scholarly journals Electrophysiological Biomarkers of Epileptogenicity in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Tingting Yu ◽  
Xiao Liu ◽  
Jianping Wu ◽  
Qun Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Frequency ◽  
Cortical Network ◽  
Accurate Identification ◽  
New Approach ◽  
Epileptiform Discharges ◽  
Scalp Electroencephalogram ◽  
Electroencephalogram Eeg

Cortical network hyperexcitability is an inextricable feature of Alzheimer’s disease (AD) that also might accelerate its progression. Seizures are reported in 10–22% of patients with AD, and subclinical epileptiform abnormalities have been identified in 21–42% of patients with AD without seizures. Accurate identification of hyperexcitability and appropriate intervention to slow the compromise of cognitive functions of AD might open up a new approach to treatment. Based on the results of several studies, epileptiform discharges, especially those with specific features (including high frequency, robust morphology, right temporal location, and occurrence during awake or rapid eye movement states), frequent small sharp spikes (SSSs), temporal intermittent rhythmic delta activities (TIRDAs), and paroxysmal slow wave events (PSWEs) recorded in long-term scalp electroencephalogram (EEG) provide sufficient sensitivity and specificity in detecting cortical network hyperexcitability and epileptogenicity of AD. In addition, magnetoencephalogram (MEG), foramen ovale (FO) electrodes, and computational approaches help to find subclinical seizures that are invisible on scalp EEGs. We performed a comprehensive analysis of the aforementioned electrophysiological biomarkers of AD-related seizures.

Detection of Alzheimer’s Disease Electroencephalogram Temporal Events

2013 ◽  
Vol 2 (3) ◽  
pp. 44-61 ◽  
Author(s):  
Pedro Miguel Rodrigues ◽  
Diamantino Rui Freitas ◽  
João Paulo Teixeira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
The Elderly ◽  
Clinical Settings ◽  
Brain Disorder ◽  
New Approach ◽  
Self Organized ◽  
Available Technology ◽  
Temporal Events ◽  
Electroencephalogram Eeg

Alzheimer’s Disease (AD) is a chronic progressive and irreversible neurodegenerative brain disorder. The aging population has been increasing significantly in recent decades. Therefore, AD will continue to increase because the disease affects mainly the elderly. Its diagnostic accuracy is relatively low, and there is not a biomarker able to detect AD without invasive tests. The electroencephalogram (EEG) test is a widely available technology in clinical settings. It may help diagnosis of brain disorders, once it can be used in patients who have cognitive impairment involving a general decrease in overall brain function or in patients with a located deficit. This study is a new approach to detect EEG temporal events in order to improve the AD diagnosis. For that, K-means and Self-Organized Maps were used, and the results suggested that there are sequences of EEG energy variation that appear more frequently in AD patients than in healthy subjects.

scholarly journals Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease

2020 ◽  
Vol 21 (23) ◽  
pp. 9318
Author(s):  
Sofia Toniolo ◽  
Arjune Sen ◽  
Masud Husain
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Viral Vectors ◽  
Epileptiform Activity ◽  
Long Term Potentiation ◽  
Therapeutic Interventions ◽  
Epileptiform Discharges ◽  
Aβ Amyloid ◽  
Brain Hyperexcitability

People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology.

scholarly journals Seizure in Alzheimer’s Disease: An Underestimated Phenomenon

2018 ◽  
Vol 34 (2) ◽  
pp. 81-88 ◽  
Author(s):  
Marjan Asadollahi ◽  
Musa Atazadeh ◽  
Maryam Noroozian
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Options ◽  
Cognitive Domains ◽  
Inhibitory Circuits ◽  
Epileptiform Discharges ◽  
Cerebrospinal Fluid Biomarkers ◽  
Clinical Presentations ◽  
Underlying Mechanisms ◽  
Electroencephalogram Eeg

Alzheimer’s disease (AD) is considered as a potential risk factor for the development of seizure due to neurodegeneration and imbalance between stimulatory and inhibitory circuits in the brain. Seizure could occur in any point during the course of AD, and its presentation varies from fluctuation in cognitive domains to more typical seizures. The clinical diagnosis of seizure in patients with dementia may be challenging due to difficulty in history taking and clinical assessment. No paraclinic methods other than electroencephalogram (EEG) could provide arguments for the diagnosis of AD-related seizures (neither imaging modalities nor cerebrospinal fluid biomarkers). Standard 30-minute EEG may not be sufficiently sensitive to detect epileptiform discharges. In the present study, we aim to review different aspects of seizure in AD, including seizure prevalence, risk factors, underlying mechanisms, electroencephalographic findings, clinical presentations, impact of seizures on AD, and treatment options.

Integrated Biomarkers for Depression in Alzheimer’s Disease: A Critical Review

2017 ◽  
Vol 14 (4) ◽  
pp. 441-452 ◽  
Author(s):  
Sofia Wenzler ◽  
Christian Knochel ◽  
Ceylan Balaban ◽  
Dominik Kraft ◽  
Juliane Kopf ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Affect Regulation ◽  
Current Evidence ◽  
Diagnostic Process ◽  
Neuropsychiatric Manifestation ◽  
The Brain ◽  
Control Functional

Depression is a common neuropsychiatric manifestation among Alzheimer’s disease (AD) patients. It may compromise everyday activities and lead to a faster cognitive decline as well as worse quality of life. The identification of promising biomarkers may therefore help to timely initiate and improve the treatment of preclinical and clinical states of AD, and to improve the long-term functional outcome. In this narrative review, we report studies that investigated biomarkers for AD-related depression. Genetic findings state AD-related depression as a rather complex, multifactorial trait with relevant environmental and inherited contributors. However, one specific set of genes, the brain derived neurotrophic factor (BDNF), specifically the Val66Met polymorphism, may play a crucial role in AD-related depression. Regarding neuroimaging markers, the most promising findings reveal structural impairments in the cortico-subcortical networks that are related to affect regulation and reward / aversion control. Functional imaging studies reveal abnormalities in predominantly frontal and temporal regions. Furthermore, CSF based biomarkers are seen as potentially promising for the diagnostic process showing abnormalities in metabolic pathways that contribute to AD-related depression. However, there is a need for standardization of methodological issues and for replication of current evidence with larger cohorts and prospective studies.

NF-κB as a Key Mediator of Brain Inflammation in Alzheimer’s Disease

2019 ◽  
Vol 18 (1) ◽  
pp. 3-10 ◽  
Author(s):  
Chul Ju Hwang ◽  
Dong-Young Choi ◽  
Mi Hee Park ◽  
Jin Tae Hong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Strategies ◽  
Close Correlation ◽  
Specific Protein ◽  
Brain Inflammation ◽  
Cytokines And Chemokines ◽  
Inflammatory Drugs ◽  
Peptide Fibrils

Alzheimer’s disease is the most common form of dementia. It is characterized by betaamyloid peptide fibrils which are extracellular deposition of a specific protein, accompanied by extensive neuroinflammation. Various studies show the presence of a number of inflammation markers in the AD brain: elevated inflammatory cytokines and chemokines, and an accumulation of activated microglia in the damaged regions. NF-κB is a family of redox sensitive transcriptional factors, and it is known that NF-κB has binding sites in the promoter region of the genes involved in amyloidogenesis and inflammation. Long-term use of non-steroidal anti-inflammatory drugs prevents progression of AD and delays its onset, suggesting that there is a close correlation between NF-κB and AD pathogenesis. This study aims to (1) assess the association between NF-κB activity and AD through discussion of a variety of experimental and clinical studies on AD and (2) review treatment strategies designed to treat or prevent AD with NF-κB inhibitors.

Neurobehavioral Consequences Associated with Long Term Tramadol Utilization and Pathological Mechanisms

2020 ◽  
Vol 18 (10) ◽  
pp. 758-768 ◽  
Author(s):  
Khadga Raj ◽  
Pooja Chawla ◽  
Shamsher Singh
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Serotonin Syndrome ◽  
Dopamine Synthesis ◽  
Synthetic Analog

: Tramadol is a synthetic analog of codeine used to treat pain of moderate to severe intensity and is reported to have neurotoxic potential. At therapeutic dose, tramadol does not cause major side effects in comparison to other opioid analgesics, and is useful for the management of neurological problems like anxiety and depression. Long term utilization of tramadol is associated with various neurological disorders like seizures, serotonin syndrome, Alzheimer’s disease and Parkinson’s disease. Tramadol produces seizures through inhibition of nitric oxide, serotonin reuptake and inhibitory effects on GABA receptors. Extensive tramadol intake alters redox balance through elevating lipid peroxidation and free radical leading to neurotoxicity and produces neurobehavioral deficits. During Alzheimer’s disease progression, low level of intracellular signalling molecules like cGMP, cAMP, PKC and PKA affect both learning and memory. Pharmacologically tramadol produces actions similar to Selective Serotonin Reuptake Inhibitors (SSRIs), increasing the concentration of serotonin, which causes serotonin syndrome. In addition, tramadol also inhibits GABAA receptors in the CNS has been evidenced to interfere with dopamine synthesis and release, responsible for motor symptoms. The reduced level of dopamine may produce bradykinesia and tremors which are chief motor abnormalities in Parkinson’s Disease (PD).

Learning Deficits Accompanied by Microglial Proliferation After the Long-Term Post-Injection of Alzheimer’s Disease Brain Extract in Mouse Brains

2021 ◽  
Vol 79 (4) ◽  
pp. 1701-1711
Author(s):  
Tetsuo Hayashi ◽  
Shotaro Shimonaka ◽  
Montasir Elahi ◽  
Shin-Ei Matsumoto ◽  
Koichi Ishiguro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Brain ◽  
Functional Decline ◽  
Brain Regions ◽  
Insoluble Fraction ◽  
Brain Extract ◽  
Post Injection ◽  
Learning Deficits

Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions.

scholarly journals Disruption of the astrocyte–neuron interaction is responsible for the impairments in learning and memory in 5XFAD mice: an Alzheimer’s disease animal model

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Moonseok Choi ◽  
Sang-Min Lee ◽  
Dongsoo Kim ◽  
Heh-In Im ◽  
Hye-Sun Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Memory Formation ◽  
Long Term Memory ◽  
Term Memory ◽  
Stat3 Phosphorylation ◽  
Neuron Interactions ◽  
5Xfad Mice

AbstractThe morphological dynamics of astrocytes are altered in the hippocampus during memory induction. Astrocyte–neuron interactions on synapses are called tripartite synapses. These control the synaptic function in the central nervous system. Astrocytes are activated in a reactive state by STAT3 phosphorylation in 5XFAD mice, an Alzheimer’s disease (AD) animal model. However, changes in astrocyte–neuron interactions in reactive or resting-state astrocytes during memory induction remain to be defined. Here, we investigated the time-dependent changes in astrocyte morphology and the number of astrocyte–neuron interactions in the hippocampus over the course of long-term memory formation in 5XFAD mice. Hippocampal-dependent long-term memory was induced using a contextual fear conditioning test in 5XFAD mice. The number of astrocytic processes increased in both wild-type and 5XFAD mice during memory formation. To assess astrocyte–neuron interactions in the hippocampal dentate gyrus, we counted the colocalization of glial fibrillary acidic protein and postsynaptic density protein 95 via immunofluorescence. Both groups revealed an increase in astrocyte–neuron interactions after memory induction. At 24 h after memory formation, the number of tripartite synapses returned to baseline levels in both groups. However, the total number of astrocyte–neuron interactions was significantly decreased in 5XFAD mice. Administration of Stattic, a STAT3 phosphorylation inhibitor, rescued the number of astrocyte–neuron interactions in 5XFAD mice. In conclusion, we suggest that a decreased number of astrocyte–neuron interactions may underlie memory impairment in the early stages of AD.

Lentivirus-Mediated Expression of Human Secreted Amyloid Precursor Protein-Alpha Promotes Long-Term Induction of Neuroprotective Genes and Pathways in a Mouse Model of Alzheimer’s Disease

2020 ◽  
pp. 1-16
Author(s):  
Margaret Ryan ◽  
Valerie T.Y. Tan ◽  
Nasya Thompson ◽  
Diane Guévremont ◽  
Bruce G. Mockett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Integrated Analysis ◽  
Empty Vector ◽  
Mouse Transcriptome

Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter, and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival, and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo

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