Potential Pathogenetic Factors Research Articles

Exploration of the Shared Gene Signatures and Molecular Mechanisms Between Ischemic Stroke and Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory vascular disease and the predominant cause of ischemic stroke (IS). AS is a potential pathogenetic factor in IS. However, the processes by which they interact remain unknown. The purpose of this paper was to investigate the shared gene signatures and putative molecular processes in AS and IS. Gene Expression Omnibus (GEO) data for AS and IS microarrays were retrieved. The co-expression modules associated with AS and IS were identified using the Weighted Gene Co-Expression Network Analysis (WGCNA). We constructed an interaction network of shared differentially expressed genes in AS and IS and conducted an enrichment analysis using ClueGO software. We validated the results in a separate cohort through differential gene analysis. Additionally, we retrieved AS and IS-related miRNAs from the Human microRNA Disease Database (HMDD) and predicted their target genes using miRWalk. We then built a network of miRNAs-mRNAs-KEGG pathways using the shared genes. Through WGCNA, we identified five modules and six modules as significant in AS and IS, respectively. A ClueGO enrichment analysis of common genes showed that highly active CCR1 chemokine receptor binding is critical to AS and IS pathogenesis. The differential analysis expression results in another cohort closely matched these findings. The miRNA-mRNA network suggested that hsa-miR-330-5p, hsa-miR-143-3p, hsa-miR-16-5p, hsa-miR-152-3p might regulate the shared gene KRAS, which could be a key player in AS and IS. We integrated ischemic stroke and carotid atherosclerosis public database data and found that ATF3, CCL3, CCL4, JUNB, KRAS, and ZC3H12A may affect both, making them novel biomarkers or therapeutic target genes. Clinical samples and expression trends supported our analyses of pivotal genes.

Regulatory T Cells in the Pathogenesis of Graves' Disease.

Maintaining a delicate balance between the prompt immune response to pathogens and tolerance towards self-antigens and commensals is crucial for health. T regulatory (Treg) cells are pivotal in preserving self-tolerance, serving as negative regulators of inflammation through the secretion of anti-inflammatory cytokines, interleukin-2 neutralization, and direct suppression of effector T cells. Graves' disease (GD) is a thyroid-specific autoimmune disorder primarily attributed to the breakdown of tolerance to the thyroid-stimulating hormone receptor. Given the limitations of currently available GD treatments, identifying potential pathogenetic factors for pharmacological targeting is of paramount importance. Both functional impairment and frequency reduction of Tregs seem likely in GD pathogenesis. Genome-wide association studies in GD have identified polymorphisms of genes involved in Tregs' functions, such as CD25 (interleukin 2 receptor), and Forkhead box protein P3 (FOXP3). Clinical studies have reported both functional impairment and a reduction in Treg frequency or suppressive actions in GD, although their precise involvement remains a subject of debate. This review begins with an overview of Treg phenotype and functions, subsequently delves into the pathophysiology of GD and into the existing literature concerning the role of Tregs and the balance between Tregs and T helper 17 cells in GD, and finally explores the ongoing studies on target therapies for GD.

Gender-related Characteristics of Oxidative Stress Severity and Cognitive Impairment in Patients With Schizophrenia.

The gender specificity of the clinical and psychopathological features of schizophrenia is an important factor in this disease. Gender features of neurocognitive deficit in schizophrenia and associated functional and structural disorders of the brain activity are of particular interest to researchers. There are several potential pathogenetic factors of this disease associated with gender, one of which is considered to be oxidative stress. Stress-induced cell death in the prefrontal and anterior frontal regions and reduced brain volume in these regions lead to cognitive and executive decline in patients with schizophrenia. Despite the great interest in the gender factor in schizophrenia pathogenesis, there are currently very few studies on gender differences in the severity of redox imbalance in patients with schizophrenia and their association with neurocognitive deficit.The aim of the study was to reveal the gender specificity of oxidative stress severity in patients with schizophrenia and assess its association with the severity of neurocognitive deficit.The study included 125 patients with schizophrenia and 75 sex- and age-matched healthy volunteers. Sociodemographic and clinical data were studied. Cognitive functions were evaluated using BACS. Blood samples were taken for biochemical studies of the levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) in erythrocyte hemolysate, malonic dialdehyde (MDA), aldehyde-2,4-dinitrophenylhydrazones (ADNPH), ketone-2,4-dinitrophenylhydrazones (KDNPH) in plasma. Levels of oxidative stress markers were assessed by spectrophotometric method.In a sample of patients with schizophrenia, a statistically significantly higher activity of CAT was revealed among women compared to men (T=2.25; p=0.025), however, it was lower than in healthy volunteers. But, at the same time, a higher concentration of protein peroxidation products was found in the peripheral blood of women than in men (ADNPH MCO: T=2.52; p=0.013; KDNPH MCO: Z=-2.26; p=0.017). In the group of healthy volunteers, in contrast to patients with schizophrenia, gender differences in markers of oxidative stress were not found. In women with schizophrenia, single correlations were found between the level of the lipid peroxidation product MDA and the test scores for verbal memory (R=-0.36; p=0.006) and working memory (R=-0.36; p=0.006), antioxidant enzyme activity SOD and motor skills (R=-0.26; p=0.047). In men, on the contrary, multiple correlations of both antioxidants and, mainly, products of lipid and protein peroxidation with cognitive functions assessed using BACS were found.Despite the fact that oxidative stress is more pronounced in women than in men with schizophrenia, associations of redox imbalance with neurocognitive deficit in women is much less pronounced than in men.

Sudden infant death syndrome (SIDS) - How to reduce the risk?

Sudden infant death syndrome (SIDS) is a complex, multifactorial phenomenon with an etiology that has not been fully clarified to this day. Despite a noticeable decrease in the number of SIDS cases worldwide, sudden infant death syndrome remains one of the most common causes of death among children in infancy. Sudden infant death syndrome is still the subject of scientific research aimed to clearly determine and identify potential pathogenetic factors responsible for the occurrence of SIDS. Many years of efforts to clarify the etiology of the discussed issue have made it possible to characterize important factors that increase the risk of sudden infant death syndrome. In addition, research has made it possible to develop important approaches that make a significant contribution to reduce the risk of SIDS in an infant. Complete knowledge of the specific conditions that have a protective effect against SIDS will significantly reduce the risk of sudden infant death syndrome, so a very important aspect is not only their precise analysis, but also their propagation among the public.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

TREM2 as an evolving therapeutic target in Alzheimer's disease.

Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome

Long-COVID syndrome is associated with high healthcare costs, but its pathophysiology is not yet fully understood. Inflammation, renal impairment or disturbance of the NO system emerge as potential pathogenetic factors. We aimed to investigate the relationship between symptoms of long-COVID syndrome and serum levels of cystatin-c (CYSC), orosomucoid (ORM), l-arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). A total of 114 patients suffering from long-COVID syndrome were included in this observational cohort study. We found that serum CYSC was independently associated with the anti-spike immunoglobulin (S-Ig) serum level (OR: 5.377, 95% CI: 1.822-12.361; p = 0.02), while serum ORM (OR: 9.670 (95% CI: 1.34-9.93; p = 0.025) independently predicted fatigue in patients with long-COVID syndrome, both measured at baseline visit. Additionally, the serum CYSC concentrations measured at the baseline visit showed a positive correlation with the serum SDMA levels. The severity of abdominal and muscle pain indicated by patients at the baseline visit showed a negative correlation with the serum level of L-arginine. In summary, serum CYSC may indicate subclinical renal impairment, while serum ORM is associated with fatigue in long-COVID syndrome. The potential role of l-arginine in alleviating pain requires further studies.

Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis/chronic fatigue syndrome stimulates human microglia to release IL-1β.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise, and cognitive problems. The pathogenesis of ME/CFS is presently unknown, and serum levels of potential biomarkers have been inconsistent. Here, we show that mitochondrial DNA (mtDNA) associated with serum exosomes, is increased in ME/CFS patients only after exercise. Moreover, exosomes isolated from patients with ME/CFS stimulate significant release of IL-1β from cultured human microglia. These results provide evidence that activation of microglia by serum-derived exosomes may serve as a potential novel pathogenetic factor and target for treatment of ME/CFS.

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

BackgroundOverexpression of the transsulfuration enzyme cystathionine-β-synthase (CBS), and overproduction of its product, hydrogen sulfide (H2S) are recognized as potential pathogenetic factors in Down syndrome (DS). The purpose of the study was to determine how the mitochondrial function and core metabolic pathways are affected by DS and how pharmacological inhibition of CBS affects these parameters. Methods8 human control and 8 human DS fibroblast cell lines have been subjected to bioenergetic and fluxomic and proteomic analysis with and without treatment with a pharmacological inhibitor of CBS. ResultsDS cells exhibited a significantly higher CBS expression than control cells, and produced more H2S. They also exhibited suppressed mitochondrial electron transport and oxygen consumption and suppressed Complex IV activity, impaired cell proliferation and increased ROS generation. Inhibition of H2S biosynthesis with aminooxyacetic acid reduced cellular H2S, improved cellular bioenergetics, attenuated ROS and improved proliferation. 13C glucose fluxomic analysis revealed that DS cells exhibit a suppression of the Krebs cycle activity with a compensatory increase in glycolysis. CBS inhibition restored the flux from glycolysis to the Krebs cycle and reactivated oxidative phosphorylation. Proteomic analysis revealed no CBS-dependent alterations in the expression level of the enzymes involved in glycolysis, oxidative phosphorylation and the pentose phosphate pathway. DS was associated with the dysregulation of several components of the autophagy network; CBS inhibition normalized several of these parameters. ConclusionsIncreased H2S generation in DS promotes pseudohypoxia and contributes to cellular metabolic dysfunction by causing a shift from oxidative phosphorylation to glycolysis.

Changes in the gut bacteria composition associated with metabolic syndrome

Obesity, arterial hypertension, disorders of carbohydrate and lipid metabolism, which form the metabolic syndrome, remain the leading risk factors for the development of cardiovascular complications and oncological diseases. Overnutrition and a sedentary lifestyle leading to the metabolic syndrome formation are also interconnected with another potential pathogenetic factor of obesity, the gut microbiota. The study of its composition, as well as its metabolites, can serve as a basis for predicting metabolic disorders and for the development of an integrated approach to the metabolic syndrome treatment using probiotic therapy. The clinical assessment of the gut microbiota composition in patients with MS was carried out to identify bacterial taxa potentially associated with the development of MS. Materials (feces) were collected from 113 patients: the first group (n = 59) consisted of overweight patients (body mass index > 25.0) with metabolic disorders in the form of lipid and/or carbohydrate disorders (the average age 44 years). The control group (n = 54) consisted of patients with normal body weight (18.5 < body mass index < 25.0), without metabolic disorders, without arterial hypertension (the average age — 38 years). Fecal samples from patients were studied using 16S rRNA gene sequencing on the Illumina platform (MiSeq sequencer). The CDHIT-OTU-Miseq program was used to search for taxonomic units. Deoxyribonucleic acid libraries were prepared using the Illumina Nextera sample preparation kit with deoxyribonucleic acid primers corresponding to the V3–V4 regions of the 16S rRNA gene. In the gut microbiota composition of patients with metabolic syndrome we can highlight the phylum Actinobacteria, its 2 genera Actynomyces spp. and Bifidobacterium spp., as well as the genus Prevotella spp. and the class Gammaproteobacteria. It is assumed that bacterial species belonging to these type, class, and genera can be considered as potential marker bacteria of the metabolic syndrome.

High-throughput sequencing reveals that microRNA from exosomes as potential pathogenetic factors and biomarkers of moyamoya disease

High-throughput sequencing reveals that microRNA from exosomes as potential pathogenetic factors and biomarkers of moyamoya disease

Adult-Onset Still’s Disease: Novel Biomarkers of Specific Subsets, Disease Activity, and Relapsing Forms

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17–32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options.

Circulating myomiRs in Muscle Denervation: From Surgical to ALS Pathological Condition.

ALS is a fatal neurodegenerative disease that is associated with muscle atrophy, motoneuron degeneration and denervation. Different mechanisms have been proposed to explain the pathogenesis of the disease; in this context, microRNAs have been described as biomarkers and potential pathogenetic factors for ALS. MyomiRs are microRNAs produced by skeletal muscle, and they play an important role in tissue homeostasis; moreover, they can be released in blood circulation in pathological conditions, including ALS. However, the functional role of myomiRs in muscle denervation has not yet been fully clarified. In this study, we analyze the levels of two myomiRs, namely miR-206 and miR-133a, in skeletal muscle and blood samples of denervated mice, and we demonstrate that surgical denervation reduces the expression of both miR-206 and miR-133a, while miR-206 but not miR-133a is upregulated during the re-innervation process. Furthermore, we quantify the levels of miR-206 and miR-133a in serum samples of two ALS mouse models, characterized by different disease velocities, and we demonstrate a different modulation of circulating myomiRs during ALS disease, according to the velocity of disease progression. Moreover, taking into account surgical and pathological denervation, we describe a different response to increasing amounts of circulating miR-206, suggesting a hormetic effect of miR-206 in relation to changes in neuromuscular communication.

Along the fringes of Agency: neurodevelopmental account of the obsessive mind.

The experiential core of the obsessive mind rests on subtle, primary mental phenomena (such as obsessions and so called "sensory phenomena") which precede and trigger behavioral compulsions. Converging evidence supports a possible pathophysiological role for altered corollary discharge (phenotypically expressed in sensorimotor symptoms and contributing to a reduced Sense of Agency [SoA]), in the neurodevelopment of obsessions and "sensory phenomena." In phenomenological terms, "sensory phenomena" may represent the subjective experiential resonance of an individual history of persistent inaccurate sensory predictions, whereas accompanying manifestations, such as the obsessive need for order and symmetry, may represent a compensatory attempt to mitigate "sensory phenomena" (eg, by increasing the sensory predictability of the surrounding world). Since disturbances of both SoA and Sense of Ownership have been thematized as potential pathogenetic factors in the neurodevelopment of the psychotic mind, a dimensional account of altered sensorimotor prediction may partly explain the affinities (and high comorbidity) between obsessive-compulsive disorder and schizophrenia spectrum disorders.

Arousal and Executive Alterations in Attention Deficit Hyperactivity Disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in childhood and can significantly affect a child’s personal and social development and academic achievement. Taking into account the model of attentional networks proposed by Posner et al., the aim of the present study was to review the literature regarding two main explicative models of ADHD, i.e., the inhibition model and the cognitive-energetic model, by discussing behavioral and neurological evidence of both models and the limitations of each model. The review highlights evidence that favors the energetic model and points to an unstable arousal as a potential pathogenetic factor in ADHD.

Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide.

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon inflammatory disease of the central nervous system, manifesting clinically as optic neuritis, myelitis, and certain brain and brainstem syndromes. Cases clinically diagnosed as NMOSD may include aquaporin 4 (AQP4)-antibody-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive inflammatory demyelinating disease, and double-seronegative disease. AQP4-antibody disease has a high female-to-male ratio (up to 9:1), and its mean age at onset of ~40 years is later than that seen in multiple sclerosis. For MOG-antibody disease, its gender ratio is closer to 1:1, and it is more common in children than in adults. Its clinical phenotypes differ but overlap with those of AQP4-antibody disease and include acute disseminated encephalomyelitis, brainstem and cerebral cortical encephalitis, as well as optic neuritis and myelitis. Double-seronegative disease requires further research and clarification. Population-based studies over the past two decades report the prevalence and incidence of NMOSD in different populations worldwide. One relevant finding is the varying prevalence observed in different racial groups. Consistently, the prevalence of NMOSD among Whites is ~1/100,000 population, with an annual incidence of <1/million population. Among East Asians, the prevalence is higher, at ~3.5/100,000 population, while the prevalence in Blacks may be up to 10/100,000 population. For MOG-antibody disease, hospital-based studies largely do not observe any significant racial preponderance so far. This disorder comprises a significant proportion of NMOSD cases that are AQP4-antibody-seronegative. A recent Dutch nationwide study reported the annual incidence of MOG-antibody disease as 1.6/million population (adult: 1.3/million, children: 3.1/million). Clinical and radiological differences between AQP4-antibody and MOG-antibody associated diseases have led to interest in the revisions of NMOSD definition and expanded stratification based on detection of a specific autoantibody biomarker. More population-based studies in different geographical regions and racial groups will be useful to further inform the prevalence and incidence of NMOSD and their antibody-specific subgroups. Accessibility to AQP4-antibody and MOG-antibody testing, which is limited in many centers, is a challenge to overcome. Environmental and genetic studies will be useful accompaniments to identify other potential pathogenetic factors and specific biomarkers in NMOSD.

Local Progression Kinetics of Geographic Atrophy in Age-Related Macular Degeneration Are Associated With Atrophy Border Morphology.

To assess the impact of distinct atrophy border characteristics based on spectral-domain optical coherence tomography (SD-OCT) imaging on local atrophy progression. Patients with geographic atrophy (GA) secondary to AMD were recruited in the context of the Longitudinal Fundus Autofluorescence in Age-related Macular Degeneration and Directional Spread in Geographic Atrophy studies (NCT00393692, NCT02051998). Horizontal and vertical SD-OCT scans were acquired at sequential visits using a device allowing for anatomically accurate registration of follow-up to baseline scans. For quantification of local atrophy progression, the lateral spread of GA (LSGA) was measured. Further, border types were independently graded. Comparison of LSGA between the different border types was performed using linear mixed-effects models. Seventy-two eyes of 49 patients (27 female) aged 74.0 years (Inter quartile range [IQR], 68.1-79.0) were included into this analysis. A total of 258 border sections were analyzed longitudinally over a median period of 1.2 years (IQR, 0.9-1.6). At baseline, 17.1% borders were classified as 'regular', 47.7% as 'irregular', and 35.3% as 'splitting'. Sixty-two percent of the eyes exhibited more than one border type. LSGA was slowest in 'regular' borders (62.85 ± 25.29 μm/y), followed by 'irregular' borders (91.15 ± 15.05 μm/y) and fastest in 'splitting' borders (183.15 ± 18.17 μm/y). Differences between the 'splitting' and each other border type were statistically significant (P < 0.001). The results indicate that SD-OCT-based assessment of local GA border morphology can serve as a predictor for local atrophy progression. These observations help to better understand the natural history and potential pathogenetic factors of GA development and progression.

Extracellular DNA is Increased in Dextran Sulphate Sodium-Induced Colitis in Mice

Ulcerative colitis and Crohn’s disease constitute the two main forms of inflammatory bowel disease. Prevalence of these diseases increases. In the present day, inadequate and inefficient therapy causes complications and frequent relapse. Extracellular DNA (ecDNA) is the DNA that is outside of cells and may be responsible for activation of the inflammatory response. To determine whether colitis is associated with higher concentration of ecDNA we used male mice of the C57BL/6 strain. Colitis was induced by 2% dextran sulphate sodium (DSS). After 7 days, mice exhibited considerable weight loss compared to the control group. Also, there was a higher stool consistency score and the colon was significantly shorter in comparison to the control group. Higher concentration of ecDNA was found in the DSS group. Interestingly, deoxyribonuclease activity was lower in the colon of the DSS group compared with the negative control. These findings may point to ecDNA as a potential pathogenetic factor and marker of inflammation.

The fecal microbiome of ALS patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disease accompanied by both systemic and central nervous system–specific inflammation as well as deregulated energy metabolism. These potential pathogenetic factors have recently been found to mutually interact with the gut microbiota, raising the hypothesis of a link between microbiome alterations and ALS pathogenesis. The aim of our study was to assess whether ALS is associated with an altered composition of the fecal microbiota. We compared the fecal microbiota of 25 ALS patients with 32 age- and gender-matched healthy persons using 16S rRNA gene sequencing analysis. Confounding factors and secondary disease effects on the microbiome were minimized by selection of patients without dysphagia, gastrostomy, noninvasive ventilation, or reduced body mass index. Comparing the 2 carefully matched groups, the diversity and the abundance of the bacterial taxa on the different taxonomic levels as well as PICRUSt-predicted metagenomes were almost indistinguishable. Significant differences between ALS patients and healthy controls were only observed with regard to the overall number of microbial species (operational taxonomic units) and in the abundance of uncultured Ruminococcaceae. Conclusively, ALS patients do not exhibit a substantial alteration of the gut microbiota composition.

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n=2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n=1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p<0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.

Surgery under Propofol Anesthesia Induced Behavioral Changes Associated With Increased Cerebral Apoptosis in Rats

It is not known whether prolonged propofol anesthesia and/or surgery are responsible for postoperative cerebral deterioration, including Alzheimer-like histological changes, apoptosis and cognitive dysfunction. Therefore, the aim of the present study was to use partial liver resection as a surgical rat model in middle-aged rats in order to distinguish postoperative cerebral changes brain from those in rats after propofol anesthesia without surgery. In this randomized, controlled study, behavioral changes were investigated in n=36 rats (12- to 14-month-old) using the hole board test system and Morris water maze. Cerebral glycogen synthase kinase-3s (GSK-3s) and tau protein were analyzed using ELISA technique. Cerebral amyloid was determined using congo red staining with subsequent fluorescence analysis. Apoptosis in rat brain was analyzed using TUNEL test and caspase-3 immunhistochemistry. Alzheimer-like specific histological markers were not markedly increased up to 28 days after propofol anesthesia without partial hepatectomy. In contrast, propofol combined with partial liver resection caused long-term deterioration in spatial cognitive behavior in the rats. These postoperative cognitive dysfunctions were associated with pronounced cerebral apoptosis and increased GSK-3s. We conclude that a surgical procedure in the form of partial hepatectomy, but not propofol anesthesia alone, induced persistent cognitive deterioration and increased apoptosis in middle-aged rats. Although apoptotic changes seem to be mediated via GSK-3s, further studies are now necessary to investigate the underlying mechanisms and other potential pathogenetic factors for postoperative cognitive dysfunction.