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1.
PLoS One ; 19(5): e0300005, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38753617

RESUMEN

Strategies to prevent or delay Alzheimer's disease and related dementias (AD/ADRD) are urgently needed, and blood pressure (BP) management is a promising strategy. Yet the effects of different BP control strategies across the life course on AD/ADRD are unknown. Randomized trials may be infeasible due to prolonged follow-up and large sample sizes. Simulation analysis is a practical approach to estimating these effects using the best available existing data. However, existing simulation frameworks cannot estimate the effects of BP control on both dementia and cardiovascular disease. This manuscript describes the design principles, implementation details, and population-level validation of a novel population-health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP-COG) study of the effect of BP levels over the life course on dementia and cardiovascular disease. MICROSIM is an agent-based Monte Carlo simulation designed using computer programming best practices. MICROSIM estimates annual vascular risk factor levels and transition probabilities in all-cause dementia, stroke, myocardial infarction, and mortality in a nationally representative sample of US adults 18+ using the National Health and Nutrition Examination Survey (NHANES). MICROSIM models changes in risk factors over time, cognition and dementia using changes from a pooled dataset of individual participant data from 6 US prospective cardiovascular cohort studies. Cardiovascular risks were estimated using a widely used risk model and BP treatment effects were derived from meta-analyses of randomized trials. MICROSIM is an extensible, open-source framework designed to estimate the population-level impact of different BP management strategies and reproduces US population-level estimates of BP and other vascular risk factors levels, their change over time, and incident all-cause dementia, stroke, myocardial infarction, and mortality.


Asunto(s)
Simulación por Computador , Humanos , Michigan/epidemiología , Enfermedad Crónica , Masculino , Demencia/epidemiología , Anciano , Femenino , Factores de Riesgo , Método de Montecarlo , Presión Sanguínea , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Adulto , Enfermedad de Alzheimer , Anciano de 80 o más Años
3.
Transl Neurodegener ; 13(1): 25, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773569

RESUMEN

The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.


Asunto(s)
Enfermedad de Alzheimer , Biomarcadores , Ensayos Clínicos como Asunto , Proteínas tau , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Proteínas tau/metabolismo , Biomarcadores/análisis , Ensayos Clínicos como Asunto/métodos
4.
Lipids Health Dis ; 23(1): 152, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773573

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that poses a substantial economic burden. The Random forest algorithm is effective in predicting AD; however, the key factors influencing AD onset remain unclear. This study aimed to analyze the key lipoprotein and metabolite factors influencing AD onset using machine-learning methods. It provides new insights for researchers and medical personnel to understand AD and provides a reference for the early diagnosis, treatment, and early prevention of AD. METHODS: A total of 603 participants, including controls and patients with AD with complete lipoprotein and metabolite data from the Alzheimer's disease Neuroimaging Initiative (ADNI) database between 2005 and 2016, were enrolled. Random forest, Lasso regression, and CatBoost algorithms were employed to rank and filter 213 lipoprotein and metabolite variables. Variables with consistently high importance rankings from any two methods were incorporated into the models. Finally, the variables selected from the three methods, with the participants' age, sex, and marital status, were used to construct a random forest predictive model. RESULTS: Fourteen lipoprotein and metabolite variables were screened using the three methods, and 17 variables were included in the AD prediction model based on age, sex, and marital status of the participants. The optimal random forest modeling was constructed with "mtry" set to 3 and "ntree" set to 300. The model exhibited an accuracy of 71.01%, a sensitivity of 79.59%, a specificity of 65.28%, and an AUC (95%CI) of 0.724 (0.645-0.804). When Mean Decrease Accuracy and Gini were used to rank the proteins, age, phospholipids to total lipids ratio in intermediate-density lipoproteins (IDL_PL_PCT), and creatinine were among the top five variables. CONCLUSIONS: Age, IDL_PL_PCT, and creatinine levels play crucial roles in AD onset. Regular monitoring of lipoproteins and their metabolites in older individuals is significant for early AD diagnosis and prevention.


Asunto(s)
Enfermedad de Alzheimer , Lipoproteínas , Aprendizaje Automático , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/metabolismo , Femenino , Masculino , Anciano , Lipoproteínas/sangre , Anciano de 80 o más Años , Algoritmos , Biomarcadores/sangre
5.
Alzheimers Res Ther ; 16(1): 116, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773640

RESUMEN

Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer's disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, "loss-of-function" profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte "loss-of-function" profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.


Asunto(s)
Enfermedad de Alzheimer , Colitis , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Ratones , Colitis/inducido químicamente , Colitis/patología , Sulfato de Dextran/toxicidad , Microbioma Gastrointestinal , Fenotipo , Masculino , Hipocampo/patología , Hipocampo/metabolismo , Femenino , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Disfunción Cognitiva/etiología
6.
Alzheimers Res Ther ; 16(1): 114, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773642

RESUMEN

Alzheimer's disease (AD) poses a significant public health problem, affecting millions of people across the world. Despite decades of research into therapeutic strategies for AD, effective prevention or treatment for this devastating disorder remains elusive. In this review, we discuss the potential of photobiomodulation (PBM) for preventing and alleviating AD-associated pathologies, with a focus on the biological mechanisms underlying this therapy. Future research directions and guidance for clinical practice for this non-invasive and non-pharmacological therapy are also highlighted. The available evidence indicates that different treatment paradigms, including transcranial and systemic PBM, along with the recently proposed remote PBM, all could be promising for AD. PBM exerts diverse biological effects, such as enhancing mitochondrial function, mitigating the neuroinflammation caused by activated glial cells, increasing cerebral perfusion, improving glymphatic drainage, regulating the gut microbiome, boosting myokine production, and modulating the immune system. We suggest that PBM may serve as a powerful therapeutic intervention for AD.


Asunto(s)
Enfermedad de Alzheimer , Terapia por Luz de Baja Intensidad , Enfermedad de Alzheimer/radioterapia , Enfermedad de Alzheimer/terapia , Terapia por Luz de Baja Intensidad/métodos , Animales , Humanos , Modelos Animales de Enfermedad , Investigación Biomédica Traslacional/métodos
7.
Brain Behav ; 14(5): e3503, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38775292

RESUMEN

BACKGROUND: Crocin has a good prospect in the treatment of Alzheimer's disease (AD), but the mechanisms underlying its neuroprotective effects remain elusive. This study aimed to investigate the neuroprotective effects of Crocin and its underlying mechanisms in AD. METHODS: AD mice were set up by injecting Aß25-35 solution into the hippocampus. Then, the AD mice were injected intraperitoneally with 40 mg/kg/day of Crocin for 14 days. Following the completion of Crocin treatment, an open-field test, Y-maze test and Morris water maze test were conducted to evaluate the impact of Crocin on spatial learning and memory deficiency in mice. The effects of Crocin on hippocampal neuron injury, proinflammatory cytokine expressions (IL-1ß, IL-6, and TNF-α), and PI3K/AKT signaling-related protein expressions were measured using hematoxylin and eosin staining, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, respectively. RESULTS: Crocin attenuated Aß25-35-induced spatial learning and memory deficiency and hippocampal neuron injury. Furthermore, the Western blot and qRT-PCR results showed that Crocin effectively suppressed inflammation and activated the PI3K/AKT pathway in Aß25-35-induced mice. CONCLUSION: Crocin restrained neuroinflammation via the activation of the PI3K/AKT pathway, thereby ameliorating the cognitive dysfunction of AD mice.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Carotenoides , Disfunción Cognitiva , Hipocampo , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Carotenoides/farmacología , Carotenoides/administración & dosificación , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Péptidos beta-Amiloides/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Modelos Animales de Enfermedad , Fragmentos de Péptidos/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo
8.
Biometrics ; 80(2)2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38775703

RESUMEN

It has become consensus that mild cognitive impairment (MCI), one of the early symptoms onset of Alzheimer's disease (AD), may appear 10 or more years after the emergence of neuropathological abnormalities. Therefore, understanding the progression of AD biomarkers and uncovering when brain alterations begin in the preclinical stage, while patients are still cognitively normal, are crucial for effective early detection and therapeutic development. In this paper, we develop a Bayesian semiparametric framework that jointly models the longitudinal trajectory of the AD biomarker with a changepoint relative to the occurrence of symptoms onset, which is subject to left truncation and right censoring, in a heterogeneous population. Furthermore, unlike most existing methods assuming that everyone in the considered population will eventually develop the disease, our approach accounts for the possibility that some individuals may never experience MCI or AD, even after a long follow-up time. We evaluate the proposed model through simulation studies and demonstrate its clinical utility by examining an important AD biomarker, ptau181, using a dataset from the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study.


Asunto(s)
Enfermedad de Alzheimer , Teorema de Bayes , Biomarcadores , Disfunción Cognitiva , Simulación por Computador , Progresión de la Enfermedad , Modelos Estadísticos , Humanos , Proteínas tau , Estudios Longitudinales
9.
J Mol Neurosci ; 74(2): 55, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38776015

RESUMEN

The dysregulation of lipid metabolism has been strongly associated with Alzheimer's disease (AD) and has intricate connections with various aspects of disease progression, such as amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. Here, a comprehensive bioinformatic assessment was conducted on lipid metabolism genes in the brains and peripheral blood of AD-derived transcriptome datasets, characterizing the correlation between differentially expressed genes (DEGs) of lipid metabolism and disease pathologies, as well as immune cell preferences. Through the application of weighted gene co-expression network analysis (WGCNA), modules eigengenes related to lipid metabolism were pinpointed, and the examination of their molecular functions within biological processes, molecular pathways, and their associations with pathological phenotypes and molecular networks has been characterized. Analysis of biological networks indicates notable discrepancies in the expression patterns of the DEGs between neuronal and immune cells, as well as variations in cell type enrichments within both brain tissue and peripheral blood. Additionally, drugs targeting the DEGs from central and peripheral and a diagnostic model for hub genes from the blood were retrieved and assessed, some of which were shown to be useful for therapeutic and diagnostic. These results revealed the distinctive pattern of transcriptionally abnormal lipid metabolism in central, peripheral, and immune cell activation, providing valuable insight into lipid metabolism for diagnosing and guiding more effective treatment for AD.


Asunto(s)
Enfermedad de Alzheimer , Metabolismo de los Lípidos , Transcriptoma , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Humanos , Metabolismo de los Lípidos/genética , Encéfalo/metabolismo , Redes Reguladoras de Genes
10.
PLoS One ; 19(5): e0293053, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38768123

RESUMEN

Resting-state functional magnetic resonance imaging (rs-fMRI) has increasingly been used to study both Alzheimer's disease (AD) and schizophrenia (SZ). While most rs-fMRI studies being conducted in AD and SZ compare patients to healthy controls, it is also of interest to directly compare AD and SZ patients with each other to identify potential biomarkers shared between the disorders. However, comparing patient groups collected in different studies can be challenging due to potential confounds, such as differences in the patient's age, scan protocols, etc. In this study, we compared and contrasted resting-state functional network connectivity (rs-FNC) of 162 patients with AD and late mild cognitive impairment (LMCI), 181 schizophrenia patients, and 315 cognitively normal (CN) subjects. We used confounder-controlled rs-FNC and applied machine learning algorithms (including support vector machine, logistic regression, random forest, and k-nearest neighbor) and deep learning models (i.e., fully-connected neural networks) to classify subjects in binary and three-class categories according to their diagnosis labels (e.g., AD, SZ, and CN). Our statistical analysis revealed that FNC between the following network pairs is stronger in AD compared to SZ: subcortical-cerebellum, subcortical-cognitive control, cognitive control-cerebellum, and visual-sensory motor networks. On the other hand, FNC is stronger in SZ than AD for the following network pairs: subcortical-visual, subcortical-auditory, subcortical-sensory motor, cerebellum-visual, sensory motor-cognitive control, and within the cerebellum networks. Furthermore, we observed that while AD and SZ disorders each have unique FNC abnormalities, they also share some common functional abnormalities that can be due to similar neurobiological mechanisms or genetic factors contributing to these disorders' development. Moreover, we achieved an accuracy of 85% in classifying subjects into AD and SZ where default mode, visual, and subcortical networks contributed the most to the classification and accuracy of 68% in classifying subjects into AD, SZ, and CN with the subcortical domain appearing as the most contributing features to the three-way classification. Finally, our findings indicated that for all classification tasks, except AD vs. SZ, males are more predictable than females.


Asunto(s)
Enfermedad de Alzheimer , Aprendizaje Automático , Imagen por Resonancia Magnética , Esquizofrenia , Humanos , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/diagnóstico por imagen , Femenino , Esquizofrenia/fisiopatología , Esquizofrenia/diagnóstico por imagen , Masculino , Imagen por Resonancia Magnética/métodos , Anciano , Persona de Mediana Edad , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Conectoma/métodos , Descanso/fisiología , Estudios de Casos y Controles
11.
PLoS One ; 19(5): e0303111, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38768188

RESUMEN

BACKGROUND: The use of amyloid-PET in dementia workup is upcoming. At the same time, amyloid-PET is costly and limitedly available. While the appropriate use criteria (AUC) aim for optimal use of amyloid-PET, their limited sensitivity hinders the translation to clinical practice. Therefore, there is a need for tools that guide selection of patients for whom amyloid-PET has the most clinical utility. We aimed to develop a computerized decision support approach to select patients for amyloid-PET. METHODS: We included 286 subjects (135 controls, 108 Alzheimer's disease dementia, 33 frontotemporal lobe dementia, and 10 vascular dementia) from the Amsterdam Dementia Cohort, with available neuropsychology, APOE, MRI and [18F]florbetaben amyloid-PET. In our computerized decision support approach, using supervised machine learning based on the DSI classifier, we first classified the subjects using only neuropsychology, APOE, and quantified MRI. Then, for subjects with uncertain classification (probability of correct class (PCC) < 0.75) we enriched classification by adding (hypothetical) amyloid positive (AD-like) and negative (normal) PET visual read results and assessed whether the diagnosis became more certain in at least one scenario (PPC≥0.75). If this was the case, the actual visual read result was used in the final classification. We compared the proportion of PET scans and patients diagnosed with sufficient certainty in the computerized approach with three scenarios: 1) without amyloid-PET, 2) amyloid-PET according to the AUC, and 3) amyloid-PET for all patients. RESULTS: The computerized approach advised PET in n = 60(21%) patients, leading to a diagnosis with sufficient certainty in n = 188(66%) patients. This approach was more efficient than the other three scenarios: 1) without amyloid-PET, diagnostic classification was obtained in n = 155(54%), 2) applying the AUC resulted in amyloid-PET in n = 113(40%) and diagnostic classification in n = 156(55%), and 3) performing amyloid-PET in all resulted in diagnostic classification in n = 154(54%). CONCLUSION: Our computerized data-driven approach selected 21% of memory clinic patients for amyloid-PET, without compromising diagnostic performance. Our work contributes to a cost-effective implementation and could support clinicians in making a balanced decision in ordering additional amyloid PET during the dementia workup.


Asunto(s)
Tomografía de Emisión de Positrones , Humanos , Tomografía de Emisión de Positrones/métodos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Imagen por Resonancia Magnética/métodos , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/metabolismo , Demencia Vascular/diagnóstico por imagen , Demencia Vascular/metabolismo , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Amiloide/metabolismo
12.
JAMA Netw Open ; 7(5): e2412824, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38776079

RESUMEN

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.


Asunto(s)
Presión Sanguínea , Enfermedades de los Pequeños Vasos Cerebrales , Demencia , Humanos , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/epidemiología , Femenino , Masculino , Anciano , Demencia/genética , Demencia/epidemiología , Presión Sanguínea/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/epidemiología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Factores de Riesgo , Predisposición Genética a la Enfermedad , Anciano de 80 o más Años , Estudios Prospectivos
13.
Anal Chem ; 96(19): 7506-7515, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38690851

RESUMEN

Alzheimer's disease (AD) is a progressive neurological disorder featuring abnormal protein aggregation in the brain, including the pathological hallmarks of amyloid plaques and hyperphosphorylated tau. Despite extensive research efforts, understanding the molecular intricacies driving AD development remains a formidable challenge. This study focuses on identifying key protein conformational changes associated with the progression of AD. To achieve this, we employed quantitative cross-linking mass spectrometry (XL-MS) to elucidate conformational changes in the protein networks in cerebrospinal fluid (CSF). By using isotopically labeled cross-linkers BS3d0 and BS3d4, we reveal a dynamic shift in protein interaction networks during AD progression. Our comprehensive analysis highlights distinct alterations in protein-protein interactions within mild cognitive impairment (MCI) states. This study accentuates the potential of cross-linked peptides as indicators of AD-related conformational changes, including previously unreported site-specific binding between α-1-antitrypsin (A1AT) and complement component 3 (CO3). Furthermore, this work enables detailed structural characterization of apolipoprotein E (ApoE) and reveals modifications within its helical domains, suggesting their involvement in MCI pathogenesis. The quantitative approach provides insights into site-specific interactions and changes in the abundance of cross-linked peptides, offering an improved understanding of the intricate protein-protein interactions underlying AD progression. These findings lay a foundation for the development of potential diagnostic or therapeutic strategies aimed at mitigating the negative impact of AD.


Asunto(s)
Enfermedad de Alzheimer , Apolipoproteínas E , Espectrometría de Masas , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico , Humanos , Apolipoproteínas E/química , Apolipoproteínas E/metabolismo , Reactivos de Enlaces Cruzados/química , Conformación Proteica , alfa 1-Antitripsina/química , alfa 1-Antitripsina/metabolismo , Disfunción Cognitiva/metabolismo
14.
Sci Rep ; 14(1): 9970, 2024 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-38693203

RESUMEN

Alzheimer's disease (AD) shows a high pathological and symptomatological heterogeneity. To study this heterogeneity, we have developed a patient stratification technique based on one of the most significant risk factors for the development of AD: genetics. We addressed this challenge by including network biology concepts, mapping genetic variants data into a brain-specific protein-protein interaction (PPI) network, and obtaining individualized PPI scores that we then used as input for a clustering technique. We then phenotyped each obtained cluster regarding genetics, sociodemographics, biomarkers, fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, and neurocognitive assessments. We found three clusters defined mainly by genetic variants found in MAPT, APP, and APOE, considering known variants associated with AD and other neurodegenerative disease genetic architectures. Profiling of these clusters revealed minimal variation in AD symptoms and pathology, suggesting different biological mechanisms may activate the neurodegeneration and pathobiological patterns behind AD and result in similar clinical and pathological presentations, even a shared disease diagnosis. Lastly, our research highlighted MAPT, APP, and APOE as key genes where these genetic distinctions manifest, suggesting them as potential targets for personalized drug development strategies to address each AD subgroup individually.


Asunto(s)
Enfermedad de Alzheimer , Apolipoproteínas E , Tomografía de Emisión de Positrones , Proteínas tau , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Humanos , Proteínas tau/genética , Apolipoproteínas E/genética , Masculino , Femenino , Anciano , Predisposición Genética a la Enfermedad , Precursor de Proteína beta-Amiloide/genética , Mapas de Interacción de Proteínas/genética , Biomarcadores , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/metabolismo
15.
Zh Nevrol Psikhiatr Im S S Korsakova ; 124(4. Vyp. 2): 72-76, 2024.
Artículo en Ruso | MEDLINE | ID: mdl-38696154

RESUMEN

The prevalence of cognitive impairment is steadily increasing compared to previous years. According to the World Health Organization, the number of people living with dementia will increase reaching 82 million in 2030 and 152 million in 2050. The most common cause is Alzheimer's disease (AD). The pathophysiological process in AD begins several years before the onset of clinical symptoms; so identifying it at an early stage would likely improve the clinical prognosis. The article presents EEG changes in patients with AD, and discusses the possibility of using EEG as a screening method for examining patients with cognitive impairment.


Asunto(s)
Enfermedad de Alzheimer , Electroencefalografía , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/diagnóstico , Humanos , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/diagnóstico , Pronóstico
16.
BMC Genomics ; 25(1): 440, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38702606

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is a heritable neurodegenerative disease whose long asymptomatic phase makes the early diagnosis of it pivotal. Blood U-p53 has recently emerged as a superior predictive biomarker for AD in the early stages. We hypothesized that genetic variants associated with blood U-p53 could reveal novel loci and pathways involved in the early stages of AD. RESULTS: We performed a blood U-p53 Genome-wide association study (GWAS) on 484 healthy and mild cognitively impaired subjects from the ADNI cohort using 612,843 Single nucleotide polymorphisms (SNPs). We performed a pathway analysis and prioritized candidate genes using an AD single-cell gene program. We fine-mapped the intergenic SNPs by leveraging a cell-type-specific enhancer-to-gene linking strategy using a brain single-cell multimodal dataset. We validated the candidate genes in an independent brain single-cell RNA-seq and the ADNI blood transcriptome datasets. The rs279686 between AASS and FEZF1 genes was the most significant SNP (p-value = 4.82 × 10-7). Suggestive pathways were related to the immune and nervous systems. Twenty-three candidate genes were prioritized at 27 suggestive loci. Fine-mapping of 5 intergenic loci yielded nine cell-specific candidate genes. Finally, 15 genes were validated in the independent single-cell RNA-seq dataset, and five were validated in the ADNI blood transcriptome dataset. CONCLUSIONS: We underlined the importance of performing a GWAS on an early-stage biomarker of AD and leveraging functional omics datasets for pinpointing causal genes in AD. Our study prioritized nine genes (SORCS1, KIF5C, TMEFF2, TMEM63C, HLA-E, ATAT1, TUBB, ARID1B, and RUNX1) strongly implicated in the early stages of AD.


Asunto(s)
Enfermedad de Alzheimer , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/sangre , Anciano , Masculino , Femenino , Predisposición Genética a la Enfermedad , Biomarcadores/sangre , Anciano de 80 o más Años
17.
Brain Behav ; 14(5): e3524, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38702902

RESUMEN

INTRODUCTION: The combination of apolipoprotein E ε4 (ApoE ε4) status, odor identification, and odor familiarity predicts conversion to mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: To further understand olfactory disturbances and AD risk, ApoE ε4 carrier (mean age 76.38 ± 5.21) and ε4 non-carrier (mean age 76.8 ± 3.35) adults were given odor familiarity and identification tests and performed an odor identification task during fMRI scanning. Five task-related functional networks were detected using independent components analysis. Main and interaction effects of mean odor familiarity ratings, odor identification scores, and ε4 status on network activation and task-modulation of network functional connectivity (FC) during correct and incorrect odor identification (hits and misses), controlling for age and sex, were explored using multiple linear regression. RESULTS: Findings suggested that sensory-olfactory network activation was positively associated with odor identification scores in ε4 carriers with intact odor familiarity. The FC of sensory-olfactory, multisensory-semantic integration, and occipitoparietal networks was altered in ε4 carriers with poorer odor familiarity and identification. In ε4 carriers with poorer familiarity, connectivity between superior frontal areas and the sensory-olfactory network was negatively associated with odor identification scores. CONCLUSIONS: The results contribute to the clarification of the neurocognitive structure of odor identification processing and suggest that poorer odor familiarity and identification in ε4 carriers may signal multi-network dysfunction. Odor familiarity and identification assessment in ε4 carriers may contribute to the predictive value of risk for MCI and AD due to the breakdown of sensory-cognitive network integration. Additional research on olfactory processing in those at risk for AD is warranted.


Asunto(s)
Apolipoproteína E4 , Imagen por Resonancia Magnética , Humanos , Femenino , Masculino , Anciano , Apolipoproteína E4/genética , Percepción Olfatoria/fisiología , Olfato/fisiología , Reconocimiento en Psicología/fisiología , Anciano de 80 o más Años , Disfunción Cognitiva/fisiopatología , Odorantes , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/genética , Heterocigoto , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología
19.
Stem Cell Res Ther ; 15(1): 136, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38715083

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. MAIN CONTENT: Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidß (Aß) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron-glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. CONCLUSION: Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.


Asunto(s)
Enfermedad de Alzheimer , Trasplante de Células Madre , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Humanos , Trasplante de Células Madre/métodos , Animales , Células Madre/metabolismo , Células Madre/citología
20.
J Transl Med ; 22(1): 430, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38715084

RESUMEN

Passive immunotherapy with specific antibodies targeting Amyloid ß (Aß) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aß peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aß antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aß antibodies, such as lecanemab (a humanized mAb binds to soluble Aß protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aß peptides) and aducanumab (a human mAb binds to the aggregated form of Aß), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aß antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aß antibodies and other pharmaceutical agents should also be explored.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/inmunología , Inmunización Pasiva , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales/uso terapéutico , Animales
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