Cause Of Alzheimer's Disease Research Articles

Microglia-targeting nanosystems that cooperatively deliver Chinese herbal ingredients alleviate behavioral and cognitive deficits in Alzheimer’s disease model mice

The effective treatment of Alzheimer’s disease (AD) is challenging because of its complex and controversial pathological mechanisms. Moreover, multiple barriers, such as the blood–brain barrier (BBB), reduce drug delivery efficiency. Microglia-related neuroinflammation has recently attracted increasing attention as a possible cause of AD and has become a novel therapeutic target. Therefore, overcoming the BBB and targeted delivery of anti-inflammatory agents to microglia seem to be effective practical strategies for treating AD. A large proportion of natural active extracts possess exceptional immunomodulating capabilities. In this study, the cooperative delivery of berberine (Ber) and palmatine (Pal) by transferrin-decorated extracellular vesicles (Tf-hEVs-Ber/Pal), which can cross the BBB and precisely target microglia, was performed. This nanosystem effectively cleared amyloid β-protein (Aβ) aggregates, significantly regulated the neuroinflammatory environment both in vitro and in vivo and markedly altered the behavior and improved the cognitive and learning abilities of AD model mice. The efficacy of a microglia-targeting combined therapeutic approach for AD was demonstrated, which broadens the potential application of Chinese herbal ingredients.Graphical abstract

Natural Bioactive Compounds in Alzheimer’s Disease Therapy

Dementia is the primary cause of Alzheimer’s disease (AD), a progressive neurodegenerative disorder (NDD) that increases with age. AD is one of the world's most serious healthcare issues. About 60–80% of dementia cases worldwide are caused by AD. It is characterised by the biological presence of tau-containing neurofibrillary tangles (NFT) and the β-amyloid (Aβ) peptide. The main focus for the development of AD therapy has been Aβ. Consequently, the Aβ removal from the brain is a prerequisite for effective treatment. Peptide was identified as the pathogenic agent of NDD by the Amyloid Cascade Hypothesis (ACH). Currently, very few medications available can delay the disease progression. Compounds with pharmacological activity isolated from plants, animals, and microorganisms help to treat AD. Phytochemicals possess anti-inflammatory, anti-oxidative, and anticholinesterase properties. A nutritional diet regulates health and prevents chronic inflammation and oxidative stress. AD development is influenced by phenolic compounds, omega-3 fatty acids, fat-soluble vitamins, and carotenoids, in addition to their roles as antioxidants and anti-inflammatory mediators. AD treatment has used marine-derived bioactive substances from microalgae (seaweeds). Nutraceuticals occur in pomegranate fruit. Fruit juice and peels contain significant bioactive substances used in traditional Chinese, Unani, and Ayurvedic medicine. Since AD is a complex illness, natural remedies offer the benefit of a multitarget strategy. However, many medications have undesirable side effects. Drug discovery is made easier by natural product extracts with bioactive components that combine to show neuroprotective effects.

Health data preparation framework for unsupervised models (HealthDataPrep): A study with Alzheimer's disease mortality data from Brazil

Healthcare data preparation challenges often arise from its complexity and heterogeneity. This study introduces a framework for preparing structured and non-temporal healthcare data, tailored for unsupervised learning models. The HealthDataPrep framework extends CRISP-DM, guiding data preparation in four key areas: data selection, data cleaning, feature engineering, and data privacy. Validated using a dataset on Alzheimer's disease mortality in Brazil, the framework generated two datasets utilized in unsupervised algorithms, K-Modes for clustering and Apriori for association rules. Results revealed sociodemographic profiles vulnerable to the disease, predominantly featuring Alzheimer's mortality in women over 80, widowed, and with low education in the Southeast region. Furthermore, the study identified associated causes of Alzheimer's mortality, such as pneumonia, respiratory failure, and sepsis. These insights are crucial for shaping public policies and intervention programs aimed at reducing Alzheimer's mortality. The research contributes methodologically to healthcare data preparation and enhances our understanding of Alzheimer's mortality in Brazil.

Modulation of microRNA-502-3p significantly influences synaptic activity, dendritic spine density and mitochondrial morphology in the mice brain.

Synapse dysfunction is the root cause of Alzheimer's disease (AD). Uninterrupted and regulated synapse action is crucial to maintain healthy brain function. Our previous study discovered microRNA-502-3p (miR-502-3p), a synapse-specific miRNA, highly expressed at the AD synapses. Further, in vitro studies unveiled the biological relevance of miR-502-3p in modulating GABA receptor function, synaptic activity and mitochondrial morphology. Current study focuses to investigate the role of miR-502-3p in vivo using stereotaxic injection of miR-502-3p overexpression (OE) and suppression (sponge) lentivirus (LV) into the hippocampus of C57BL/6 wild-type (WT) mice. MiR-502-3p OE and sponge LV were characterized by transducing HT22 cells followed by QRT-PCR and miRNAScope analysis of miR-502-3p. MiR-502-3p OE LV showed a very high-fold upregulation and sponge LV showed significant reduction in miR-502-3p levels. MiR-502-3p OE and sponge LV were injected into three months old WT mice brain hippocampus. Overexpression and suppression effects of miR-502-3p were studied on synaptic proteins, synapse number, mitochondrial morphology and dendritic spine density at eight-weeks post-injection. Mice injected with miR-502-3p OE LV showed reduced levels of synaptic proteins, diminished synapse formation, defective mitochondrial morphology and reduced dendritic spine density relative to control LV treated mice. While mice treated with sponge LV showed elevated levels of synaptic proteins, augmented synapses, improved mitochondrial morphology and elongated dendrites and spine density. Our in vivo study unveiled translational abilities of miR-502-3p to restore synapse dysfunction in AD and other neurological disorders.

Cytotoxicity of Amyloid β1-42 Fibrils to Brain Immune Cells.

Alzheimer's disease (AD) is a progressive pathology that is linked to abrupt aggregation of amyloid β1-42 (Aβ1-42) peptide in the central nervous system. Aβ1-42 aggregation yields amyloid oligomers and fibrils, toxic protein aggregates that cause progressive neuronal degeneration in the frontal lobe of the brain. Although neurons remain the focus of AD for decades, a growing body of evidence suggests that the degeneration of immune cells in the brain can be the major cause of AD. However, the extent to which Aβ1-42 aggregates are toxic to the major classes of immune cells in the brain remains unclear. In the current study, we examine the cytotoxic effects of Aβ1-42 fibrils on macrophages, dendritic cells, and microglia. These cells play vitally important roles in development and homeostasis of the central nervous system. We found that Aβ1-42 fibrils caused calcium release and enhanced levels of reactive oxygen species in macrophages, dendritic cells, and microglia as well as neurons. We also investigated the extent to which the lysozymes of these immune cells could alter the aggregation properties of Aβ1-42. Our results showed that lysosomes extracted from macrophages, dendritic cells, and microglia drastically accelerated Aβ1-42 aggregation as well as altered cytotoxicity of these protein aggregates. These results indicate that impairment of immune cells in the brain can be a critically important aspect of neurodegenerative processes that are taking place upon the onset of AD.

Astaxanthin nanoemulsion improves cognitive function and synaptic integrity in Streptozotocin-induced Alzheimer's disease model.

Astaxanthin derived from natural sources has excellent antioxidant and anti-inflammatory effects, and it is currently being widely researched as a neuroprotectant. However, astaxanthin possesses low oral bioavailability, and thus, astaxanthin extract from Haematococcus pluvialis was formulated into a nanoemulsion to improve its bioavailability and administered to Alzheimer's disease (AD)-like rats to study its possible neuroprotective benefits. Astaxanthin nanoemulsion was administered orally once a day for 28 days to streptozotocin (STZ)-induced AD rats at concentrations of 160, 320, and 640mg/kg of body weight (bw) and subsequently assessed for cognitive function using behavioral assessments. Brain samples were collected for the assessment of AD biomarkers. Astaxanthin nanoemulsion at a dosage of 640mg/kg bw significantly improved spatial learning, spatial memory, and recognition memory against STZ-AD rats. At 320 and 640mg/kg bw, astaxanthin nanoemulsion significantly reduced levels of hippocampus synaptosomal amyloid beta and paired-helical fibrillary tau protein while increasing neuron survival. Additionally, astaxanthin nanoemulsion at 640mg/kg bw significantly increased acetylcholine levels in the hippocampus and cerebellum. Astaxanthin nanoemulsion at all treatment dosages significantly reduced malondialdehyde, a lipid peroxidation product, and neuroinflammatory mediators (GFAP and TNF-α). Astaxanthin nanoemulsion supplementation has the potential to improve cognitive function and synaptic function by lowering amyloid beta and tau levels, as well as preserve neuron integrity by reducing neuroinflammation and lipid peroxidation, indicating that it may be able to treat some of the underlying causes of AD.

An efficient vision transformer for Alzheimer’s disease classification using magnetic resonance images

An efficient vision transformer for Alzheimer’s disease classification using magnetic resonance images

Recent Advances in the Diagnosis of Alzheimer's Disease: A Brief Overview of Tau PET Tracers in Nuclear Medicine.

Dementia (the most common cause of Alzheimer's disease) is defined as a chronic or progressive syndrome with disturbance of multiple cortical functions, the most important of them including memory, learning capacity, comprehension, orientation, calculation, language, and judgement. These cognitive impairments affect the quality of life, behavior, and social relations. Techniques of nuclear medicine provide feasible ways to record the intracellular alterations of disease and deficiencies. In these non-invasive manners, the hippocampal-neocortical disconnection may partly explain the hypo-metabolism incident found in Alzheimer's disease. Based on this fact, the study of all these mechanisms of action is conceivable and achievable by radiopharmaceuticals. This review is aimed at the presentation of radiopharmaceuticals that are developed for the detection of Alzheimer's disease in preclinical and clinical trials.

Biochanin-A: A Potential Candidate for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia, is a multifactorial neurological condition characterized by progressive loss of memory and learning, uncontrollable movement, difficulty processing visual images, and impairment of reasoning and/or judgment skills. Although the exact cause of AD is still unknown, recent evidence suggests that environmental, lifestyle, and genetic factors are common contributors to the disease's progression. Pathophysiological features of AD include amyloid beta (Aβ) accumulation, abnormal deposition of neuritic plaques and neurofibrile tangles, cholinergic dysfunction, neuroinflammation, and oxidative stress burden along with mitochondrial dysfunction. There are currently no pharmaceutical methods or medications that can stop the progression of a disease. More attention is now being paid to natural products, herbal medicines, and different bioactive phytoconstituents, particularly flavonoids, as alternative therapies and useful resources for finding new drug candidates for the treatment of AD-like symptoms. A dietary isoflavone, biochanin-A, which is isolated from the leaves and stems of Trifolium pretense L. (family: Leguminosae), possesses remarkable anti-inflammatory and antioxidant properties along with cognitive-enhancing effects. Biochanin-A exhibits notable neuroprotective effects by reducing Aβ deposition, decreasing apoptosis, and preventing the production of pro-inflammatory mediators, including TNF-α, IL- 1β, and NO. Various preclinical reports explore the pharmacological role of biochanin-A against experimentally-induced AD and highlight that it can alter numerous signaling pathways, including Nrf2, NF-κB, JNK, MAPK, and Bcl-2/Bax. The present review article summarizes the numerous research studies that have evaluated the role of biochanin-A for dementia associated with AD. As part of a comprehensive program, biochanin-A has very exceptional potential to prevent and treat AD-related cognitive impairment. It is envisaged that these potential chemical moieties can be employed in the drug discovery process to identify efficacious and safe therapy for the treatments for AD-like manifestation.

Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome-Alzheimer's disease.

Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer's disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimer's disease (DSAD) to demographically matched cases of early-onset AD and healthy ageing controls. We find wide dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD. To understand the cell types that may contribute to changes in protein abundance, we undertook a matched single-nuclei RNA-sequencing study, which demonstrated that APOE expression was elevated in subtypes of astrocytes, endothelial cells and pericytes in DSAD. We further investigate how trisomy 21 may cause increased APOE. Increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people with DSAD, altering disease mechanisms with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people with DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this vulnerable group of individuals who have high-risk of early-onset dementia.

Alzheimer's disease in the Kingdom of Saudi Arabia: Current perspectives and genetic insights.

The prevalence of dementia and mild cognitive disorder has markedly risen in recent years. Alzheimer's disease (AD) stands out as the most common form of neurodegenerative dementia among the elderly, featuring progressive memory loss and cognitive decline. Although the exact biological causes of AD are complex and multifactorial, genetics is considered a prominent contributor. To date, around 80 genetic loci have been identified, primarily in European ancestry groups, though a considerable portion of AD's genetic architecture remains elusive. Recognizing the impending rise in AD cases, both governmental and private sectors in Saudi Arabia are making efforts to enhance formal care and services for older adults. While few studies have investigated AD-susceptible genes within the Saudi population, further attention is needed to explore the genetic background and identify molecular biomarkers associated with AD. This review provides an overview of the current understanding of AD and recent genetic research in Saudi Arabia.

Newer Therapeutic Approaches in Treating Alzheimer's Disease: A Comprehensive Review.

Alzheimer's disease (AD) is an aging-related irreversible neurodegenerative disease affecting mostly the elderly population. The main pathological features of AD are the extracellular Aβ plaques generated by APP cleavage through the amyloidogenic pathway, the intracellular neurofibrillary tangles (NFT) resulting from the hyperphosphorylated tau proteins, and cholinergic neurodegeneration. However, the actual causes of AD are unknown, but several studies suggest hereditary mutations in PSEN1 and -2, APOE4, APP, and the TAU genes are the major perpetrators. In order to understand the etiology and pathogenesis of AD, various hypotheses are proposed. These include the following hypotheses: amyloid accumulation, tauopathy, inflammation, oxidative stress, mitochondrial dysfunction, glutamate/excitotoxicity, cholinergic deficiency, and gut dysbiosis. Currently approved therapeutic interventions are donepezil, galantamine, and rivastigmine, which are cholinesterase inhibitors (ChEIs), and memantine, which is an N-methyl-d-aspartate (NMDA) antagonist. These treatment strategies focus on only symptomatic management of AD by attenuating symptoms but not regeneration of neurons or clearance of Aβ plaques and hyperphosphorylated Tau. This review focuses on the pathophysiology, novel therapeutic targets, and disease-altering treatments such as α-secretase modulators, active immunotherapy, passive immunotherapy, natural antioxidant products, nanomaterials, antiamyloid therapy, tau aggregation inhibitors, transplantation of fecal microbiota or stem cells, and microtubule stabilizers that are in clinical trials or still under investigation.

Beliefs About the Causes of Alzheimer's Disease Among Latinos in New York City.

Latinos face health disparities in Alzheimer's disease (AD), with high disease prevalence relative to non-Latino whites and barriers to healthcare access. Several studies have found misconceptions about AD among Latinos that were linked to reduced preventative or help-seeking behavior. To improve understanding of illness perceptions among Latinos, we examined beliefs about the causes of AD, one of the five dimensions of illness representations from Leventhal's Self-Regulation Theory, among a sample of N = 216 Latinos. We conducted in-depth, semi-structured interviews with participants aged 40 to 64 (average age 53 years) living in northern Manhattan. Seven distinct causes of AD were identified, though participants demonstrated a general understanding of AD as a multifactorial disease. Genetics was found to be the most endorsed cause of AD, followed by unhealthy lifestyle factors. Most Latinos who believed psychosocial factors played a critical role in AD development were first-generation immigrants. No participants attributed AD to a normal process of aging, and few ascribed the disease to brain damage from stroke or head injuries. Several participants expressed the belief that environmental contaminants can cause AD, which has received little mention in prior studies. Though only a small number thought AD could occur by chance, most participants remained uncertain about the exact causes of the disease and used lay knowledge to explain their beliefs. Our findings help identify areas where educational interventions would be beneficial in improving community knowledge and offer perspectives that can foster cultural competency in healthcare.

Lignans from Schisandra chinensis (Turcz.) Baill ameliorates cognitive impairment in Alzheimer's disease and alleviates ferroptosis by activating the Nrf2/FPN1 signaling pathway and regulating iron levels.

Lignans from Schisandra chinensis (Turcz.) Baill ameliorates cognitive impairment in Alzheimer's disease and alleviates ferroptosis by activating the Nrf2/FPN1 signaling pathway and regulating iron levels.

Synaptic and synchronic impairments in subcortical brain regions associated with early non-cognitive dysfunction in Alzheimer's disease.

For many decades, Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions, which are thought to be related to cognitive dysfunctions such as memory and language deficits. The exact cause of Alzheimer's disease is still under debate, making it challenging to establish an effective therapy or early diagnosis. It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction, a critical step in Alzheimer's disease development. The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language. However, while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies, cognitive symptoms do not necessarily improve. Interestingly, recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer's disease. A body of recent evidence suggests that early Alzheimer's disease is associated with alterations (e.g., motivation, anxiety, and motor impairment) in subcortical areas, such as the striatum and amygdala, in both human and animal models. Also, recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens, locus coeruleus, and raphe nucleus, even without extracellular amyloid plaques. The reported effects are mainly excitatory, increasing glutamatergic transmission and neuronal excitability. In agreement, data in Alzheimer's disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy. The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety, irritability, and motivation deficits, which precede memory loss and language alterations. Overall, the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression. Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer's disease beyond the traditionally studied hippocampal and cortical circuits.

Valosin-containing Protein is Cargo in Amyloid Precursor Protein Extracellular Vesicles.

The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer's disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-in App mutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App. The presence of Vcp suggests a role for App-EVs in the clearance of protein aggregates.

Molecular Mechanisms of Alzheimer's Disease Induced by Amyloid-β and Tau Phosphorylation Along with RhoA Activity: Perspective of RhoA/Rho-Associated Protein Kinase Inhibitors for Neuronal Therapy.

Amyloid-β peptide (Aβ) is a critical cause of Alzheimer's disease (AD). It is generated from amyloid precursor protein (APP) through cleavages by β-secretase and γ-secretase. γ-Secretase, which includes presenilin, is regulated by several stimuli. Tau protein has also been identified as a significant factor in AD. In particular, Tau phosphorylation is crucial for neuronal impairment, as phosphorylated Tau detaches from microtubules, leading to the formation of neurofibrillary tangles and the destabilization of the microtubule structure. This instability in microtubules damages axons and dendrites, resulting in neuronal impairment. Notably, Aβ is linked to Tau phosphorylation. Another crucial factor in AD is neuroinflammation, primarily occurring in the microglia. Microglia possess several receptors that bind with Aβ, triggering the expression and release of an inflammatory factor, although their main physiological function is to phagocytose debris and pathogens in the brain. NF-κB activation plays a major role in neuroinflammation. Additionally, the production of reactive oxygen species (ROS) in the microglia contributes to this neuroinflammation. In microglia, superoxide is produced through NADPH oxidase, specifically NOX2. Rho GTPases play an essential role in regulating various cellular processes, including cytoskeletal rearrangement, morphology changes, migration, and transcription. The typical function of Rho GTPases involves regulating actin filament formation. Neurons, with their complex processes and synapse connections, rely on cytoskeletal dynamics for structural support. Other brain cells, such as astrocytes, microglia, and oligodendrocytes, also depend on specific cytoskeletal structures to maintain their unique cellular architectures. Thus, the aberrant regulation of Rho GTPases activity can disrupt actin filaments, leading to altered cell morphology, including changes in neuronal processes and synapses, and potentially contributing to brain diseases such as AD.

Use ER stress inhibitor BiP Inducer X in ZIKV-infected brain organoid to see if reducing ER stress through ATF6 pathway can alleviate pathological feature of Alzheimers disease

Alzheimers disease (AD), a gradually worsening neurodegenerative disorder, typically affects the elderly people. Widely acknowledged as the primary cause of AD is the accumulation of -amyloid (A) outside cells and the formation of neurofibrillary tangles inside cells. Presently, there exists no efficacious therapy to slow down the emergence and progression of AD and many scientists are finding ways to cure AD through different aspects. There are some experiments have indicated that ER stress contributes to the onset and development of AD. Therefore, some scientists are having experiments on AD by inhibit ER stress using different inhibitors through different pathways. Zika virus (ZIKV) have been proved to be able to increase a accumulation and p-tau level in AD brain organoid. After ZIKV infection, phenotypes linked to AD in brain organoids saw an increase due to stress in the endoplasmic reticulum (ER) and the unfolded protein response (UPR).The BiP Inducer X(BIX)is used in this experiment to investigate the effect of inhibitor on AD via activating transcription factor 6(ATF6)pathway in ZIKV-infected brain organoid models. The A accumulation and p-tau level is recorded by immunostaining to form image. This paper only provides theoretical experiment design and possible result about whether the inhibition on ER stress through ATF6 pathway would reduce AD features, which need further research in the pathology of AD.

Evidence Suggesting That Alzheimer's Disease May Be a Transmissible Disorder.

Alzheimer's disease (AD) is characterised by progressive neurodegeneration with the formation of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain parenchyma. The causes of AD have been attributed to a combination of age-related changes within the brain as well as genetic, environmental and lifestyle factors. However, a recent study by Banerjee et al. highlights the possibility that AD may be a transmissible disease and that iatrogenic AD could be environmentally acquired, similar to iatrogenic Creutzfeldt-Jakob disease (iCJD). The study reports that contaminated Aβ in cadaver-derived pituitary growth hormone (c-hGH) therapy, which patients received during childhood inoculation, may accidentally transmit into their brains, triggering neurodegeneration and AD onset in older age. Furthermore, corroborating evidence from various animal model studies and human case reports suggests that AD can be potentially transmissible.

Iron Homeostasis Dysregulation, Oro-Gastrointestinal Microbial Inflammatory Factors, and Alzheimer's Disease: A Narrative Review.

Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that profoundly impacts cognitive function and the nervous system. Emerging evidence highlights the pivotal roles of iron homeostasis dysregulation and microbial inflammatory factors in the oral and gut microbiome as potential contributors to the pathogenesis of AD. Iron homeostasis disruption can result in excessive intracellular iron accumulation, promoting the generation of reactive oxygen species (ROS) and oxidative damage. Additionally, inflammatory agents produced by pathogenic bacteria may enter the body via two primary pathways: directly through the gut or indirectly via the oral cavity, entering the bloodstream and reaching the brain. This infiltration disrupts cellular homeostasis, induces neuroinflammation, and exacerbates AD-related pathology. Addressing these mechanisms through personalized treatment strategies that target the underlying causes of AD could play a critical role in preventing its onset and progression.