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Objective: Little is known about the amyloid load impact on depressive symptoms or disorders, although it can modulate the cognitive trajectory in older adults. Here, we analyzed, in individuals at risk of Alzheimer's dementia, the relationship between amyloid load and depressive symptoms changes over time.Methods: This study included ≥ 70-year-old participants from the French Multidomain Alzheimer Preventive Trial (MAPT) (May 2008 to February 2011) who underwent brain amyloid load measurement by ß-amyloid-[18F] florbetapir-PET at baseline and had spontaneous memory complaints and/or limitation in 1 instrumental activity of daily living or slow walking gait (N = 264). Symptoms of depression were measured with the Geriatric Depression Scale-15 items (GDS) at baseline and 6, 12, 24, and 36 months of follow-up. Four GDS factors were determined by principal component analysis (PCA): life satisfaction, level of apathy, self-esteem, and anxiety. Amyloid positive status was defined based on the amyloid load in 6 Alzheimer's dementia-related regions. Regional amyloid load was based on 3 dimensions defined by PCA. The longitudinal links between depressive symptomatology and amyloid load (ie, cortical AV45 and amyloid load dimensions) were analyzed using linear mixed-multivariate models.Results: At baseline, 11% of participants had depressive symptoms (GDS > 5) and 34% were amyloid-positive. The global amyloid load was not associated with worsening of the total GDS score but only with the impairment of self-esteem factor during the follow-up after adjustment for age, sex, education level, and drug intake, dementia, and Mini-Mental State Examination score (ß = -0.029, 95% CI [-0.052 to -0.007], P = .003). Regional amyloid load in hippocampus and bilateral caudate nucleus protected significantly from self-esteem decrease during the 3-year follow-up.Conclusions: Although amyloid load shows no impact on GDS score in subjects at risk of Alzheimer's dementia, amyloid load may influence the progression of depressive dimension (self-esteem) with different effects according to the regional burden.Trial Registration: ClinicalTrials.gov identifier: NCT00672685.
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Disfunción Cognitiva/etiología , Depresión/etiología , Placa Amiloide/complicaciones , Anciano , Anciano de 80 o más Años , Ansiedad/psicología , Apatía , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Disfunción Cognitiva/psicología , Progresión de la Enfermedad , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Satisfacción Personal , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/patología , Placa Amiloide/psicología , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Factores de Riesgo , AutoimagenRESUMEN
BACKGROUND: Epidemiological studies have shown that tooth loss is associated with Alzheimer's disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. OBJECTIVE: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. METHODS: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-ß (Aß) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aß ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. RESULTS: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. CONCLUSION: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Gliosis/metabolismo , Trastornos de la Memoria/metabolismo , Placa Amiloide/metabolismo , Pérdida de Diente/complicaciones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Femenino , Gliosis/patología , Gliosis/psicología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Trastornos de la Memoria/patología , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Placa Amiloide/patología , Placa Amiloide/psicología , Pérdida de Diente/patologíaRESUMEN
Advancing age is typically associated with declining memory capacity and increased risk of Alzheimer's disease (AD). Markers of AD such as amyloid plaques (AP) and neurofibrillary tangles (NFTs) are commonly found in the brains of cognitively average elderly but in more limited distribution than in those at the mild cognitive impairment and dementia stages of AD. Cognitive SuperAgers are individuals over age 80 who show superior memory capacity, at a level consistent with individuals 20-30 years their junior. Using a stereological approach, the current study quantitated the presence of AD markers in the memory-associated entorhinal cortex (ERC) of seven SuperAgers compared with six age-matched cognitively average normal control individuals. Amyloid plaques and NFTs were visualized using Thioflavin-S histofluorescence, 6E10, and PHF-1 immunohistochemistry. Unbiased stereological analysis revealed significantly more NFTs in ERC in cognitively average normal controls compared with SuperAgers (P < 0.05) by a difference of ~3-fold. There were no significant differences in plaque density. To highlight relative magnitude, cases with typical amnestic dementia of AD showed nearly 100 times more entorhinal NFTs than SuperAgers. The results suggest that resistance to age-related neurofibrillary degeneration in the ERC may be one factor contributing to preserved memory in SuperAgers.
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Envejecimiento/fisiología , Enfermedad de Alzheimer , Corteza Entorrinal/fisiología , Memoria/fisiología , Ovillos Neurofibrilares/fisiología , Placa Amiloide , Anciano de 80 o más Años , Envejecimiento/patología , Envejecimiento/psicología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Bancos de Muestras Biológicas/tendencias , Cognición/fisiología , Corteza Entorrinal/patología , Femenino , Humanos , Masculino , Ovillos Neurofibrilares/patología , Pruebas Neuropsicológicas , Placa Amiloide/patología , Placa Amiloide/psicologíaRESUMEN
INTRODUCTION: As clinical trials move toward earlier intervention, we sought to redefine the ß-amyloid (Aß)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aß accumulation and cognitive decline in 3 independent samples of clinically normal individuals. METHODS: Sequential Aß cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aß-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356). RESULTS: Within samples, cutoffs derived from future Aß-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5). DISCUSSION: These optimized thresholds can help to inform future research and clinical trials targeting early Aß. Threshold convergence raises the possibility of contemporaneous early changes in Aß and cognition. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among clinically normal individuals a specific Aß-PET threshold is predictive of cognitive decline.
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Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Tomografía de Emisión de Positrones/tendencias , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/psicología , Femenino , Estudios de Seguimiento , Predicción , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Placa Amiloide/psicología , Estudios ProspectivosRESUMEN
OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients. METHODS: One hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC). RESULTS: One hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies. INTERPRETATION: In our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.
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Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Demencia Frontotemporal/diagnóstico por imagen , Placa Amiloide/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Tiazoles , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Autopsia , Encéfalo/metabolismo , Encéfalo/patología , Proteínas de Unión al ADN/metabolismo , Femenino , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Degeneración Lobar Frontotemporal/metabolismo , Degeneración Lobar Frontotemporal/patología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Pick/diagnóstico por imagen , Enfermedad de Pick/metabolismo , Enfermedad de Pick/patología , Placa Amiloide/metabolismo , Placa Amiloide/psicología , Sensibilidad y Especificidad , Proteínas tau/metabolismoRESUMEN
It is well accepted by the scientific community that the accumulation of beta-amyloid (Aß) may be involved in endothelial dysfunction during Alzheimer's disease (AD) progression; however, anti-Aß anti-bodies, which remove Aß plaques, do not improve cerebrovascular function in AD animal models. The reasons for these paradoxical results require investigation. We hypothesized that Aß exposure may cause persistent damage to cerebral endothelial cells even after Aß is removed (referred to as cerebrovascular endothelial damage memory). In this study, we aimed to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. hCMEC/D3 cells were treated with Aß1-42 for 12 h and then Aß1-42 was withdrawn for another 12 h incubation to investigate whether cerebrovascular endothelial damage memory exists in endothelial cells. A mechanism-based kinetics progression model was developed to investigate the dynamic characters of the cerebrovascular endothelial damage. After Aß1-42 was removed, the sirt-1 levels returned to normal but the cell vitality did not improve, which suggests that cerebrovascular endothelial damage memory may exist in endothelial cells. Sirt-1 activator SRT2104 and NAD+ (Nicotinamide Adenine Dinucleotide) supplement may dose-dependently relieve the cerebrovascular endothelial damage memory. sirt-1 inhibitor EX527 may exacerbate the cerebrovascular endothelial damage memory. Kinetics analysis suggested that sirt-1 is involved in initiating the cerebrovascular endothelial damage memory; otherwise, NAD+ exhaustion plays a vital role in maintaining the cerebrovascular endothelial damage memory. This study provides a novel feature of cerebrovascular endothelial damage induced by Aß.
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Péptidos beta-Amiloides/toxicidad , Células Endoteliales/efectos de los fármacos , Memoria/efectos de los fármacos , Sirtuina 1/fisiología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Carbazoles/farmacología , Células Cultivadas , Células Endoteliales/fisiología , Humanos , Modelos Teóricos , Placa Amiloide/complicaciones , Placa Amiloide/metabolismo , Placa Amiloide/fisiopatología , Placa Amiloide/psicología , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/antagonistas & inhibidoresRESUMEN
BACKGROUND: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer's disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel AppNL-G-F knock-in mouse model for AD, simulating an early stage of the disease. METHODS: Urine and serum samples were analyzed using a validated LC-MS/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-ß (Aß) plaque deposition. RESULTS: Behavioral testing data indicated subtle cognitive deficits in AppNL-G-F compared to C57BL/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified Aß plaque deposition in 35-week-old AppNL-G-F mice. CONCLUSION: Despite prominent Aß plaque deposition, the AppNL-G-F model merely displays a very mild AD-like phenotype at the investigated age. Older AppNL-G-F mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.
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Enfermedad de Alzheimer/etiología , Cognición , Dieta/métodos , Hiperhomocisteinemia/dietoterapia , Hiperhomocisteinemia/psicología , Péptidos beta-Amiloides/metabolismo , Animales , Conducta Animal , Disfunción Cognitiva/etiología , Dieta/efectos adversos , Modelos Animales de Enfermedad , Homocisteína/análogos & derivados , Homocisteína/sangre , Homocisteína/orina , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Placa Amiloide/etiología , Placa Amiloide/psicología , Deficiencia de Vitamina B/dietoterapia , Deficiencia de Vitamina B/psicologíaRESUMEN
Amyloid-ß (Aß) accumulation is a pathological hallmark of Alzheimer's disease (AD). The receptor for advanced glycation end products (RAGE) is involved in the production and accumulation of Aß. RP1, a peptide antagonist of RAGE, was screened by phage display technology in our previous studies, and its neuroprotective effects on an AD cell model have been confirmed. However, its efficacy in vivo remains unclear. Here, the intranasal delivery of RP1 to APPSwe/PS1dE9 (APP/PS1) mice significantly improved memory impairment and relieved the Aß burden by decreasing the expression of amyloid precursor protein and ß-secretase. RNA-sequencing (RNA-seq) was utilized to identify differentially expressed genes (DEGs) in APP/PS1 mice after RP1 administration. Several DEGs in RAGE downstream signalling pathways were downregulated. Some transcription factors (such as Fos) and the pathways enriched in the remarkable modules may also be related to the efficacy of RP1. In conclusion, RP1 significantly improves the AD symptoms of APP/PS1 mice, and the RNA-seq results provide new ideas for elucidating the possible mechanisms of RP1 treatment.
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Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide , Trastornos de la Memoria/tratamiento farmacológico , Proteínas Asociadas a Microtúbulos/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Presenilina-1 , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Precursor de Proteína beta-Amiloide/genética , Animales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/psicología , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/farmacología , Placa Amiloide/genética , Placa Amiloide/psicología , Presenilina-1/genética , Receptor para Productos Finales de Glicación Avanzada/genéticaRESUMEN
BACKGROUND: Alzheimer's disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. OBJECTIVE: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). METHODS: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. RESULTS: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. CONCLUSION: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Catecolaminas/metabolismo , Simulación por Computador , Placa Amiloide/metabolismo , Enfermedad de Alzheimer/psicología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Locus Coeruleus/metabolismo , Locus Coeruleus/patología , Placa Amiloide/patología , Placa Amiloide/psicología , Desempeño Psicomotor/fisiología , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/patologíaRESUMEN
BACKGROUND: Amyloid plaque and tau-containing neurofibrillary tangles are important features of Alzheimer's disease (AD). However, the relationship between these processes is still debated. OBJECTIVE: We aimed to investigate local and distant relationships between tau and amyloid deposition in the cortex in mild cognitive impairment (MCI) and AD using PET imaging. METHODS: Seventy-nine subjects (51 controls, 13 amyloid-positive MCI subjects, and 15 amyloid positive AD subjects) underwent MRI and 18F-flutemetamol PET. All MCI/AD subjects and 8 healthy controls as well as 33 healthy control subjects from the ADNI dataset also had 18F-AV1451 PET. Regional and distant correlations were examined after sampling target-to-cerebellar ratio images. Biological parametric mapping was used to evaluate voxel level correlations locally. RESULTS: We found multiple clusters of voxels with highly significant positive correlations throughout the association cortex in both MCI and AD subjects. CONCLUSION: The multiple clusters of positive correlations indicate that tau and amyloid may interact locally and be involved in disease progression. Our findings suggest that targeting both pathologies may be required.
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Enfermedad de Alzheimer/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Placa Amiloide/diagnóstico por imagen , Agregado de Proteínas/fisiología , Proteínas tau , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Placa Amiloide/metabolismo , Placa Amiloide/psicología , Tomografía de Emisión de Positrones/métodos , Proteínas tau/metabolismoRESUMEN
The biomarkers of Alzheimer's disease (AD) have enabled the identification of its pathological features, many years before the onset of clinical symptoms. Positon emission tomography (PET) using radiotracers binding the amyloid plaques has, indeed, paved the way for new perspectives. However, these biomarkers have only been studies in small populations so far, with limited follow-up. The objectives of this work were to assess the interest of amyloid PET in elderly but also to study the relationship of amyloid deposition to Instrumental Activities of Daily Living (IADL) performance. METHODS: Our population included 271 participants from the MAPT trial aged 70 and over, without major cognitive impairment, who performed amyloid PET examination. In a cross-sectional study we examined the association between brain amyloid load and IADL abilities. Moreover, in a longitudinal analysis, we studied the changes in IADL performance between amyloid positive and amyloid negative participants over the 3-year follow-up without and with adjustments for confounding factors (age, randomization group, ApoE genotyping, timespan between baseline and PET examination). RESULTS: Amyloid positive subjects showed poorer abilities in IADL compared to their amyloid negative counterparts, despite similar cognitive performance. Brain amyloid load also impacted the daily functioning of individuals over time, taking in consideration confounding factors. The difference after 3 years between the amyloid positive and negative participants was not significant (p=0.08; in adjusted models p=0.06). Amyloid negative individuals also improved in memory-related instrumental activities (p<0.001) throughout the study, unlike amyloid positive participants. CONCLUSION: These findings confirmed the relationship of brain amyloid deposition with subtle changes in IADL abilities, even in the absence of cognitive impairment. Yet, the absence of disease modifying agents as well as uncertainties regarding the long-term evolution of asymptomatic individuals showing a positive biomarker are still to be determined.
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Encéfalo/diagnóstico por imagen , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/psicología , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Cognición , Estudios Transversales , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND: Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce Aß without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined Aß plaque formation and reactive gliosis in these mice. RESULTS: In the Morris water maze, a spatial task, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-G-F/NL-G-F mice developed massive Aß plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human Aß40 and Aß42 in their brains. CONCLUSIONS: Aß plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice.
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Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Gliosis/metabolismo , Placa Amiloide/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Gliosis/patología , Gliosis/psicología , Humanos , Inflamación/metabolismo , Inflamación/patología , Inflamación/psicología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Placa Amiloide/patología , Placa Amiloide/psicología , Memoria Espacial/fisiologíaRESUMEN
BACKGROUND: Some individuals, called Supernormals (SN), maintain excellent memory in old age. While brain structural and functional integrity in SN seem to be aging-resistant, their amyloidosis and neural injury status has not been well studied. OBJECTIVE: The goal of this study was to compare cortical amyloid deposition and glucose metabolism between SN and older adults with normal cognition (NC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD). METHODS: Subjects from the ADNI database were included if they received T1-weighted MRI, amyloid PET, FDG-PET, and cognitive testing within a 6-month period, yielding 27 AD, 69 MCI, 172 NC, and 122 SN. PET standardized uptake value ratios (SUVrs) were calculated for the whole cortex and 68 regions of interest, with whole cerebellum serving as reference. RESULTS: SN had lower whole cortex amyloid than MCI, and higher glucose metabolism than all others. Regional analysis revealed that amyloid burden and glucose metabolism in the right isthmus cingulate cortex differed in SN compared to others, while SN glucose metabolism also differed from others in several frontal and temporal regions. CONCLUSION: Preserved cortical glucose metabolism, and lower levels of amyloidosis and glucose hypometabolism in the right isthmus cingulate cortex, contributes to the Supernormal phenomenon. These findings may be informative for development of early screening biomarkers and therapeutic targets for modification of cognitive trajectories.
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Envejecimiento Cognitivo/fisiología , Glucosa/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/metabolismo , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Tomografía de Emisión de Positrones/tendencias , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Envejecimiento Cognitivo/psicología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Estudios Transversales , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Placa Amiloide/psicologíaRESUMEN
BACKGROUND: The pathological processes underlying cognitive impairment in Parkinson's disease (PD) are heterogeneous and the contribution of cerebral amyloid deposits is poorly defined, particularly in the early stages of the disease. OBJECTIVE: To investigate regional [18F]florbetaben binding to amyloid-ß (Aß) and its contribution to cognitive dysfunction in early stage PD. METHODS: A multicenter cohort of 48 PD patients from the Parkinson's Progression Marker Initiative (PPMI) underwent [18F]florbetaben positron emission tomography (PET) scanning. Clinical features, including demographic characteristics, motor severity, cerebrospinal fluid (CSF), and cognitive testing were systematically assessed according to the PPMI study protocol. For the purpose of this study, we analyzed various neuropsychological tests assessing all cognitive functions. RESULTS: There were 10/48 (21%) amyloid positive PD patients (PDAß+). Increased [18F]florbetaben uptake in widespread cortical and subcortical regions was associated with poorer performance on global cognition, as assessed by Montreal Cognitive Assessment (MoCA), and impaired performance on Symbol Digit Modality test (SDMT). Further, we found that PDAß+ patients had higher CSF total-tau/Aß1 - 42 (pâ=â0.001) and phosphorylated-tau/Aß1 - 42 in (pâ=â0.002) compared to amyloid-negative PD. CONCLUSION: These findings suggest that multiple disease processes are associated with PD cognitive impairment and amyloid deposits may be observed already in early stages. However, prevalence of amyloid positivity is in the range of literature age-matched control population. Increased cortical and subcortical amyloid is associated with poor performance in attentive-executive domains while cognitive deficits at MoCA and SDMT may identify amyloid-related dysfunction in early PD.
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Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Progresión de la Enfermedad , Enfermedad de Parkinson/diagnóstico por imagen , Placa Amiloide/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/psicología , Placa Amiloide/epidemiología , Placa Amiloide/psicología , Tomografía de Emisión de Positrones/tendenciasRESUMEN
OBJECTIVES: To examine the evolution of instrumental activity of daily living (IADL) performance according to the presence of brain amyloid deposition. DESIGN: Longitudinal analysis of a randomized controlled trial. SETTING: Neuroimaging ancillary study from the Multidomain Alzheimer Prevention Trial (MAPT). PARTICIPANTS: Community-dwelling individuals aged 70 and older without dementia (N = 269; 60% female, mean age 75±4). MEASUREMENTS: Linear mixed models were used to assess the 36-month evolution of the performance of an IADL questionnaire for primary prevention studies in dementia, the Activity of Daily Living Prevention Instrument (ADL-PI), according to the presence of amyloid deposition using florbetapir positron emission tomography (PET) (standardized uptake value≥1.17). Additional analyses were also conducted to examine the changes in specific domains of daily functioning with and without adjustment for age, sex, apolipoprotein E, randomization group, and time between baseline and PET examination. RESULTS: One hundred two (37.9%) participants were amyloid positive. Amyloid-negative participants had statistically significant improvement in ADL-PI total score between baseline and 36 months (p=.04). The difference after 3 years between amyloid-positive and -negative participants was not significant (ß=-0.95±0.53 at 36 months, p=.08; adjusted models: ß=-1.07±0.56, p=.06). Amyloid-negative participants also improved in memory-related IADLs (p<.001) throughout the study, unlike amyloid-positive participants. CONCLUSION: Amyloid-positive and -negative older adults are likely to have different trajectories in IADL performance. Future research is needed to better understand the relationship between amyloid plaques and functional limitations.
Asunto(s)
Actividades Cotidianas/psicología , Rendimiento Físico Funcional , Placa Amiloide/psicología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/prevención & control , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Glicoles de Etileno , Femenino , Humanos , Vida Independiente , Modelos Lineales , Estudios Longitudinales , Masculino , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/fisiopatología , Tomografía de Emisión de Positrones/métodosRESUMEN
Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Caracteres Sexuales , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Inflamación/psicología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Placa Amiloide/psicología , Presenilina-1/genética , Presenilina-1/metabolismo , Memoria Espacial/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Alzheimer's disease (AD) is characterized by accumulations of amyloid-ß (Aß42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10âmg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (nâ=â6-9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aß plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1ß cytokine in treated mice were detected. The Aß plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.
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Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Péptidos/farmacología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Cognición/fisiología , Modelos Animales de Enfermedad , Humanos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , MAP Quinasa Quinasa 4/antagonistas & inhibidores , MAP Quinasa Quinasa 4/metabolismo , Masculino , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/metabolismo , Placa Amiloide/patología , Placa Amiloide/psicologíaRESUMEN
OBJECTIVE: The goal of this study is to identify risk factors for the presence of amyloid accumulation in the brains of patients reporting subjective cognitive decline (SCD). Identifying such risk factors will help better identify patients who ought to receive neuroimaging studies to confirm plaque presence and begin intervention, as well as enhancing the study of the pathogenesis of Alzheimer's disease. METHODS: Ninety-nine SCD participants (72.2±5.6years, 57.6% female) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent florbetapir PET. Logistic regression analysis was conducted to examine the relationship between the presence of an increased amyloid signal (amyloid positivity) and several potential risk factors, including: demographics, APOE ε4 genotype, family history of dementia, history of hypertension, history of cigarettes smoking, cognitive function and depressive symptoms. RESULTS: Being female was a significant risk factor for amyloid positivity (OR=4.915, 95% CI=1.709-14.139), as was being an APOE ε4 carrier (OR=2.985, 95% CI=1.084-8.219) and having a history of cigarette smoking (OR=4.091, 95% CI=1.483-11.285). CONCLUSION: Our study demonstrates that female gender, APOE ε4 genotype, and history of cigarettes smoking are associated with amyloid positivity in patients with SCD.
Asunto(s)
Encéfalo/diagnóstico por imagen , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/psicología , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/psicología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Apolipoproteína E4/genética , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Estudios Transversales , Femenino , Humanos , Masculino , Trastornos de la Memoria/genética , Persona de Mediana Edad , Placa Amiloide/genética , Factores de Riesgo , Factores Sexuales , Fumar/efectos adversos , Fumar/genética , Fumar/psicologíaRESUMEN
BACKGROUND: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. OBJECTIVE: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. METHOD: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the "ABC" score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. RESULTS: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-ß (Aß) deposits (A score) present no significant correlation with any of ECog domains. CONCLUSION: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Encéfalo/patología , Disfunción Cognitiva/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Procesos Mentales , Persona de Mediana Edad , Pruebas Neuropsicológicas , Placa Amiloide/genética , Placa Amiloide/patología , Placa Amiloide/psicologíaRESUMEN
Alzheimer's disease has a long preclinical phase during which amyloid pathology and neurodegeneration accumulate in the brain without producing overt cognitive deficits. It is currently unclear whether these early disease stages are associated with a progressive disruption in the communication between brain regions that subsequently leads to cognitive decline and dementia. In this study we assessed the organization of structural networks in cognitively normal (CN) individuals harboring amyloid pathology (A+N-), neurodegeneration (A-N+), or both (A+N+) from the prospective and longitudinal Swedish BioFINDER study. We combined graph theory with diffusion tensor imaging to investigate integration, segregation, and centrality measures in the brain connectome in the previous groups. At baseline, our findings revealed a disrupted network topology characterized by longer paths, lower efficiency, increased clustering and modularity in CN A-N+ and CN A+N+, but not in CN A+N-. After 2 years, CN A+N+ showed significant abnormalities in all global network measures, whereas CN A-N+ only showed abnormalities in the global efficiency. Network connectivity and organization were associated with memory in CN A+N+ individuals. Altogether, our findings suggest that amyloid pathology is not sufficient to disrupt structural network topology, whereas neurodegeneration is.