Connectomic Analysis of Alzheimer’s Disease using Percolation Theory

Abstract Alzheimer’s disease (AD) is a severe neurodegenerative disorder that affects a growing worldwide elderly population. Identification of brain functional biomarkers is expected to help determine preclinical stages for targeted mechanistic studies and development of therapeutic interventions to deter disease progression. Connectomic analysis, a graph theory-based methodology used in the analysis of brain-derived connectivity matrices was used in conjunction with percolation theory targeted attack model to investigate the network effects of AD-related amyloid deposition. We used matrices derived from resting state functional magnetic resonance imaging collected on mice with extracellular amyloidosis (TgCRND8 mice, n = 17) and control littermates (n = 17). Global, nodal, spatial, and percolation-based analysis was performed comparing AD and control mice. These data indicate a short-term compensatory response to neurodegeneration in the AD brain via a strongly connected core network with highly vulnerable or disconnected hubs. Targeted attacks demonstrated a greater vulnerability of AD brains to all types of attacks and identified progression models to mimic AD brain functional connectivity through betweenness centrality and collective influence metrics. Furthermore, both spatial analysis and percolation theory identified a key disconnect between the anterior brain of the AD mice to the rest of the brain network.

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Distinct network topology in Alzheimer’s disease and behavioral variant frontotemporal dementia

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00752-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Adeline Su Lyn Ng ◽

Juan Wang ◽

Kwun Kei Ng ◽

Joanna Su Xian Chong ◽

Xing Qian ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Network Topology ◽

Neuropsychiatric Symptoms ◽

Brain Network ◽

Salience Network ◽

Behavioral Variant Frontotemporal Dementia ◽

Control Networks ◽

And Control

Abstract Background Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social–emotional functional deficits. Methods In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. Results Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. Conclusions Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

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Graph Theory-Based Brain Network Connectivity Analysis and Classification of Alzheimer’s Disease

International Journal of Image and Graphics ◽

10.1142/s021946782240006x ◽

2021 ◽

Author(s):

A. Thushara ◽

C. Ushadevi Amma ◽

Ansamma John

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Graph Theory ◽

Neurodegenerative Disorder ◽

Brain Networks ◽

Network Connectivity ◽

Brain Regions ◽

Brain Network ◽

Fiber Tracts ◽

The Brain

Alzheimer’s Disease (AD) is basically a progressive neurodegenerative disorder associated with abnormal brain networks that affect millions of elderly people and degrades their quality of life. The abnormalities in brain networks are due to the disruption of White Matter (WM) fiber tracts that connect the brain regions. Diffusion-Weighted Imaging (DWI) captures the brain’s WM integrity. Here, the correlation betwixt the WM degeneration and also AD is investigated by utilizing graph theory as well as Machine Learning (ML) algorithms. By using the DW image obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, the brain graph of each subject is constructed. The features extracted from the brain graph form the basis to differentiate between Mild Cognitive Impairment (MCI), Control Normal (CN) and AD subjects. Performance evaluation is done using binary and multiclass classification algorithms and obtained an accuracy that outperforms the current top-notch DWI-based studies.

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Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.748388 ◽

2021 ◽

Vol 13 ◽

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Qingwei Huo ◽

Sumaiya Tabassum ◽

Jinxiang Jiang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Neuronal Morphology ◽

Therapeutic Interventions ◽

Early Event ◽

Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

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Investigation of five polymorphic DNA markers associated with late onset Alzheimer disease

Genetika ◽

10.2298/gensr1302503g ◽

2013 ◽

Vol 45 (2) ◽

pp. 503-514 ◽

Cited By ~ 7

Author(s):

Jalal Gharesouran ◽

Maryam Rezazadeh ◽

Mohaddes Mojtaba

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Markers ◽

Neurodegenerative Disorder ◽

Late Onset ◽

The Elderly ◽

Healthy Controls ◽

Genotype Frequencies ◽

Significant Difference ◽

And Control

Alzheimer's disease is a complex neurodegenerative disorder characterized by memory and cognitive impairment and is the leading cause of dementia in the elderly. The aim of our study was to examine the polymorphic DNA markers CCR2 (+190 G/A), CCR5?32, TNF-? (-308 G/A), TNF-? (-863 C/A) and CALHM1 (+394 C/T) to determine the relationship between these polymorphisms and the risk of late onset Alzheimer's disease in the population of Eastern Azerbaijan of Iran. A total of 160 patient samples and 163 healthy controls were genotyped by PCR-RFLP and the results confirmed using bidirectional sequencing. Statistical analysis of obtained data revealed non-significant difference between frequency of CCR5?32 in case and control groups. The same result was observed for TNF-? (-863 C/A) genotype and allele frequencies. Contrary to above results, significant differences were detected in frequency of TNF-? (-308 G/A) and CCR2-64I genotypes between the cases and healthy controls. A weak significant difference observed between allele and genotype frequencies of rs2986017 in CALHM1 (+394 C/T; P86L) in patient and control samples. It can be concluded that the T allele of P86L variant in CALHM1 & +190 G/A allele of CCR2 have a protective role against abnormal clinical features of Alzheimer's disease.

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In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180115162422 ◽

2018 ◽

Vol 17 (1) ◽

pp. 54-68 ◽

Cited By ~ 12

Author(s):

Kanzal Iman ◽

Muhammad Usman Mirza ◽

Nauman Mazhar ◽

Michiel Vanmeert ◽

Imran Irshad ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Silico ◽

Neurodegenerative Disorder ◽

In Silico Analysis ◽

Acetylcholinesterase Inhibitors ◽

Binding Energies ◽

Therapeutic Interventions ◽

Ache Inhibitors

Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progression in this neurodegenerative disorder causes deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function. The multifactorial AD pathology calls for Multitarget-directed ligands (MTDLs) to follow up on various components of the disease. Considering this approach, other related AD targets were also selected. Structure-based virtual screening was relied upon for the identification of lead compounds with anti-AD effect. Method: Several chemoinformatics approaches were used in this study, reporting four multi-target inhibitors: MCULE-7149246649-0-1, MCULE-6730554226-0-4, MCULE-1176268617-0-6 and MCULE-8592892575-0-1 with high binding energies that indicate better AChE inhibitory activity. Additional in-silico analysis hypothesized the abundant presence of aromatic interactions to be pivotal for interaction of selected compounds to the acetyl-cholinesterase. Additionally, we presented an alternative approach to determine protein-ligand stability by calculating the Gibbs-free energy change over time. Furthermore, this allows to rank potential hits for further in-vitro testing. Results and Conclusion: With no predicted indication of adverse effects on humans, this study unravels four active multi-target inhibitors against AChE with promising affinities and good ADMET profile for the potential use in AD treatment.

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Strategies Targeting Soluble β-Amyloid Oligomers and their Application to Early Diagnosis of Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205016666191031163504 ◽

2020 ◽

Vol 16 (12) ◽

pp. 1132-1142 ◽

Cited By ~ 1

Author(s):

Fantian Zeng ◽

Yuyan Li ◽

Yungen Xu ◽

Jian Yang ◽

Zhengshi Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Diagnosis ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Therapeutic Interventions ◽

Detection Methods ◽

Fluorescence Probes ◽

Amyloid Oligomers ◽

Β Amyloid

Background: Alzheimer’s Disease (AD) is the most common neurodegenerative disorder, and it is still incurable. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. Mounting evidence indicates that the neurotoxic effects might be attributed to Soluble β-Amyloid Oligomers (SAβO). The SAβO are believed to be neurotoxic peptides more predominant than Aβ plaques in the early stage, and their key role in AD is self-evident. Unfortunately, identification of SAβO proves to be difficult due to their heterogeneous and transient nature. In spite of many obstacles, multiple techniques have recently been developed to target SAβO effectively. This review focuses on the recent progress in the approaches towards SAβO detection in order to shed some light on the future development of SAβO assays. Methods : Literatures were obtained from the following libraries: Web of Science, PubMed, EPO, SIPO, USPTO. Articles were critically reviewed based on their titles, abstracts, and contents. Results: A total of 85 papers are referenced in the review. Results are divided into three categories based on the types of detection methods: small molecule fluorescence probes, oligomer-specific antibodies and electrochemical biosensors. Finally, the improvements and challenges of these approaches applied in the early diagnosis of AD were discussed. Conclusion: This review article covers three kinds of strategies that could be translated into clinic practice and lead to earlier diagnosis and therapeutic interventions of AD.

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Brain network remodelling reflects tau-related pathology prior to memory deficits in Thy-Tau22 mice

Brain ◽

10.1093/brain/awaa312 ◽

2020 ◽

Author(s):

Laetitia Degiorgis ◽

Meltem Karatas ◽

Marion Sourty ◽

Emilie Faivre ◽

Julien Lamy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Connectivity ◽

Dorsal Hippocampus ◽

Brain Network ◽

Prodromal Phase ◽

Compensatory Response ◽

Major Mechanism ◽

Brain Connectome

Abstract In Alzheimer’s disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer’s disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus—encompassing dorsal HIP-SS communication—in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead toward an early biomarker of tauopathy as well as new targets for future treatments.

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Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure

International Journal of Molecular Sciences ◽

10.3390/ijms21030908 ◽

2020 ◽

Vol 21 (3) ◽

pp. 908 ◽

Cited By ~ 10

Author(s):

Silvia Pelucchi ◽

Ramona Stringhi ◽

Elena Marcello

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Actin Cytoskeleton ◽

Dendritic Spine ◽

Neurodegenerative Disorder ◽

Synaptic Strength ◽

Synaptic Activity ◽

Therapeutic Interventions ◽

Actin Dynamics ◽

Synaptic Failure

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD.

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Therapeutic Approaches for Alzheimer’s Disease: New Perspectives

10.5772/intechopen.97081 ◽

2021 ◽

Author(s):

Ivo Ilvan Kerppers ◽

Andressa Panegalli Hosni ◽

Andressa Leticia Miri ◽

Maria Elvira Ribeiro Cordeiro ◽

Flávio Klinpovous Kerppers ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Therapeutic Approaches ◽

Treatment Protocols ◽

Brain Functions ◽

New Therapeutic Approaches ◽

And Control

Alzheimer’s disease (AD) was defined as a neurodegenerative disorder, being more affected in the elderly. It is estimated that every 3.2 seconds a person in the world is affected by the high disease that rate in 2050 to 1 second. Therefore, research has been carried out on new therapeutic approaches, such as Transcranial Photobiomodulation and treatment based on antioxidants, such as Resveratrol. Therefore, the objective is to conduct a literature review on these two approaches and their effects on the treatment of AD. It was carried out according to the PRISMA recommendation and the articles were selected according to the years of publication (between 2015 and 2020) and extracted from the following databases: Science Direct, PubMed PMC, Scopus, PubMed NCBI, SciELO, LILACS, MEDLINE and PEDro. In several studies it has been reported that both therapies provide improvements at the molecular and behavioral level, recovering brain functions, acting in a neuroprotective way, improving quality of life, with few adverse effects and in a less invasive way. Thus, both treatments have numerous benefits that can be useful in the treatment of AD. However, there is a need for further research that includes interventions with greater specificity and control, so that they are defined as ideal doses and treatment protocols.

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Increased astrocyte representation in the hippocampus of 5xFAD mice

Medicinski podmladak ◽

10.5937/mp72-32451 ◽

2021 ◽

Vol 72 (2) ◽

pp. 5-10

Author(s):

Violeta Jovanović ◽

Jelica Despotović ◽

Mario Balo ◽

Ivan Zaletel ◽

Sanja Despotović ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dentate Gyrus ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Amyloid Plaques ◽

Control Group ◽

Significant Difference ◽

5Xfad Mice ◽

And Control

Introduction: Alzheimer's disease is the most common neurodegenerative disorder, characterized by the formation of amyloid plaques and the neurofibrillary tangles in the brain of an ill person, leading to neuronal damage and loss. Activation of astrocytes and astrogliosis occurs along with this process. Due to ethical limitations in working with human tissue, numerous transgenic animal models have been developed to study the pathogenesis of these processes. Early Ab deposition is observed in the cortex and the hippocampus. Aim: This study aimed to determine the difference in the presence of GFAP positive cells in the hippocampus between transgenic 5xFAD mice aged 36 weeks and their corresponding controls. Material and Methods: The 5xFAD mice model of Alzheimer's disease was used, characterized by early formation of amyloid plaques but without the presence of neurofibrillar tangles. Transgenic and control animals were sacrificed at 36 weeks of age. The visualization of GFAP-positive cells in the hippocampus of their brains was done by using immunohistochemistry and antibody for glial fibrillary acidic protein - GFAP, the major marker of astrocytes. Quantification of immuno-reactivity was done by using the Icy software system. Results: There was a statistically significant difference in the expression of GFAP in the dentate gyrus and the granular zone of the hippocampus between the transgenic and control group at 36 weeks of age, while the significant change in the CA1-3 regions was not observed between investigated groups. Conclusion: Obtained results confirm the involvement of astrogliosis in the pathophysiology of Alzheimer's disease and indicate an earlier occurrence of astrogliosis in the dentate gyrus and granular zone, in relation to other regions of the hippocampus, in the 36-week-old 5xFAD mice.

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