Osthole Improves Cognitive Function of Vascular Dementia Rats: Reducing Aß Deposition via Inhibition NLRP3 Inflammasome.

Vascular dementia (VD) is a common neurodegenerative disease, and the cognitive dysfunction is a major manifestation of VD. Lots of evidences showed that beta-amyloid (Aß) deposition and neuroinflammation act as vital elements in the progress of VD. The previous studies showed that osthole (OST) can improve the cognitive function of VD and Alzheimer's disease (AD). However, the effect of OST on Aß in VD brain is still unclear. Chronic cerebral hypoperfusion (CCH) of rats were used to investigate the effect of OST on Aß through nod-like receptor protein 3 (NLRP3) inflammasome in this study. Morris Water Maze and Y-maze were used to test the spatial learning, memory and working abilities. Hematoxylin-eosin (H&E) and Nissl staining were used to observe the morphology and number of hippocampal neurons. Immunofluorescence staining was used to observe the number of microglia activated. Western blot was used to detect the expression of proteins. The study results showed that OST obviously enhanced the spatial learning, memory and working abilities induced by modified bilateral common carotid artery occlusion (BCCAO) in rats, improved the pathological damage of hippocampal neurons induced by BCCAO in rats, inhibited the activation of microglia induced by BCCAO in rats. Furthermore, this study also discovered that OST reduced Aß deposition in VD hippocampus via inhibition the NLRP3 inflammasome. Together, these results suggest that OST reduces Aß deposition via inhibition NLRP3 inflammasome in microglial in VD.

New approaches to understanding dementia.

Improving understanding of brain disorders is likely to be one of the core aims of physiological research in the 21st century. This article, the second in a four-part series, looks at the main types of dementia and explores emerging theories about how the condition develops. These theories are improving our understanding of the neurodegeneration that characterises the most common forms of dementia, and will help improve care for those living with dementia.

Exploring the causal role of immune cells in vascular dementia: A bidirectional mendelian randomization study.

BACKGROUND: The aim of this study was to explore the causal association between immune cells and VaD based on a two-sample bidirectional Mendelian randomization study. METHODS: Bidirectional two-sample MR analyses based on pooled datasets from publicly available genome-wide association studies were performed using inverse variance weighted (IVW), weighted median (WE), and MR-Egger regressions to evaluate the causal relationships between immune cells and vascular dementia. Heterogeneity was assessed using Cochran's Q statistic. The reliability of the MR analysis results was verified by using the MR-PRESSO method for outlier detection, the MR-Egger method for horizontal multivariate analysis, and the leave-one-out method for sensitivity analysis. RESULTS: Specifically, 27 immunophenotypes were associated with VaD pathogenesis, including Sw mem %lymphocyte (P = 0.043), CD38 on CD20- (P = 0.039), CD11c+ monocyte AC (P = 0.024), DC AC (P = 0.002), CCR2 on CD62L+ myeloid DC (P = 0.039), Resting Treg %CD4 (P = 0.042), Activated & resting Treg %CD4+ (P = 0.038), CD28+ CD45RA- CD8br %CD8br (P = 0.047), NK %CD3- lymphocyte (P = 0.042), CD45 on B cell (P = 0.029), FSC-A on NKT (P = 0.033), CD45 on CD33br HLA DR+ CD14- (P = 0.039) were significantly correlated with increased VaD risk. Additionally, four immune phenotypes, namely, CD19 on CD20-, Resting Treg %CD4, Activated & resting Treg %CD4+, and CD11c+ monocyte AC, showed bidirectional effects on VaD. CONCLUSIONS: MR analysis revealed potential causal relationships between certain immune cells and VaD. Our preliminary exploration through immune cell infiltration analysis highlights the significant value of immune cells in VaD. Therefore, this study may provide a new perspective for the prevention and treatment of VaD.

Exploring the common mechanism of vascular dementia and inflammatory bowel disease: a bioinformatics-based study.

Objective: Emerging evidence has shown that gut diseases can regulate the development and function of the immune, metabolic, and nervous systems through dynamic bidirectional communication on the brain-gut axis. However, the specific mechanism of intestinal diseases and vascular dementia (VD) remains unclear. We designed this study especially, to further clarify the connection between VD and inflammatory bowel disease (IBD) from bioinformatics analyses. Methods: We downloaded Gene expression profiles for VD (GSE122063) and IBD (GSE47908, GSE179285) from the Gene Expression Omnibus (GEO) database. Then individual Gene Set Enrichment Analysis (GSEA) was used to confirm the connection between the two diseases respectively. The common differentially expressed genes (coDEGs) were identified, and the STRING database together with Cytoscape software were used to construct protein-protein interaction (PPI) network and core functional modules. We identified the hub genes by using the Cytohubba plugin. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were applied to identify pathways of coDEGs and hub genes. Subsequently, receiver operating characteristic (ROC) analysis was used to identify the diagnostic ability of these hub genes, and a training dataset was used to verify the expression levels of the hub genes. An alternative single-sample gene set enrichment (ssGSEA) algorithm was used to analyze immune cell infiltration between coDEGs and immune cells. Finally, the correlation between hub genes and immune cells was analyzed. Results: We screened 167 coDEGs. The main articles of coDEGs enrichment analysis focused on immune function. 8 shared hub genes were identified, including PTPRC, ITGB2, CYBB, IL1B, TLR2, CASP1, IL10RA, and BTK. The functional categories of hub genes enrichment analysis were mainly involved in the regulation of immune function and neuroinflammatory response. Compared to the healthy controls, abnormal infiltration of immune cells was found in VD and IBD. We also found the correlation between 8 shared hub genes and immune cells. Conclusions: This study suggests that IBD may be a new risk factor for VD. The 8 hub genes may predict the IBD complicated with VD. Immune-related coDEGS may be related to their association, which requires further research to prove.

Agonistic autoantibodies to the α(1) -adrenergic receptor and the ß(2) -adrenergic receptor in Alzheimer's and vascular dementia.

Although primary causes of Alzheimer's and vascular dementia are unknown, the importance of preceding vascular lesions is widely accepted. Furthermore, there is strong evidence for the involvement of autoimmune mechanisms. Here, we report the presence of agonistic autoantibodies directed at adrenergic receptors in the circulation of patients with mild to moderate Alzheimer's and vascular dementia. In 59% of these patients, agonistic autoantibodies against the α(1) -adrenergic receptor and the ß(2) -adrenergic receptor were identified. The majority of positive patients (66%) contained both types of autoantibodies in combination. In a control group of patients with neurological impairments others than Alzheimer's and vascular dementia, only 17% were found to harbour these autoantibodies. The autoantibodies to the α(1) -adrenergic receptor interacted preferably with the extracellular loop1 of the receptor. They were further studied in IgG preparations from the column regenerate of a patient who underwent immunoadsorption. The α(1) -adrenergic receptor autoantibodies specifically bound to the extracellular loop1 peptide of the receptor with an apparent EC(50) value of 30 nm. They mobilized intracellular calcium in a clonal cell line expressing the human form of the α(1) -adrenergic receptor. Our data support the notion that autoimmune mechanisms play a significant role in the pathogenesis of Alzheimer's and vascular dementia. We suggest that agonistic autoantibodies to the α(1) -adrenergic and the ß(2) -adrenergic receptor may contribute to vascular lesions and increased plaque formation.

Novel domain-selective ACE-inhibiting activity of synthetic growth hormone secretagogues.

The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain ß-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aßin vitro, reducing its ability to aggregate in fibrillar Aß. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of ß-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.

Decreased Levels of Serum IL-34 Associated with Cognitive Impairment in Vascular Dementia.

OBJECTIVE: Interleukin- (IL-) 34 is a new type of cytokine with neuroprotective effects discovered in recent years. However, the relationship between IL-34 and vascular dementia (VaD) has not yet been elucidated. The purpose of this study is to determine whether IL-34 is involved in cognitive impairment of VaD. METHODS: From January 2017 to December 2020, 84 VaD patients and 60 healthy controls who attended Qingpu Branch of Zhongshan Hospital were prospectively included in the study. Once included in the study, demographic features of all research subjects are collected. They include age, gender, education, white blood cells (WBC), neutrophil, lymphocyte, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), triglycerides (TG), and total cholesterol (TC). Meanwhile, the Montreal Cognitive Assessment (MoCA) scale was used to assess the cognitive function of participants. The serum IL-34 level was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: There was no significant difference between the demographic features of VaD patients and healthy controls (p > 0.05). However, the serum IL-34 levels of VaD patients and healthy controls are 27.6 ± 3.9 pg/ml and 41.8 ± 6.0 pg/ml, respectively, and there is a significant statistical difference between them (p < 0.001). The results of bivariate correlation analysis showed that serum IL-34 levels were significantly positively correlated with MoCA scores (r = 0.371, p = 0.023). Further regression analysis showed that IL-34 was still correlated with MoCA after adjusting for demographic features (ß = 0.276, p = 0038). CONCLUSIONS: Serum IL-34 levels in VaD patients were significantly reduced, which may be an independent predictor of cognitive impairment in VaD patients.

Endothelial Immune Activation by Medin: Potential Role in Cerebrovascular Disease and Reversal by Monosialoganglioside-Containing Nanoliposomes.

Background The function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell (EC) immune activation and neuroinflammation. We also tested whether monosialoganglioside-containing nanoliposomes could reverse medin's adverse effects. Methods and Results Cerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors. ECs were exposed to physiologic dose of medin (5 µmol/L), and viability and immune activation (interleukin-8, interleukin-6, intercellular adhesion molecule-1, and plasminogen activator inhibitor-1) were measured without or with monosialoganglioside-containing nanoliposomes (300 µg/mL). Astrocytes were exposed to vehicle, medin, medin-treated ECs, or their conditioned media, and interleukin-8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced EC immune activation (increased interleukin-8, interleukin-6, intercellular adhesion molecule-1, and plasminogen activator inhibitor-1) and reduced EC viability, which were reversed by monosialoganglioside-containing nanoliposomes. Interleukin-8 production was augmented when astrocytes were exposed to medin-treated ECs or their conditioned media. Conclusions Cerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside-containing nanoliposomes. Medin is a candidate novel risk factor for aging-related cerebrovascular disease and VaD.

Novel isolated cerebral ALlambda amyloid angiopathy with widespread subcortical distribution and leukoencephalopathy due to atypical monoclonal plasma cell proliferation, and terminal systemic gammopathy.

Neuropathologic and biochemical findings in a 34-year-old man whose disease began 2 years before death appearing as chronic progressive encephalitis and culminated in mutism are reported. Cerebrospinal fluid and serum of the patient showed a brain-restricted monoclonal lambda-light chain apparently produced by a small monoclonal immunoglobulin Glambda plasma cell population. In the preterminal stage, there was a systemic monoclonal gammopathy, the source of which could not be identified. At autopsy, there was extensive amyloid deposition in most vessels throughout the cerebral and cerebellar white matter, basal ganglia, and thalamus and diffuse leukoencephalopathy; cerebral and cerebellar cortices, other portions of the CNS, and non-CNS tissues were spared. Partial amino acid sequence analysis demonstrated that the amyloidogenic protein originated from immunoglobulin lambda-light chains which were produced by monoclonal plasma cells. There are 2 similar cases reported in the literature. The distribution of ALlambda deposits in these 3 cases indicates that widespread subcortical vascular amyloidosis with leukoencephalopathy is a novel clinicopathologic entity distinguished from other cerebral diseases with local amyloid light chain deposition, including amyloidoma, leptomeningeal vascular amyloidosis, solitary intracerebral plasmacytoma, primary intracerebral lymphoma with plasmacytic differentiation, and multiple sclerosis with demyelination-associated amyloid deposition.

Evaluation of Peripheral Immune Dysregulation in Alzheimer's Disease and Vascular Dementia.

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.

Antibodies against GM1 in demented patients.

The aim of this study was to evaluate the levels of anti-GM1 in demented patients, correlating them with the type and severity of dementia as well as with the eventually coexistent polyneuropathy. Anti-GM1 concentrations were measured in the sera of 33 demented patients with a male-to-female ratio of 1:2.7 (the mean age was 69.7 years for males and 70.1 years for females). Eighty-two percent of the patients revealed increased values of anti-GM1, but only 18.2% demonstrated polyneuropathies. Fifty-nine percent of the patients suffered from vascular dementia. The most severely demented patients demonstrated a Mini-Mental State Examination score of 5 to 23 out of 30 and revealed the most increased levels of anti-GM1 (>40 EU/mL). The findings of this study are indicative of a possible correlation between the levels of anti-GM1 and the severity of dementia, mainly of the vascular type.

Cytokines in Alzheimer's disease and vascular dementia.

The levels of interleukin 1beta, interleukin 6, and interleukin 10 were elevated in the serum of patients with dementia. No statistically significant correlation was recorded in the interleukin levels among patients with Alzheimer's disease and vascular dementia. Also, no significant correlation was observed in the interleukin levels in the serum and the severity of dementia. However, a significant correlation was found between IL-6 and tumor necrosis factor-alpha (TNF-alpha) levels and age. The levels of IL-1beta and IL-6 were positively correlated with hypertension, and IL-2 levels were negatively correlated. No correlation was found between depressive symptoms and levels of cytokines in the serum.

IL-10 targets Th1/Th2 balance in vascular dementia.

OBJECTIVE: The pathogenesis of vascular dementia (VD) is not fully elucidated. Th1/Th2 balance may change in VD, leading to numerous inflammatory cytokines secretion. Interleukin-10 (IL-10) is an immune suppressor, while its function in VD and correlation with Th1/Th2 balance are still unclear. MATERIALS AND METHODS: The healthy male rats were randomly divided into three groups, including sham group, model group, and IL-10 group. Th1 and Th2 cytokines IL-2, IL-4, IL-6, and tumor necrosis factor-α (TNF-α) expressions in the serum were tested by enzyme-linked immunosorbent assay (ELISA). IL-10 expression in brain tissue and peripheral blood was detected by Real-Time PCR and ELISA. The correlation relationship between IL-10 and T helper cells 1/2 (Th1/Th2) cytokines was analyzed. Hippocampus cell apoptosis was determined by caspase 3 activity kit. Nuclear transcription factor 2 κB (NF-κB) expression was evaluated by Western blot. RESULTS: IL-10 levels were decreased, caspase 3 activity was enhanced, NF-κB expression was declined, IL-2 and TNF-α secretion were up-regulated, while IL-4 and IL-6 secretion were reduced in hippocampus tissue and peripheral blood from VD model rat compared to sham group (p<0.05). IL-10 significantly attenuated caspase 3 activity, up-regulated NF-κB expression, reduced IL-2 and TNF-α secretion, and enhanced IL-4 and IL-6 secretion (p<0.05). IL-10 was negatively correlated with Th1 cytokines and positively correlated with Th2 cytokines (p<0.05). CONCLUSIONS: IL-10 expression declined in VD and participated in regulating Th1/Th2 balance. IL-10 participated in VD incidence and development through regulating cell apoptosis and NF-κB expression.

Effects of IL-1ß on hippocampus cell apoptosis and learning ability of vascular dementia rats.

OBJECTIVE: Vascular dementia (VD) is a type of memory, cognition, and behavior disorder caused by ischemic stroke or hemorrhagic stroke. It is a common pathogenesis of dementia that is only second to Alzheimer's disease. Inflammation plays a key role in VD. Interleukin-1ß (IL-1ß) is a kind of pro-inflammatory cytokine, while its mechanism in VD occurrence and development is still unclear. MATERIALS AND METHODS: The healthy male rats were randomly divided into three groups, including sham group, VD model group (established by bilateral common carotid artery ligation), and IL-1ß group (treated by IL-1ß monoclonal antibody intracerebroventricular injection on based on model group). Rat learning ability was evaluated by Morris water maze assay. IL-1ß expression in brain tissue and peripheral blood was examined by using Real Time-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Hippocampus apoptosis was detected by caspase 3 activity detection kit. B-cell lymphoma-2 (Bcl-2) and p38 mitogen-activated protein kinase (MAPK) protein levels were assessed by Western blot assay. RESULTS: IL-1ß expression was increased, caspase 3 activity was enhanced, Bcl-2 level was declined, and p-P38 phosphorylation was elevated in brain tissue and peripheral blood from VD model group compared to sham group (p<0.05). IL-1ß monoclonal antibody significantly reduced IL-1ß expression, improved learning ability, attenuated caspase 3 activity, increased Bcl-2 level, and declined p-P38 expression in VD rats compared to model group (p<0.05). CONCLUSIONS: IL-1ß can delay VD occurrence and development through the P38-MAPK signaling pathway to regulate cell apoptosis and improve learning ability.

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium.

Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted "lipid-coated microbubble" [LCM]/"nanoparticle-derived" [ND] (or LCM/ND) nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly class B type I), or SR-BI, making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such film-stabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia.

Some cytokines have been involved in the pathogenesis of late onset Alzheimer's disease (LOAD). A possible increase in plasma cytokines levels has been reported in LOAD and vascular dementia (VD), but the results of previous studies are conflicting. We evaluated the plasma levels of IL-6, TNF-alpha, IL-1beta, and IL-10 in four groups of older individuals: 60 patients with LOAD, 80 patients with VD, 40 subjects with cerebrovascular disease but without dementia (CDND), and 42 controls (C). By analysis of covariance (adjustment for age, gender, coronary heart disease, diabetes, hypertension, smoking, and alcohol consumption) we found that: *IL-1beta was higher in VD, LOAD, and CDND compared with controls (p<0.005). *TNF-alpha was higher in VD and LOAD compared to C (p<0.05), and in VD compared to LOAD (p<0.03). *IL-6 was higher in VD compared with LOAD (p<0.03). No differences in IL-10 values were found (Kruskal-Wallis, Asymp. Sig. 0.14). By logistic regression analysis, we demonstrated that high levels (defined as above the median) of IL-1beta and TNF-alpha, but not of IL-6, were associated with increased likelihood of having VD and LOAD compared to C, while high IL-6 levels were associated with a increased probability of having VD, compared with LOAD. Our study support the notion of a low-grade systemic inflammation in older patients with LOAD or VD, characterized by an increase in plasma IL-1beta and TNF-alpha levels. The high IL-6 levels found in VD might be not a specific finding, as it might come from several conditions including atherosclerosis and related vascular risk factors, comorbidity, and frailty.

Two cases of Cryptococcus meningitis presenting as leukoencephalopathy prior to amphotericin therapy.

We report two patients with cryptococcal meningitis and combined immunodeficiency with unusual magnetic resonance imaging findings of gadolinium-enhancing white matter lesions, quite different from cryptococcomas and seen prior to anti-fungal treatment. The lesions resembled demyelinating plaques and resolved. In one patient, biopsy of the lesion revealed cryptococci, non-specific inflammatory changes and occasional small perivascular lymphocyte collections, but not demyelination. Leukoencephalopathy, previously rarely observed in Cryptococcal meningitis, was thought to be the sequelae of amphotericin toxicity. Our cases demonstrate cryptococcal meningitis may present with leukoencephalopathy, possibly as an immune response to the organism.

Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID).

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent co-morbidity with AD. Despite its prevalence, little is known about the molecular mechanisms underlying the cognitive dysfunction resulting from cerebrovascular disease. Astrocytic end-feet almost completely surround intraparenchymal blood vessels in the brain and express a variety of channels and markers indicative of their specialized functions in the maintenance of ionic and osmotic homeostasis and gliovascular signaling. These functions are mediated by end-foot enrichment of the aquaporin 4 water channel (AQP4), the inward rectifying potassium channel Kir4.1 and the calcium-dependent potassium channel MaxiK. Using our hyperhomocysteinemia (HHcy) model of VCID we examined the time-course of astrocytic end-foot changes along with cognitive and neuroinflammatory outcomes. We found that there were significant astrocytic end-foot disruptions in the HHcy model. AQP4 becomes dislocalized from the end-feet, there is a loss of Kir4.1 and MaxiK protein expression, as well as a loss of the Dp71 protein known to anchor the Kir4.1, MaxiK and AQP4 channels to the end-foot membrane. Neuroinflammation occurs prior to the astrocytic changes, while cognitive impairment continues to decline with the exacerbation of the astrocytic changes. We have previously reported similar astrocytic changes in models of cerebral amyloid angiopathy (CAA) and therefore, we believe astrocytic end-foot disruption could represent a common cellular mechanism of VCID and may be a target for therapeutic development.

Alterations in the Peripheral Immune System in Dementia.

Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer's disease (AD; n = 60), vascular dementia (VaD; n = 20), and frontotemporal dementia (FTD; n = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology.

Consensus statement for diagnosis of subcortical small vessel disease.

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger's disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.