Serum Exosomal miRNA-125b and miRNA-451a are Potential Diagnostic Biomarker for Alzheimer’s Diseases

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

ObjectiveTo investigate the differential expression of exosomal miRNAs in the bone marrow tissue of Modified Qing’ E Formula (MQEF) on steroid-induced ischemic necrosis of the femoral head (INFH) model.MethodsSteroid hormones were used to establish the INFH model and treated with MQEF. After successful modeling, femoral tissue exosomes were isolated for miRNA sequencing to obtain femoral tissue exosomal differential miRNAs. By GO analysis and KEGG analysis of the differential genes in both groups, the major exosomal miRNAs of MQEF exerting anti-INFH as well as the major signaling pathways were identified. Next, a quantitative metabolomic validation of MQEF with broad targeting was performed to obtain the main active components of MQEF and to perform biological analysis and signaling pathway prediction of the active components by network pharmacology. Finally, the sequencing results were validated by using RT-qPCR. The results of miRNA sequencing were verified by double examination of network pharmacology and RT-qPCR, and the exosomal miRNAs regulated by the anti-INFH effect of MQEF and the specific signaling pathway of the effect were clarified.ResultsA total of 65,389 target genes were predicted in the exosomes of two groups of mice, and 18 significant differentially expressed miRNAs were obtained, of which 14 were up-regulated and 4 down-regulated. GO enrichment analysis showed that these predicted target genes were enriched in 12371 biological processes, 1727 cell components, and 4112 molecular functions. KEGG analysis showed that the predicted miRNA target genes were annotated to 342 signal pathways, in which the highly enriched pathways closely related to bone metabolism were PI3K-Akt signal pathway, MAPK signal pathway, and Wnt signal pathway. The most significantly up-regulated miRNAs were miR-185-3p and miR-1b-5p and the most significantly down-regulated miRNAs were miR-129b-5p and miR-223-5p, of which the targeted genes were closely related to the PI3K-Akt signal pathway. MQEF aqueous decoction extract targeted metabolomics quantitatively combined with network pharmacology predicted targets also closely related to PI3K-Akt signaling pathway. Real-time quantitative PCR validation showed that miR-185-3p was up-regulated 7.2-fold and miR-129b-5p was down-regulated 2.2-fold in the treatment group, and the difference was significant (P < 0.05).ConclusionsMQEF can regulate exosomal miRNA expression in steroid-induced INFH models, miR-185-3p or miR-129b-5p/PI3K-Akt signal axis may be part of the mechanism of MQEF against steroid-induced INFH.

High Activities of BACE1 in Brains with Mild Cognitive Impairment

BackgroundAlzheimer’s disease (AD) has high a prevalence rate, high medical costs, and care difficulties, and has become a serious social and economic problem in our aging society. So far, there has not been a reliable and objective diagnostic criteria for AD found. In recent years, there have been many domestic and foreign studies on the biological markers of cerebrospinal fluid in the patients with AD, and high levels of the T-tau, P-tau found in cerebrospinal fluid (CSF) is at this point an indisputable fact. However, the relationship between these markers and the severity of dementia, as well as the development of the disease, should be further studied.ObjectiveCompare the CSF level of total tau (T-tau) and phosphorylated tau at threonine 231 (P-tau231) between patients with moderate to severe Alzheimer’s disease (AD) and those with vascular dementia (VD) at baseline, and 6 month follow-up. Observe the differences between patients with AD and control group, as well as the changes as the disease develops.MethodsThere were 11 patients with moderate AD (10 ≤ MMSE ≤ 20), 10 patients with severe AD (MMSE ≤ 9), and 7 age-matched patients with severe VD at baseline, among which 7 AD patients and 6 VD patients completed the 6 months follow-up. CSF levels of T-tau, P-tau231 were measured with sandwich ELISA.ResultAt baseline, the concentrations of the CSF level of T-tau were 470.08 (263.58) pg/mL in the AD group and 208.76 (42.24) pg/mL in the VD group. This difference was statistically significant (Z= -3.369, p <0.001). The concentrations of CSF level of P-tau231 were 90.94 (49.86) pg/mL in the AD group and 42.96 (13.10) pg/mL in the VD group. This difference was also statistically significant (Z = -3.237, p <0.001). Compared to patients with severe VD, the concentration of CSF T-tau in patients with severe AD was significantly higher (Z= -2.830, p = 0.005), as well as the concentration of CSF P-tau231 (Z = -2.392, p = 0.017). The concentration of CSF P-tau231 in the patients with moderate AD was significantly higher than that in the patients with severe VD (Z = -2.605, p = 0.009). At the 6 months follow-up, there were no statistically significant differences in the changes of CSF T-tau and CSF P-tau231 concentrations between the AD group and VD group.ConclusionThe CSF level of T-tau and P-tau231 in the AD patients was significantly higher than that in the VD patients. The concentration of CSF P-tau231 in the moderate AD patients was significantly higher than that in the patients with severe AD. During the 6 months follow-up, the changes of the CSF concentrations of T-tau and P-tau231 between AD group and VD group were not statistically significant.

Neuropsychological assessment and cortisol levels in biofluids from early Alzheimer's disease patients.

Alzheimer's disease (AD) is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly. Considering AD to be an epidemic, an increase from the current 50 million to more than 150 million patients is expected by the year 2050. AD is characterized by a slow, progressive and asymptomatic onset; making it difficult to decipher the precise etiology. It is well established that AD presents two characteristic features, extracellular β-amyloid plaques and intracellular tau tangles, that eventually lead to the impairment of cognitive functions. Unfortunately, AD symptomatology shares many similarities with other dementias once is present, which makes it difficult an accurate premortem diagnosis. Although AD is mainly considered an aging-related condition that affects cognitive function, several cardio- and cerebrovascular comorbidities such as hypertension or diabetes are also risk factors for cognitive impairment. Accordingly, brain vascular-associated alterations underlie many pathophysiological mechanisms of AD. We have recently reviewed the latest evidence supporting the detrimental role of vascular and angiogenic alterations during AD (Custodia et al., 2022). Remarkably, cerebral blood-brain barrier (BBB) leakage and microbleeds are associated with cognitive decline in patients with mild cognitive impairment (MCI) and early AD. Accordingly, the two-hit vascular hypothesis points at initial damage in cerebral vasculature (hit one) that eventually induces the accumulation of β-amyloid (Aβ) in the brain (hit two; Zlokovic, 2005). CD34+ bone marrow-derived progenitor cells (BMPCs) define a group of stem and progenitor cell populations released by the bone marrow that covers different subpopulations of cells from the hematopoietic linage, including endothelial progenitor cells (EPCs). EPCs exhibit characteristics of both endothelial and stem cells, and, accordingly, proangiogenic early EPCs expressing both CD34 and CD133 (a progenitor surface marker) can be distinguished from late EPCs additionally expressing KDR and/or CD146 (endothelial markers), which participate in the process of angiogenesis and vasculogenesis (Figure 1). Therefore, EPCs participate in angiogenesis and the maintenance of the endothelium by acting as a cellular reservoir for the replacement of dysfunctional endothelial cells, or by the secretion of angiogenic growth factors.Figure 1: Beneficial roles of CD34+ BMPCs following CNS injury.CD34+ BMPCs and the EPCs subtypes, early and late, can promote both angiogenesis and vasculogenesis following CNS injury by specializing in endothelial cells, and/or indirectly by secreting free and exosome-enveloped growth factors. G-CSF is a glycoprotein that acts in the bone marrow to mobilize both EPCs and CD34+ BMPCs after damage. BMPCs: Bone marrow progenitor cells; CNS: central nervous system; EPCs: endothelial progenitor cells; G-CSF: granulocyte colony-stimulating factor. Created with BioRender.com.Given that both dysfunctional angiogenesis and compromised BBB integrity seem critical in the onset and/or progression of AD, CD34+ progenitor cells, primarily EPCs, appear as potential targets for the early diagnosis and/or treatment of the disease. In this way, early and late EPCs would work synergistically: early EPCs reach the site of injury due to the high concentration of angiogenic factors and inflammatory cytokines, from which they paracrinally release different factors promoting angiogenesis and recruiting late EPCs, which either restore the endothelium or form new vessels guided by the early EPCs. Here, we discuss recent work and ongoing human clinical trials testing the feasibility of CD34+ BMPCs and EPCs as early biomarkers of AD and pharmacological targets for future treatments. Association of circulating levels of CD34+ BMPCs and cognitive decline in healthy and MCI subjects: Several cross-sectional studies have shown that the number of circulating CD34+ BMPCs decreases with age, and this may impact cognition. In this regard, a longitudinal study regarding cognition and CD34+ BMPCs levels reported that older healthy subjects had lower levels of CD34+ BMPCs than younger counterparts at baseline measurements (Hajjar et al., 2016). Moreover, this investigation revealed that subjects with higher baseline levels of several subgroups of CD34+ BMPCs such as early and late EPCs, and CD34+/KDR+ cells, among others, had better executive-derived and working memory scores over 4 years of follow-up (Hajjar et al., 2016). Recently, a large transverse study has shown the association between CD34+ BMPCs and different memory-related tests in cognitively normal subjects with coronary artery disease (Moazzami et al., 2020). Notably, circulating numbers of late EPCs were positively correlated with a better performance in tasks assessing visual, logical, and verbal immediate/delayed memory. Therefore, the amount of circulating CD34+ BMPCs subtypes appears to be negatively correlated to the cognitive decline of both healthy subjects and patients with vascular-associated conditions. Although more longitudinal clinical studies are needed to fully confirm the harmful effect of low levels of CD34+ BMPCs on the cognitive state, and other factors may be also taking part in this cognitive decline, it is still plausible that larger amounts of circulating endothelial progenitors exert a protective effect, probably by the maintenance of vascular endothelium integrity. MCI often precedes clinical symptoms of AD, and MCI patients show an increased risk of developing dementia in the future. Thus, it is very interesting to study CD34+ BMPCs/EPCs levels in patients with MCI in order to test whether such levels can be used as potential non-invasive diagnostic biomarkers to detect cognitive decline or its progression from MCI to dementia. Some studies have observed a decrease in CD34+ BMPCs and EPCs populations from MCI patients (Nation et al., 2018; Callahan et al., 2020). In this sense, MCI patients with lower levels of circulating CD34+ BMPCs and both subtypes of EPCs exhibited worse scores in memory tests and reduced cortical thickness compared to control subjects (Nation et al., 2018). Considering the angiogenesis ratio (pro-angiogenic/non-angiogenic BMPCs, including early and late EPCs), Callahan et al. (2020) showed a positive association between angiogenesis ratio and white matter hyperintensities, but not with global cerebral blood flow, hippocampal volume, or accumulation of tau and Aβ. By contrast, measurements in an older cohort of MCI patients did not show significant changes in CD34+, early EPCs, and late EPCs circulating levels compared to control subjects (Breining et al., 2016). This discrepancy may highlight that aging decreases CD34+ BMPCs to such a reduced level that is no longer different in controls compared to MCI. In summary, it seems that the reduction in CD34+ BMPCs is directly related to vascular dysfunction, increasing brain white matter microlesions and impairing cognition in MCI patients. Association of circulating levels of CD34+ BMPCs and AD: Several studies have been performed in order to determine the relationship between CD34+ BMPCs/EPCs circulating levels and the progression of AD (Maler et al., 2006; Lee et al., 2009; Stellos et al., 2010; Bigalke et al., 2011; Kong et al., 2011; Breining et al., 2016; Callahan et al., 2020; Haiyuan et al., 2020). In this way, AD patients in the early symptomatic phase already showed lower levels of CD34+ and CD34+/KDR+ cells compared to their control counterparts (Maler et al., 2006; Haiyuan et al., 2020). Notably, CD34+ BMPCs counts have negatively correlated with levels of Aβ1–42 in cerebrospinal fluid and the Aβ ratio 42/40, two well-known biomarkers for AD, as well as with age, only in the early AD group (Maler et al., 2006). Furthermore, the homing capacity of EPCs from early AD patients was already impaired (Haiyuan et al., 2020). Overall, it is becoming clear that dysfunctional CD34+ BMPCs are related to a reduced ability to repair brain endothelial cells, which appears to mediate neurotoxicity by affecting the BBB permeability. On the other hand, different outcomes were described in studies assessing the number of progenitor cells during AD progression. Specifically, lower counts of CD34+ BMPCs and EPCs have been observed in moderate and severe AD patients compared to both early AD stage (Haiyuan et al., 2020) and control subjects (Lee et al., 2009; Kong et al., 2011; Haiyuan et al., 2020). Such studies also revealed that homing and adhesion features of EPCs from AD patients were impaired (Haiyuan et al., 2020), as well as EPCs levels were inversely correlated with the mini-mental state exam (MMSE) score (Lee et al., 2009; Stellos et al., 2010; Kong et al., 2011). Furthermore, moderate to severe AD patients displayed a reduced flow velocity of the middle cerebral artery (Kong et al., 2011). In contrast, other studies reported higher levels of CD34+ BMPCs and EPCs compared to controls (Stellos et al., 2010; Bigalke et al., 2011), or even no changes (Breining et al., 2016). Intriguingly, the work from Stellos and colleagues reported an increase in both CD34+ BMPCs and early EPCs counting when comparing moderate to severe AD patients versus control subjects; however, within the AD group, there was an inverse correlation between CD34+ BMPCs and early EPCs counting and the MMSE score. Although these results seem contrary to each other, it is noteworthy that most AD patients from this study (Stellos et al., 2010) were treated with cholinesterase inhibitor; a drug involved in EPCs proliferation. Therefore, this fact may bias the results and it could explain why cell counting in the AD group was higher than in controls, but they were inversely correlated with MMSE scores. The other study that showed increased levels of CD34+ BMPCs/EPCs (Bigalke et al., 2011) only measured the numbers of CD34+ BMPCs in early to moderate AD compared to controls, with no information regarding cholinesterase inhibitor treatment. In summary, most of the studies in later AD stages support the studies performed on MCI and early AD stages. Therefore, AD-mediated loss of CD34+ BMPCs/EPCs, as well as loss of EPCs-intrinsic features, are likely present in AD patients and may constitute novel diagnostic and therapeutic targets. Potential therapy with granulocyte colony-stimulating factor (G-CSF) in AD: The G-CSF is a glycoprotein secreted by endothelial and immune cells that acts as a hematopoietic growth factor (Figure 1). Among other beneficial mechanisms following vascular injury, the G-CSF can promote angiogenesis by mobilizing EPCs (Figure 1). Therefore, G-CSF may be a potential target to enhance vascular repair in AD patients. Indeed, it has been recently shown that a G-CSF treatment improved memory as well as reduced blood levels of amyloid and tau in mild to moderate patients of AD (Potter et al., 2021). Based on these achievements, it is currently conducting a phase2b clinical trial in order to evaluate the long-term treatment of G-CSF in AD patients (NCT04902703; ClinicalTrials.gov). It would be interesting to look at CD34+ BMPCs and EPCs levels from those clinical trials in order to elucidate whether such potential benefits promoted by G-CSF therapy are totally or partially mediated by increasing CD34+ BMPCs/EPCs mobilization. Future challenges: The body of evidence supporting a vascular component underlying AD onset and/or progression is growing. However, further studies are mandatory to elucidate whether such vascular component triggers AD, is a consequence of AD, or both. Moreover, longitudinal studies are needed to confirm the relationship between CD34+ BMPCs/EPCs levels and AD progression. Given that vascular-related diseases may influence the amount of circulating progenitor cells, especially in AD patients, comorbidities present in those subjects deserve special attention when interpreting the results. Likewise, pharmacological treatments, such as a cholinesterase inhibitor, may bias the results from studies giving uncorrected information. Despite the promising results in animal models of AD, the number of published results and clinical trials regarding the direct application of EPCs as a potential therapy in AD patients is absent. This is remarkable when there is compelling evidence that supports the role of endothelial dysfunction in the onset and progression of AD, and the potential of EPCs as a diagnostic biomarker and/or therapeutic target (Custodia et al., 2022). However, we were unable to find published data or ongoing clinical trials in humans using the application of EPCs to treat AD; as already seen in a stroke clinical trial (NCT01468064). Moreover, several recent studies have highlighted the beneficial role of EPCs secretome/exosomes by protecting and repairing the BBB following damage without using a cell-based therapy. So, clinical trials based on EPCs-derived secretome/exosomes might be a safer and more promising approach in AD research. Finally, only the GCSF-based treatment is being tested in AD patients at later stages, with modest but promising results. Given that endothelium-related impairments are already seen in MCI patients, it would be really interesting to test this GCSF-based treatment in those subjects in order to increase the benefits and protect against the progression to AD. This work was partially supported by grants from the Xunta de Galicia (IN607A2018/3 to TS, IN607D 2020/09 to TS, IN606A-2021/015 to AC; IN606B-2021/010 to DRS), and Science Ministry of Spain (RTI2018-102165-B-I00 to TS, RTC2019-007373-1 to TS). Furthermore, this work was also supported by grants from the INTERREG Atlantic Area (EAPA_791/2018_ NEUROATLANTIC project to TS), INTER-REG V A España Portugal (POCTEP) (0624_2IQBIONEURO_6_E to TS), and the European Regional Development Fund (ERDF). Moreover, DRS (CD21/00166) and TS (CPII17/00027) are recipients of research contracts from the Sara Borrell and Miguel Servet Programs, respectively, from the Instituto de Salud Carlos III. Availability of data and materials:All data generated or analyzed during this study are included in this published article and its supplementary information files. Open peer reviewers:Yali Jia, Beijing Institute of Radiation Medicine, China; Rongcan Luo, Kunming Institute of Zoology Chinese Academy of Sciences, China. Additional file:Open peer review reports 1 and 2.P-Reviewers: Jia Y, Luo R; C-Editors: Zhao M, Liu WJ, Wang Lu; T-Editor: Jia Y

Objective: To explore the relationship between apolipoprotein E (ApoE) gene polymorphism and hydrogen proton magnetic resonance spectroscopy ((1)H-MRS) in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment(aMCI). Methods: The cognitive function of 35 AD patients (AD group), 35 aMCI patients (aMCI group) and 36 normal controls (NC group) were evaluated by neuropsychological scales, including Mini-mental State Examination (MMSE) and Cambridge Cognitive Examination-Chinese version (CAMCOG-C). The genotypes of ApoE were analyzed by high-resolution melting assay. Brain regional metabolites were measured via (1)H-MRS technique with the regions of interest (ROIs) located in the left frontal lobe and left hippocampus. Results: The CAMCOG-C (NC group 94.00 (8.50);aMCI group 86.00(8.00);AD group 61.00(18.0)) and MMSE (NC group 29.00 (2.00);aMCI group 26.00(2.00);AD group 13.00(9.5)) scores in AD and aMCI group were significantly lower in comparison with that in NC group (P<0.05). There was multi-domain cognitive impairment both in AD and aMCI. The CAMCOG-C (ε4 carriers 76.00(28.00);no-ε4 carriers 89.00 (17.00)) and MMSE (ε4 carriers 23.00(16.00);no-ε4 carriers (27.00 (6.00))scores in ε4 carriers were significantly lower than those in no-ε4 carriers (P<0.05). The AD and aMCI groups showed decreased NAA/Cr ratio in the left hippocampus as well as elevated Cho/Cr ratio and MI/Cr in the left frontal lobe compared to the NC group (P<0.05). This change was even more pronounced in AD group when compared to aMCI group. The NAA/Cr ratio and Cho/Cr ratio in the left hippocampus in ε4 carriers were lower, the MI/Cr ratio in left frontal lobe in ε4 carriers was higher (P<0.05). Conclusions: ApoE gene polymorphism affects the alteration of (1)H-MRS in AD and aMCI patients. The combination of ApoE gene polymorphism and (1)H-MRS may be more useful to differentiate and diagnose AD and aMCI early.

Hypoperfusion, Mitochondria Failure, Oxidative Stress, and Alzheimer Disease

The amyloid precursor protein (APP) and its proteolytic product amyloid beta (Abeta) are associated with both familial and sporadic forms of Alzheimer disease (AD). Aberrant expression and function of microRNAs has been observed in AD. Here, we show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. Using site-directed mutagenesis, a microRNA responsive element (RE) for miR-101 was identified in the 3'-untranslated region (UTR) of APP. The inhibition of endogenous miR-101 increased APP levels, whereas lentiviral-mediated miR-101 overexpression significantly reduced APP and Abeta load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1beta (IL-lbeta). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of Abeta, suggesting a possible role for miR-101 in neuropathological conditions.

To examine whether emotional factor influences the depression onset in Alzheimer's disease (AD). Twenty mild AD patients conforming to the of DSM-IV criteria with a clinical dementia rating score of 1.0 were divided into 2 groups: 11 patients without depression (AD group), and 9 patients with depression confirming to the National Institute of Mental Health-dAD criteria with a Cornell scale for depression in dementia score>12 (dAD group), without significant differences in age, gender, educational level, onset duration, and MMSE scores between these 2 groups. Ten age-and gender ratio-matched healthy elderly subjects were used as controls. Emotion Stroop task was performed to these 3 groups: emotion Stroop task images were presented with colored positive or negative emotion words (such as HAPPY or SUICIDE, etc.) at the left part of the image to induce emotional responses and with pure color at the right part of the image. The subjects were asked to press the right button when the ink color of the emotion word was congruent with the color at the right part, and press the left button when the ink color of the word was not congruent with the color at the right part. Neutral words were used in the test of general word task. The reaction time, false ratio, and missing ratio were recorded. Functional MRI (fMRI) was conducted. The behavioral data were analyzed with SPSS 11.0 software and the fMRI data were analyzed with SPM2 software. The emotion Stroop task showed that the reaction time of the normal control group was 848 ms+/-320 ms, significantly shorter than those of the dAD and AD groups (1528 ms+/-302 ms and 1173 ms+/-237 ms respectively, both P<0.01), and the reaction time of the AD group was significantly shorter than that of the dAD group too (P=0.04). The false ratio of the normal control group was 0.5%, significantly lower than those of the AD and dAD groups (7.6% and 9.7% respectively, both P<0.01), and there was not a significant difference between the latter 2 groups (P=0.22). The missing ratio of the normal control group was 0, significantly lower than those of the AD and dAD groups (3.1% and 2.5% respectively, both P<0.01), and there was not a significant difference between the latter 2 groups (P=0.29). The fMRI results showed that the bilateral amygdala, left parietal lobe, and left prefrontal lobe were activated in the normal control group, bilateral parietal lobe were activated in the AD group; and bilateral prefrontal cortex in dAD group. The subtraction of the results of emotion Stroop task and general word task showed the brain function area activation images as follows simple emotion factors activated the right amygdala, left parietal lobe, and bilateral prefrontal cortices and occipital lobes in the normal control group; bilateral parietal lobes and left dorsal lateral frontal cortex in the AD group; and bilateral prefrontal cortices in the dAD group; With quite different brain activation pattern, the dAD patients are more susceptible to the influence of emotional factors than AD patients. Impaired emotional neurocircus and emotional reaction may play an important role in the depression onset in AD.

BackgroundTo explore the retinal vascular density changes in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients using optical coherence tomography angiography (OCTA).MethodsWe recruit 62 AD patients, 47 MCI patients, and 49 cognitively healthy controls (HC) in this study. All participants in the study received a comprehensive ophthalmological and neurological evaluation, including global cognitive screening, as well as the Mini-Mental State Examination (MMSE), and completed the following eye examinations: visual acuity (VA), intraocular pressure (IOP), examination with slit-lamp, fundus photography (Version 1.5.0.0, NIDEK CO, LTD) and Optical coherence tomography imaging (software ReVue version 2017.1.0.155, Optovue Inc., Fremont, CA, United States). The visual rating scales for atrophy and white matter lesion in MRI was evaluated for all the patients with AD and MCI.ResultsIn the AD patient group, the superficial vascular density in the superior, inferior and whole retina was 44.64 ± 3.34, 44.65 ± 3.55, and 44.66 ± 3.36, respectively. These values were 44.24 ± 3.15, 43.72 ± 3.16, and 44 ± 3.07, respectively, in the MCI patient group. After multivariate analysis of the generalized linear model, adjustments for the confounding factors of sex, age, hypertension, diabetes and the quality index of OCTA image, the superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group (P < 0.05): 46.94 ± 2.04, 46.67 ± 2.26, and 46.82 ± 2.08, respectively. No difference in the area of the FAZ among the three groups was observed (AD group: 0.34 ± 0.11 mm2; MCI group: 0.36 ± 0.12 mm2; control group: 0.33 ± 0.12 mm2, p > 0.05). The ganglion cell complex (GCC) thickness, inner parafovea thickness, and peripapillary retinal nerve fiber layer (p-RNFL) thickness were associated with the superficial vascular density. We found no significant correlation between the global cognition (MMSE scores) or between the Fazekas score and retinal OCT angiogram flow density.ConclusionThe superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group. Our findings suggest the retinal microvascular dysfunction occurred in MCI and AD.

To characterize the response of adrenocorticotropic hormone (ACTH) and cortisol in the patients with Alzheimer disease (AD) and those with mild cognition impairment (MCI). The AD or MCI patients at our department from July 5, 2007 to August 31, 2009 were enrolled. The levels of 8am serum ACTH and cortisol were measured by chemiluminescence in 54 AD patients, 41 MCI patients and 42 age-matched controls. The serum ACTH values in 3 groups were (16 ± 5), (16 ± 5) and (17 ± 4) ng/L respectively. The serum ACTH values had insignificant changes in 3 groups (P > 0.05). The serum cortisol values were (595 ± 58), (568 ± 70) and (410 ± 81) nmol/L in 3 groups respectively. And the serum cortisol values significantly increased in AD and MCI groups (P < 0.01). The levels of serum cortisol in MCI group were lower than those in AD group. But there was no significant difference (P > 0.05). Through an analysis of rank correlation, the severity of AD had a positive correlation with serum concentration of cortisol (P < 0.05); there was a negative correlation between the serum level of cortisol and the scores of MMSE in AD patients (P < 0.05). There was no significant change of serum level of cortisol for different genders in 3 groups (P > 0.05). The level of serum ACTH has no significant change. A high level of serum cortisol is observed in AD and MCI groups. There is a positive correlation between serum level of cortisol and the severity of AD and a negative correlation between serum level of cortisol and the scores.

The combination of deep learning with whole-brain computational models reveals the low-dimensional representation of neurodegenerative diseases, which emerges from a highly multidimensional brain, providing valuable insight into pathological states' diagnostic, prognosis, and treatment response.

The combination of deep learning with whole-brain computational models reveals the low-dimensional representation of neurodegenerative diseases, which emerges from a highly multidimensional brain, providing valuable insight into pathological states' diagnostic, prognosis, and treatment response.

Background: Lipids and lipoproteins are significantly involved in maintaining structural and functional components of the human brain and neurons, but their role in the development of Alzheimer’s disease (AD) and vascular dementia (VD) remains unclear. Objective: The aim of the present study was to explore the differences in the standard and novel lipid profile parameters in patients with AD and VD, stratified by the degree of cognitive impairment (CI). Methods: Present study included 66 patients with AD, 50 patients with VD, and 60 control subjects. For an evaluation of the global cognitive function the Montreal Cognitive Assessment (MoCA) test was used. In order to distinguish patients with VD from those with AD the Hachinski ischemic score was used. Plasma total cholesterol (TC), high-density lipoprotein -cholesterol (HDL-C), and triglycerides (TG) levels were determined using standard enzymatic colorimetric techniques, whereas the Friedewald formula was used to calculate low-density lipoprotein-cholesterol (LDL-C) levels. The non-traditional lipid indices such as TG/HDL-C, TC/HDL-C, and LDL-C/HDL-C ratio were separately calculated. The differences between the groups were analyzed with the Kruskal Wallis test followed by the Mann-Whitney test or with ANOVA followed by the Tuckey posthoc test. Results: Results of the conducted study have found that the patients in AD group with moderate CI and patients in AD group with severe CI exhibited significantly lower levels of serum TC, TG, LDL-C, VLDL-C, Non-HDL-C, atherogenic index, TG/HDL-C, TC/HDL-C and LDL-C/HDL-C compared to cognitively normal control subjects. Moreover, patients in VD group with severe and moderate CI had significantly lower level of TG compared to control group of subjects. Our results have also shown that patients in AD group with moderate CI had significantly lower level of TC, TG, LDL-C, Non-HDL-C, atherogenic index, TG/HDL-C, TC/HDL-C compared to VD patients with moderate CI. In addition, patients in AD group with severe CI had significantly lower level of TC, LDL-C, Non-HDL-C and TC/HDL-C compared to VD patients with severe CI. Conclusion: The results of this study have shown dysregulation of lipid metabolism in AD and VD patients with different degree of CI. In both moderate and in severe CI, patients with AD had lower levels of majority of standard and novel lipid parameters compared to patients with VD. Further larger prospective studies are required to elucidate the accuracy of standard and novel lipid parameters in the assessment of different degree of CI in AD and VD.