum ox-LDL levels (r=0.358, P<0.01). In conclusion, elevation in serum levels of NO was present in probable AD patients but not in VaD patients, and this seems to be related to both ox-LDL levels and cognitive status.

Effects of piracetam on the dexamethasone suppression test in Alzheimer's and multi-infarct dementias