Neurodegenerative Changes Research Articles

Synergistically enhanced apoptotic and oxidative DNA damaging pathways in the rat brain with lead and/or aluminum metals toxicity: Expression pattern of genes OGG1 and P53

BackgroundLead (Pb) and aluminum (Al) are ubiquitous environmental pollutants and are known to induce neurodegenerative disorders. They enhance neuronal changes and may involve glial alterations and other consequences. We intend to evaluate the mechanism through which the long-term exposure to Pb acetate alone or in combination with aluminum-chloride induced neurological impacts in rats. MethodsFor this aim, a total number of forty male Sprague Dawley rats were assigned into four groups. Control (DW), Pb acetate (12.5 mg/kg BW), Al chloride (64 mg/kg BW), and the combination group were experimentally exposed for 60 days. Biochemical evaluation of oxidative stress biomarkers, transcriptional-mediated changes in the expression pattern of OGG1 and P53 genes by qRT-PCR were applied. Histopathological modifications in the brain tissue with immunohistochemical reactivity of GFAP were also detected. ResultsOur findings revealed that lipid peroxidation was markedly enhanced but inhibited antioxidant enzyme activity in brain tissue in all exposed groups regarding the control. Pb-acetate elevated the biochemical concentration of dopamine and serotonin while AlCl3 declined their levels in the brain homogenate of rats. Furthermore, the exposure to one or both metals elevated the comet assay indices and serum level of 8-hydroxy-2′ –deoxyguanosine, up-regulated the expression of P53, OGG1 and GFAP immunoreactivity in the central nervous system. Histologically, they caused several brain tissue alterations. ConclusionThe exposure to Pb and/or Al could be key candidates for neurodegenerative changes in the brain of rats via oxidative, apoptotic, and DNA damaging pathways. Besides, according to our findings, exposure to both Pb acetate and Aluminium chloride have synergistic damaging effects on the central nervous system of rats. Also, they have opposing effects on the secretion of monoamine neurotransmitters DA and 5 H T.

Potential neuroprotection by Dendrobium nobile Lindl alkaloid in Alzheimer's disease models.

At present, treatments for Alzheimer's disease can temporarily relieve symptoms but cannot prevent the decline of cognitive ability and other neurodegenerative changes. Dendrobium nobile Lindl alkaloid is the main active component of Dendrobium nobile Lindl. Dendrobium nobile Lindl alkaloid has been shown to resist aging, prolong life span, and exhibit immunomodulatory effects in animals. This review summarizes the mechanisms behind the neuroprotective effects reported in Alzheimer's disease animal models. The neuroprotective effects of Dendrobium nobile Lindl alkaloid have not been studied in patients. The mechanisms by which Dendrobium nobile Lindl alkaloid has been reported to improve cognitive dysfunction in Alzheimer's disease animal models may be associated with extracellular amyloid plaque production, regulation of tau protein hyperphosphorylation, inhibition of neuroinflammation and neuronal apoptosis, activation of autophagy, and enhanced synaptic connections.

Neural Correlates of Autobiographical Memory: Evidence From a Positron Emission Tomography Study in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

Background: Autobiographical memory (AM) changes are the hallmark of Alzheimer's disease (AD) and mild cognitive impairment (MCI). In recent neuroimaging studies, AM changes have been associated with numerous cerebral sites, such as the frontal cortices, the mesial temporal lobe, or the posterior cingulum. Regional glucose uptake in these sites was investigated for underlying subdimensions using factor analysis. Subsequently, the factors were examined with respect to AM performance in a subgroup of patients.Methods: Data from 109 memory clinic referrals, who presented with MCI (n = 60), mild AD (n = 49), or were cognitively intact, were analyzed. The glucose metabolic rates determined by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in 34 cerebral sites important for AM were investigated for underlying subdimensions by calculating factor analysis with varimax rotation. Subsequently, the respective factor scores were correlated with the episodic and semantic AM performance of 22 patients, which was measured with a semi-structured interview assessing episodic memories (characterized by event-related emotional, sensory, contextual, and spatial–temporal details) and personal semantic knowledge from three periods of life (primary school, early adulthood, and recent years).Results: Factor analysis identified seven factors explaining 69% of the variance. While patients with MCI and AD showed lower values than controls on the factors frontal cortex, mesial temporal substructures, and occipital cortex, patients with MCI presented with increased values on the factors posterior cingulum and left temporo-prefrontal areas. The factors anterior cingulum and right temporal cortex showed only minor, non-significant group differences. Solely, the factor mesial temporal substructures was significantly correlated with both episodic memories (r = 0.424, p < 0.05) and personal semantic knowledge (r = 0.547, p < 0.01) in patients with MCI/AD.Conclusions: The factor structure identified corresponds by large to the morphological and functional interrelations of the respective sites. While reduced glucose uptake on the factors frontal cortex, mesial temporal substructures, and occipital cortex in the patient group may correspond to neurodegenerative changes, increased values on the factors posterior cingulum and left temporo-prefrontal areas in MCI may result from compensatory efforts. Interestingly, changes of the mesial temporal substructures were correlated with both semantic and episodic AM. Our findings suggest that AM deficits do not only reflect neurodegenerative changes but also refer to compensatory mechanisms as they involve both quantitative losses of specific memories and qualitative changes with a semantization of memories.

Beta Amyloid, Tau Protein, and Neuroinflammation: An Attempt to Integrate Different Hypotheses of Alzheimer\u2019s Disease Pathogenesis

Alzheimer’s disease (AD) is a neurodegenerative disease that inevitably results in dementia and death. Currently, there are no pathogenetically grounded methods for the prevention and treatment of AD, and all current treatment regimens are symptomatic and unable to significantly delay the development of dementia. The accumulation of β-amyloid peptide (Aβ), which is a spontaneous, aggregation-prone, and neurotoxic product of the processing of signaling protein APP (Amyloid Precursor Protein), in brain tissues, primarily in the hippocampus and the frontal cortex, was for a long time considered the main cause of neurodegenerative changes in AD. However, attempts to treat AD based on decreasing Aβ production and aggregation did not bring significant clinical results. More and more arguments are arising in favor of the fact that the overproduction of Aβ in most cases of AD is not the initial cause, but a concomitant event of pathological processes in the course of the development of sporadic AD. The concept of neuroinflammation has come to the fore, suggesting that inflammatory responses play the leading role in the initiation and development of AD, both in brain tissue and in the periphery. The hypothesis about the key role of neuroinflammation in the pathogenesis of AD opens up new opportunities in the search for ways to treat and prevent this socially significant disease.

Perivascular (Virchow–Robin) spaces

Perivascular spaces; also known as the Virchow-Robin Spaces, they are pleurally lined, interstitial fluid-filled areas that surround certain blood vessels in various organs, especially the perforating arteries in the brain, with an immunological function. Dilated perivascular spaces are divided into three types. The first of these is on the lenticulostriate artery, the second is in the cortex following the path of the medullary artery, and the third is in the midbrain. Perivascular spaces can be detected as areas of dilatation on MR images. Although a limited number of perivascular spaces can be seen in a normal brain, the increase in the number of these spaces has been associated with the incidence of various neurodegenerative diseases. Different theories have been suggested about the tendency of the perivascular spaces to expand. Current theories include mechanical trauma due to cerebrospinal fluid pulsing, elongation of penetrating blood vessels, unusual vascular permeability, and increased fluid exudation. In addition, the brain tissue atrophy that occurs with aging; It is thought to contribute to the widening of perivascular spaces by causing shrinkage of arteries, altered arterial wall permeability, obstruction of lymphatic drainage pathways and vascular demyelination. It is assumed that the clinical significance of the dilation tendencies of the perivascular spaces is based on shape change rather than size. These spaces have been mostly observed in brain regions such as corpus callosum, cingulate gyrus, dentate nucleus, substantia nigra and various arterial basins including lenticulostriate artery and mesencephalothalamic artery. In conclusion, when sections are taken on MR imaging, it is possible that perivascular spaces may be confused with microvascular diseases and some neurodegenerative changes. In addition, perivascular spaces can be seen without pathological significance. Therefore, it would be appropriate to investigate the etiological relationship by evaluating the radiological findings and clinical picture together.

Direct and Indirect Neurological Signs of COVID-19.

Objective. To systematize the neurological manifestations of COVID-19. Materials and methods. A systematic computerized analysis of all currently available publications on the neurological manifestations of COVID-19 was undertaken (2374 reports in PubMed) by topological data analysis. Results. A set of interactions between infection with SARS-CoV-2, metabolic impairments affecting neurotransmitters (acetylcholine, dopamine, serotonin, and GABA), enkephalins, and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia, and neurodegeneration (including demyelination) was described. The most typical neurological manifestations of COVID-19 were anosmia/ageusia due to ischemia, neurodegeneration, and/or systematic increases in proinflammatory cytokine levels. COVID-19 provoked ischemic stroke, Guillain–Barré syndrome, polyneuropathy, encephalitis, meningitis, and parkinsonism. Coronavirus infection increased the severity of multiple sclerosis and myopathies. The possible roles of the human virome in the pathophysiology of COVID-19 are considered. A clinical case of a patient with neurological complications of COVID-19 is described. Conclusions. In the long-term perspective, COVID-19 promotes increases in neurodegenerative changes, which requires special neurological rehabilitation programs. Use of cholinergic drugs and antihypoxic agents compatible with COVID-19 therapy is advised.

A-4 Cerebrospinal Fluid and Plasma Neurofilament Light in Relation to Longitudinal Objective and Subjective Cognitive Decline in Older Adults

Abstract Objective Cerebrospinal fluid (CSF) and plasma neurofilament light (NFL) concentrations were assessed in relation to longitudinal objective and subjective cognitive outcomes in older adults ranging from normal cognition to mild cognitive impairment. Interactive effects were assessed for apolipoprotein E ϵ4 (APOE4) carriership, a strong genetic risk factor for Alzheimer’s disease and molecular moderator of vascular disease. Method Vanderbilt Memory &amp; Aging Project participants (CSF n = 149, 72 ± 6 years; plasma n = 333, 73 ± 7 years) underwent fasting blood draw and lumbar puncture at baseline for NFL quantification. Serial neuropsychological assessments and subjective cognitive decline (SCD) questionnaires were completed at 18-month increments. Linear mixed effects regression models adjusted for age, sex, race/ethnicity, education, APOE4 carriership (for main effect models), and depressed mood. NFL x APOE4 interaction terms were used as predictors in follow-up models. Results CSF NFL predicted steeper declines in an executive functioning composite score (β = −0.0001, p = 0.001) and WAIS-IV Coding (β = −0.001, p = 0.001). An APOE4 interaction was present for executive functioning (β = −0.0002, p = 0.005) such that CSF NFL associations with longitudinal decline were stronger among APOE4+ participants. Plasma NFL predicted worsening SCD (β = 0.27, p = 0.002) and objective cognitive decline across all domains (p-values &amp;lt;0.05), with multiple APOE4 interactions (p-values &amp;lt;0.05) suggesting stronger associations with objective cognitive decline among APOE4+ participants. Conclusions Both CSF and plasma NFL detect neuropathology associated with cognitive decline among non-demented older adults, especially among APOE4 carriers. Findings further support the value of SCD as reflecting neurodegenerative changes associated with accelerated cognitive aging.

Ways to Address Perinatal Mast Cell Activation and Focal Brain Inflammation, including Response to SARS-CoV-2, in Autism Spectrum Disorder.

The prevalence of autism spectrum disorder (ASD) continues to increase, but no distinct pathogenesis or effective treatment are known yet. The presence of many comorbidities further complicates matters, making a personalized approach necessary. An increasing number of reports indicate that inflammation of the brain leads to neurodegenerative changes, especially during perinatal life, “short-circuiting the electrical system” in the amygdala that is essential for our ability to feel emotions, but also regulates fear. Inflammation of the brain can result from the stimulation of mast cells—found in all tissues including the brain—by neuropeptides, stress, toxins, and viruses such as SARS-CoV-2, leading to the activation of microglia. These resident brain defenders then release even more inflammatory molecules and stop “pruning” nerve connections, disrupting neuronal connectivity, lowering the fear threshold, and derailing the expression of emotions, as seen in ASD. Many epidemiological studies have reported a strong association between ASD and atopic dermatitis (eczema), asthma, and food allergies/intolerance, all of which involve activated mast cells. Mast cells can be triggered by allergens, neuropeptides, stress, and toxins, leading to disruption of the blood–brain barrier (BBB) and activation of microglia. Moreover, many epidemiological studies have reported a strong association between stress and atopic dermatitis (eczema) during gestation, which involves activated mast cells. Both mast cells and microglia can also be activated by SARS-CoV-2 in affected mothers during pregnancy. We showed increased expression of the proinflammatory cytokine IL-18 and its receptor, but decreased expression of the anti-inflammatory cytokine IL-38 and its receptor IL-36R, only in the amygdala of deceased children with ASD. We further showed that the natural flavonoid luteolin is a potent inhibitor of the activation of both mast cells and microglia, but also blocks SARS-CoV-2 binding to its receptor angiotensin-converting enzyme 2 (ACE2). A treatment approach should be tailored to each individual patient and should address hyperactivity/stress, allergies, or food intolerance, with the introduction of natural molecules or drugs to inhibit mast cells and microglia, such as liposomal luteolin.

Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer's disease mouse model.

Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer’s disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

Cognitive training modified age-related brain changes in older adults with subjective memory decline

Objectives Neuroimaging findings suggest that older adults with subjective memory decline (SMD) demonstrate some neurodegenerative brain changes and have high risk of developing dementia, but relatively little is known about the effectiveness of interventions for SMD. This study aimed to examine the effects of cognitive training on resting-state brain activity in SMD. Method This study employed the amplitude of low frequency fluctuations (ALFF) and resting state functional connectivity (rs-FC) analyses. After baseline evaluations, participants were randomly allocated to the intervention and control group to receive a four-week cognitive training and lectures on health and aging, respectively. All participants were scanned before and after training with an interval of about three months. Results (1) Participants in the intervention group showed significant improvements on the Associative Learning Test (ALT) and the Digit Span Forward task compared to the control group; (2) ALFF in the occipital lobe for the control group increased significantly, while that for the intervention group remained the same; ALFF changes were negatively correlated with ALT performance in the control group; (3) The mean value of rs-FC for the intervention group decreased, while that for the control group showed a trend of increase; rs-FC changes were also negatively correlated with ALT performance in the control group. Conclusions Resting-state brain activities in occipital region increased with aging. The cognitive training could counteract this brain function changes associated with aging or even reverse the changes. These findings provide new insights into the understanding of brain plasticity in posterior areas in SMD. Trial Registration ChiCTR-IOR-15006165 in the Chinese Clinical Trial Registry.

D-galactose induced dysfunction in mice hippocampus and the possible antioxidant and neuromodulatory effects of selenium.

Aging is an ultimate reality that everyone has to face. D-galactose (D-gal) has been used extensively to develop aging model. Trace elements such as selenium (Se) have been used as a potential antioxidant for neuro-protection. The present work aims to develop therapeutic agents such as Se for the treatment of aging-induced neurological ailments such as anxiety, depression, and memory impairment. For this purpose, mice were treated with D-gal at a dose of 300 mg/ml/kg and various doses of Se (0.175 and 0.35mg/ml/kg) for 28 days. Behavioral tests were monitored after treatment days. After the behavioral assessment, mice were decapitated and their brains were collected. Hippocampi were removed from the brain for biochemical, neurochemical, and histopathological analysis. The present findings of behavioral analysis showed that D-gal-induced anxiety- and depression-like symptoms were inhibited by both doses of Se. D-gal-induced memory alteration was also prevented by repeated doses of Se (0.175 and 0.35mg/ml/kg). Biochemical analysis showed that D-gal-induced increase of oxidative stress and inflammatory markers and decrease of antioxidant enzymes and total protein contents in the hippocampus were prevented by Se administration. An increase in the activity of acetylcholinesterase was also diminished by Se. The neurochemical assessment showed that D-gal-induced increased serotonin metabolism and decreased acetylcholine levels in the hippocampus were restored by repeated treatment of Se. Histopathological estimations also exhibited; normalization of D-gal induced neurodegenerative changes. It is concluded that D-gal-induced dysfunction in mice hippocampus caused anxiety, depression, memory impairment, oxidative stress, neuro-inflammation, and histological alterations that were mitigated by Se via its antioxidant potential, anti-inflammatory property, and modulating capability of serotonergic and cholinergic functions.

Evaluation of the Postnatal Effects Induced by Diazinon on the Growth of the Mice Offspring and the Development of Their Cerebellar Cortex

Diazinon (DZN) is a commonly used organophosphorus pesticide. Exposure to the residuals of DZN may lead to toxic effects. The current work was performed to clarify the possible physical variations and cellular changes in the developing cerebellar cortex of mice offspring after administration of DZN to their pregnant mothers. 27 adult males and 54 adult females were housed for mating. In the morning, vaginal smears were done to detect vaginal plug. Pregnant mice were divided into 3 groups: GI (control), GII (DZN), and GIII (sham control). Their offspring were subdivided into 3 subgroups (a) at birth, (b) on postnatal day 7 (PD7), and (c) on postnatal day 14 (PD14). At the end of the experiment, fetal crown-rump length and weight were measured. The cerebellar cortex was extracted, and samples were prepared for tissue homogenate, light and electron microscopic examination, morphometric and statistical studies. DZN treatment induced a statistically significant difference in pups’ crown-rump length and weight associated with a highly statistically significant decrease in acetylcholinesterase enzyme level. A histopathological degenerative change was observed in the cerebellum of GII. Postnatally, a separation between cerebellar layers occurred along with shrunken cells leading to multiple enfolding and vacuolated matrix. At PD14, pericellular halos and hemorrhage between the pia matter and external granular layer were noticed. Ultrastructural examination revealed dilated rough endoplasmic reticulum, swollen mitochondria, and shrunken hyperchromatic nuclei. Moreover, morphometric studies detected a statistically significant increase in external granular layer thickness and a statistical decrease in Purkinje cell numbers. These findings demonstrated that prenatal administration of DZN to pregnant mice adversely influenced the developing cerebellum of the offspring and leads to neurodegenerative changes.

Optical Coherence Tomography and Optical Coherence Tomography Angiography Findings in Multiple Sclerosis Patients

ABSTRACT In addition to ocular neurodegeneration in multiple sclerosis (MS), accompanying microvascular changes in the retina are thought to occur. In this study we sought to compare retinal neurodegenerative changes using optical coherence tomography (OCT) and microvascular changes using OCT angiography (OCTA) of MS patients and healthy controls. This cross-sectional study included 164 eyes of 83 MS patients and 114 eyes of 57 healthy control subjects. There were significant differences in retinal nerve fibre layer (RNFL), ganglion cell complex (GCC), and radial peripapillary capillary (RPC) vessel density (VD) between the MS group and the control group, but no significant differences in superficial capillary plexus (SCP) VD and deep capillary plexus (DCP) VD, foveal avascular zone (FAZ), non-flow area (NFA), and choriocapillary flow (CCF) values. Comparing the eyes with and without previous optic neuritis showed no significant differences in the OCT and OCTA measurements. A negative correlation was found between the expanded disability status scale score and disease duration and the RNFL and GCC values. A positive correlation was found between the RNFL and GCC values and the SCP VD and RPC VD. In MS patients, RPC VD values decreased in correlation with decreases in RNFL and GCC. This reduction increased as the disease duration and disability criteria increased. OCT and OCTA may be important biomarkers in MS.

Brain diffusion tensor imaging in dogs with degenerative myelopathy.

BackgroundDegenerative myelopathy (DM) in dogs shares similarities with superoxide dismutase 1‐associated human amyotrophic lateral sclerosis (ALS). Brain microstructural lesions are quantified using diffusion tensor imaging (DTI) in ALS patients.ObjectiveCharacterize brain neurodegenerative changes in DM‐affected dogs using DTI.AnimalsSixteen DM‐affected and 8 control dogs.MethodsProspective observational study. Brain DTI was performed at baseline and every 3 months on DM‐affected dogs and compared to controls. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated on specified regions of interest. Gait scores (0, normal to 14, tetraplegia) were assigned at each scan. Diffusion tensor imaging values in DM‐affected dogs were compared to controls, gait scores, and evaluated over time.ResultsMean age was 5.7 years (SD 3.2) in controls and 9.7 years (SD 1.4) in DM‐affected dogs. In DM‐affected dogs, mean baseline gait score was 4 (SD 1), and mean score change from baseline to last scan was 4.82 (SD 2.67). Nine dogs had ≤3 scans; 7 had >3 scans. Accounting for age, no differences in DTI indices were identified for any brain or proximal spinal cord regions between DM‐affected dogs and controls (P > .05). Diffusion tensor imaging values poorly correlated with gait scores (R 2 < .2). No significant changes were identified in diffusion indices over time (P > .05).Conclusions and Clinical ImportanceDiffusion tensor imaging indices did not differentiate DM‐affected from control dogs, detect longitudinal changes, or differentiate disease severity. Findings do not yet support brain DTI as an imaging biomarker.

Helicobacter Pylori Infection Is Associated with Neurodegeneration in Cognitively Normal Men.

An association between Helicobacter pylori (H. pylori) infection and dementia was reported in previous studies; however, the evidence is inconsistent. In the present study, the association between H. pylori infection and brain cortical thickness as a biomarker of neurodegeneration was investigated. A cross-sectional study of 822 men who underwent a medical health check-up, including an esophagogastroduodenoscopy and 3.0 T magnetic resonance imaging, was performed. H. pylori infection status was assessed based on histology. Multiple linear regression analyses were conducted to evaluate the relationship between H. pylori infection and brain cortical thickness. Men with H. pylori infection exhibited overall brain cortical thinning (p = 0.022), especially in the parietal (p = 0.008) and occipital lobes (p = 0.050) compared with non-infected men after adjusting for age, educational level, alcohol intake, smoking status, and intracranial volume. 3-dimentional topographical analysis showed that H. pylori infected men had cortical thinning in the bilateral lateral temporal, lateral frontal, and right occipital areas compared with non-infected men with the same adjustments (false discovery rate corrected, Q < 0.050). The association remained significant after further adjusting for inflammatory marker (C-reactive protein) and metabolic factors (obesity, dyslipidemia, fasting glucose, and blood pressure). Our results indicate H. pylori infection is associated with neurodegenerative changes in cognitive normal men. H. pylori infection may play a pathophysiologic role in the neurodegeneration and further studies are needed to validate this association.

Magnetic Resonance Imaging Findings Among Individuals With Olfactory and Cognitive Impairment

The underlying mechanism of the association between olfactory impairment and dementia may be explained by neurodegenerative changes detected on magnetic resonance imaging (MRI). The purpose of this systematic review is to describe neurodegenerative changes on MRI in patients with olfactory impairment and mild cognitive impairment (MCI) or dementia. Systematic review. A literature search encompassing PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Google Scholar for studies with MRI and olfactory testing among participants diagnosed with MCI or dementia was performed. Sample size, study design, cognitive impairment type, olfactory testing, and MRI findings were abstracted. Two investigators independently reviewed all articles. The search yielded 556 nonduplicate abstracts, from which 86 articles were reviewed and 24 were included. Seventeen (71%) of 24 studies reported hippocampal volume findings, with 14 studies reporting a relationship between hippocampal volume and olfactory performance. Two (50%) of four prospective studies reported the potential utility of baseline hippocampal volume as a marker of dementia conversion from MCI. Five (21%) of 24 studies reporting olfactory functional MRI (fMRI) findings highlighted the utility of olfactory fMRI to identify individuals in the early stages of cognitive decline. Current evidence suggests hippocampal volume correlates with olfactory performance in individuals with cognitive impairment, and that olfactory fMRI may improve early detection of AD. However, the predictive utility of these imaging markers is limited in prospective studies. MRI may be a useful modality for selecting patients at high risk of future cognitive decline for enrollment in early treatment trials. Laryngoscope, 132:177-187, 2022.

TPEN attenuates amyloid-\u03b225\u201335-induced neuronal damage with changes in the electrophysiological properties of voltage-gated sodium and potassium channels

To understand the role of intracellular zinc ion (Zn2+) dysregulation in mediating age-related neurodegenerative changes, particularly neurotoxicity resulting from the generation of excessive neurotoxic amyloid-β (Aβ) peptides, this study aimed to investigate whether N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+-specific chelator, could attenuate Aβ25–35-induced neurotoxicity and the underlying electrophysiological mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of hippocampal neurons and performed single-cell confocal imaging to detect the concentration of Zn2+ in these neurons. Furthermore, we used the whole-cell patch-clamp technique to detect the evoked repetitive action potential (APs), the voltage-gated sodium and potassium (K+) channels of primary hippocampal neurons. The analysis showed that TPEN attenuated Aβ25–35-induced neuronal death, reversed the Aβ25–35-induced increase in intracellular Zn2+ concentration and the frequency of APs, inhibited the increase in the maximum current density of voltage-activated sodium channel currents induced by Aβ25–35, relieved the Aβ25–35-induced decrease in the peak amplitude of transient outward K+ currents (IA) and outward-delayed rectifier K+ currents (IDR) at different membrane potentials, and suppressed the steady-state activation and inactivation curves of IA shifted toward the hyperpolarization direction caused by Aβ25–35. These results suggest that Aβ25–35-induced neuronal damage correlated with Zn2+ dysregulation mediated the electrophysiological changes in the voltage-gated sodium and K+ channels. Moreover, Zn2+-specific chelator-TPEN attenuated Aβ25–35-induced neuronal damage by recovering the intracellular Zn2+ concentration.

Aluminium chloride-induced hippocampal damage: CA3 hippocampal subfield involvement and the neuroprotective role of Buchholzia coriacea ethanolic seed extract

Early signs of neurodegenerative events of Alzheimer's disease manifest within the hippocampus and presents as cognitive and memory impairment. Aluminium-chloride (AlCl 3 ), a neurotoxicant interferes with the structure and functions of the hippocampus as well as its neurogenesis, thereby causing cognitive and memory impairment. Buchholzia coriacea (BC), a plant of nutraceutical value is traditionally reputed to boost memory and cognitive functions. This study elucidated the neuroprotective role of Buchholzia coriacea seed extract on AlCl 3 -induced hippocampal neuronal damage in Wistar rat model by examining the biochemical, histological, immunohistochemical, and neurobehavioural changes. Twenty-five male Wistar rats were randomly assigned into five groups A-E (n = 5). Group A served as the control, groups B-E were given 200 mg/kg of AlCl 3 for 14 days and then received 2 mLs/kg distilled water, 50mg/kg BC, 100mg/kg BC and 2.5mg/kg donepezil respectively for 14 days orally. Glutathione and neurotransmitters (Glutamate, dopamine, and acetylcholine) levels, G6PDH and neurobehavioral activities, as well as histological (H and E, LFB and Cresyl violet stains) and immunohistochemical (ionized calcium-binding adapter molecule 1, Iba-1) changes were evaluated AlCl 3 impaired spatial working memory with observable improvements in the treated groups. Enzymatic activity and neurotransmitter levels were augmented in the group treated with the highest dose of BC compared to the control. Histological assessment showed that BC high-dose mitigated neurodegenerative changes in the CA3 hippocampal subfield. Taken together, BC exhibited neuroprotective ability on AlCl 3 -induced CA3 hippocampal field neuronal damage and demonstrated memory impairment reversing ability.

Therapeutic potential of glial cell line-derived neurotrophic factor and cell reprogramming for hippocampal-related neurological disorders.

Hippocampus serves as a pivotal role in cognitive and emotional processes, as well as in the regulation of the hypothalamus-pituitary axis. It is known to undergo mild neurodegenerative changes during normal aging and severe atrophy in Alzheimer’s disease. Furthermore, dysregulation in the hippocampal function leads to epilepsy and mood disorders. In the first section, we summarized the most salient knowledge on the role of glial cell-line-derived neurotrophic factor and its receptors focused on aging, cognition and neurodegenerative and hippocampal-related neurological diseases mentioned above. In the second section, we reviewed the therapeutic approaches, particularly gene therapy, using glial cell-line-derived neurotrophic factor or its gene, as a key molecule in the development of neurological disorders. In the third section, we pointed at the potential of regenerative medicine, as an emerging and less explored strategy for the treatment of hippocampal disorders. We briefly reviewed the use of partial reprogramming to restore brain functions, non-neuronal cell reprogramming to generate neural stem cells, and neural progenitor cells as source-specific neuronal types to be implanted in animal models of specific neurodegenerative disorders.

Sleep Time Estimated by an Actigraphy Watch Correlates With CSF Tau in Cognitively Unimpaired Elders: The Modulatory Role of APOE.

There is increasing evidence of the relationship between sleep and neurodegeneration, but this knowledge is not incorporated into clinical practice yet. We aimed to test whether a basic sleep parameter, as total sleep estimated by actigraphy for 1 week, was a valid predictor of CSF Alzheimer’s Disease core biomarkers (amyloid-β-42 and –40, phosphorylated-tau-181, and total-tau) in elderly individuals, considering possible confounders and effect modifiers, particularly the APOE ε4 allele. One hundred and twenty-seven cognitively unimpaired volunteers enrolled in the Valdecilla Study for Memory and Brain Aging participated in this study. Seventy percent of the participants were women with a mean age of 65.5 years. After adjustment for covariates, reduced sleep time significantly predicted higher t-tau and p-tau. This association was mainly due to the APOE ε4 carriers. Our findings suggest that total sleep time, estimated by an actigraphy watch, is an early biomarker of tau pathology and that APOE modulates this relationship. The main limitation of this study is the limited validation of the actigraphy technology used. Sleep monitoring with wearables may be a useful and inexpensive screening test to detect early neurodegenerative changes.