Short-term Memory Reduction Research Articles

Obesity as Inducer of Cognitive Function Decline via Dysbiosis of Gut Microbiota in Rats.

Diet-induced obesity is a global phenomenon that affects the population worldwide with manifestations at both the phenotypic and genotypic levels. Cognitive function decline is a major global health challenge. The relation between obesity and cognitive function is a debatable issue. The main goal of the current research was to study the implications of obesity on cognitive function and gut microbiota diversity and its impact on plasma and brain metabolic parameters in rats. Obesity was induced in rats by feeding on a high-fat (HF) or a high-fat/high-sucrose (HFHS) diet. The results reveal that both the HF (0.683) and HFHS (0.688) diets were effective as obesity inducers, which was confirmed by a significant increase in the body mass index (BMI). Both diet groups showed dyslipidemia and elevation of oxidative stress, insulin resistance (IR), and inflammatory markers with alterations in liver and kidney functions. Obesity led to a reduction in cognitive function through a reduction in short-term memory by 23.8% and 30.7% in the rats fed HF and HFHS diets, respectively, and learning capacity and visuo-spatial memory reduced by 8.9 and 9.7 s in the rats fed an HF or HFHS diet, respectively. Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, and Spirochaetes phyla were detected. The Firmicutes/Bacteroidetes ratio (F/B) significantly decreased in the HF group, while it increased in the HFHS group compared to the normal control. The two species, Bacteroides acidifaciens and Bacteroides ovatus, which are associated with IR, were drastically compromised by the high-fat/high-sucrose diet. Some species that have been linked to reduced inflammation showed a sharp decrease in the HFHS group, while Prevotella copri, which is linked to carbohydrate metabolism, was highly enriched. In conclusion: Obesity led to cognitive impairment through changes in short-term and visuo-spatial memory. A metagenomic analysis revealed alterations in the abundance of some microbial taxa associated with obesity, inflammation, and insulin resistance in the HF and HFHS groups.

The Effect of Reduced Fibrinogen on Cerebrovascular Permeability during Traumatic Brain Injury in Fibrinogen Gene Heterozygous Knockout Mice.

Vascular contribution to cognitive impairment and dementia (VCID) is a term referring to all types of cerebrovascular and cardiovascular disease-related cognitive decline, spanning many neuroinflammatory diseases including traumatic brain injury (TBI). This becomes particularly important during mild-to-moderate TBI (m-mTBI), which is characterized by short-term memory (STM) decline. Enhanced cerebrovascular permeability for proteins is typically observed during m-mTBI. We have previously shown that an increase in the blood content of fibrinogen (Fg) during m-mTBI results in enhanced cerebrovascular permeability. Primarily extravasated via a transcellular pathway, Fg can deposit into the parenchyma and exacerbate inflammatory reactions that can lead to neurodegeneration, resulting in cognitive impairment. In the current study, we investigated the effect of a chronic reduction in Fg concentration in blood on cerebrovascular permeability and the interactions of extravasated Fg with astrocytes and neurons. Cortical contusion injury (CCI) was used to generate m-mTBI in transgenic mice with a deleted Fg γ chain (Fg γ+/-), resulting in a low blood content of Fg, and in control C57BL/6J wild-type (WT) mice. Cerebrovascular permeability was tested in vivo. Interactions of Fg with astrocytes and neurons and the expression of neuronal nuclear factor-кB (NF-кB) were assessed via immunohistochemistry. The results showed that 14 days after CCI, there was less cerebrovascular permeability, lower extravascular deposition of Fg, less activation of astrocytes, less colocalization of Fg with neurons, and lower expression of neuronal pro-inflammatory NF-кB in Fg γ+/- mice compared to that found in WT mice. Combined, our data provide strong evidence that increased Fg extravasation, and its resultant extravascular deposition, triggers astrocyte activation and leads to potential interactions of Fg with neurons, resulting in the overexpression of neuronal NF-кB. These effects suggest that reduced blood levels of Fg can be beneficial in mitigating the STM reduction seen in m-mTBI.

Literature review of Alzheimer’s disease aetiology

Introduction: The most prevalent neurodegenerative illness and kind of dementia is Alzheimer’s disease (AD). It shows up as a reduction in short-term memory and cognitive function that affects day-to-day functioning. The majority of Alzheimer’s cases are idiopathic, but a tiny percentage of hereditary instances provide gene identification, which when combined with neuropathology provides crucial hints regarding the broader causes. The development and course of the illness are influenced by metabolic and environmental risk factors, such as vascular impairment and inflammation. We still don’t fully grasp how neuronal shrinkage and synaptic loss occur across the cerebral cortex. The aim of this review paper is to give a concise overview of AD and its pathogenesis. Methods: Relevant terms were applied to several databases (including CENTRAL; CINAHL; EMBASE; Medline Ovid; and PubMed NCBI) to search for studies exploring aetiology of AD. Result and discussion: Eight etiological theories have been identified based our database search. These include: 1) The aging process; 2) The deterioration of cholinergic and cortical anatomic channels; 3) Environmental factors; 4) Genetic causes; 5) Metabolic malfunction resulting from defects in the mitochondria; 6) Blood/brain barrier impairments; 7) Immune and viral aetiology. Keywords: Alzheimer’s disease, aetiology, Theory of Aging, Cholinergic hypothesis.

Fibrinogen Interaction with Astrocyte ICAM-1 and PrPC Results in the Generation of ROS and Neuronal Death

Many neuroinflammatory diseases, like traumatic brain injury (TBI), are associated with an elevated level of fibrinogen and short-term memory (STM) impairment. We found that during TBI, extravasated fibrinogen deposited in vasculo-astrocyte interfaces, which was associated with neurodegeneration and STM reduction. The mechanisms of this fibrinogen-astrocyte interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain astrocytes were treated with fibrinogen in the presence or absence of function-blocking antibody or peptide against its astrocyte receptors intercellular adhesion molecule-1 (ICAM-1) or cellular prion protein (PrPC), respectively. Fibrinogen interactions with astrocytic ICAM-1 and PrPC were characterized. The expression of pro-inflammatory markers, generations of reactive oxygen species (ROS) and nitric oxide (NO) in astrocytes, and neuronal death caused by astrocyte-conditioned medium were assessed. Data showed a strong association between fibrinogen and astrocytic ICAM-1 or PrPC, overexpression of pro-inflammatory cytokines and overproduction of ROS and NO, resulting in neuronal apoptosis and death. These effects were reduced by blocking the function of astrocytic ICAM-1 and PrPC, suggesting that fibrinogen association with its astrocytic receptors induce the release of pro-inflammatory cytokines, resulting in oxidative stress, and ultimately neuronal death. This can be a mechanism of neurodegeneration and the resultant STM reduction seen during TBI.

Effects of fibrinogen synthesis inhibition on vascular cognitive impairment during traumatic brain injury in mice

Traumatic brain injury (TBI) is associated with increased blood content of fibrinogen (Fg), called hyperfibrinogenemia (HFg), which results in enhanced cerebrovascular permeability and leads to short-term memory (STM) reduction. Previously, we showed that extravasated Fg was deposited in the vasculo-astrocyte interface and was co-localized with cellular prion protein (PrPC) during mild-to-moderate TBI in mice. These effects were accompanied by neurodegeneration and STM reduction. However, there was no evidence presented that the described effects were the direct result of the HFg during TBI. We now present data indicating that inhibition of Fg synthesis can ameliorate TBI-induced cerebrovascular permeability and STM reduction. Cortical contusion injury (CCI) was induced in C57BL/6J mice. Then mice were treated with either Fg antisense oligonucleotide (Fg-ASO) or with control-ASO for two weeks. Cerebrovascular permeability to fluorescently labeled bovine serum albumin was assessed in cortical venules following evaluation of STM with memory assessement tests. Separately, brain samples were collected in order to define the expression of PrPC via Western blotting while deposition and co-localization of Fg and PrPC, as well as gene expression of inflammatory marker activating transcription factor 3 (ATF3), were characterized with real-time PCR. Results showed that inhibition of Fg synthesis with Fg-ASO reduced overexpression of AFT3, ameliorated enhanced cerebrovascular permeability, decreased expression of PrPC and Fg deposition, decreased formation of Fg-PrPC complexes in brain, and improved STM. These data provide direct evidence that a CCI-induced inflammation-mediated HFg could be a triggering mechanism involved in vascular cognitive impairment seen previously in our studies during mild-to-moderate TBI.

Fibrinogen and Neuroinflammation During Traumatic Brain Injury.

Many neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis, and traumatic brain injury (TBI) are associated with systemic inflammation. Inflammation itself results in increased blood content of fibrinogen (Fg), called hyperfibrinogenemia (HFg). Fg is not only considered an acute phase protein and a marker of inflammation, but has been shown that it can cause inflammatory responses. Fibrin deposits have been associated with memory reduction in neuroinflammatory diseases such as AD and TBI. Reduction in short-term memory has been seen during the most common form of TBI, mild-to-moderate TBI. Fibrin deposits have been found in brains of patients with mild-to-moderate TBI. The vast majority of the literature emphasizes the role of fibrin-activated microglia as the mediator in the neuroinflammation pathway. However, the recent discovery that astrocytes, which constitute approximately 30% of the cells in the mammalian central nervous system, manifest different reactive states warrants further investigations in the causative role of HFg in astrocyte-mediated neuroinflammation. Our previous study showed that Fg deposited in the vasculo-astrocyte interface-activated astrocytes. However, little is known of how Fg directly affects astrocytes and neurons. In this review, we summarize studies that show the effect of Fg on different types of cells in the vasculo-neuronal unit. We will also discuss the possible mechanism of HFg-induced neuroinflammation during TBI.

Behavioral Evaluation of rotenone model of Parkinson’s disease in male Wistar rats

Introduction: Parkinson’s disease (PD) is a prevalent neurodegenerative disorder in elderly people. The condition is associated with damage to the dopaminergic neurons in the substantia nigra pars compacta, a great decrement of dopamine neurotransmitter in the striatum, and a deficiency of tyrosine hydroxylase; the rate-determining enzyme during dopamine formation. In rats, rotenone has been administered to induce a syndrome that mimics the behavioral and pathophysiological finding of Parkinson's disease.Aim of the work: To evaluate the behavioral aspects of PD in rotenone-treated Wistar rats.Materials and Methods: Rotenone at 2 mg/kg was injected subcutaneously to male adult Wistar rats in the rotenone-treated group once a day for 4 weeks for induction of PD. Open Field test, object recognition test, Rota-rod test, footprint test and forced swim test were performed at the end of induction. Tyrosine hydroxylase levels in the brain were measured.Results: Our data showed deteriorated behavioral aspects after rotenone treatment, with a decrease in exploration and locomotion, impaired motor coordination, asymmetrical impaired gait, increased depressive-like behaviors, reduction in short-term memory and reduction in tyrosine hydroxylase levels. Conclusion: in this study, rotenone subcutaneously at a dose of 2 mg/kg daily for 4 weeks, in adult male Wistar rats, caused the appearance of the motor and the non-motor features of PD with a marked drop-off tyrosine hydroxylase levels in the striatum.

Cerebrovascular Hyper‐permeability and Memory Impairment after Cortical Contusion Injury during Hyperhomocysteinemia in Mice

Traumatic brain injury (TBI) is the devastating public health problem worldwide. It is accompanied with inflammation, cerebrovascular dysfunction, and memory impairment. The latter is known to be greatly affected by cellular prion protein (PrPC). Elevated blood level of Homocysteine (Hcy), called hyperhomocysteinemia (HHcy) is considered to be an independent inflammatory and high risk factor for many cerebrovascular diseases. HHcy was found in TBI patients. High level of Hcy is associated with increased levels of another inflammatory marker fibrinogen (Fg). In the present study, we tested the hypothesis that HHcy exacerbates TBI‐induced macromolecular protein extravasation resulting in enhanced Fg‐PrPC complex formation leading to reduction in short‐term memory.Cerebrovascular permeability was studied in cystathionine‐β‐synthase heterozygote knockout (CBS+/−) mice, a well‐known model of HHcy. As a control we used wild type (WT, C57BL/6J) mice. Mice were subjected to cortical contusion injury (CCI) or sham operation (sham). Cerebrovascular permeability was assessed by measuring the fluorescence intensity of Alexaflour 647‐labeled bovine serum albumin (647‐BSA) in extravascular space using an intravital fluorescence microscopy. Formation of Fg‐PrPC complex in brain sample cryosections was studied using immunohistochemistry and confocal microscopy. Short‐term memory changes were evaluated by a novel object recognition test (NORT) and Y maze spontaneous alternation and two trial recognition tests.Pial venular permeability to 647‐BSA was greater in all experimental animals with CCI compared to that in respective sham‐operated mice. However, in injured CBS+/− mice the protein leakage was greater (201±6 % of baseline) than that (166±9 % of baseline) in WT animals with CCI. Enhanced Fg‐PrPC complex formation was found in WT animals after CCI compared to that in sham mice. Increased depositions of Fg and PrPC and their complex formations were detected in CBS+/− mice compared to those in control WT group. Short‐term memory deficiency after CCI was noted in both mice groups. However, reduction in short‐term memory (difference in discrimination ratios between sham and CCI groups) defined by NORT was greater (0.4±0.05) in CBS+/− mice compared to that (0.2±0.04) in control WT mice.Thus, our study reveals a novel, additive effect of HHcy in TBI‐induced memory impairment, which can be therapeutically targeted in future.Support or Funding InformationSupported in part by NIH grant NS084823, AHA grant 17SDG33670372, and UofL SOM Basic grant 57139This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Localization of Fibrinogen in the Vasculo-Astrocyte Interface after Cortical Contusion Injury in Mice.

Besides causing neuronal damage, traumatic brain injury (TBI) is involved in memory reduction, which can be a result of alterations in vasculo-neuronal interactions. Inflammation following TBI is involved in elevation of blood content of fibrinogen (Fg), which is known to enhance cerebrovascular permeability, and thus, enhance its deposition in extravascular space. However, the localization of Fg in the extravascular space and its possible interaction with nonvascular cells are not clear. The localization of Fg deposition in the extravascular space was defined in brain samples of mice after cortical contusion injury (CCI) and sham-operation (control) using immunohistochemistry and laser-scanning confocal microscopy. Memory changes were assessed with new object recognition and Y-maze tests. Data showed a greater deposition of Fg in the vascular and astrocyte endfeet interface in mice with CCI than in control animals. This effect was accompanied by enhanced neuronal degeneration and reduction in short-term memory in mice with CCI. Thus, our results suggest that CCI induces increased deposition of Fg in the vasculo-astrocyte interface, and is accompanied by neuronal degeneration, which may result in reduction of short-term memory.

Cerebrovascular disorders caused by hyperfibrinogenaemia.

Hyperfibrinogenaemia (HFg) results in vascular remodelling, and fibrinogen (Fg) and amyloid β (Aβ) complex formation is a hallmark of Alzheimer's disease. However, the interconnection of these effects, their mechanisms and implications in cerebrovascular diseases are not known. Using a mouse model of HFg, we showed that at an elevated blood level, Fg increases cerebrovascular permeability via mainly caveolar protein transcytosis. This enhances deposition of Fg in subendothelial matrix and interstitium making the immobilized Fg a readily accessible substrate for binding Aβ and cellular prion protein (PrPC ), the protein that is thought to have a greater effect on memory than Aβ. We showed that enhanced formation of Fg-Aβ and Fg-PrPC complexes are associated with reduction in short-term memory. The present study delineates a new mechanistic pathway for vasculo-neuronal dysfunctions found in inflammatory cardiovascular and cerebrovascular diseases associated with an elevated blood level of Fg. Many cardiovascular diseases are associated with inflammation and as such are accompanied by an increased blood level of fibrinogen (Fg). Besides its well-known prothrombotic effects Fg seems to have other destructive roles in developing microvascular dysfunction that include changes in vascular reactivity and permeability. Increased permeability of brain microvessels has the most profound effects as it may lead to cerebrovascular remodelling and result in memory reduction. The goal of the present study was to define mechanisms of cerebrovascular permeability and associated reduction in memory induced by elevated blood content of Fg. Genetically modified, transgenic hyperfibrinogenic (HFg) mice were used to study cerebrovascular transcellular and paracellular permeability in vivo. The extent of caveolar formation and the role of caveolin-1 signalling were evaluated by immunohistochemistry (IHC) and Western blot (WB) analysis in brain samples from experimental animals. Formation of Fg complexes with amyloid β (Aβ) and with cellular prion protein (PrPC ) were also assessed with IHC and WB analysis. Short-term memory of mice was assessed by novel object recognition and Y-maze tests. Caveolar protein transcytosis was found to have a prevailing role in overall increased cerebrovascular permeability in HFg mice. These results were associated with enhanced formation of caveolae. Increased formation of Fg-PrPC and Fg-Aβ complexes were correlated with reduction in short-term memory in HFg mice. Using the model of hyperfibrinogenaemia, the present study shows a novel mechanistic pathway of inflammation-induced and Fg-mediated reduction in short-term memory.

Impaired Thinking in Patients with Breast Cancer and Depression

Background: Brain-derived neurotrophic factor (BDNF) levels have been implicated in cognitive function and in the regulation of mood disorders, like depression. The aim of this study was to investigate the cognitive deficits of advanced cancer patients with depression and to assess the influence of various clinical factors on depression and cognition. Methods: Serum BDNF and plasma IL-6 were measured in patients treated for metastatic breast cancer diagnosed with depression according to DSM IV criteria. Cognitive function was assessed by the Piaget tasks and Verbal Learning and Memory Test, as a measure of short-term memory (STM) and long-term memory (LTM). Results: 29 patients with depression were compared to 27 matched controls without depression in this study. Even though both patient groups were of similar age, patients with clinical depression presented with a reduced Karnofsky performance status 66%. The presence of clinical depression was dependant on higher IL-6 levels (29.3 vs. 7.1 pg/ml; p=0.001) and cancer activity (p=0.002, χ2-test). BDNF had no direct association with depression. However, IL-6 level was an independent predictor of BDNF (b=-0.41, p=0.005). Patients with depression showed impairment of their ability to perform the Piaget tasks and a reduction in STM (4.0 vs. 6.8; p<0.001 and 18.9 vs. 32.3; p=0.003, respectively). Piaget tasks performance and STM were associated with lower BDNF levels (b=0.46, p=0.001 and b=0.23, p=0.043). Conclusions: Unlike IL-6, BDNF showed no association with depression in this population. Patients with low BDNF-levels and depression however, achieved lower scores in STM and Piaget tasks. The inability to perform the Piaget tasks adequately in this situation, demonstrates substantial difficulties in reasoning.

Variation in to Neural Physiology and Anatomy Due to Diet Related Factors as a Possible Cause to Neurodegeneration

Neurodegenerative disorders have been linked to an array of external factors ranging from atmospheric pollutants to diet related additives. In our study we have investigated BMAA a neurotoxin produced by cyanobacteria, which gets an easy entry into human food chain via sea food and water, Aluminium which is believed to be present more in bottled water in comparison to tap water; and MSG, a derivative of glutamate; extensively used as flavour enhancer. LD50 for the three chemicals used in this study were determined. Our results suggest that BMAA leads to a significant loss of long term memory, reduction in geotaxic response, and reduction in both, fertility and life span. Short term memory was not significantly affected by BMAA. Aluminium deposits caused loss of long and short term memory and reduction in geotaxic response. MSG caused reduction in short term memory. In combination with BMAA, MSG produced reduction in all the parameters. Dementia has a direct bearing on quality of life. Dementia can set in as early as 40 years of age in humans. This has been attributed to life-style and stress related factors. The present study establishes a direct cause and effect relationship between dementia, stress and diet. These effects are established when Drosophila melanogaster are treated with neurotoxins, singly or in combinations. Experiments are in progress to understand the mechanisms that underlie these processes.

Neuropsychological sequelae of 50 Hz magnetic fields

Purpose : The effects of occupational levels of 50 Hz magnetic fields on cognitive function were studied on 30 human volunteers. Materials and methods : The exposure system consisted of Merrit-type modified Helmholtz coils forming a 2 m cube, employing two orthogonal sets of coils producing a 28 μ T (resultant) circularly polarized 50 Hz magnetic field. Subjects sat at a desk within the coils where they undertook a series of verbal and written tests of cognitive function. After these tests were concluded (~30min) subjects were either exposed or sham-exposed to fields (double-blinded) for 50min. A second set of tests (employing alternate versions) was administered 20min from the start of this period. Each subject returned after 7 days to repeat the sequence, but with the opposite field/sham status. Results and conclusions : The majority of the results indicated no significant effect of exposure on cognition. However, verbal recall of a list of 15 words after an interference (the different list) was significantly impaired in the 'field on' condition. This is indicative of a reduction in short-term memory of words. The mean baseline score was somewhat higher in the 'field on' condition. However, this difference is within the parameters of normal variation. The other significant result occurred during performance of a trail-making task (alternating 1-A-2-B-3-C, etc.), with a decrease in performance as a result of exposure to the 50 Hz field. This task requires executive functioning with a working memory load, involving parietal spatial processing coordinated by prefrontal executive processing. In summary, the data are suggestive of detrimental effects on cognitive processes, particularly short-term learning and executive functioning. However, larger sample sizes are required to demonstrate statistically a more specific pattern of cognitive effects.

Retrieval failure, rehearsal deficiency, and short-term memory loss in the aphasic adult

Studies show that aphasic patients typically are grossly impaired in short-term memory performance. Since aphasics generally experience difficulty in word retrieval, it is conceivable that short-term memory loss is partially the result of verbal rehearsal deficiency which, in turn, is caused by the word retrieval problem. This paper reports an experiment in which five aphasic adults were nonverbally to recall individualized lists of pictures they could easily name and lists of pictures they could not name. Final items in the two lists were recalled with equal accuracy; this was expected in that the recency effect usually reflects sensory rather than verbal storage. Initial items were recalled with greater accuracy than middle-list items in the nameable sets but not in the unnameable sets. This primacy effect suggests the aphasics rehearsed the nameable pictures, but both lists were recalled so poorly that rehearsal deficit was considered responsible for no more than a fraction of the aphasics' reduction in short-term memory.