RESUMO
INTRODUCTION: The implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A-. METHODS: We evaluated 98 participants from the Mayo Clinic who were T+ and A-. Participants were matched 2:1 to A- and T- cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups. RESULTS: The A-T+ group demonstrated lower performance than the A-T- group on the Mini-Mental Status Exam (MMSE) (p < 0.001), Wechsler Memory Scale-Revised Logical Memory I (p < 0.001) and Logical Memory II (p < 0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p = 0.004), category fluency (animals p = 0.005; vegetables p = 0.021), Trail Making Test A and B (p < 0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A-T+ and CI A-T+. DISCUSSION: A-T+ participants show an association with lower cognitive performance.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Encéfalo/metabolismo , Proteínas tau/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/psicologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Tomografia por Emissão de Pósitrons , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologiaRESUMO
INTRODUCTION: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease. METHODS: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans. RESULTS: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB. DISCUSSION: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença por Corpos de Lewy , Transtorno do Comportamento do Sono REM , Humanos , Doença de Alzheimer/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Peptídeos beta-Amiloides , Proteínas tau , Biomarcadores/metabolismo , Disfunção Cognitiva/diagnósticoRESUMO
Plasma pharmacokinetic (PK) data are required as an input function for graphical analysis of single positron emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography/CT (PET/CT) data to evaluate tissue influx rate of radiotracers. Dynamic heart imaging data are often used as a surrogate of plasma PK. However, accumulation of radiolabel in the heart tissue may cause overprediction of plasma PK. Therefore, we developed a compartmental model, which involves forcing functions to describe intact and degraded radiolabeled proteins in plasma and their accumulation in heart tissue, to deconvolve plasma PK of 125I-amyloid beta 40 (125I-Aß 40) and 125I-insulin from their dynamic heart imaging data. The three-compartment model was shown to adequately describe the plasma concentration-time profile of intact/degraded proteins and the heart radioactivity time data obtained from SPECT/CT imaging for both tracers. The model was successfully applied to deconvolve the plasma PK of both tracers from their naïve datasets of dynamic heart imaging. In agreement with our previous observations made by conventional serial plasma sampling, the deconvolved plasma PK of 125I-Aß 40 and 125I-insulin in young mice exhibited lower area under the curve than aged mice. Further, Patlak plot parameters extracted using deconvolved plasma PK as input function successfully recapitulated age-dependent plasma-to-brain influx kinetics changes. Therefore, the compartment model developed in this study provides a novel approach to deconvolve plasma PK of radiotracers from their noninvasive dynamic heart imaging. This method facilitates the application of preclinical SPECT/PET imaging data to characterize distribution kinetics of tracers where simultaneous plasma sampling is not feasible. SIGNIFICANCE STATEMENT: Knowledge of plasma pharmacokinetics (PK) of a radiotracer is necessary to accurately estimate its plasma-to-brain influx. However, simultaneous plasma sampling during dynamic imaging procedures is not always feasible. In the current study, we developed approaches to deconvolve plasma PK from dynamic heart imaging data of two model radiotracers, 125I-amyloid beta 40 (125I-Aß 40) and 125I-insulin. This novel method is expected to minimize the need for conducting additional plasma PK studies and allow for accurate estimation of the brain influx rate.
Assuntos
Insulinas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Camundongos , Peptídeos beta-Amiloides , Elétrons , Tomografia Computadorizada por Raios X , Tomografia por Emissão de Pósitrons/métodosRESUMO
Background: Alcohol use disorder (AUD) has been associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). However, recent studies demonstrate that moderate alcohol consumption may be protective against dementia and cognitive decline. Methods: We examined astrocyte function, low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), and the NF-κB p65 and IKK-α/ß signaling pathways in modulating neuroinflammation and amyloid beta (Aß) deposition. We assessed apolipoprotein E (ApoE) in the mouse brain using IHC and ELISA in response to moderate ethanol exposure (MEE). First, to confirm the intracerebral distribution of ApoE, we co-stained with GFAP, a marker for astrocytes that biosynthesize ApoE. We sought to investigate whether the ethanol-induced upregulation of LRP1 could potentially inhibit the activity of IL-1ß and TNF-α induced IKK-α/ß towards NF-κB p65, resulting in a reduction of pro-inflammatory cytokines. To evaluate the actual Aß load in the brains of APP/PS1 mice, we performed with a specific antibody Aß (Thioflavin S) on both air- and ethanol-exposed groups, subsequently analyzing Aß levels. We also measured glucose uptake activity using 18F-FDG in APP/PS1 mice. Finally, we investigated whether MEE induced cognitive and memory changes using the Y maze, noble objective recognition (NOR) test, and Morris water maze (MWM). Results: Our findings demonstrate that MEE reduced astrocytic glial fibrillary acidic protein (GFAP) and ApoE levels in the cortex and hippocampus in presymptomatic APP/PS1 mice. Interestingly, increased LRP1 protein expression is accompanied by dampening the IKK-α/ß-NF-κB p65 pathway, resulting in decreased IL-1ß and TNF-α levels in male mice. Notably, female mice show reduced anti-inflammatory cytokines, IL-4, and IL-10 levels without altering IL-1ß and TNF-α concentrations. In both males and females, Aß plaques, a hallmark of AD, were reduced in the cortex and hippocampus of ethanol-exposed presymptomatic APP/PS1 mice. Consistently, MEE increased fluorodeoxyglucose (FDG)-positron emission tomography (PET)-based brain activities and normalized cognitive and memory deficits in the APP/PS1 mice. Conclusions: Our findings suggest that MEE may benefit AD pathology via modulating LRP1 expression, potentially reducing neuroinflammation and attenuating Aß deposition. Our study implies that reduced astrocyte derived ApoE and LDL cholesterol levels are critical for attenuating AD pathology.
RESUMO
PET imaging with ß-amyloid ligands is emerging as a molecular imaging technique targeting white matter integrity and demyelination. ß-amyloid PET ligands such as 11C-Pittsburgh compound B (11C-PiB) have been considered for quantitative measurement of myelin content changes in multiple sclerosis, but 11C-PiB is not commercially available given its short half-life. A 18F PET ligand such as flutemetamol with a longer half-life may be an alternative, but its ability to differentiate white matter hyperintensities (WMH) from normal-appearing white matter (NAWM) and its relationship with age remains to be investigated. Methods: Cognitively unimpaired (CU) older and younger adults (n = 61) were recruited from the community responding to a study advertisement for ß-amyloid PET. Participants prospectively underwent MRI, 11C-PiB, and 18F-flutemetamol PET scans. MRI fluid-attenuated inversion recovery images were segmented into WMH and NAWM and registered to the T1-weighted MRI. 11C-PiB and 18F-flutemetamol PET images were also registered to the T1-weighted MRI. 11C-PiB and 18F-flutemetamol SUV ratios (SUVrs) from the WMH and NAWM were calculated using cerebellar crus uptake as a reference for both 11C-PiB and 18F-flutemetamol. Results: The median age was 38 y (range, 30-48 y) in younger adults and 67 y (range, 61-83 y) in older adults. WMH and NAWM SUVrs were higher with 18F-flutemetamol than with 11C-PiB in both older (P < 0.001) and younger (P < 0.001) CU adults. 11C-PiB and 18F-flutemetamol SUVrs were higher in older than in younger CU adults in both WMH (P < 0.001) and NAWM (P < 0.001). 11C-PiB and 18F-flutemetamol SUVrs were higher in NAWM than WMH in both older (P < 0.001) and younger (P < 0.001) CU adults. There was no apparent difference between 11C-PiB and 18F-flutemetamol SUVrs in differentiating WMH from NAWM in older and in younger adults. Conclusion:11C-PiB and 18F-flutemetamol show a similar topographic pattern of uptake in white matter with a similar association with age in WMH and NAWM. 11C-PiB and 18F-flutemetamol can also effectively distinguish between WMH and NAWM. However, given its longer half-life, commercial availability, and higher binding potential, 18F-flutemetamol can be an alternative to 11C-PiB in molecular imaging studies specifically targeting multiple sclerosis to evaluate white matter integrity.
Assuntos
Doença de Alzheimer , Esclerose Múltipla , Substância Branca , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/metabolismo , Benzotiazóis/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Tiazóis , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismoRESUMO
Inflammatory bowel disease (IBD) pathogenesis is associated with dysregulated CD4⺠Th cell responses, with intestinal homeostasis depending on the balance between IL-17-producing Th17 and Foxp3⺠Tregs. Differentiation of naive T cells into Th17 and Treg subsets is associated with specific gene expression profiles; however, the contribution of epigenetic mechanisms to controlling Th17 and Treg differentiation remains unclear. Using a murine T cell transfer model of colitis, we found that T cell-intrinsic expression of the histone lysine methyltransferase G9A was required for development of pathogenic T cells and intestinal inflammation. G9A-mediated dimethylation of histone H3 lysine 9 (H3K9me2) restricted Th17 and Treg differentiation in vitro and in vivo. H3K9me2 was found at high levels in naive Th cells and was lost following Th cell activation. Loss of G9A in naive T cells was associated with increased chromatin accessibility and heightened sensitivity to TGF-ß1. Pharmacological inhibition of G9A methyltransferase activity in WT T cells promoted Th17 and Treg differentiation. Our data indicate that G9A-dependent H3K9me2 is a homeostatic epigenetic checkpoint that regulates Th17 and Treg responses by limiting chromatin accessibility and TGF-ß1 responsiveness, suggesting G9A as a therapeutic target for treating intestinal inflammation.
Assuntos
Diferenciação Celular/imunologia , Colite/imunologia , Histona-Lisina N-Metiltransferase/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular/genética , Cromatina/genética , Cromatina/imunologia , Colite/tratamento farmacológico , Colite/genética , Colite/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/imunologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Histonas/imunologia , Metilação/efeitos dos fármacos , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/patologia , Células Th17/patologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologiaRESUMO
The migration of lymphocytes to the small intestine is controlled by expression of the integrin α4ß7 and the chemokine receptor CCR9. However, the molecules that specifically regulate migration to the large intestine remain unclear. Immunity to infection with the large intestinal helminth parasite Trichuris muris is dependent upon CD4(+) T cells that migrate to the large intestine. We examine the role of specific chemokine receptors, adhesion molecules and glycosyltransferases in the development of protective immunity to Trichuris. Mice deficient in expression of the chemokine receptors CCR2 or CCR6 were resistant to infection with Trichuris. Similarly, loss of CD34, CD43, CD44 or PSGL-1 had no effect on resistance to infection. In contrast, simultaneous deletion of the Core2 ß1,6-N-acetylglucosaminyltransferase (C2GnT) enzymes C2GnT1 and C2Gnt2 resulted in delayed expulsion of worms. These results suggest that C2GnT-dependent modifications may play a role in migration of protective immune cells to the large intestine.
Assuntos
Intestino Grosso/metabolismo , Intestino Grosso/parasitologia , Polissacarídeos/metabolismo , Tricuríase/metabolismo , Trichuris/patogenicidade , Animais , Antígenos CD34/genética , Antígenos CD34/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Leucossialina/genética , Leucossialina/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores CCR6/genética , Receptores CCR6/metabolismo , Tricuríase/genéticaRESUMO
Methylation of nonhistone proteins is emerging as a regulatory mechanism to control protein function. Set7 (Setd7) is a SET-domain-containing lysine methyltransferase that methylates and alters function of a variety of proteins in vitro, but the in vivo relevance has not been established. We found that Set7 is a modifier of the Hippo pathway. Mice that lack Set7 have a larger progenitor compartment in the intestine, coinciding with increased expression of Yes-associated protein (Yap) target genes. Mechanistically, monomethylation of lysine 494 of Yap is critical for cytoplasmic retention. These results identify a methylation-dependent checkpoint in the Hippo pathway.