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Childhood Onset Dementia

Asta Literature Retrieval: Disease Pathophysiology Research Template Target Disease Disease Name: Childhood Onset Dementia MONDO ID: (if availab...

2026-03-24
Asta Model: Asta Scientific Corpus Retrieval 19 citations

Asta Literature Retrieval: Disease Pathophysiology Research Template Target Disease Disease Name: Childhood Onset Dementia MONDO ID: (if availab...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] Molecular basis of dementia

  • Authors: O. Szymanowicz, S. Pawlak, E. Potocka, U. Goutor, W. Kozubski et al.
  • Year: 2024
  • Venue: Journal of Multiscale Neuroscience
  • URL: https://www.semanticscholar.org/paper/1b9fd42d307473984bd46688a7b50c8d1b81c5b3
  • DOI: 10.56280/1605703412
  • Summary: Current research in the field of dementia is summarized and the significance of molecular factors in its pathogenesis is highlighted, which may allow for faster diagnosis of the disease and facilitate the creation of more efficient patient care plans.
  • Evidence snippets:
  • Snippet 1 (score: 0.619) > Dementia is a set of symptoms characterized by deterioration of memory and cognitive functions. Dementia diseases include Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementia. This disease represents an escalating social issue, particularly in a society with an increasing elderly population. In 2019, 271,998 people succumbed to dementia, making Alzheimer's disease the sixth most prevalent cause of death. The pathophysiology of Alzheimer's disease is complex and not fully understood. It is a multifaceted disease, with its pathogenesis influenced by a combination of genetic, environmental, and lifestyle factors. One of the genes involved in the pathogenesis of the disease is the apolipoprotein E (APOE) gene, which is one of the most common risk factors for Alzheimer's disease. The significance of other genes, including presenilin genes (PSEN1 and PSEN2), the TREM2 gene, the MAPT gene, and the APP gene, linked to various forms of dementia, is also emphasized. Another issue is the growing number of identified genetic variants within genes implicated in the onset of dementia. Dementia diseases are also characterized by chemical alterations in the brain, including the accumulation of abnormal excitotoxic proteins, varying degrees of inflammation, and metabolic disorders. This review summarizes current research in the field of dementia and highlights the significance of molecular factors in its pathogenesis. Gaining insight into the pathogenic mechanisms of dementia may allow for faster diagnosis of the disease and facilitate the creation of more efficient patient care plans.

[2] Amyloid Precursor Protein (APP) processing and potential targets for Alzheimer’s Disease

  • Authors: Andrew B. Bonner
  • Year: 2019
  • Venue: Biomedical Genetics and Genomics
  • URL: https://www.semanticscholar.org/paper/4e84769f76b613df6e460f40ff416689acf3c3be
  • DOI: 10.15761/bgg.1000146
  • Summary: The goal of this short review is to outline the major aspects of the biology of APP and the importance of APP in Alzheimer’s Disease and to briefly review current concepts regarding the potential targeting of APP processing in order to influence the ramifications of AD.
  • Evidence snippets:
  • Snippet 1 (score: 0.615) > Post-translational modifications of Amyloid Precursor Protein (APP) are related to the Dementia disorder; Alzheimer's Disease (AD) [1][2][3]. The incidence and pathophysiology of Dementia and Alzheimer's Disease is important to consider when assessing genetic implications. Dementia is a broad category of many disorders that involve memory and cognitive impairment [1][2][3]. As the U.S. population continues to age, this problem will continue to increase as most types of dementia occur in later stages of life. Due to the immense physical, emotional, and financial toll that dementia can have on patients and their families, the importance of the development of therapies for this disorder continues to grow. Alzheimer's Disease (AD) is the most common type of dementia with approximately 30 million patients currently affected by this disease around the world. It is estimated that 75% of all patients with dementia have AD [1]. The two main types of AD include early onset disease, which is generally caused by inherited genetic factors and late onset disease, which is hypothesized to be caused by a combination of genetic and environmental factors [1,4]. Early onset AD is rare, accounting for around 5% of cases of AD. As its name suggests, this type of AD displays symptoms in individuals at an earlier age than late onset AD. Early onset AD generally occurs during the fourth or fifth decade of life. Late onset AD is the more common form of AD and less likely to have identifiable genetic origins. Symptoms of late onset AD usually begin during the sixth or seventh decades of life. Many of the factors that contribute to late onset AD have yet to be determined and will be the focus of many ongoing research efforts [4]. The two primary pathophysiological hallmarks of Alzheimer's disease are Neurofibrillary Tangles (NFTs) and β-amyloid (Aβ) plaques. These hallmarks have been studied since the early description of the disease by Alois Alzheimer in 1906 [5]. Although this review focuses on the formation of Aβ from APP, a brief introduction of NFT's and Tau is warranted.

[3] Shared Neuroinflammatory Mechanisms Across Dementia Types: An Integrative Review

  • Authors: Subramanian Thangaleela, Asif Ali, Yohanes Tandoro, Chin‐Kun Wang
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/5c8299601e478f22a2db44275b964ec71a97cb1d
  • DOI: 10.3390/ijms27010179
  • PMID: 41516057
  • PMCID: 12785365
  • Citations: 1
  • Summary: This review focuses on shared and distinct neuroinflammatory mechanisms to unravel significant therapeutic strategies for dementia and explores the underlying mechanisms linking neuroinflammation to various types of dementia.
  • Evidence snippets:
  • Snippet 1 (score: 0.604) > The research stage of development in treating multiple dementias through shared pathways is complex due to translational challenges. The spectrum of dementia disorders shares neurochemical mechanisms that provide both opportunities, as well as gaps in therapeutic interventions [252]. Another significant challenge is to diagnose and monitor the disorders before they progress into the dementia stage. Although various biomarkers are available to distinguish between different forms of dementia, they facilitate more accurate treatments for each type. Transforming biomarkers into clinical practice is more challenging. While advancements in biomarker research and understanding of the molecular mechanisms underlying dementia offer promising pathways, translating these findings into clinical practice remains an ongoing challenge. Future directions should focus on personalized treatment strategies, comprehensive research frameworks, and holistic management approaches to effectively bridge the existing gaps. Future research in dementia risk reduction requires a multidomain approach, population health approaches, brain health-improving methods, and person-centered outcomes that improve cognition [207]. The International Research Network on Dementia Prevention was established to bring together researchers and policymakers working on dementia prevention and dementia risk reduction. The goal of this network is to develop research into practice to reduce the risk of dementia worldwide [208]. The translational gaps are not only due to the application of pharmacological interventions, but also in the management of dementia and comorbid conditions. > Although neuroinflammation is increasingly recognized as a common feature across several NDs, important contradictions exist. Though heterogeneity in different brain regions reflects multiple interacting factors, cell types, brain region differences, neurotransmitter systems, connectivity between the cells, biochemical and metabolic differences, the core inflammatory signaling pathways and their mediators (e.g., cytokines, complement activation, NF-κB-driven cascades) are common across the CNS. Therefore, the inflammatory machinery may be fundamentally similar, but the spatial manifestation of these responses varies according to regional vulnerability, local cellular composition, and disease-specific protein pathology.

[4] Pathogenesis and Therapeutic Perspectives of Tubular Injury in Diabetic Kidney Disease: An Update

  • Authors: Jiamian Geng, Sijia Ma, Hui Tang, Chun-di Zhang
  • Year: 2025
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/889b3498a05a86b303b0fc3bd0f89915c65f39f0
  • DOI: 10.3390/biomedicines13061424
  • PMID: 40564143
  • PMCID: 12189843
  • Citations: 3
  • Summary: Advances in stem cell-based interventions and precision gene editing techniques have unveiled novel therapeutic paradigms for DKD, fundamentally expanding the treatment arsenal beyond conventional pharmacotherapy and highlighting promising therapeutic strategies for managing this condition.
  • Evidence snippets:
  • Snippet 1 (score: 0.602) > The adaptive mechanisms of cellular stress responses play a pivotal role in maintaining organismal homeostasis, conferring remarkable resilience against pathological processes and disease progression [65]. In the context of DKD, three primary forms of stress response mechanisms have been implicated in disease pathogenesis and clinical progression. These maladaptive responses manifest as oxidative stress-mediated cellular damage, ERS-induced protein homeostasis disruption, and mitochondrial dysfunction-related metabolic disturbances. Each pathway contributes distinctively to the complex pathophysiology of DKD through interconnected mechanisms of cellular injury and aberrant signaling cascades.

[5] Dementia spectrum disorders: lessons learnt from decades with PET research

  • Authors: H. Wilson, G. Pagano, M. Politis
  • Year: 2019
  • Venue: Journal of Neural Transmission
  • URL: https://www.semanticscholar.org/paper/f054fd119dbce7fd7097884e2a9d493df1dfec96
  • DOI: 10.1007/s00702-019-01975-4
  • PMID: 30762136
  • PMCID: 6449308
  • Citations: 40
  • Influential citations: 2
  • Summary: The dementia spectrum encompasses a range of disorders with complex diagnosis, pathophysiology and limited treatment options, and PET tracers have been developed to target specific proteinopathies (amyloid, tau and α-synuclein), glucose metabolism, cholinergic system and neuroinflammation.
  • Evidence snippets:
  • Snippet 1 (score: 0.597) > The dementia spectrum encompasses a range of disorders with complex diagnosis, pathophysiology and limited treatment options. Positron emission tomography (PET) imaging provides insights into specific neurodegenerative processes underlying dementia disorders in vivo. Here we focus on some of the most common dementias: Alzheimer’s disease, Parkinsonism dementias including Parkinson’s disease with dementia, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal syndrome, and frontotemporal lobe degeneration. PET tracers have been developed to target specific proteinopathies (amyloid, tau and α-synuclein), glucose metabolism, cholinergic system and neuroinflammation. Studies have shown distinct imaging abnormalities can be detected early, in some cases prior to symptom onset, allowing disease progression to be monitored and providing the potential to predict symptom onset. Furthermore, advances in PET imaging have identified potential therapeutic targets and novel methods to accurately discriminate between different types of dementias in vivo. There are promising imaging markers with a clinical application on the horizon, however, further studies are required before they can be implantation into clinical practice.

[6] Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models

  • Authors: A. Kodamullil, Anandhi Iyappan, Reagon Karki, S. Madan, E. Younesi et al.
  • Year: 2017
  • Venue: Journal of Alzheimer's Disease
  • URL: https://www.semanticscholar.org/paper/55820fd5fc6231bc4bf3c0330cb6cbfea9a4827c
  • DOI: 10.3233/JAD-170255
  • PMID: 28731442
  • PMCID: 5545904
  • Citations: 27
  • Summary: This paper investigates the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species and assesses to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level.
  • Evidence snippets:
  • Snippet 1 (score: 0.592) > Mouse models are extensively used in biomedical research mainly to understand the etiology of the disease. Complex diseases like AD may involve several simultaneous alterations in molecular and processual activities, including neuroinflammation, aggregation of A␤ peptides, or tau phosphorylation, which are likely to contribute to pathophysiology. In this paper, we have compared the mouse and human at molecular, cellular, and pathway levels to shed light on mechanistic differences with important implications for translation outcomes. Mechanistic modelling specific to species allows us to "embed" and "represent" similarities and differences in innate immunity which can lead to the development of "conflictious information detection engine". It is important to note that our analysis is purely based on the research and publication bias in mouse and human experiments as many mouse experiments are mainly focused on particular explorative areas, and experiments with human tissues are also concentrated on limited areas of disease mechanism. We found that mouse experiments often reveal new molecular interactions between different entities that are not observed or reported in human experiments. Differential analysis of mouse and human model for neuroinflammation shows that mouse and human differ at the molecular and cellular levels, but have more similarities at the pathway levels as numbers indicate. More explicitly, the underlying molecular patterns which lead to a particular bioprocess differ between the two species. This finding implies that although the two species share some similarities at the cellular or pathway level, the pattern of molecular interactions that form, govern, and regulate those pathways is substantially different between mouse and human. > It is notable that mouse models have provided significant insights into many disease areas like cancer; acute promyelocytic leukemia. However, recent drug failures in the area of neurodegeneration have put a question mark behind the extent to which mouse models have been used in preclinical drug discovery and to what extent transgenic mice mimic human brain pathophysiology mechanisms. Pathophysiology mechanisms are likely to act together and they seem to be organized in a temporal cascade of events that ultimately result in a severe disease phenotype. Experiments with single gene knock-out in mice can reveal only minor aspects of the disease perturbations and do not usually allow us to decipher the full complexity of the mechanisms underlying the disease.

[7] Solving neurodegeneration: common mechanisms and strategies for new treatments

  • Authors: L. K. Wareham, Shane A. Liddelow, S. Temple, L. Benowitz, A. Di Polo et al.
  • Year: 2022
  • Venue: Molecular Neurodegeneration
  • URL: https://www.semanticscholar.org/paper/78c4ea13cd38fca6b80972e564424f86ca299b70
  • DOI: 10.1186/s13024-022-00524-0
  • PMID: 35313950
  • PMCID: 8935795
  • Citations: 238
  • Influential citations: 3
  • Summary: Major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.590) > The symptoms associated with neurodegenerative disease are largely dependent on the CNS tissue affected, which varies across diseases such as Alzheimer's Disease (AD), Huntington's Disease (HD), Parkinson's Disease (PD), and Amyotrophic lateral sclerosis (ALS). Although each neurodegenerative disease is distinct in terms of etiology, severity, and rate of progression, shared molecular changes and mechanisms can be identified offering potential avenues for research across multiple diseases. > Alzheimer's Disease represents the most common form of dementia, predominantly afflicting the aged population [3]. Over time, patients develop gradual but progressive memory loss and cognitive decline associated with the degeneration of neurons [4]. In AD, severity of symptoms is correlated with pathophysiological events caused by protein aggregations in the cerebral cortex [5][6][7][8]. These have been shown histologically as the deposition of β-amyloid (Aβ) aggregated fibrils and plaques, and neurofibrillary tangles containing hyperphosphorylated Tau protein [5]. Amyloid precursor protein (APP) can be cleaved to form varying lengths (from 38 to 43 amino-acids) of Aβ peptides [9]. Aβ monomers can bind to one another to eventually form oligomers and insoluble plaques. The deposition and accumulation of Aβ oligomers is generally accepted as central to pathogenesis of AD and the most toxic to neurons; however, other pathological events such as tau aggregation, as well as neuroinflammation also play a major role and contribute to synaptic loss and neurodegeneration [3]. > While AD accounts for 60-80% of dementia cases, vascular cognitive impairment and dementia (VCID) are the second leading cause of dementia [10]. Recent mounting evidence supports an underlying vascular element in the pathophysiology of AD [11]; abnormal microvasculature in AD patients is present post-mortem in the brains of patients [11][12][13]. In fact, the role of cerebrovascular alterations in dementia-associated neurodegenerative diseases has been highlighted as a primary cause of cognitive impairments and

[8] Integrative human and murine multi-omics: Highlighting shared biomarkers in the neuronal ceroid lipofuscinoses.

  • Authors: N. Gammaldi, F. Pezzini, E. Michelucci, N. Di Giorgi, A. Simonati et al.
  • Year: 2023
  • Venue: Neurobiology of disease
  • URL: https://www.semanticscholar.org/paper/2c50113653b538549410afe59f69ce70a4184a43
  • DOI: 10.1016/j.nbd.2023.106349
  • PMID: 37952681
  • Citations: 3
  • Summary: The results offer promising targets for potential new therapeutic strategies and reinforce the hypothesis of a connection between NCLs and other forms of dementia, particularly Alzheimer's disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.586) > Recent methodological advances in multi-omics approaches have revolutionized research in rare diseases by balancing the low availability of samples and the poor information about pathophysiology with the generation of "big data", which has greatly enhanced our understanding of the molecular complexity underlying these diseases. Omics data can be integrated correlating them from different sources and technologies in order to identify affected disease pathways, biomarkers, as well as new pharmaceutical targets. > In the brain, common dysregulated pathways have been identified not only in NCLs, but also in almost every late-onset neurodegenerative and aging-related disorder, suggesting that targeting these common pathways may open up promising new therapeutic opportunities (Kline et al., 2020;Kodam et al., 2023;Schilder et al., 2022). > In this review, we explored the pathogenesis of NCL disease, evaluating human data in order to define common molecular networks underlying the top dysregulated processes. Moreover, by distinguishing between pre-symptomatic and symptomatic stages, we were able to evaluate disease progression in murine models from both a cell-specific and an anatomical point of view. We evaluated the cellular microenvironment, highlighting the main altered pathways and pinpointing processes implicated across species and in single forms. The results generated pave the way for identifying the different brain regions primarily affected by the disease.

[9] Cardiovascular and Retinal Vascular Changes in Preclinical Alzheimer's Disease

  • Authors: C. Santos
  • Year: 2018
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/8ed88ae8f31a41c804545688a3c36afc43bbf22d
  • DOI: 10.23860/diss-santos-claudia-2018
  • Citations: 2
  • Summary: Current understanding of the epidemiology, genetics, and pathophysiology of AD as well as the intersection between AD and vascular causes of dementia are reviewed, including shared genetic contributions and lifestyle, behavioral and environmental risk factors, and possible mechanistic pathways of AD are explored.
  • Evidence snippets:
  • Snippet 1 (score: 0.582) > One in three adults over 85 years old suffer from Alzheimer’s disease (AD) or other forms of dementia. This already widespread condition is expected to increase further in both incidence and prevalence in coming years. As a result, the need to understand the etiology and pathogenesis of dementia becomes ever more urgent. AD, in addition to its steep cost of care, is the most common form of dementia and the sixth leading cause of death in the United States. It is a complex disease and its mechanisms are poorly understood. The more we learn about AD, the more questions are raised about our current conceptual models of disease. Despite the rapid advancement of medical technology, reliable and sensitive diagnostic markers to identify individuals at risk to AD prior onset of clinical symptoms remain in the developmental phase resulting in inefficient diagnostic procedures. Diagnosis is further hampered by the heterogeneity of behavioral presentations, cognitive impairments, and functional statuses observed in AD, all of which may be the result of varying etiologies. Furthermore, older AD patients often suffer from comorbid medical conditions that further complicate accurate disease monitoring. In the absence of an effective AD treatment, it is prudent to apply our current knowledge of the intersection between AD, cardiovascular disease (CVD), and cerebrovascular disease to foster efforts to delay the onset of dementia more generally. The purpose of MANUSCRIPT I is to review our current understanding of the epidemiology, genetics, and pathophysiology of AD as well as the intersection between AD and vascular causes of dementia. The epidemiology and shared risk factors and etiologies for these three disease “clusters” are explored, including shared genetic contributions and lifestyle, behavioral and environmental risk factors. In this first publication, we also explore possible mechanistic pathways of AD and the shared pathophysiology and neuropathological substrates of these three disease clusters. CVD and cerebrovascular pathology is present for most individuals with AD, although the converse is not necessarily true. Given this relationship, it is important to address how early in the disease course those vascular changes can be observed. Such research is needed to enable early interventions to maintain quality of life in premorbid AD and reduce the burden of disease. To determine whether there is cardiovascular alteration in the early stages of AD, MANUSCRIPT

[10] Understanding the Pathophysiology of Atopic Dermatitis – insights into Immune Dysregulation and Skin Barrier Dysfunction

  • Authors: Maja Kucharska, Kacper Kwiliński, Barbara Wawrzyńska, Marlena Cąkała, Adrian Kruszewski et al.
  • Year: 2024
  • Venue: Quality in Sport
  • URL: https://www.semanticscholar.org/paper/9ba8ec050f511e04ecb6b80a72906f5c9323e629
  • DOI: 10.12775/qs.2024.19.54073
  • Summary: Atopic dermatitis is a complex, chronic inflammatory skin disease with a multifaceted pathophysiology involving genetic, immunological, and environmental factors including filaggrin mutations, Th2 cytokine-mediated inflammation, and the skin microbiome.
  • Evidence snippets:
  • Snippet 1 (score: 0.571) > Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disrupted skin barrier and immune dysregulation. The exact pathophysiology of atopic dermatitis despite extensive research remains complex. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. Recent advances in research have provided deeper insights into the molecular mechanisms including the role of filaggrin mutations, Th2 cytokine-mediated inflammation, and the skin microbiome. Understanding the intricate interplay between these components is crucial for developing targeted therapeutic strategies. > Aim of the study: This review provides a comprehensive overview of the current knowledge on the pathophysiological mechanisms underlying AD, highlighting recent advances and areas for future research. > Material and methods: Comprehensive literature searches were performed across the main electronic databases of PubMed and GoogleScholar using the keywords: “atopic dermatitis”, “eczema pathophysiology”, “skin barrier”. > Conclusions: Atopic dermatitis (AD) is a complex, chronic inflammatory skin disease with a multifaceted pathophysiology involving genetic, immunological, and environmental factors. Recent advances in understanding the molecular mechanisms underlying AD have highlighted the importance of skin barrier dysfunction, immune system dysregulation, and microbial interactions in the disease's progression.

[11] Action Plan for Stroke in Europe 2018–2030

  • Authors: B. Norrving, J. Barrick, A. Dávalos, M. Dichgans, C. Cordonnier et al.
  • Year: 2018
  • Venue: European Stroke Journal
  • URL: https://www.semanticscholar.org/paper/0f21747f78323fb499a020962145d0be1cb425a9
  • DOI: 10.1177/2396987318808719
  • PMID: 31236480
  • PMCID: 6571507
  • Citations: 470
  • Influential citations: 28
  • Summary: The ESAP provides a basic road map and sets targets for the implementation of evidence-based preventive actions and stroke services to 2030 and overall, 30 targets and 72 research priorities were identified for the seven domains.
  • Evidence snippets:
  • Snippet 1 (score: 0.568) > c strokes, and a major cause of intracerebral haemorrhage, vascular cognitive impairment or dementia. Incomplete understanding of SVD pathogenesis and a lack of appropriate animal models are obstacles to progress. Large-scale studies of systems biology can provide insights into the underlying mechanisms of complex diseases and responses to treatment. 109 Key priorities in this area include: better understanding of the pathogenic contribution of endothelial dysfunction or BBB disruption, inflammation and hemodynamic factors; understanding the role of proteins and pathways involved in monogenic forms of SVD and (multifactorial) sporadic SVD; 110 understanding the mechanisms leading to cognitive impairment and deciphering the intricate relationship with Alzheimer's disease; designing protective approaches to reduce progression of white matter damage; expanding the identification of genetic and other molecular biomarkers and translating the new putative targets discovered through genetic, molecular and cellular biology data into diseasemodifying therapies. > Functional recovery and rehabilitation. A key objective is to expand our knowledge on functional recovery mechanisms and potential therapeutic targets to enhance the effects of physical rehabilitation in the chronic phase after stroke. Research is needed on neuronal plasticity and network recovery, and their interaction with delayed pathophysiological mechanisms such as neuroinflammation, apoptosis, neurogenesis and angiogenesis. This will require the adoption of methodology from stem cell research, gene therapy, optogenetics, non-invasive brain stimulation and other fields. The methodology for evaluating functional recovery in experimental stroke models should be improved.

[12] Research models to study lewy body dementia

  • Authors: S. L. Boschen, Aarushi A Mukerjee, Ayman H Faroqi, Ben E Rabichow, John Fryer
  • Year: 2025
  • Venue: Molecular Neurodegeneration
  • URL: https://www.semanticscholar.org/paper/71ccdd588b37725f1c623b9f2bf7286fb02a8d35
  • DOI: 10.1186/s13024-025-00837-w
  • PMID: 40269912
  • PMCID: 12020038
  • Citations: 4
  • Summary: This review assesses widely used PD and AD models in terms of their relevance to LBD, particularly focusing on their ability to replicate human disease pathology and assess treatment efficacy.
  • Evidence snippets:
  • Snippet 1 (score: 0.562) > Lewy body dementia (LBD) is an umbrella term for neurodegenerative dementias, including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). These conditions are clinically characterized by cognitive fluctuations, visual hallucinations, sleep behavior The primary clinical distinction between PDD and DLB lies in the timing of dementia symptoms relative to the onset of parkinsonism. Specifically, approximately 83% of PD patients develop dementia symptoms after one year of parkinsonism onset classifying them as PDD patients [5]. Conversely, patients who exhibit parkinsonism within or after one year of cognitive or behavioral symptoms are diagnosed with DLB. Notably, around 25% of DLB patients never develop parkinsonism [6]. > Much of our current understanding of these neurodegenerative diseases has been achieved through research models that replicate certain hallmarks of the diseases enabling controlled investigation of specific pathophysiological mechanisms and potential treatments [7]. As with most models of disease, it is rare to find a disease model that recapitulates the entirety of the etiological, clinical, and pathological features of the disease. While numerous animal and cellular models that mimic human degenerative diseases to a certain extent exist for PD and AD, the pathogenic processes that differentiate LBD from PD and AD remain poorly understood due to the lack of mixedpathology models with sufficient etiological, face, predictive, and construct validity. > In this review, we describe some of the most commonly used research models for PD and AD research focusing on their ability to represent the true nature of these diseases, replicate human pathological features, and evaluate the effectiveness of new therapies. Additionally, given that LBD may fall within a spectrum of ataxias and dementias, we propose new research directions to study the mechanisms of LBD based on adaptations of existing PD and AD models.

[13] Neurodegenerative Disease: From Molecular Basis to Therapy

  • Authors: Claudia Ricci
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/7fae6e1ef5d570ef2daaa06b673099efb1a379e1
  • DOI: 10.3390/ijms25020967
  • PMID: 38256040
  • PMCID: 10815646
  • Citations: 21
  • Summary: Neurodegenerative diseases are a heterogeneous group of age-related disorders characterised by the progressive degeneration or death of neurons in the central or peripheral nervous system [...].
  • Evidence snippets:
  • Snippet 1 (score: 0.558) > Neurodegenerative diseases are a heterogeneous group of age-related disorders characterised by the progressive degeneration or death of neurons in the central or peripheral nervous system. The prevalence of these diseases is increasing-in part due to the ageing population-and the economic burden on healthcare systems is growing as a result. Although in some cases these diseases can be managed with treatments, current therapies are mostly symptomatic, do not address the underlying cause of the disease and have very little effect on disease progression. Recent advances in neurobiology and neurogenetics have provided valuable insights into the pathogenesis of neurodegenerative diseases. Genetic, environmental and lifestyle factors contribute to neurodegenerative diseases. Common underlying processes contribute to the degeneration of neurons, but the molecular mechanisms of neurodegenerative diseases are complex and diverse and may differ between conditions. As progress is made in understanding critical aspects of the underlying molecular pathophysiology, therapeutic strategies are evolving and new treatments are being evaluated. > Several papers in this Special Issue focus on Alzheimer's disease (AD), the most common cause of dementia, characterised by memory loss, behavioural disturbances and impaired judgment [1]. The presence of senile plaques, characterised by the aggregation of amyloid beta (Aβ), and the formation of neuronal neurofibrillary tangles (NFTs) are well-known neuropathological hallmarks of AD [2]. Symptoms of AD generally begin with mild memory impairment and progress to various degrees of severe cognitive impairment, including memory loss and difficulty with complex activities of daily living [3,4]. These pre-dementia stages could play a key role in preventive interventions: the development of early and accessible diagnostic methods could help to prevent or delay the progression of cognitive deficits and the onset of AD dementia [5,6]. > In this respect, Hunjong Na and colleagues [7] developed the QPLEX™ kit for the early clinical diagnosis of Alzheimer's disease.

[14] Profiling the autoantibody repertoire reveals autoantibodies associated with mild cognitive impairment and dementia

  • Authors: Hanan Ehtewish, Areej G Mesleh, G. Ponirakis, Katie Lennard, Hanadi Al Hamad et al.
  • Year: 2023
  • Venue: Frontiers in Neurology
  • URL: https://www.semanticscholar.org/paper/57a691ef16daad248937127cebbc57ff3e66702f
  • DOI: 10.3389/fneur.2023.1256745
  • PMID: 38107644
  • PMCID: 10722091
  • Citations: 11
  • Influential citations: 1
  • Summary: Several proteins targeted by autoantibodies dysregulated in dementia were significantly enriched in the neurotrophin signaling pathway, axon guidance, cholinergic synapse, long-term potentiation, apoptosis, glycolysis and gluconeogenesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.558) > Dementia is a complex neurodegenerative syndrome that affects millions of people worldwide. Pathologically characterised by disease-specific protein aggregation in the brain. The pathogenic role of abnormal protein deposition in dementia is established (1,2); however, the exact mechanisms for the initiation and progression of neurodegeneration remain unclear. There is increasing evidence for the role of immune dysregulation in the pathogenesis of dementia. Genome-wide association studies have demonstrated common genetic variations in the immune system processes associated with neurodegeneration in Alzheimer's disease (AD), Parkinson's disease dementia, and frontotemporal dementia (FTD) (3)(4)(5). Indeed, the role of autoimmune mechanisms is increasingly recognized in the pathophysiology of dementia (6)(7)(8). Autoantibodies are self-antigens recognizing antibodies, produced during B cell development in healthy individuals and play a role in immune tolerance and homeostasis (9). However, through various genetic and environmental processes, the ability to distinguish "self " from "nonself " antigens deteriorates, enabling autoantibodies to initiate and maintain the inflammatory cascade responsible for tissue injury (10,11). > Autoantibodies have been detected in the blood and cerebrospinal fluid of patients with different forms of dementia, including autoimmune dementia and neurodegenerative dementias such as AD, vascular dementia (VD), FTD, and Lewy body dementia (DLB) (12)(13)(14)(15)(16). Autoimmune dementia is a progressive cognitive impairment characterised by early onset, atypical clinical presentation and rapid progression associated with neural antibodies, inflammation in cerebrospinal fluid, brain changes in MRI atypical for neurodegenerative disease, and a good response to immunotherapy (17). Various neural autoantibodies were frequently detected in individuals experiencing progressive cognitive decline.

[15] The need for better AD animal models

  • Authors: M. Medina, J. Ávila
  • Year: 2014
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/afc76a9e93a293e7b3eae64095cf6c7b65d17f7d
  • DOI: 10.3389/fphar.2014.00227
  • PMID: 25386142
  • PMCID: 4208405
  • Citations: 14
  • Influential citations: 1
  • Summary: The study of the genetics of familial AD (FAD) has provided a wealth of knowledge on the elements that affect the molecular mechanisms underlying AD pathogenesis and established that, apart from the age of onset, sporadic AD is clinically and neuropathologically similar to the most common familial forms.
  • Evidence snippets:
  • Snippet 1 (score: 0.556) > Aβ, essentially focused on the amyloid cascade hypothesis, with disappointing results until now. On the other hand, tau-based strategies (and targets other than Aβ) have received little consideration until very recently even though extensive tau pathology is crucial to the disease and that recent genetic studies have discovered mutations within the tau gene leading to frontotemporal dementia, demonstrating that tau dysfunction per se, in the absence of amyloid pathology, is enough to cause neurodegeneration and clinical dementia. > During the last decade, the study of the genetics of familial AD (FAD) has provided a wealth of knowledge on the elements that affect the molecular mechanisms underlying AD pathogenesis and established that, apart from the age of onset, sporadic AD is clinically and neuropathologically similar to the most common familial forms. These phenotypic resemblance has inspired the development of a wide variety of genetically modified cellular and animal models, based on the mutations present in FAD. Genetics of FAD has also provided the strongest support for a critical role for Aβ in AD pathophysiology, but the fact that some of the mutations in presenilin 1 (PS1), the most commonly mutated gene in FAD, are not directly related to Aβ pathology suggests that there is something else to it. > Albeit they might not be the best species for mimicking the human disease, transgenic mice are still undoubtedly the most popular and extensively used animal models for studying AD. The studies carried on in animal models have also rendered invaluable information on the pathogenesis and pathophysiology of AD including, for instance, novel insights into the molecular mechanisms underlying the pathological aggregation of pivotal proteins, the pathways toward neuronal damage, the contribution of genetic risk factors and the role of neuroinflammation in neurodegeneration. Yet, these models appears to have contributed only partially to shed light on the actual mechanisms triggering the disease, thus preventing a true translation into new therapies, diagnosis and prevention. Even though an impressive amount of knowledge has been generated from the use of animal models, it has only marginally enriched our therapeutic potential. Actually, the hopes often raised by encouraging preclinical results have evanesced when the new strategies have been tested in clinical trials. > Besides an excessive

[16] Too narrow and too broad: Differentiating late-onset dementia from its historical entanglement with Alzheimer’s disease

  • Authors: Kristine F. Moseholm, K. Tybjerg, M. Jensen, R. Westendorp
  • Year: 2021
  • Venue: Aging Brain
  • URL: https://www.semanticscholar.org/paper/d9ff6526b1f6af88811f2d63e2a7206808148b67
  • DOI: 10.1016/j.nbas.2021.100010
  • PMID: 36911504
  • PMCID: 9997125
  • Citations: 1
  • Summary: This research presents a novel probabilistic procedure called “spot-spot analysis” that allows for real-time analysis of the response of the immune system to natural catastrophes.
  • Evidence snippets:
  • Snippet 1 (score: 0.556) > pathways also entails moving across a broader disciplinary landscape integrating different scientific fields such as epidemiology, systems biology, medicine, cellular-and molecular biology. And thus, as did Kraepelin and Alzheimer, we aim to estimate clinical prognosis anew and unravel the causal pathophysiological mechanisms. II) Reject ''normal" senility and combining a search for causal mechanisms with optimism about treatment Until well into the 20th century, what was characterized as senile dementia was rarely regarded as pathology, but simply as part of aging itself. The relationship of 'normal' aging to dementia has never been adequately resolved and the debate of AD pathology revolves around interpretations of the significance of specific neuropathological changes associated with both aging and dementia. However, we wish to disentangle aging and dementia and to eliminate the concept of 'normal' cognitive decline and senility due to aging, as was effectively done in the 1970 0 s. Although we wish to sever the connection between AD and late-onset dementia, we do not take it to be part of a 'normal' aging', as an agerelated degenerative disease such as late-onset dementia is caused by a pathological process leading to the accumulation of permanent damages to the brain [33,34]. For Alzheimer, both presenile and senile dementia were pathological conditions; he wished that the medical community recognized that these clinically separate mental illnesses had an undeniable material reality that could be located in the brain [5]. It provides us with a window of opportunity to investigate different pathophysiological mechanisms of cognitive impairment in old age and thereby bring us one step closer to potential drug targets and treatment for dementia. III) Retain the ambition to standardize pathophysiological mechanisms with a view to subdivide dementia patients. > The current research definition, the AT(N) biomarker system, proposed by NIA-AA reveals the challenges in defining and standardizing AD and dementia. According to Jack et al., the distinction between neuropathologic changes and clinical symptoms in AD was becoming blurred, resulting in the term AD often being used to describe two very different entities: prototypical clinical syndromes without neuropathologic verification and AD pathology [12]. > The framework was an attempt to standardize AD definition
  • Snippet 2 (score: 0.555) > The suggestion to reject the amyloid cascade hypothesis as the main pathological cause of AD is by no means new, and it is widely debated whether pure AD 'exists' [5,6]. Yet to this day, the main focus of basic research and drug therapy in dementia is on the amyloid cascade hypothesis. Therefore, we would like to, once more, argue for the urgent redefinition of dementia. We would like to learn from both the uncertainties and successes of the history of dementia and the AD diagnosis, both by acknowledging the complex and multicausal nature of late-onset dementia as a 'black box disease' with several interlocking component causes, and by integrating approaches and insights from three different historical periods. Our approach to dementia is to: I) Use exploratory categories to challenge existing notions of late-onset dementia. > In the early 20th century Alzheimer and Kraepelin used AD diagnosis with its combination of clinical representation and histopathological plaques and neurofibrillary tangles as an 'exploratory category' to investigate their understanding of dementia by considering unusual cases with particular care and connecting clinical and pathological observations. We suggest using this explorative attitude, but this time challenging the pathological role of plaques and neurofibrillary tangles in late-onset dementia and studying it at a level playing field along with other biomarkers and clinical observations. In this way, we want to create space and opportunity for new causal explanations and introduce other biomarkers and pathologies to disease etiology such as neuroinflammation, mitochondrial dysfunction, cerebral hypometabolism, cerebral vascular dysfunction, etc. Last, there are also social and environmental factors at play. These many theories can coexist, because the biological mechanisms are not mutually exclusive, (partially) overlap, and may well interact, which emphasizes that the underlying pathological mechanisms of late-onset dementia are multifactorial, heterogeneous and complex. > Opening up for more causal pathways also entails moving across a broader disciplinary landscape integrating different scientific fields such as epidemiology, systems biology, medicine, cellular-and molecular biology. And thus, as did Kraepelin and Alzheimer, we aim to estimate clinical prognosis anew and unravel the causal pathophysio

[17] Current Status of Drug Targets and Emerging Therapeutic Strategies in the Management of Alzheimer's Disease

  • Authors: Shampa Ghosh, Shantanu Durgvanshi, Shreya Agarwal, M. Raghunath, J. Sinha
  • Year: 2020
  • Venue: Current Neuropharmacology
  • URL: https://www.semanticscholar.org/paper/5adf9c9c4d847395ef33cea3457a312bb8012062
  • DOI: 10.2174/1570159x18666200429011823
  • PMID: 32348223
  • PMCID: 7569315
  • Citations: 27
  • Influential citations: 1
  • Summary: Different strategies based on anti-amyloid pathology, glutamatergic pathway, anti-tau, neuroprotection through neurotrophic factors and cholinergic neurotransmission have been discussed and the use of anti-inflammatory drugs, nutraceuticals, and dietary interventions has been explained in the management of AD.
  • Evidence snippets:
  • Snippet 1 (score: 0.554) > Alzheimer's disease (AD) is the most common cause of dementia and a type of untreatable neurodegenerative condition. It is the third most expensive medical condition [1,2]. Multiple cognitive and non-cognitive functions get disturbed in AD, thereby impacting the quality of life. A wide range of genetic and environmental factors lead to late-onset AD (LOAD). Beta-amyloid and abnormal tau proteins play a major role in disease development. The basic pathways of the basal forebrain and cerebral cortex are compromised in AD with the neurotransmitter acetylcholine being affected [2]. This degenerative disease is progressive in nature, with the entorhinal cortex being one of the first regions to get affected, which then spreads to other Neighboring parts, such as the hippocampus [3]. The appearance of neurofibrillary tangles (made of tau proteins) and plaques (aggregates of amyloid-beta protein) are the characteristics of the onset of The lack of understanding of the underlying molecular mechanisms and the unavailability of credible strategies for its early prediction make the prevention and treatment of AD difficult. Understanding the exact pathophysiology of AD would facilitate the finding of appropriate biomarkers and drug--targets to tackle the growing burden of the disease. The development of efficient and potent therapeutic drugs is the key to tackle the situation. Hence, the search for a diverse range of treatments for this multifactorial disease has shifted the therapy dynamics since the past decade as researchers are inclining towards other non-conventional means of treatment.

[18] Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

  • Authors: Sarah C. Kelly, Bin He, S. Perez, S. Ginsberg, E. Mufson et al.
  • Year: 2017
  • Venue: Acta Neuropathologica Communications
  • URL: https://www.semanticscholar.org/paper/1358acc568c86bacc2dc75613c76d43b6d498bf8
  • DOI: 10.1186/s40478-017-0411-2
  • Summary: Observations suggest that noradrenergic LC cellular and molecular pathology is a prominent feature of prodromal disease that contributes to cognitive dysfunction and lend support to a rational basis for targeting LC neuroprotection as a disease modifying strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.554) > The present findings point to the continuing need to consider noradrenergic system pathophysiology as a key and early component associated with the progression of AD. We posit that strategies aimed at LC neuroprotection or NE replacement are viable therapeutic options [98]. Moreover, as prominent LC degeneration is also evident in cases of Parkinson's disease with dementia and dementia with Lewy bodies [57], maintaining LC projection system integrity may provide a common therapeutic mechanism for combating cognitive decline in multiple late-onset dementia subtypes. Here, we present several candidate molecular pathways that are dysregulated in LC neurons early in the cascade of pathogenic events prior to the onset of AD, which may form the basis for novel neuroprotective approaches for dementia.

[19] Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

  • Authors: Sarah C. Kelly, Bin He, S. Perez, S. Ginsberg, E. Mufson et al.
  • Year: 2017
  • Venue: Acta Neuropathologica Communications
  • URL: https://www.semanticscholar.org/paper/146fd81f89a1808470cb2a754e4cfdc697c0cc30
  • DOI: 10.1186/s40478-017-0411-2
  • PMID: 28109312
  • PMCID: 5251221
  • Citations: 245
  • Influential citations: 11
  • Summary: Observations suggest that noradrenergic LC cellular and molecular pathology is a prominent feature of prodromal disease that contributes to cognitive dysfunction and lend support to a rational basis for targeting LC neuroprotection as a disease modifying strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.553) > The present findings point to the continuing need to consider noradrenergic system pathophysiology as a key and early component associated with the progression of AD. We posit that strategies aimed at LC neuroprotection or NE replacement are viable therapeutic options [98]. Moreover, as prominent LC degeneration is also evident in cases of Parkinson's disease with dementia and dementia with Lewy bodies [57], maintaining LC projection system integrity may provide a common therapeutic mechanism for combating cognitive decline in multiple late-onset dementia subtypes. Here, we present several candidate molecular pathways that are dysregulated in LC neurons early in the cascade of pathogenic events prior to the onset of AD, which may form the basis for novel neuroprotective approaches for dementia.

Notes

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