Cognitive Decline In Vascular Dementia Research Articles

Synaptic Vesicle-Related Proteins and Ubiquilin 2 in Cortical Synaptosomes Mediate Cognitive Impairment in Vascular Dementia Rats.

Synaptic dysfunction is considered the best neuropathological correlate of cognitive decline in vascular dementia (VaD). However, the alterations of synaptic proteins at the synaptosomal level in VaD remain unclear. In this study, a VaD model was established in male rats using bilateral common carotid artery occlusion (2VO). We performed a novel object recognition task to evaluate cognitive impairment. Immunohistochemistry was used to assess the expression of neuron-specific nuclear binding protein (NeuN). Brain synaptosomes were isolated and subjected to label-free proteomic analysis to quantify and identify the synaptic features of differentially expressed proteins (DEPs). Synaptic and hub protein expression was detected in synaptosomes using western blotting. We found that male rats with VaD presented impaired memory and decreased NeuN protein expression in the cortex. Synaptosome proteomic analysis revealed 604 DEPs, with 493 and 111 markedly downregulated and upregulated proteins, respectively. KEGG analysis and SynGO annotation revealed that the synaptic vesicle (SV) cycle may be a key signaling pathway in VaD. Hub protein analysis of the main nodes in the protein network identified UBQLN2 and SV-related proteins, including CLTC, SNAP91, AP2S1, CLTA, VAMP2, EPN1, UBQLN2, AP2B1, AP2A2, and AP2M1. Western blotting showed that the levels of SV2A, CLTC, AP2S1, and VAMP2 decreased in the synaptosomes of 2VO rats, while UBQLN2 expression significantly increased. Our results suggest that the disruption in the presynaptic SV cycle is a key event in male rats with VaD, which could be characterized by the aberrant SV2A expression. SV-related proteins and UBQLN2 may be essential in synaptopathy. Thus, targeting the specific molecular markers in synaptosomes may be critical for the development of mechanism-directed therapies against VaD.

SARS‐CoV‐2 infection worsens Vascular Dementia (VaD)‐associated neuropathology in mice

AbstractBackgroundVascular Dementia (VaD) is the second leading cause of dementia behind Alzheimer’s disease (AD) and has a profound association with the morbidity and mortality of COVID‐19. Recent evidence demonstrates that preexisting vascular dementia is associated with increased COVID‐19 incidence and worsened outcomes after COVID‐19 infection. Collectively, these observations suggest that vascular pathology in VaD such as blood‐brain barrier (BBB) disruption, directly contributes to this association. Previously we and others have demonstrated that SARS‐CoV‐2 binds to the vascular integrin α5β1 receptor and that inhibition of α5β1 integrin with the clinically‐validated peptide ATN‐161 can improve acute SARS‐CoV‐2 infection and reduce SARS‐CoV‐2‐mediated vascular disruption. Furthermore, we have previously demonstrated that ATN‐161 reduces BBB disruption in models of brain ischemia (stroke) and VaD‐modeled chronic bilateral carotid artery stenosis (BCAS), which models reduced blood flow, BBB disruption, neuroinflammation, white matter damage and cognitive decline in VaD. In the present study, we tested the hypothesis that experimental VaD worsens COVID‐19‐associated neuroinflammation and exacerbates subsequent neurovascular damage, which may be targeted therapeutically by ATN‐161.Method10‐week‐old wild‐type (WT) BALB/c male mice were infected with 2×105 PFU mouse‐adapted (MA10) SARS‐CoV‐2 or mock infection 1‐week after BCAS surgery to model the effects of preexisting VaD in mice and subsequent SARS‐CoV‐2 infection. Body weight was monitored daily. The brain was isolated 3‐days post‐infection (dpi) and analyzed for immunohistochemical and mRNA expression of selected markers of neuroinflammation and immune response.ResultBCAS+SARS‐CoV‐2 infected mice exhibited a significant reduction in body weight at 3 dpi compared with the BCAS+mock infected group. Immunohistochemical analysis demonstrated a significant increase in α5 integrin signal in the cortex. SARS‐CoV‐2 infection after BCAS worsened brain and vascular inflammation and glial activation, indicated by increased Iba‐1 (microglia) and GFAP (astrocyte) immunofluorescence and brain (proinflammatory) IL‐1β cytokine transcript levels. Lastly, SARS‐CoV‐2 infection worsens white matter (myelin) integrity as measured by myelin basic protein (MBP) immunofluorescence.ConclusionSARS‐CoV‐2 aggravated VaD‐associated morbidity indicated by elevated white matter damage, glial activation, and neuroinflammation along with increased integrin α5 expression. Integrin α5β1 could, therefore, be a therapeutic target for improving both acute SARS‐CoV‐2 infection, and VaD post‐COVID morbidity and cognitive decline.

Reducing excess dietary saturated fat intake to improve cognition in vascular dementia

Reducing excess dietary saturated fatty acids (SFAs) may be a therapy to slow cognitive decline in vascular dementia (VaD). It has been well established that lower levels of dietary SFAs reduce risk of cognitive decline and vascular dementia. In patients who consume high amounts of SFAs, limiting intake of SFAs could improve cognition. Some trials have seen a reduction in atherosclerotic lesions and memory problems with diets reduced in total and saturated fat. It has also been well established that excess dietary SFAs increase serum cholesterol and risk of atherosclerosis, so reducing dietary SFAs could reduce arterial clogging, potentially improving perfusion and cognition. Many studies show that those with lower dietary SFAs have decreased blood-brain barrier damage and neuroinflammation, so reducing excess dietary SFAs could reduce neuroinflammation. Excess dietary SFAs impair neurovascular coupling, potentially leading to brain pathologies ranging from subtle cognitive deficits to severe dementia. Studies on stroke survivors show that limiting the consumption of SFAs improves cognitive functions after stroke. We will show that reducing excess dietary SFAs can produce protective effects on cognitive functioning. More studies are needed to determine if reducing excess dietary SFAs can improve memory and other cognitive functioning in those with vascular dementia.

Serum Irisin as a Potential Biomarker for Cognitive Decline in Vascular Dementia.

Background: Irisin, a new exercise-related myokine, has been shown to be associated with a variety of diseases including serious neurological disorders. However, whether irisin is involved in the pathogenesis of vascular dementia (VD) has not yet been reported. Our aim is to determine the serum irisin level in patients with VD and investigate its relationship with cognitive function.Methods: The subjects of the study were VD patients and controls with normal cognitive function who were hospitalized in the Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University from July 2018 to June 2020. Upon admission, a cognitive function assessment was performed. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of irisin in serum.Results: During the study period, 187 subjects (82 controls and 105 VD patients) were included in the analysis. The serum irisin level of VD patients was significantly lower than that of the control group (p < 0.001). Spearman analysis showed that irisin was positively correlated with HLD-C and MoCA, and negatively correlated with all clinical characteristics except for HCY. Logistic regression analysis showed that after adjusting for all clinical characteristics, the serum irisin of VD patients still had a significant correlation with MoCA (β = 0.304, p = 0.029). According to receiver operating characteristic (ROC) curve analysis, the diagnostic accuracy for serum irisin levels on VD was 76% with the sensitivity and 71% with specificity respectively.Conclusions: These data indicate that a decrease in serum irisin levels is a powerful biological marker for cognitive decline in patients with VD, even after adjustment for risk factors. Further multi-center studies need to confirm this connection, which may pave the way for new treatment options.

Curcumin protects against cognitive impairments in a rat model of chronic cerebral hypoperfusion combined with diabetes mellitus by suppressing neuroinflammation, apoptosis, and pyroptosis

BackgroundChronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline in vascular dementia (VaD). We have previously shown that diabetes mellitus (DM) synergistically promotes CCH-induced cognitive dysfunction via exacerbating neuroinflammation. Furthermore, curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. However, the effects of curcumin on CCH-induced cognitive impairments in DM have remained unknown. MethodsRats were fed with a high-fat diet (HFD) and injected with low-dose streptozotocin (STZ), followed by bilateral common carotid artery occlusion (BCCAO), to model DM and CCH in vivo. After BCCAO, curcumin (50 mg/kg) was administered intraperitoneally every two days for eight weeks to evaluate its therapeutic effects. Additionally, mouse BV2 microglial cells were exposed to hypoxia and high glucose to model CCH and DM pathologies in vitro. ResultsCurcumin treatment significantly improved DM/CCH-induced cognitive deficits and attenuated neuronal cell death. Molecular analysis revealed that curcumin exerted protective effects via suppressing neuroinflammation induced by microglial activation, regulating the triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, alleviating apoptosis, and reducing nod-like receptor protein 3 (NLRP3)-dependent pyroptosis. ConclusionsTaken together, our findings suggest that curcumin represents a promising therapy for DM/CCH-induced cognitive impairments.

Elevated Levels of Serum Neurofilament Light Chain Associated with Cognitive Impairment in Vascular Dementia.

Objective Vascular dementia (VaD) is a progressive neurodegenerative disease with cognitive decline caused by cerebrovascular factors. Despite the great progress made in the past decade, VaD still lacks effective treatments and peripheral blood biomarkers. In this study, we tested the level of peripheral blood neurofilament light chain (NfL) in VaD patients and explored its relationship with cognitive impairment. Method A total of 176 study subjects including 80 normal controls (NC) and 96 VaD patients were included in our study. Upon admission, we collected clinical and biochemical characteristics of all research subjects. We also evaluate the Montreal cognitive assessment scale (MoCA) scores of all subjects. The serum NfL level was measured by the single-molecule array (Simoa) method. Results The years of education in the NC group and VaD group were (11.65 ± 3.04) years and (10.53 ± 3.87) years, respectively. Compared with VaD patients, the NC group has a higher level of education (p = 0.037). Furthermore, the results of Simoa indicated that VaD subjects had higher serum NfL levels compared with the NC group [(8.49 ± 2.37) pg/ml vs. (19.26 ± 4.71) pg/ml, p < 0.001]. In terms of other clinical and biochemical characteristics, there was no significant difference between VaD and NC. The Spearman correlation analysis indicated that educational years have a significant positive correlation with MoCA scores (r = 0.238, p = 0.041), while age and serum NfL levels have a significantly negative correlation with MoCA scores (age: r = −0.213, p = 0.040; NfL: r = −0.395, p = 0.027). However, further multiple regression analysis showed that only serum NfL level might serve as an independent risk factor for cognitive decline in VaD (β = 0.317, p = 0.021). Conclusion The serum NfL levels in VaD subjects are significantly elevated, which may be used as a potential peripheral blood marker for predicting cognitive impairment in patients with VaD.

Association study of serum soluble TREM2 with vascular dementia in Chinese Han population

Objective: Recent extensive evidence suggests that the triggering receptor expressed on myeloid cells 2 (TREM2) is closely implicated in the pathogenesis of Alzheimer’s disease (AD). However, no relative data exist regarding vascular dementia (VD). This study aimed to investigate the association between serum soluble TREM2 (sTREM2) and vascular dementia in Chinese Han population.Methods: A total of 120 VD patients and 120 cognitively normal controls matched for age and gender were enrolled for this study. Demographic and clinical characteristics were recorded at admission. Cognitive functions were assessed by the Mini-Mental State Examination (MMSE) and serum sTREM2 levels were detected using sandwich ELISA method.Results: Demographic and clinical characteristics did not differ dramatically between groups. Serum sTREM2 levels in VD patients are significantly decreased compared with normal controls. In VD patients, the serum sTREM2 levels were positively correlated with MMSE scores (r = 0.387, p = 0.008), and the association was independent of demographic and clinical characteristics (β = 0.396, p < 0.001).Conclusion: VD patients have significantly lower serum sTREM2 levels in comparison to normal controls. Serum sTREM2 levels may be used as a potential predictive biomarker of cognitive decline in VD.

Temporal lobe proteins implicated in synaptic failure exhibit differential expression and deamidation in vascular dementia

Progressive synaptic failure precedes the loss of neurons and decline in cognitive function in neurodegenerative disorders, but the specific proteins and posttranslational modifications that promote synaptic failure in vascular dementia (VaD) remain largely unknown. We therefore used an isobaric tag for relative and absolute proteomic quantitation (iTRAQ) to profile the synapse-associated proteome of post-mortem human cortex from vascular dementia patients and age-matched controls. Brain tissue from VaD patients exhibited significant down-regulation of critical synaptic proteins including clathrin (0.29; p < 1.0⋅10−3) and GDI1 (0.51; p = 3.0⋅10−3), whereas SNAP25 (1.6; p = 5.5⋅10−3), bassoon (1.4; p = 1.3⋅10−3), excitatory amino acid transporter 2 (2.6; p = 9.2⋅10−3) and Ca2+/calmodulin dependent kinase II (1.6; p = 3.0⋅10−2) were substantially up-regulated. Our analyses further revealed divergent patterns of protein modification in the dementia patient samples, including a specific deamidation of synapsin1 predicted to compromise protein structure. Our results reveal potential molecular targets for intervention in synaptic failure and prevention of cognitive decline in VaD.

Role of vitamin B 12 , folate, and thyroid stimulating hormone in dementia: A hospital-based study in north Indian population

Background:Vitamin B12 and folate represent modifiable risk factors for dementia. They may increase the risk of Alzheimer′s dementia (AD) and vascular dementia (VaD) as their deficiency can increase the homocysteine level due to slowed methylation reaction. Homocysteine has a neurotoxic effect that could lead to neurologic disturbances. Hence, it is important to explore the status of serum B12 and folate in AD and VaD to evolve the treatment strategies for the same.Objectives:A retrospective study was conducted to assess the levels of vitamin B12, folate, and thyroid stimulating hormone (TSH) in serum and the relationship of these factors, including age and sex to cognitive decline in VaD, AD, and dementia due to other causes (DOC).Materials and Methods:Serum vitamin B12, folate, TSH, and total cholesterol were studied in 32 AD patients (mean age: 65 years), 12 VaD patients (mean age: 61 years), 83 DOC (mean age: 65 years), and 127 control subjects (mean age: 49 years). Results: In AD, VaD, and DOC, the levels of vitamin B12 and folate were significantly lower (P < 0.002; 0.026; 0.002 for vitamin B12 and P < 0.000 in all the 3 groups for folate) as compared with the controls. Similarly, TSH levels were significantly lower in AD and DOC (P < 0.008; 0.038) as compared with the controls.Conclusion:Vitamin B12 and folate were significantly low in both AD and VaD patients. Hence, B vitamin supplementation should be considered as possible targets for the therapeutic intervention in dementia.

Progressive morphometric and cognitive changes in vascular dementia

Evidence for progressive cognitive decline in vascular dementia (VaD) is mixed, with some studies showing little or no decline over time. One possible explanation for these inconsistent findings is the heterogeneity of pathology encompassed by the VaD diagnosis. It is possible that subtypes of VaD (i.e. those resulting from different lesion distributions) show different patterns of cognitive decline. In the present study, a heterogeneous VaD group demonstrated cognitive decline from baseline to 12-month follow-up. Although this decline was coincident to morphometric changes (i.e. increased subcortical hyperintensities (SH), decreased whole brain volume (WBV)), no relationship emerged between cognitive decline and morphometric changes. Preliminary examination of VaD subtypes revealed patients with subcortical infarct or SH-only exhibited greater decline than VaD patients with cortical lesions. Further research is needed to determine whether this observed decline is attributable to differential lesion distribution or statistical artifact.

August 26 Highlights

Wilkinson et al. studied the effects of the acetylcholinesterase inhibitor donepezil in 616 patients with vascular dementia. At 24 weeks, patients treated with donepezil 5 mg/day or 10 mg/day demonstrated significant benefits vs placebo in both cognition and global function. see page 479 Commentary by Martin Farlow, MD The prevalence of vascular dementia (VaD) ranks only behind that of Alzheimer’s disease (AD), but no therapies until now have been established to delay disease progression or improve cognitive symptoms. The pattern of progression differs from AD, in that cognitive decline in VaD as defined by National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche en l’Enseignement en Neurosciences criteria typically occurs in sharp drops that may be associated with strokes rather than the steady decline more typically seen in AD. In a clinical trial setting, where patients with VaD may more regularly receive therapy for vascular risk factors, there may be no decline in cognitive functioning. In the double-blind, placebo-controlled trial of two doses of donepezil reported in this issue of Neurology by Wilkinson et al., exactly this result was seen, as illustrated in the figure, with the placebo group actually slightly improved versus baseline on AD Assessment Scale–Cognitive Subscale scores. This absence of progression creates a higher …

Performance on the Mattis Dementia Rating Scale in Patients with Vascular Dementia: Relationships to Neuroimaging Findings

Impairment on screening measures such as the Mattis Dementia Rating Scale (MDRS) provides evidence of dementia in patients with cerebrovascular disease. However, the relationships between neuroimaging findings and performance on the MDRS in vascular dementia (VD) have not been determined. In the present study, we examined the relationships between subcortical hyperintensity (SH) volume and whole brain volume (WBV) on the subscales and total score of the MDRS. Results revealed that SH accounted for a significant amount of variance on the Initiation/Perseveration and Construction subscales, whereas WBV accounted for a significant amount of variance on the Memory subscale. The total score on the MDRS was found to be significantly related to WBV but not SH. These results suggest that subcortical damage and brain volume account for different aspects of cognitive decline in VD and that overall cognitive impairment may reflect cortical and subcortical involvement.

Vascular dementia: perfusional and metabolic disturbances and effects of therapy.

Positron emission tomography (PET) has elucidated basic pathophysiological mechanism that produce the cognitive decline in vascular dementia (VD). The typical pattern of glucose metabolism seen in VD with scattered areas of focal cortical and subcortical hypometabolism differs from that in AD with marked hypometabolism affecting the association areas. The total volume of metabolically inactive tissue is significantly related to severity of dementia. Rather than the quantity of tissue destruction, the critical effect may be the quantity of cortical hypometabolism caused by subcortically induced disconnection. Studies with HMPAO SPECT have shown focal deficits in VD and AD patients that are comparable to those seen with FDG PET. In mildly demented patients performance for the classification AD versus VD is much better by PET because it might be more sensitive for imaging small functional pathological changes. A longitudinal analysis of rCMRGl in VD showed that the progression of dementia can be delayed by the adenosine uptake blocker propentofylline and that neuropsychological and metabolic changes are closely related.