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Multimodal analysis using [11C]PiB-PET/MRI for functional evaluation of patients with Alzheimer's disease.

使用 [11C]PiB-PET/MRI 进行阿尔茨海默病患者功能评价的多模态分析。

  • 影响因子:3.0000
  • DOI:10.1186/s13550-020-00619-z
  • 作者列表:"Okazawa H","Ikawa M","Jung M","Maruyama R","Tsujikawa T","Mori T","Rahman MGM","Makino A","Kiyono Y","Kosaka H
  • 发表时间:2020-03-30
Abstract

BACKGROUND:Multimodal PET/MRI image data simultaneously obtained from patients with early-stage of Alzheimer's disease (eAD) were assessed in order to observe pathophysiologic and functional changes, as well as alterations of morphology and connectivity in the brain. Fifty-eight patients with mild cognitive impairment and early dementia (29 males, 69 ± 12 years) underwent [11C]Pittsburgh compound-B (PiB) PET/MRI with 70-min PET and MRI scans. Sixteen age-matched healthy controls (CTL) (9 males, 68 ± 11 years) were also studied with the same scanning protocol. Cerebral blood flow (CBF) was calculated from the early phase PET images using the image-derived input function method. A standardized uptake value ratio (SUVr) was calculated from 50 to 70 min PET data with a reference region of the cerebellar cortex. MR images such as 3D-T1WI, resting-state functional MRI (RS-fMRI), diffusion tensor image (DTI), and perfusion MRI acquired during the dynamic PET scan were also analyzed to evaluate various brain functions on MRI. RESULTS:Twenty-seven of the 58 patients were determined as eAD based on the results of PiB-PET and clinical findings, and a total of 43 subjects' data including CTL were analyzed in this study. PiB SUVr values in all cortical regions of eAD were significantly greater than those of CTL. The PiB accumulation intensity was negatively correlated with cognitive scores. The regional PET-CBF values of eAD were significantly lower in the bilateral parietal lobes and right temporal lobe compared with CTL, but not in MRI perfusion; however, SPM showed regional differences on both PET- and MRI-CBF. SPM analysis of RS-fMRI delineated regional differences between the groups in the anterior cingulate cortex and the left precuneus. VBM analysis showed atrophic changes in the AD group in a part of the bilateral hippocampus; however, analysis of fractional anisotropy calculated from DTI data did not show differences between the two groups. CONCLUSION:Multimodal analysis conducted with various image data from PiB-PET/MRI scans showed differences in regional CBF, cortical volume, and neuronal networks in different regions, indicating that pathophysiologic and functional changes in the AD brain can be observed from various aspects of neurophysiologic parameters. Application of multimodal brain images using PET/MRI would be ideal for investigating pathophysiologic changes in patients with dementia and other neurodegenerative diseases.

摘要

背景: 为了观察阿尔茨海默病 (eAD) 早期患者的病理生理和功能变化,对同时获得的多模态 PET/MRI 图像数据进行了评估。以及大脑中形态和连接的改变。58 例轻度认知功能障碍和早期痴呆患者 (29 例男性,69 ± 12 岁) 接受 [11C] 匹兹堡化合物-B (PiB) PET/MRI,PET 和 MRI 扫描 70 min。16 例年龄匹配的健康对照 (CTL) (9 例男性,68 ± 11 岁) 也采用相同的扫描方案进行了研究。采用图像衍生输入函数法从早期 PET 图像计算脑血流量 (CBF)。用小脑皮质的参考区域从 50 到 70 min PET 数据计算标准化摄取值比 (SUVr)。MR 图像如 3D-T1WI 、静息态功能 MRI (RS-fMRI) 、弥散张量成像 (DTI) 、对动态 PET 扫描过程中获得的灌注 MRI 进行分析,以评价 MRI 上的各种脑功能。 结果: 根据 PiB-PET 和临床结果,58 例患者中 27 例被确定为 eAD,本研究共分析了包括 CTL 在内的 43 例受试者的资料。EAD 所有皮质区域的 PiB SUVr 值均显著大于 CTL。PiB 累积强度与认知得分呈负相关。与 CTL 相比,eAD 的局部 PET-CBF 值在双侧顶叶和右侧颞叶中显著降低,但在 MRI 灌注中不显著; 然而,SPM 在 PET-和 MRI-CBF 上都显示出区域差异。RS-fMRI 的 SPM 分析描绘了前扣带回皮层和左侧楔前叶组之间的区域差异。VBM 分析显示 AD 组双侧部分海马出现萎缩性改变; 然而,根据 DTI 数据计算的部分各向异性分析未显示两组之间的差异。 结论: 利用来自 PiB-PET/MRI 扫描的各种图像数据进行的多模态分析显示,不同区域的局部 CBF 、皮质体积和神经元网络存在差异,表明 AD 脑的病理生理和功能变化可以从神经生理参数的各个方面观察到。应用 PET/MRI 多模态脑图像将是研究痴呆和其他神经退行性疾病患者病理生理变化的理想方法。

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DOI:10.1016/j.nbd.2019.104725
作者列表:["Aimé P","Karuppagounder SS","Rao A","Chen Y","Burke RE","Ratan RR","Greene LA"]

METHODS::Identifying disease-causing pathways and drugs that target them in Parkinson's disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.

翻译标题与摘要 下载文献
影响因子:3.92
发表时间:2020-01-01
DOI:10.1111/bpa.12761
作者列表:["Sebastián-Serrano Á","Simón-García A","Belmonte-Alfaro A","Pose-Utrilla J","Santos-Galindo M","Del Puerto A","García-Guerra L","Hernández IH","Schiavo G","Campanero MR","Lucas JJ","Iglesias T"]

METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

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影响因子:3.66
发表时间:2020-01-24
DOI:10.3233/JAD-191069
作者列表:["Mendes FR","Leclerc JL","Liu L","Kamat PK","Naziripour A","Hernandez D","Li C","Ahmad AS","Doré S"]

METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.

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