Pathogenesis Of Cognitive Impairment Research Articles

Acupuncture and moxibustion therapy for cognitive impairment: the microbiome-gut-brain axis and its role.

Cognitive impairment poses a significant burden on individuals, families, and society worldwide. Despite the lack of effective treatment strategies, emerging evidence suggests that the microbiome-gut-brain (MGB) axis may play a critical role in the pathogenesis of cognitive impairment. While targeted treatment is not yet comprehensive, recently, acupuncture and moxibustion therapy has participated increasingly in the treatment of degenerative diseases and has achieved a certain therapeutic effect. In this review, the possible mechanisms by which acupuncture and moxibustion therapy may improve cognitive impairment through the MGB axis are reviewed, including regulating gut microbial homeostasis, improving intestinal inflammation mediated by the neuroendocrine-immune system, and enhancing intestinal barrier function. We also discuss common acupoints and corresponding mechanism analysis to provide insights into further exploration of mechanisms that target the MGB axis and thereby intervene in cognitive impairment.

Topological regularization of networks in temporal lobe epilepsy: a structural MRI study.

Patients with temporal lobe epilepsy (TLE) often exhibit neurocognitive disorders; however, we still know very little about the pathogenesis of cognitive impairment in patients with TLE. Therefore, our aim is to detect changes in the structural connectivity networks (SCN) of patients with TLE. Thirty-five patients with TLE were compared with 47 normal controls (NC) matched according to age, gender, handedness, and education level. All subjects underwent thin-slice T1WI scanning of the brain using a 3.0 T MRI. Then, a large-scale structural covariance network was constructed based on the gray matter volume extracted from the structural MRI. Graph theory was then used to determine the topological changes in the structural covariance network of TLE patients. Although small-world networks were retained, the structural covariance network of TLE patients exhibited topological irregularities in regular architecture as evidenced by an increase in the small world properties (p < 0.001), normalized clustering coefficient (p < 0.001), and a decrease in the transfer coefficient (p < 0.001) compared with the NC group. Locally, TLE patients showed a decrease in nodal betweenness and degree in the left lingual gyrus, right middle occipital gyrus and right thalamus compared with the NC group (p < 0.05, uncorrected). The degree of structural networks in both TLE (Temporal Lobe Epilepsy) and control groups was distributed exponentially in truncated power law. In addition, the stability of random faults in the structural covariance network of TLE patients was stronger (p = 0.01), but its fault tolerance was lower (p = 0.03). The objective of this study is to investigate the potential neurobiological mechanisms associated with temporal lobe epilepsy through graph theoretical analysis, and to examine the topological characteristics and robustness of gray matter structural networks at the network level.

Mechanism of cognitiveimpairment induced by d-galactose and l-glutamate through gut-brain interaction in tree shrews.

d-Galactose (d-gal) and l-glutamate (l-glu) impair learning and memory. The mechanism of interaction between the gutmicrobiome and brain remains unclear. In this study, a model of cognitive impairment was induced in tree shrews by intraperitoneal (ip) injection of d-gal (600mg/kg/day), intragastric (ig) administration with l-glu (2000mg/kg/day), and the combination of d-gal (ip, 600mg/kg/day) and l-glu (ig, 2000mg/kg/day). The cognitive function of tree shrews was tested by the Morris water maze method. The expression of Aβ1-42 proteins, the intestinal barrier function proteins occludin and P-glycoprotein (P-gp), and the inflammatory factors NF-κB, TLR2, and IL-18 was determined by immunohistochemistry. The gutmicrobiome was analyzed by 16SrRNA high-throughput sequencing. After administering d-gal and l-glu, the escape latency increased (p<.01), and the times of crossing the platform decreased (p<.01). These changes were greater in the combinedadministration of d-gal and l-glu (p<.01). The expression of Aβ1-42 was higher in the perinuclear region of the cerebral cortex (p<.01) and intestinal cell (p<.05). There was a positive correlation between the cerebral cortex and intestinal tissue. Moreover, the expression of NF-κB, TLR2, IL-18, and P-gp was higher in the intestine (p<.05), while the expression of occludin and the diversity of gut microbes were lower, which altered the biological barrier of intestinal mucosal cells. This study indicated that d-gal and l-glu could induce cognitiveimpairment, increase the expression of Aβ1-42 in the cerebral cortex and intestinal tissue, decrease the gut microbial diversity, and alter theexpression of inflammatory factors in the mucosal intestines. The dysbacteriosis may produce inflammatory cytokines to modulate neurotransmission, causing the pathogenesis of cognitiveimpairment. This study provides a theoretical basis to explore the mechanism of learning and memory impairment through the interaction of microbes in the gut and the brain.

Pathomechanisms of cognitive impairment in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by early postural instability and falls, oculomotor dysfunction (vertical supranuclear gaze palsy), parkinsonism with poor response to levodopa, pseudobulbar palsy, and cognitive impairment. This four-repeat tauopathy is morphologically featured by accumulation of tau protein in neurons and glia causing neuronal loss and gliosis in the extrapyramidal system associated with cortical atrophy and white matter lesions. Cognitive impairment being frequent in PSP and more severe than in multiple system atrophy and Parkinson disease, is dominated by executive dysfunction, with milder difficulties in memory, and visuo-spatial and naming dysfunctions. Showing longitudinal decline, it has been related to a variety of pathogenic mechanisms associated with the underlying neurodegenerative process, such as involvement of cholinergic and muscarinergic dysfunctions, and striking tau pathology in frontal and temporal cortical regions associated with reduced synaptic density. Altered striatofrontal, fronto-cerebellar, parahippocampal, and multiple subcortical structures, as well as widespread white matter lesions causing extensive connectivity disruptions in cortico-subcortical and cortico-brainstem connections, support the concept that PSP is a brain network disruption disorder. The pathophysiology and pathogenesis of cognitive impairment in PSP, as in other degenerative movement disorders, are complex and deserve further elucidation as a basis for adequate treatment to improve the quality of life of patients with this fatal disease.

Cognitive Healthy Aging in Mice: Boosting Memory by an Ergothioneine-Rich Hericium erinaceus Primordium Extract

Brain aging is a crucial risk factor for several neurodegenerative disorders and dementia. The most affected cognitive function is memory, worsening early during aging. Inflammation and oxidative stress are known to have a role in pathogenesis of cognitive impairments, and a link exists between aging/frailty and immunosenescence/inflammaging. Based on anti-aging properties, medicinal mushrooms represent a source to develop medicines and functional foods. In particular, Hericium erinaceus (He) displays several actions ranging from boosting the immune system to fighting senescence, due to its active ingredients/metabolites. Among these, Ergothioneine (ERGO) is known as the longevity vitamin. Currently, we demonstrated the efficacy of an ERGO-rich He primordium extract (He2) in preventing cognitive decline in a murine model of aging. We focused on recognition memory deterioration during aging, monitored through spontaneous behavioral tests assessing both memory components and frailty index. A parallel significant decrease in key markers of inflammation and oxidative stress, i.e., IL6, TGFβ1, GFAP, Nrf2, SOD1, COX2, NOS2, was revealed in the hippocampus by immunohistochemistry, accompanied by an enhancement of NMDAR1and mGluR2, crucially involved in glutamatergic neurotransmission. In summary, we disclosed a selective, preventive and neuroprotective effect of He2 on aged hippocampus, both on recognition memory as well on inflammation/oxidative stress/glutamate receptors expression.

HIV-1 Subtype C Vpr Amino Acid Residue 45Y and Specific Conserved Fragments Are Associated with Neurocognitive Impairment and Markers of Viral Load.

There is increasing evidence that HIV-1 viral protein R (Vpr) plays an important role in the pathogenesis of cognitive impairment. We investigated the relationship between HIV-1 subtype C Vpr sequence variation and HIV-associated neurocognitive impairment as measured by global deficit score (GDS) in treatment-naive individuals. We used different bioinformatic tools and statistical models to correlate vpr variation and cognitive function. We identified a tyrosine at position 45 (45Y) as a signature for neurocognitive impairment and histidine (45H) as a signature in the non-impaired individuals. The presence of signature 45Y was associated by 3.66 times higher GDS, 525 times higher plasma viral load, 15.84 times higher proviral load, and 60% lower absolute CD4-T cell count compared with those without the signature. Additionally, we identified four conserved Vpr fragment sequences, PEDQGPQREPYNEWTLE (5-21), LGQYIY (42-47), TYGDTW (49-54), and PEDQGPQREPYNEW (5-18), that were associated with higher plasma viral load and proviral load. The implication of these findings is that variation of Vpr leads to neurocognitive impairment in HIV infection and worsens the progression of disease in general by promoting the production of provirus, promoting HIV replication and depletion of CD4+ T cells in the periphery.

Implication of Hypotension in the Pathogenesis of Cognitive Impairment and Brain Injury in Chronic Liver Disease.

The incidence of chronic liver disease is on the rise. One of the primary causes of hospital admissions for patients with cirrhosis is hepatic encephalopathy (HE), a debilitating neurological complication. HE is defined as a reversible syndrome, yet there is growing evidence stating that, under certain conditions, HE is associated with permanent neuronal injury and irreversibility. The pathophysiology of HE primarily implicates a strong role for hyperammonemia, but it is believed other pathogenic factors are involved. The fibrotic scarring of the liver during the progression of chronic liver disease (cirrhosis) consequently leads to increased hepatic resistance and circulatory anomalies characterized by portal hypertension, hyperdynamic circulatory state and systemic hypotension. The possible repercussions of these circulatory anomalies on brain perfusion, including impaired cerebral blood flow (CBF) autoregulation, could be implicated in the development of HE and/or permanent brain injury. Furthermore, hypotensive insults incurring during gastrointestinal bleed, infection, or liver transplantation may also trigger or exacerbate brain dysfunction and cell damage. This review will focus on the role of hypotension in the onset of HE as well as in the occurrence of neuronal cell loss in cirrhosis.

Integrated Clinical Features with Plasma and Multi-modal Neuroimaging Biomarkers to Diagnose Mild Cognitive Impairment in Early Drug-Naive Parkinson's Disease.

The pathogenesis of cognitive impairment in Parkinson's disease (PD) patients remains unclear, and there is no ideal diagnostic tool available at present. We assessed integrated clinical features with plasma and multi-modal neuroimaging biomarkers to identify mild cognitive impairment (MCI) in early drug-naive PD patients. 49 early drug-naive PD patients, including 26 with MCI (PD-MCI) and 23 with normal cognition (PD-NC), and 20 controls were recruited. Plasma markers [α-synuclein, beta-amyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), and phosphorylated Tau 181 (p-Tau181) levels], functional connectivity (FC) of the default mode network, and cortical thickness (CTh) were evaluated to identify PD-MCI. The PD-MCI group had significantly higher plasma p-Tau181 levels and p-Tau181/Aβ42 ratio and lower Aβ42/Aβ40 ratio compared to the PD-NC group. Compared to PD-NC, the PD-MCI group showed increased FC between left posterior cingulate cortex (pCC) and the left parahippocampal gyrus (PHG), and between the right hippocampal formation and the left anterior cingulate and paracingulate gyri, and the right middle temporal gyrus. Additionally, the PD-MCI group had thinner cortex thickness in the right lateral occipital and frontal pole compared to the PD-NC group. The final model combining clinical characteristics and several variables (age, sex, plasma p-Tau181 level, Aβ42/Aβ40 ratio, the right lateral occipital CTh, and the FC value between the left pCC and left PHG) had the highest diagnostic accuracy for PD-MCI (AUC = 0.987, 95% CI 0.903-1.000; p = 0.001 compared to age and sex alone). The combination of clinical features, plasma biomarkers, and multi-modal neuroimaging biomarkers can identify early cognitive decline in PD patients.

Combination of Donepezil and Memantine Attenuated Cognitive Impairment Induced by Mixed Endocrine-Disrupting Chemicals: an In Silico Study.

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.

Identifying and revealing different brain neural activities of cognitive subtypes in early course schizophrenia.

BackgroundCognitive subtypes of schizophrenia may exhibit different neurobiological characteristics. This study aimed to reveal the underlying neurobiological features between cognitive subtypes in the early course of schizophrenia (ECS). According to prior studies, we hypothesized to identify 2–4 distinct cognitive subtypes. We further hypothesized that the subtype with relatively poorer cognitive function might have lower brain spontaneous neural activity than the subtype with relatively better cognitive function.MethodCognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Resting-state functional magnetic resonance imaging scanning was conducted for each individual. There were 155 ECS individuals and 97 healthy controls (HCs) included in the subsequent analysis. Latent profile analysis (LPA) was used to identify the cognitive subtypes in ECS individuals, and amplitude of low-frequency fluctuations (ALFFs) was used to measure brain spontaneous neural activity in ECS individuals and HCs.ResultsLPA identified two cognitive subtypes in ECS individuals, containing a severely impaired subtype (SI, n = 63) and a moderately impaired subtype (MI, n = 92). Compared to HCs, ECS individuals exhibited significantly increased ALFF in the left caudate and bilateral thalamus and decreased ALFF in the bilateral medial prefrontal cortex and bilateral posterior cingulate cortex/precuneus (PCC/PCu). In ECS cognitive subtypes, SI showed significantly higher ALFF in the left precentral gyrus (PreCG) and lower ALFF in the left PCC/PCu than MI. Furthermore, ALFFs of left PreCG were negatively correlated with several MCCB cognitive domains in ECS individuals, while ALFF of left PCC/PCu presented opposite correlations.ConclusionOur findings suggest that differences in the brain spontaneous neural activity of PreCG and PCC/PCu might be the potential neurobiological features of the cognitive subtypes in ECS, which may deepen our understanding of the role of PreCG and PCC/PCu in the pathogenesis of cognitive impairment in schizophrenia.

Current modeling approaches to experimental cognitive impairment (a literature review)

The aim of the work is to review the professional literature sources from the scientific database PubMed mainly for the last 20 years analyzing the modern view on approaches to experimental modeling of cognitive impairment. Materials and methods. A review of the scientific literature over the past 20 years was performed. The lack of requisite knowledge about the pathogenesis of cognitive impairment and the wide range of risk factors for these conditions continue to be major challenges in the development of guidelines on early diagnosis and treatment. The literary analysis suggests that all modeling approaches to experimental cognitive impairment are currently divided into two groups: cell culture and animal models. Conclusions. Experimental modeling of cognitive impairment remains important in addition to clinical and population-based studies. In recent years, the problem of selecting an adequate model to study cognitive impairment, which is a central clinical manifestation of various neurological diseases (Alzheimer’s and Parkinson’s diseases, traumatic brain injury, vascular, demyelinating, and infectious diseases, metabolic aberrations and hormonal imbalance, neurodegenerative diseases of the central nervous system) is becoming increasingly relevant. The choice of model and experimental material – animals or cultures (invertebrate and mammalian cells) is based on a clear understanding of the study design and depends on the ultimate goal of research.

LONG NONCODING RNA UPREGULATES ADAPTER SHCA PROTEIN EXPRESSION TO PROMOTE COGNITIVE IMPAIRMENT AFTER CARDIAC ARREST AND RESUSCITATION.

Aim: More patients are resuscitated from cardiac arrest and cardiopulmonary resuscitation (CA/CPR) due to advances in medical care. However, the burden now lies with post-cardiac arrest cognitive impairment in CA/CPR survivors. Based on our previous study, we aimed to further confirm the correlation between the long noncoding RNA-promoting ShcA (lncRNA-PS)/Src homology and collagen A (ShcA) axis and CA/CPR-induced cognitive impairment in molecular, cellular, and tissue levels. Methods and Results: The in vivo experiments were based on a mouse model of CA/CPR, while oxygen-glucose deprivation and reoxygenation was used as a cell model in vitro. Conditional ShcA suppression in neurons of the hippocampal CA1 region was achieved by cyclization recombinase of bacteriophage P1 recognizing DNA fragment locus of x-over P1 site (Cre/LoxP recombination system). Genetic manipulation of HT22 was achieved by lentivirus targeting lncRNA-PS and ShcA. Neurological function score was remarkably decreased, and cognitive function was affected after restoration of spontaneous circulation. LncRNA-PS and ShcA overexpression after CA/CPR, mainly happened in neurons of hippocampal CA1 region, was observed by in situ hybridization and immunofluorescence. Neuronal ShcA knockdown in hippocampal CA1 region before CA/CPR attenuated cognitive impairment after CA/CPR. ShcA deficiency protected HT22 cell line against oxygen-glucose deprivation and reoxygenation by inhibiting inflammation and apoptosis. In vitro upregulation of lncRNA-PS elevated ShcA expression, which was reversed by knockdown of ShcA. Conclusions: This study revealed that lncRNA-PS/ShcA axis is critically involved in the pathogenesis of cognitive impairment after CA/CPR. By inhibiting ShcA expression in neurons of the hippocampal CA1 region could improve the survival outcomes in mice after CA/CPR.

Copolymer-1 as a potential therapy for mild cognitive impairment

Mild cognitive impairment (MCI) is a prodromal stage of memory impairment that may precede dementia. MCI is classified by the presence or absence of memory impairment into amnestic or non-amnestic MCI, respectively. More than 90% of patients with amnestic MCI who progress towards dementia meet criteria for Alzheimer’s disease (AD). A combination of mechanisms promotes MCI, including intracellular neurofibrillary tangle formation, extracellular amyloid deposition, oxidative stress, neuronal loss, synaptodegeneration, cholinergic dysfunction, cerebrovascular disease, and neuroinflammation. However, emerging evidence indicates that neuroinflammation plays an important role in the pathogenesis of cognitive impairment. Unfortunately, there are currently no Food and Drug Administration (FDA)-approved drugs for MCI.Copolymer-1 (Cop-1), also known as glatiramer acetate, is a synthetic polypeptide of four amino acids approved by the FDA for the treatment of relapsing-remitting multiple sclerosis. Cop-1 therapeutic effect is attributed to immunomodulation, promoting a switch from proinflammatory to anti-inflammatory phenotype. In addition to its anti-inflammatory properties, it stimulates brain-derived neurotrophic factor (BDNF) secretion, a neurotrophin involved in neurogenesis and the generation of hippocampal long-term potentials. Moreover, BDNF levels are significantly decreased in patients with cognitive impairment. Therefore, Cop-1 immunization might promote synaptic plasticity and memory consolidation by increasing BDNF production in patients with MCI.

Research Progress on MRI for White Matter Hyperintensity of Presumed Vascular Origin and Cognitive Impairment.

White matter hyperintensity of presumed vascular origin (WMH) is a common medical imaging manifestation in the brains of middle-aged and elderly individuals. WMH can lead to cognitive decline and an increased risk of cognitive impairment and dementia. However, the pathogenesis of cognitive impairment in patients with WMH remains unclear. WMH increases the risk of cognitive impairment, the nature and severity of which depend on lesion volume and location and the patient's cognitive reserve. Abnormal changes in microstructure, cerebral blood flow, metabolites, and resting brain function are observed in patients with WMH with cognitive impairment. Magnetic resonance imaging (MRI) is an indispensable tool for detecting WMH, and novel MRI techniques have emerged as the key approaches for exploring WMH and cognitive impairment. This article provides an overview of the association between WMH and cognitive impairment and the application of dynamic contrast-enhanced MRI, structural MRI, diffusion tensor imaging, 3D-arterial spin labeling, intravoxel incoherent motion, magnetic resonance spectroscopy, and resting-state functional MRI for examining WMH and cognitive impairment.

Anti-inflammatory effects of B vitamins protect against tau hyperphosphorylation and cognitive impairment induced by 1,2 diacetyl benzene: An in vitro and in silico study

1,2 diacetyl benzene (DAB) penetrates the blood–brain barrier, causing neuroinflammation, tau hyperphosphorylation, and cognitive impairment. Converging evidence supports the anti-inflammatory effects of B vitamins on cognitive impairment, but the effects of B vitamins on cognitive impairment induced by DAB remain unclear. Here, we investigated the anti-inflammatory properties of B vitamins in DAB-stimulated human neuroblastoma SH-SY5Y cells. In this in-silico analysis, we investigated the genes, transcription factors, miRNAs, and sponges linked with DAB, B vitamins and the pathogenesis of cognitive impairment. We found vitamins B1, B2, and B3 had anti-inflammatory properties in DAB-stimulated SH-SY5Y cells, possibly via inhibiting NF-κB activation. Furthermore, vitamins B1, B2, and B3 inhibited GSK-3β, β-amyloid, and tau hyperphosphorylation in SH-SY5Y cells. These vitamins can also modulate genes induced by DAB (IL1B, IL6, IL10, iNOS, COX2, NFκB, GSK3B, TNF, and APP) in SH-SY5Y cells. In silico analyses, inflammatory response related pathways, “Alzheimer’s disease”, “pathways of neurodegeneration-multiple disease”, and “prolactin signaling pathway”, were highlighted. Additionally, we explored a network-based approach to identify key genes, transcription factors, miRNAs, and pathways in cognitive impairment. The transcription factors NFKB2 and BATF3 were shown to be the most important in regulating genes. We also found eight significant miRNAs related to cognitive impairment, and these miRNAs were also validated by qPCR. Finally, we developed and tested in silico miRNA sponge sequences for these miRNAs.

Dynapenic abdominal obesity is associated with mild cognitive impairment in patients with cardiometabolic disease: a cross-sectional study

BackgroundDementia is an important health issue for older people and requires early intervention in the mild cognitive impairment (MCI) stage to manage risk factors. Both dynapenia (DP) and abdominal obesity (AO) are associated with inflammation and oxidative stress, which may be involved in the pathogenesis of cognitive impairment. Therefore, in this cross-sectional study, we aimed to evaluate the association between MCI and dynapenic abdominal obesity (DAO), a combination of DP and AO.MethodsA total of 417 older outpatients with cardiometabolic diseases without severe cognitive impairment were studied to compare cognitive function in four groups: control, DP, AO, and DAO groups. DAO was defined as the combination of DP (handgrip strength of < 28 kg and < 18 kg in men and women, respectively) and AO (waist circumference of ≥ 85 cm and ≥ 90 cm in men and women, respectively). MCI was defined as a score of ≤ 25 in the Japanese version of the Montreal Cognitive Assessment. Multiple regression analyses were performed to examine if MCI was independently associated with DAO, low handgrip strength, or high waist circumference.ResultsThe DAO group obtained the lowest cognitive test scores and had the highest prevalence of MCI. Furthermore, after adjusting for covariates, the logistic regression analysis showed that patients in the DAO group were at an increased risk of MCI (odds ratio [OR] = 3.98, 95% confidence interval [CI]: 1.15–13.77). Further logistic regression analyses revealed that both low handgrip strength (OR = 2.19, 95% CI: 1.11–4.29) and high waist circumference (OR = 2.03, 95% CI: 1.03–3.99) were associated with MCI.ConclusionsDAO, which can be easily diagnosed by a combination of handgrip strength and waist circumference, was associated with MCI in patents with cardiometabolic metabolic disease. This study suggests that screening for MCI in DAO patients could be important for early intervention of dementia prevention.

Exposure to a mixture of heavy metals induces cognitive impairment: Genes and microRNAs involved

Converging evidence demonstrates that microRNAs (miRNAs) play an important role in the etiology of cognitive impairment. Thus, we aim to: (i) identify the molecular mechanisms of heavy metals, particularly miRNAs involved in the development of cognitive impairment; and (ii) generate miRNA sponges to prevent them from binding with their target messenger RNAs. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org), MicroRNA ENrichment TURned NETwork (MIENTURNET, http://userver.bio.uniroma1.it/apps/mienturnet/) and the microRNA sponge generator and tester (miRNAsong, http://www.med.muni.cz/histology/miRNAsong) were used as the core data-mining approaches in the current study. We observed that lead acetate, arsenic, gold, copper, iron, and aluminum, as well as their mixtures, had significant effects on the development of cognitive impairment. Although prevalent genes obtained from investigated heavy metals of cognitive impairment were different, the "PI3K-Akt signaling pathway", "pathways of neurodegeneration-multiple diseases", "apoptosis", "apoptosis-multiple species", "p53 signaling pathway", "NF-kappa B signaling pathway", and "Alzheimer’s disease pathway" were highlighted. The mixed heavy metals altered the genes BAX, CASP3, BCL2, TNF, and IL-1B, indicating the significance of apoptosis and pro-inflammatory cytokines in the pathogenesis of cognitive impairment and the possibility of targeting these genes in future neuroprotective therapy. In addition, we used a network-based approach to identify key genes, miRNAs, pathways, and diseases related to the development of cognitive impairment. We also found 16 significant miRNAs related to cognitive impairment (hsa-miR-1–3p, hsa-let-7a-5p, hsa-miR-9–5p, hsa-miR-16–5p, hsa-miR-17–5p, hsa-miR-20a-5p, hsa-miR-26a-5p, hsa-miR-26b-5p, hsa-miR-34a-5p, hsa-miR-101–3p, hsa-miR-106a-5p, hsa-miR-128–3p, hsa-miR-144–3p, hsa-miR-199a-3p, hsa-miR-204–5p, and hsa-miR-335–5p). Finally, we created and evaluated miRNA sponge sequences for these miRNAs in silico. Further studies, including in vivo and in vitro, are needed to assess the link between these genes, miRNAs, pathways, and cognitive impairment.

Biomarkers of gut microbial transfer and their association with cognitive impairment in long-term survivors of testicular germ cell tumors.

426 Background: Survivors of testicular germ cell tumors (GCT) may suffer from long-term cognitive impairment. We hypothesized that disruption of intestinal barrier during chemotherapy and/or radiotherapy may be a contributing factor of cognitive dysfunction within the gut-blood-brain axis. Methods: GCT survivors (N = 142) from National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function questionnaires during their annual follow-up visit at 9-year median (range 4-32). Biomarkers of gut microbial transfer and dysbiosis (GMT) high mobility group box-1 (HMGB-1), lipopolysaccharide (LPS), d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Each questionnaire score was correlated with biomarkers of GMT. Survivors were treated with orchiectomy only (N = 17), cisplatin-based chemotherapy (N = 108), radiotherapy to the retroperitoneum (N = 11) or both (N = 6). Results: GCT survivors with higher sCD14 had worse cognitive function perceived by others (CogOth domain) (mean ± SEM; 14.6 ± 0.25 vs 15.4 ± 0.25, p = 0.019), lower perceived cognitive abilities (CogPCA domain) (20.0 ± 0.74 vs 23.4 ± 0.73, p = 0.025) and lower overal cognitive function score (109.2 ± 0.74 vs 116.7 ± 1.90, p = 0.021). There were no significant cognitive declines associated with HMGB-1, d-lactate and LPS. Survivors treated with ≥ 400mg/m2 of cisplatin based chemotherapy had higher LPS (567.8 ± 42.7 vs 462.9 ± 51.9, P = 0.03). Survivors treated with chemotherapy + radiotherapy vs orchiectomy only had non-significantly higher sCD14 (7279.9 ± 810.1 vs 5851.0 ± 481.7, P = 0.09). Conclusions: sCD14 may serve as a promising biomarker of cognitive impairment in long-term cancer survivors. While chemotherapy and radiotherapy-induced intestinal injury may be the underlying mechanism, further research using animal models and larger patient cohorts are needed to explore the pathogenesis of cognitive impairment in GCT survivors.

Cognitive Impairment in Anti-Phospholipid Syndrome and Anti-Phospholipid Antibody Carriers.

Cognitive impairment is frequently reported among anti-phospholipid syndrome (APS) patients as well as anti-phospholipid antibody (aPL) carriers, but it is less studied than other manifestations of this condition. Moreover, the exact prevalence of cognitive impairment in these patients has not been accurately determined, mainly due to inconsistency in the tools used to identify impairment, small sample sizes, and variability in the anti-phospholipid antibodies measured and positivity cutoffs. The notion of a direct pathogenic effect is supported by the observation that the higher the number of aPLs present and the higher the load of the specific antibody, the greater the risk of cognitive impairment. There is some evidence to suggest that besides the thrombotic process, inflammation-related pathways play a role in the pathogenesis of cognitive impairment in APS. The cornerstone treatments of APS are anti-coagulant and anti-thrombotic medications. These treatments have shown some favorable effects in reversing cognitive impairment, but solid evidence for the efficacy and safety of these treatments in the context of cognitive impairment is still lacking. In this article, we review the current knowledge regarding the epidemiology, pathophysiology, clinical associations, and treatment of cognitive impairment associated with APS and aPL positivity.

Gut Microbiome Composition Linked to Inflammatory Factors and Cognitive Functions in First-Episode, Drug-Naive Major Depressive Disorder Patients.

ObjectiveThe microbiota–gut–brain axis, especially the inflammatory pathway, may play a critical role in the pathogenesis of cognitive impairment in major depressive disorder (MDD). However, studies on the microbiota-inflammatory-cognitive function axis in MDD are lacking. The aim of the present study was to analyze the gut microbiota composition and explore the correlation between gut microbiota and inflammatory factors, cognitive function in MDD patients.MethodStudy participants included 66 first-episode, drug naïve MDD patients as well as 43 healthy subjects (HCs). The composition of fecal microbiota was evaluated using16S rRNA sequencing and bioinformatics analysis. The cytokines such as hs-CRP, IL-1β, IL-6, IL-10, and TNF-α in peripheral blood were detected via enzyme linked immunosorbent assay (ELISA); assessment of cognitive functions was performed using the Color Trail Test (CTT), The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (SCWT).ResultsWe found that compared with HCs, MDD patients had cognitive impairments and showed different α-diversity and β-diversity of gut microbiota composition. LDA effect size (LEfSe) analysis found MDD have higher Deinococcaceae and lower Bacteroidaceae, Turicibacteraceae, Clostridiaceae and Barnesiellaceae at family level. Deinococcus and Odoribacter was higher in the MDD group, however, Bacteroides, Alistipes, Turicibacter, Clostridium, Roseburia, and Enterobacter were lower at genus level. Furthermore, In MDD patients, the Bacteroidaceae and Bacteroides were both positively correlated with hsCRP, CCT1, CCT2. Alistipes was positively correlated with IL-6, Word time, Color time, Word-Color time, Color-Word time and negatively correlated with Delayed Memory, Total score and Standardized score. Turicibacteraceae and Turicibacter were both negatively correlated with IL-1β and IL-6.ConclusionThe present findings confirm that the gut microbiota in MDD patients have altered gut microbes that are closely associated with inflammatory factors and cognitive function in MDD patients.