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1.
PLoS One ; 19(1): e0295504, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38166102

RESUMO

BACKGROUND: Stroke is a major cause of death, disability, and public health problems. Its intervention is limited to early treatment with thrombolytics and/or endovascular clot removal with mechanical thrombectomy without any available subacute or chronic neuroprotective treatments. RNS60 has reduced neuroinflammation and increased neuronal survival in several animal models of neurodegeneration and trauma. The aim here was to evaluate whether RNS60 protects the brain and cognitive function in a mouse stroke model. METHODS: Male C57BL/6J mice were subjected to sham or ischemic stroke surgery using 60-minute transient middle cerebral artery occlusion (tMCAo). In each group, mice received blinded daily administrations of RNS60 or control fluids (PNS60 or normal saline [NS]), beginning 2 hours after surgery over 13 days. Multiple neurobehavioral tests were conducted (Neurological Severity Score [mNSS], Novel Object Recognition [NOR], Active Place Avoidance [APA], and the Conflict Variant of APA [APAc]). On day 14, cortical microvascular perfusion (MVP) was measured, then brains were removed and infarct volume, immunofluorescence of amyloid beta (Aß), neuronal density, microglial activation, and white matter damage/myelination were measured. SPSS was used for analysis (e.g., ANOVA for parametric data; Kruskal Wallis for non-parametric data; with post-hoc analysis). RESULTS: Thirteen days of treatment with RNS60 reduced brain infarction, amyloid pathology, neuronal death, microglial activation, white matter damage, and increased MVP. RNS60 reduced brain pathology and resulted in behavioral improvements in stroke compared to sham surgery mice (increased memory-learning in NOR and APA, improved cognitive flexibility in APAc). CONCLUSION: RNS60-treated mice exhibit significant protection of brain tissue and improved neurobehavioral functioning after tMCAo-stroke. Additional work is required to determine mechanisms, time-window of dosing, and multiple dosing volumes durations to support clinical stroke research.


Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Camundongos , Masculino , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Peptídeos beta-Amiloides , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças
2.
Commun Biol ; 5(1): 1074, 2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209301

RESUMO

Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Ceramidas , Cloridrato de Fingolimode , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Esfingolipídeos/metabolismo , Esfingolipídeos/uso terapêutico , Esfingomielinas/uso terapêutico
3.
J Biol Chem ; 298(10): 102411, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36007616

RESUMO

Sphingomyelin (SM) is an abundant plasma membrane and plasma lipoprotein sphingolipid. We previously reported that ATP-binding cassette family A protein 1 (ABCA1) deficiency in humans and mice decreases plasma SM levels. However, overexpression, induction, downregulation, inhibition, and knockdown of ABCA1 in human hepatoma Huh7 cells did not decrease SM efflux. Using unbiased siRNA screening, here, we identified that ABCA7 plays a role in the biosynthesis and efflux of SM without affecting cellular uptake and metabolism. Since loss of function mutations in the ABCA7 gene exhibit strong associations with late-onset Alzheimer's disease across racial groups, we also studied the effects of ABCA7 deficiency in the mouse brain. Brains of ABCA7-deficient (KO) mice, compared with WT, had significantly lower levels of several SM species with long chain fatty acids. In addition, we observed that older KO mice exhibited behavioral deficits in cognitive discrimination in the active place avoidance task. Next, we performed synaptic transmission studies in brain slices obtained from older mice. We found anomalies in synaptic plasticity at the intracortical synapse in layer II/III of the lateral entorhinal cortex but not in the hippocampal CA3-CA1 synapses in KO mice. These synaptic abnormalities in KO brain slices were rescued with extracellular SM supplementation but not by supplementation with phosphatidylcholine. Taken together, these studies identify a role of ABCA7 in brain SM metabolism and the importance of SM in synaptic plasticity and cognition, as well as provide a possible explanation for the association between ABCA7 and late-onset Alzheimer's disease.


Assuntos
Doença de Alzheimer , Cognição , Córtex Entorrinal , Plasticidade Neuronal , Esfingomielinas , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Córtex Entorrinal/metabolismo , Esfingomielinas/biossíntese , Camundongos Knockout
4.
J Alzheimers Dis ; 87(3): 1229-1238, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35466933

RESUMO

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. OBJECTIVE: To relate plasma amyloid-ß (Aß), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aß, measured using positron emission tomography (PET), examine the accuracy of plasma Aß to predict brain Aß positivity, and the relation of APOE ɛ4 with plasma Aß. METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aß42/Aß40 ratio measured with Simoa. Brain Aß burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. RESULTS: Plasma Aß42/Aß40 ratio was inversely associated with global Aß SUVR (ß= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aß positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p < 0.0001) showed that the optimal threshold for plasma Aß42/Aß40 ratio in relation to brain Aß positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8%. APOE ɛ4 carriers had lower Aß42/Aß40 ratio and a higher Aß positivity determined with the Aß42/Aß40 ratio threshold of 0.060. CONCLUSION: Plasma Aß42/Aß40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Amiloide , Fatores Etários , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Amiloide/sangue , Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/sangue , Apolipoproteínas E/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos Transversais , Feminino , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons
5.
Cell Rep ; 37(13): 110182, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34965419

RESUMO

Whether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion-a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal's unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD's regional vulnerability.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Endossomos/patologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Estudos de Casos e Controles , Endossomos/metabolismo , Feminino , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neuroimagem , Transporte Proteico , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética
6.
J Alzheimers Dis ; 82(1): 317-325, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34024821

RESUMO

BACKGROUND: The National Institute on Aging (NIA)/Alzheimer's Association (AA) 2018 framework conceptualizes Alzheimer's disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer's continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change. OBJECTIVE: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age. METHODS: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT). RESULTS: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-). CONCLUSION: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer's continuum, was related to verbal learning.


Assuntos
Amiloide/metabolismo , Disfunção Cognitiva/fisiopatologia , Hispânico ou Latino/estatística & dados numéricos , Aprendizagem Verbal , Biomarcadores , Encéfalo/patologia , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
7.
Neurobiol Aging ; 103: 109-116, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33894641

RESUMO

It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid ß (Aß) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 PET. Aß was measured as global SUVR with 18F-Florbetaben PET. Women had higher middle/inferior temporal gyri tau SUVR compared to men. However, no sex differences in the medial temporal cortex were observed. Women had higher brain Aß SUVR compared to men. Continuous Aß SUVR was positively correlated with medial temporal cortex and middle/inferior temporal gyri tau SUVR. However, there was no evidence of effect modification by Aß SUVR on sex and tau. Compared with men, women in late middle age show higher tau burden, independent of Aß.


Assuntos
Caracteres Sexuais , Tauopatias/diagnóstico , Lobo Temporal/metabolismo , Proteínas tau/metabolismo , Idoso , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Tomografia por Emissão de Pósitrons , Fatores Sexuais , Tauopatias/epidemiologia , Lobo Temporal/diagnóstico por imagem
8.
Neurobiol Aging ; 97: 89-96, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166929

RESUMO

Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid ß (Aß) burden ascertained with 18F-Florbetaben positron emission tomography. Neurodegeneration was ascertained as cortical thickness in AD signature regions from 3T brain MRI. MetS and its components (glucose, blood pressure, triglycerides, high-density lipoprotein, adiposity) were defined using the National Institutes of Health criteria. Neither the presence of MetS nor the MetS score was associated with Aß or neurodegeneration. Among the MetS components, elevated glucose was associated with lower Aß burden, and this association was not explained by diabetes treatment. Glucose and triglycerides were related to smaller cortical thickness. Our findings suggest that MetS as an arbitrary measure of aggregate metabolic and vascular risk does not capture the risk of AD neuropathology in late middle age and that other approaches to measure the aggregate risk should be examined.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Degeneração Neural , Fatores Etários , Doença de Alzheimer/etiologia , Compostos de Anilina , Glicemia/metabolismo , Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , New York , Risco , Estilbenos , Triglicerídeos/metabolismo
9.
Brain Commun ; 2(2): fcaa132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33215083

RESUMO

Small vessel cerebrovascular disease, visualized as white matter hyperintensities on T2-weighted magnetic resonance imaging, contributes to the clinical presentation of Alzheimer's disease. However, the extent to which cerebrovascular disease represents an independent pathognomonic feature of Alzheimer's disease or directly promotes Alzheimer's pathology is unclear. The purpose of this study was to examine the association between white matter hyperintensities and plasma levels of tau and to determine if white matter hyperintensities and tau levels interact to predict Alzheimer's disease diagnosis. To confirm that cerebrovascular disease promotes tau pathology, we examined tau fluid biomarker concentrations and pathology in a mouse model of ischaemic injury. Three hundred ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (74.5 ± 7.1 years of age) were included in this cross-sectional analysis. Participants had measurements of plasma total-tau, cerebrospinal fluid beta-amyloid, and white matter hyperintensities, and were diagnosed clinically as Alzheimer's disease (n = 97), mild cognitive impairment (n = 186) or cognitively normal control (n = 108). We tested the relationship between plasma tau concentration and white matter hyperintensity volume across diagnostic groups. We also examined the extent to which white matter hyperintensity volume, plasma tau, amyloid positivity status and the interaction between white matter hyperintensities and plasma tau correctly classifies diagnostic category. Increased white matter hyperintensity volume was associated with higher plasma tau concentration, particularly among those diagnosed clinically with Alzheimer's disease. Presence of brain amyloid and the interaction between plasma tau and white matter hyperintensity volume distinguished Alzheimer's disease and mild cognitive impairment participants from controls with 77.6% and 63.3% accuracy, respectively. In 63 Alzheimer's Disease Neuroimaging Initiative participants who came to autopsy (82.33 ± 7.18 age at death), we found that higher degrees of arteriosclerosis were associated with higher Braak staging, indicating a positive relationship between cerebrovascular disease and neurofibrillary pathology. In a transient middle cerebral artery occlusion mouse model, aged mice that received transient middle cerebral artery occlusion, but not sham surgery, had increased plasma and cerebrospinal fluid tau concentrations, induced myelin loss, and hyperphosphorylated tau pathology in the ipsilateral hippocampus and cerebral hemisphere. These findings demonstrate a relationship between cerebrovascular disease, operationalized as white matter hyperintensities, and tau levels, indexed in the plasma, suggesting that hypoperfusive injury promotes tau pathology. This potential causal association is supported by the demonstration that transient cerebral artery occlusion induces white matter damage, increases biofluidic markers of tau, and promotes cerebral tau hyperphosphorylation in older-adult mice.

10.
Front Neurol ; 11: 529930, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123070

RESUMO

Non-linear relations of brain amyloid beta (Aß) with task- based functional connectivity (tbFC) measured with functional magnetic resonance imaging (fMRI) have been reported in late middle age. Our objective was to examine the association between brain Aß and resting-state functional connectivity (rsFC) in late middle-aged adults. Global brain Aß burden was ascertained with 18F-Florbetaben Positron Emission Tomography (PET); rsFC was ascertained on 3T Magnetic Resonance Imaging (MRI) among 333 late middle-aged Hispanics adults without dementia in four major brain functional connectivity networks: default mode network (DMN), fronto-parietal control network (FPC), salience network (SAL) and dorsal attention network (DAN). We examined the relationship of global brain Aß with rsFC using multivariable linear regression adjusted for age, sex, education, and APOE-ε4 genotype. We quantified the non-linear associations both with quadratic terms and by categorizing Aß into three groups: low Aß, intermediate Aß, and positive Aß. We found no significant linear or non-linear associations between Aß, measured either continuously or categorically, with rsFC in the examined networks. Our null findings may be explained by the younger age of our participants in whom amyloid burden is relatively low. It is also possible that the recently reported non-linear relationship is exclusive to task fMRI and not rsfMRI.

11.
Neurology ; 95(15): e2086-e2094, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32847955

RESUMO

OBJECTIVE: To examine in vivo amyloid burden in relation to APOEε4 genotype in middle-aged Hispanics. We hypothesize higher amyloid levels among APOE ε4 carriers vs APOE ε4 noncarriers. METHODS: This is a cross-sectional study in a community-based sample of 249 middle-aged Hispanics in New York City who underwent a 3T brain MRI and PET with the amyloid radioligand 18F-florbetaben. APOE genotype was the primary exposure. The primary outcome was amyloid positivity. The secondary outcome was subthreshold amyloid levels examined as a continuous variable. RESULTS: APOE ε4 carriers (n = 85) had a higher frequency (15.3%) of amyloid positivity compared to APOE ε4 noncarriers (n = 164, 1.8%). In the subthreshold group of amyloid-negative participants (n = 233), APOE ε4 carriers (n = 72) had a 0.02 (95% confidence interval [CI] 0.01-0.04) higher global brain amyloid standardized uptake value ratio (SUVR) compared to APOE ε4 noncarriers (n = 161). Compared to participants with the ε3/ε3 genotype, participants with ε4/ε4 had the highest frequency of amyloid positivity (28.6%), followed by those with ε3/ε4 (11%). Among amyloid-negative participants (n = 233), compared to participants with ε3/ε3 (n = 134), those with ε4/ε4 (n = 5) had a 0.12 (95% CI 0.07-0.17) higher global brain amyloid SUVR, and those with ε3/ε4 had a 0.02 higher SUVR (95% CI 0.003-0.04). Results were similar when a median split was used for elevated amyloid, when continuous amyloid SUVR was analyzed in all participants, and in nonparametric Mann-Whitney comparisons. CONCLUSION: Middle-aged Hispanic APOE ε4 carriers have higher in vivo brain amyloid burden compared with noncarriers, as reported in non-Hispanics.


Assuntos
Amiloide/metabolismo , Apolipoproteína E4/genética , Encéfalo/metabolismo , Hispânico ou Latino/estatística & dados numéricos , Fatores Etários , Idoso , Compostos de Anilina/metabolismo , Estudos Transversais , Feminino , Genótipo , Heterozigoto , Hispânico ou Latino/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estilbenos/metabolismo
12.
J Alzheimers Dis ; 75(4): 1241-1252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32390636

RESUMO

BACKGROUND: Type 2 diabetes is a dementia risk factor, but its relation to Alzheimer's disease (AD), the most common cause of dementia, is unclear. OBJECTIVE: Our primary objective was to examine the association of pre-diabetes and type 2 diabetes with brain amyloid-ß (Aß), the putative main culprit of AD. Our secondary objective was to examine the association of pre-diabetes and type 2 diabetes with neurodegeneration, cerebrovascular disease (CVD), and memory performance. METHODS: We conducted a cross-sectional study of 350 late middle-aged Hispanics without dementia in New York City. We classified diabetes status as normal glucose tolerance (NGT), pre-diabetes, and type 2 diabetes following American Diabetes Association criteria. Brain Aß was ascertained as global Aß standardized value uptake ratio using PET with 18F-Florbetaben. Neurodegeneration was operationalized as cortical thickness in regions affected by AD using MRI. CVD was operationalized as white matter hyperintensity volume (WMH) on MRI, and memory as performance with the selective reminding test (SRT). RESULTS: Mean age was 64.15±3.34 years, 72.00% were women, and 35.43% were APOEɛ4 carriers. Pre-diabetes, but not type 2 diabetes, was associated with higher Aß compared with NGT. Type 2 diabetes treatment was related to lower Aß. Type 2 diabetes was related to lower cortical thickness, higher WMH, and lower SRT score. CONCLUSION: Pre-diabetes, but not type 2 diabetes, is associated with higher brain Aß in late middle age, and this observation could be explained by the relation of diabetes treatment with lower brain Aß. Whether type 2 diabetes treatment lowers brain Aß requires further study.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Idoso , Encéfalo/diagnóstico por imagem , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Feminino , Teste de Tolerância a Glucose , Hispânico ou Latino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Estado Pré-Diabético/diagnóstico por imagem
13.
J Alzheimers Dis ; 74(4): 1243-1252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32250303

RESUMO

BACKGROUND: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer's disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. OBJECTIVE: To examine sex differences in in vivo AD neuropathology in late middle age. METHODS: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio (SUVR) with18F-Florbetaben positron emission tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areas using brain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 in 75 of the 266 participants. RESULTS: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri than males. However, females had higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. CONCLUSION: Higher amyloid and tau in females compared to males in late middle-age may explain the reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males.


Assuntos
Doença de Alzheimer/patologia , Hispânico ou Latino/estatística & dados numéricos , Proteínas Amiloidogênicas/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Tomografia por Emissão de Pósitrons , Fatores Sexuais , Proteínas tau/metabolismo
14.
Alzheimers Dement ; 16(2): 251-261, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31668966

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is linked to neuronal calcium dyshomeostasis, which is associated with network hyperexcitability. Decreased expression of the calcium-binding protein cal- bindin-D28K (CB) might be a susceptibility factor for AD. The subiculum is affected early in AD, for unknown reasons. METHODS: In AD, CB knock-out and control mice fluorescence Ca2+ imaging combined with patch clamp were used to characterize Ca2+ dynamics, resting Ca2+ , and Ca2+ -buffering capacity in subicular neurons. CB expression levels in wild-type and AD mice were also analyzed. RESULTS: The subiculum and dentate gyrus of wild-type mice showed age-related decline in CB expression not observed in AD mice. Resting Ca2+ and Ca2+ -buffering capacity was increased in aged AD mice subicular dendrites. Modeling suggests that AD calcium changes can be explained by alterations of Ca2+ extrusion pumps rather than by buffers. DISCUSSION: Overall, abnormal Ca2+ homeostasis in AD has an age dependency that comprises multiple mechanisms, including compensatory processes.


Assuntos
Proteínas Amiloidogênicas/metabolismo , Cálcio/metabolismo , Dendritos , Hipocampo/metabolismo , Homeostase/fisiologia , Fatores Etários , Envelhecimento , Doença de Alzheimer/patologia , Animais , Giro Denteado , Eletrofisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo
15.
Nat Commun ; 8(1): 1464, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29133888

RESUMO

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Córtex Entorrinal/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Envelhecimento , Animais , Apolipoproteína E3/genética , Ondas Encefálicas/fisiologia , Metabolismo Energético/genética , Ácidos Graxos/biossíntese , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos
16.
Alzheimers Dement ; 13(2): 196-197, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28130964
17.
J Cereb Blood Flow Metab ; 37(6): 2208-2223, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27486045

RESUMO

Post-stroke cognitive impairment is a major cause of long-term neurological disability. The prevalence of post-stroke cognitive deficits varies between 20% and 80% depending on brain region, country, and diagnostic criteria. The biochemical mechanisms underlying post-stroke cognitive impairment are not known in detail. Cyclin-dependent kinase 5 is involved in neurodegeneration, and its dysregulation contributes to cognitive disorders and dementia. Here, we administered cyclin-dependent kinase 5-targeting gene therapy to the right hippocampus of ischemic rats after transient right middle cerebral artery occlusion. Cyclin-dependent kinase 5 RNA interference prevented the impairment of reversal learning four months after ischemia as well as neuronal loss, tauopathy, and microglial hyperreactivity. Additionally, cyclin-dependent kinase 5 silencing increased the expression of brain-derived neurotrophic factor in the hippocampus. Furthermore, deficits in hippocampal long-term potentiation produced by excitotoxic stimulation were rescued by pharmacological blockade of cyclin-dependent kinase 5. This recovery was blocked by inhibition of the TRKB receptor. In summary, these findings demonstrate the beneficial impact of cyclin-dependent kinase 5 reduction in preventing long-term post-ischemic neurodegeneration and cognitive impairment as well as the role of brain-derived neurotrophic factor/TRKB in the maintenance of normal synaptic plasticity.


Assuntos
Disfunção Cognitiva/prevenção & controle , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Plasticidade Neuronal/fisiologia , Acidente Vascular Cerebral/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Quinase 5 Dependente de Ciclina/genética , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Técnicas de Silenciamento de Genes , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , Ratos Wistar , Reversão de Aprendizagem/fisiologia , Teste de Desempenho do Rota-Rod , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia
18.
J Transl Med ; 14: 50, 2016 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-26873444

RESUMO

As the human population continues to age, an increasing number of people will exhibit significant deficits in cognitive function and dementia. It is now recognized that cerebrovascular, metabolic and neurodegenerative diseases all play major roles in the evolution of cognitive impairment and dementia. Thus with our more recent recognition of these relationships and our need to understand and more positively impact on this world health problem, "The Leo and Anne Albert Charitable Trust" (Gene Pranzo, Trustee with significant support from Susan Brogan, Meeting Planner) provided generous support for this inaugural international workshop that was held from April 13-16, 2015 at the beautiful Ritz Carlton Golf Resort in North Naples, Florida. Researchers from SUNY Downstate Medical Center, Brooklyn, NY organized the event by selecting the present group of translationally inclined preclinical, clinical and population scientists focused on cerebrovascular disease (CVD) risk and its progression to vascular cognitive impairment (VCI) and dementia. Participants at the workshop addressed important issues related to aging, cognition and dementia by: (1) sharing new data, information and perspectives that intersect vascular, metabolic and neurodegenerative diseases, (2) discussing gaps in translating population risk, clinical and preclinical information to the progression of cognitive loss, and (3) debating new approaches and methods to fill these gaps that can translate into future therapeutic interventions. Participants agreed on topics for group discussion prior to the meeting and focused on specific translational goals that included promoting better understanding of dementia mechanisms, the identification of potential therapeutic targets for intervention, and discussed/debated the potential utility of diagnostic/prognostic markers. Below summarizes the new data-presentations, concepts, novel directions and specific discussion topics addressed by this international translational team at our "First Leo and Anne Albert Charitable Trust 'Think Tank' VCI workshop".


Assuntos
Transtornos Cerebrovasculares/complicações , Transtornos Cognitivos/complicações , Demência/complicações , Pesquisa Translacional Biomédica , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Ratos
19.
Artigo em Inglês | MEDLINE | ID: mdl-28983321

RESUMO

Dystonia is a movement disorder that produces involuntary muscle contractions. Current pharmacological treatments are of limited efficacy. Dystonia, like epilepsy is a disorder involving excessive activty of motor areas including motor cortex and several causal gene mutations have been identified. In order to evaluate potential novel agents for multitarget therapy for dystonia, we have developed a computer model of cortex that includes some of the complex array of molecular interactions that, along with membrane ion channels, control cell excitability.

20.
Rev. colomb. anestesiol ; 43(3): 173-175, July-Sept. 2015.
Artigo em Inglês | LILACS, COLNAL | ID: lil-757251

RESUMO

The editorial presented in this issue by Dr. Ramsay, "The biological cost of depressed consciousness" is an appeal for us to bear in mind the deleterious consequences of an altered state of consciousness (sedation), particularly in the Intensive Care Unit (ICU). I believe, for example, in the need to consider the significant two-way relationship between sleep disorders and Alzheimer's disease (AD), documented more than one decade ago. Sleep disorders are early indicators of dementia and may manifest before cognitive symptoms. There are basically two pathological process happening in AD: the first is the abnormal biochemical processing of a transmembrane protein called amyloid precursor protein, leading to the production, among other substances, of a toxic pep-tide known as amyloid beta 42 (A-ß42) that accumulates and forms extracellular plaques in the brain; the second is the altered tau protein, a protein associated with the microtubules which is hyperphosphorylated and aggregated in different ways in AD. Tau protein abnormalities are also found in other fatal neurodegenerative diseases causing dementia or movement disorders. Experiments in rodents and correlation studies in humans have shown that chronic changes in sleep architecture induce amyloid and tau disorders, that is to say, a fatal vicious circle.


Assuntos
Humanos
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