BACKGROUND & AIMS: :This paper will suggest that the Down syndrome phenotype would have been well suited, physiologically, for a deprived environment and that it may represent a predictive, adaptive response to severe maternal deprivation. A trisomy of the 21st chromosome, prior to, or at conception is responsible for Down syndrome and is known to increase in incidence with advanced maternal age. One out of 11 mothers over the age of 50 conceives a Down syndrome baby, compared to one in one thousand at age 30. This article emphasizes that an older mother is more likely to die before she is able to provide the parental investment necessary to produce an ecologically self-sufficient offspring. Prolonged maternal investment is known to be essential for hunter-gatherers to master the skill intensive food procurement techniques that they will need in order to become independent of their mothers. Because Down syndrome individuals are much more likely to be born to older mothers, they must have been routinely deprived of maternal investment in the human environment of evolutionary adaptedness. This consistent paring of maternal deprivation to trisomy 21 conceptions, over time, may have caused natural selection to favor genes responsible for the energy conserving traits seen in modern day Down syndrome. These traits include muscle hypotonia, decreased cerebral metabolism, decreased hippocampal volume, a strong propensity for obesity and growth hormone and thyroid hormone paucity. Such a "thrifty phenotype" may have allowed Down syndrome individuals to become independent of their mothers at a far earlier age and allowed them to forgo the skill intensive ecological niche that non-trisomic humans are phenotypically suited for in order to take up a less cognitively and physically rigorous one.

背景与目标： ：本文将表明，唐氏综合症的表型在生理上非常适合于匮乏的环境，并且它可能代表对严重母体剥夺的预测性，适应性反应。第21号染色体的三体性在受孕之前或受孕时与唐氏综合症有关，并且已知随着高龄产妇的发生率增加。 50岁以上的11名母亲中有1名怀有唐氏综合症婴儿，而30岁时则为千分之一。本文强调，年龄较大的母亲在能够提供生产所需的父母投资之前更容易死亡。一个生态上自给自足的后代。众所周知，延长产妇投资对于猎人/采集者掌握他们需要的技能密集型食品采购技术以使其独立于母亲是必不可少的。因为唐氏综合症的个体更有可能是年长的母亲所生，所以他们必须被例行剥夺了对适应进化的人类环境的母体投资。随着时间的推移，这种对母体剥夺与21三体性观念的一致削减可能导致自然选择偏爱负责现代唐氏综合症中所见的节能特性的基因。这些特征包括肌肉张力减退，大脑代谢减少，海马体积减少，肥胖和生长激素及甲状腺激素缺乏的强烈倾向。这种“节俭的表型”可能使唐氏综合症患者在很早的年龄就变得独立于母亲，并允许他们放弃非三态性人类在表型上适合的技能密集型生态位，从而减少了认知能力。和身体上严谨的。

BACKGROUND & AIMS: :The purpose of this study was to compare the efficacy of diazepam and the pro-diazepam avizafone in preventing the severity of soman-induced pathology in guinea pig. Survival, respiration and seizures of experimental animals were investigated with on-line monitoring of respiratory and EEG parameters. Guinea pigs were pretreated with pyridostigmine (0.1mg/kg i.m.) and 30 min later challenged with 1 or 2 LD50 soman. One minute after intoxication they were treated with atropine (3 or 33.8 mg/kg), pralidoxime chloride (32 mg/kg) and either diazepam (2 mg/kg), avizafone (3.5 mg/kg) or saline solution. The highest dose of atropine (33.8 mg/kg) gave a protective effect in groups treated without anticonvulsants by reducing the severity of clinical signs and death within 24 h but also by decreasing seizure occurrence and brain injuries. When injected at the similar molar dose of 7 micromoles/kg, the protection of anticonvulsants against soman neurotoxicity was higher with the atropine/pralidoxime/avizafone combination than with atropine/pralidoxime/diazepam. Indeed, when atropine was used at the lowest dose, avizafone was found to prevent early mortality and seizures occurrence with better efficacy than diazepam. On the other hand, when added to the therapy, the both anticonvulsants did not prevent the moderate EEG depression (reduction of amplitude by 30-52%) observed under 2 LD50 soman. Moreover, the number of animals suffering from respiratory distress (defined as a decrease of minute ventilation of more than 20% from the baseline value) was enhanced when diazepam or avizafone were used in the therapy. This effect was dependent on the atropine dose and the nature of the anticonvulsant. The beneficial effects of the different therapeutics tested were assessed and compared to the previous data obtained with the same therapies against sarin and from the pharmacokinetics properties of the atropine/diazepam mixture.

背景与目标： ：本研究的目的是比较地西epa和地西p原阿维扎酮预防豚鼠梭曼病引起的病理严重程度的功效。通过在线监测呼吸和脑电参数来研究实验动物的存活，呼吸和癫痫发作。用吡啶斯的明（0.1mg / kg i.m.）预处理豚鼠，并在30分钟后用1或2个LD50梭曼攻击。中毒后一分钟，他们用阿托品（3或33.8 mg / kg），氯吡肟肟（32 mg / kg）和地西epa（2 mg / kg），阿扎酮（3.5 mg / kg）或盐溶液治疗。在未使用抗惊厥药的组中，最高剂量的阿托品（33.8 mg / kg）通过降低24小时内的临床体征和死亡严重程度，还通过减少癫痫发作和脑损伤，提供了保护作用。当以相似的7摩尔/千克的摩尔剂量注射时，阿托品/普利多肟/阿扎酮组合的抗惊厥药对人神经毒性的保护作用高于阿托品/普利多肟/地西p。的确，当以最低剂量使用阿托品时，发现阿维扎酮比地西epa具有更好的预防早死和癫痫发作的作用。另一方面，当添加到治疗中时，两种抗惊厥药均不能防止在2 LD50梭曼条件下观察到的中度EEG抑郁（幅度降低30-52％）。此外，当在治疗中使用地西epa或阿维沙酮时，遭受呼吸窘迫的动物数量（定义为每分钟通气量比基准值减少超过20％）会增加。该作用取决于阿托品的剂量和抗惊厥药的性质。评估了所测试的不同疗法的有益效果，并将其与使用相同的抗沙林疗法和阿托品/地西p混合物的药代动力学特性得到的先前数据进行了比较。

BACKGROUND & AIMS: :This article will propose that humans have an adaptive vulnerability to certain forms of mental retardation, specifically, neuropathological disorders that cause decreased energy expenditure in the hippocampus and the cerebral cortex. This hypothesis will be analyzed in terms of the thrifty phenotype paradigm according to which adverse prenatal events can cause differential gene expression resulting in a phenotype that is better suited, metabolically, for a deprived environment. For example, a malnourished mother has an increased propensity to give birth to offspring that feature a "thrifty phenotype" which permits highly efficient calorie utilization, increased fat deposition and a sedentary nature. This article interprets several prenatal occurrences, including maternal malnourishment, low birth weight, multiparity, short birth interval, advanced maternal age and maternal stress--which are currently identified by the epidemiological literature as risk factors for neuropathology--to be environmental cues that communicate to the fetus that, because it will be neglected of maternal investment, developing a metabolically conservative brain will be the most effective ecological strategy. Success in hunting and foraging in mammals, primates and especially humans is known to be dependent on prolonged maternal investment. Low levels of maternal care are known to result in low survivorship of offspring, largely because the offspring are forced to subsist using simple, low-yield foraging strategies. A predictive, adaptive response, marked by cerebral hypometabolism, may produce a level of metabolic conservancy that mitigates the risks associated with low levels of maternal care. This article will suggest that certain, human neuropathological phenotypes would have been well suited for an ecological niche that closely resembled the less skill-intensive niche of our less encephalized, primate ancestors. The forms of congenital neuropathology discussed in this article do not cause damage to vital homeostatic systems; most simply decrease the size and energy expenditure of the cerebral cortex and the hippocampus, the two structures known to show plasticity during changes in ecological rigor in vertebrates. Also, many disorders that present comorbidly with neuropathology, such as tendency toward obesity, decrement in anabolic hormones, hypotonic musculature, up-regulation of the hypothalamic-pituitary-adrenal axis, and decreased thyroid output are associated with energy conservancy and the thrifty phenotype, further implicating neuropathology in an ecological strategy. Determining the relative impact of evolutionary causation on neuropathological disease should prove informative for medical and gene therapeutic treatment modalities. Furthermore, use of the maternal deprivation paradigm presented here may help researchers more precisely identify the risk factors that determine cognitive trajectory.

背景与目标： ：本文将建议人类对某些形式的智力低下，特别是导致海马和大脑皮层能量消耗减少的神经病理性疾病具有适应性脆弱性。将根据节俭的表型范式分析该假设，根据该节制，产前不良事件可引起差异基因表达，从而导致表型在代谢上更适合于缺乏的环境。例如，营养不良的母亲生育后代的倾向增加，其后代具有“节俭表型”，可以高效利用热量，增加脂肪沉积和久坐。本文解释了几种产前事件，包括孕产妇营养不良，低出生体重，多胎性，出生间隔短，产妇高龄和产妇压力-这些在流行病学文献中目前被确定为神经病理学的危险因素-是可以传达信息的环境提示对胎儿而言，开发新陈代谢的保守大脑将是最有效的生态策略，因为它将被忽略对母亲的投资。已知在哺乳动物，灵长类动物尤其是人类中成功进行狩猎和觅食取决于长期的母体投资。众所周知，低水平的产妇护理会导致后代的存活率较低，这在很大程度上是因为使用简单，低产的觅食策略迫使后代生存。以脑代谢不足为特征的预测性，适应性反应可能会产生一定程度的代谢保守性，从而减轻与低水平孕产妇保健相关的风险。本文将建议某些人类神经病理学表型非常适合于生态位，该位生态位与我们脑部较少的灵长类祖先的技术强度较低的位十分相似。本文讨论的先天性神经病理学形式不会对重要的稳态系统造成损害；最简单的方法是减少大脑皮层和海马体的大小和能量消耗，这两个结构在脊椎动物的生态严谨性变化过程中表现出可塑性。同样，许多与神经病理学同时出现的疾病，例如肥胖倾向，合成代谢激素的减少，低渗性肌肉组织，下丘脑-垂体-肾上腺轴的上调以及甲状腺输出的减少，都与能量守恒和节俭的表型有关，进一步将神经病理学牵涉到生态策略中。确定进化因果关系对神经病理学疾病的相对影响，应为医学和基因治疗方法提供参考。此外，此处介绍的孕产剥夺范式的使用可能有助于研究人员更准确地确定决定认知轨迹的风险因素。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :CSH is a very uncommon lesion and is distinctly unusual in the brain. We report a case of CSH within the brain parenchyma in a 27-year-old woman with Crohn disease. Advanced radiologic imaging and anatomic pathology correlation allow this report to serve as a reference for future similar cases.

背景与目标： ：CSH是一种非常罕见的病变，在大脑中明显不同寻常。我们报道了一名27岁的克罗恩病女性脑实质内的CSH病例。先进的放射成像和解剖病理学相关性使该报告可作为将来类似病例的参考。

BACKGROUND & AIMS: :Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia. Patients suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation and seizures, and is associated with intellectual disability. In mice, onset is heralded by weight loss beginning around day 15; gait instability follows progressing to inability to stand and development of tail tremor with seizure-like activity and death. Here we report that hyperargininemic mice treated neonatally with an adeno-associated virus (AAV)-expressing arginase and followed long-term lack any presentation consistent with brain dysfunction. Behavioral and histopathological evaluation demonstrated that treated mice are indistinguishable from littermates, and that putative compounds associated with neurotoxicity are diminished. In addition, treatment results in near complete resolution of metabolic abnormalities early in life; however, there is the development of some derangement later with decline in transgene expression. Ammonium challenging revealed that treated mice are affected by exogenous loading much greater than littermates. These results demonstrate that AAV-based therapy for hyperargininemia is effective and prevents development of neurological abnormalities and cognitive dysfunction in a mouse model of hyperargininemia; however, nitrogen challenging reveals that these mice remain impaired in the handling of waste nitrogen.

背景与目标： ：完全精氨酸酶I缺乏症是最不严重的尿素循环疾病，其特征在于高精氨酸血症和高氨血症罕见发作。患者患有神经系统疾病，伴有皮层和锥体束恶化，痉挛，活动能力下降和癫痫发作，并伴有智力障碍。在小鼠中，体重减轻预示着发病的发生在第15天左右。步态不稳继之以无法站立并发展为发作性活动和死亡的尾部震颤。在这里，我们报告高精氨酸血症小鼠新生儿表达腺相关病毒（AAV）的精氨酸酶治疗，并随后长期缺乏任何与脑功能障碍一致的表现。行为和组织病理学评估表明，经治疗的小鼠与同窝幼仔是无法区分的，并且与神经毒性相关的推定化合物也有所减少。此外，治疗可以使生命早期的代谢异常完全消除；然而，后来随着转基因表达的下降，出现了一些紊乱。具有铵盐挑战性的结果表明，处理过的小鼠受到的外源性负载的影响要远远大于同窝出生的小鼠。这些结果表明，在高精氨酸血症小鼠模型中，基于AAV的高精氨酸血症疗法是有效的，可预防神经系统异常和认知功能障碍的发展。但是，氮挑战性表明这些小鼠在处理废氮方面仍然受到损害。

BACKGROUND & AIMS: :Background: Low-grade gliomas (LGG) in adults are usually slow growing and frequently asymptomatic brain tumors, originating from glial cells of the central nervous system (CNS). Although regarded formally as "benign" neoplasms, they harbor the potential of malignant transformation associated with high morbidity and mortality. Their complex and unpredictable tumor biology requires a reliable and conclusive presurgical magnetic resonance imaging (MRI). A promising and emerging MRI approach in this context is histogram based apparent diffusion coefficient (ADC) profiling, which recently proofed to be capable of providing prognostic relevant information in different tumor entities. Therefore, our study investigated whether histogram profiling of ADC distinguishes grade I from grade II glioma, reflects the proliferation index Ki-67, as well as the IDH (isocitrate dehydrogenase) mutation and MGMT (methylguanine-DNA methyl-transferase) promotor methylation status. Material and Methods: Pre-treatment ADC volumes of 26 LGG patients were used for histogram-profiling. WHO-grade, Ki-67 expression, IDH mutation, and MGMT promotor methylation status were evaluated. Comparative and correlative statistics investigating the association between histogram-profiling and neuropathology were performed. Results: Almost the entire ADC profile (p25, p75, p90, mean, median) was significantly lower in grade II vs. grade I gliomas. Entropy, as second order histogram parameter of ADC volumes, was significantly higher in grade II gliomas compared with grade I gliomas. Mean, maximum value (ADCmax) and the percentiles p10, p75, and p90 of ADC histogram were significantly correlated with Ki-67 expression. Furthermore, minimum ADC value (ADCmin) was significantly associated with MGMT promotor methylation status as well as ADC entropy with IDH-1 mutation status. Conclusions: ADC histogram-profiling is a valuable radiomic approach, which helps differentiating tumor grade, estimating growth kinetics and probably prognostic relevant genetic as well as epigenetic alterations in LGG.

背景与目标： 背景：成人中的低度神经胶质瘤（LGG）通常生长缓慢，并且通常是无症状的脑肿瘤，起源于中枢神经系统（CNS）的神经胶质细胞。尽管在形式上被视为“良性”肿瘤，但它们具有与高发病率和高死亡率相关的恶性转化的潜力。它们复杂且不可预测的肿瘤生物学要求可靠且结论性的术前磁共振成像（MRI）。在这种情况下，一种有前途和新兴的MRI方法是基于直方图的表观扩散系数（ADC）分析，最近被证明能够在不同肿瘤实体中提供预后相关信息。因此，我们的研究调查了ADC的直方图谱是否区分I级和II级神经胶质瘤，反映了增殖指数Ki-67以及IDH（异柠檬酸脱氢酶）突变和MGMT（甲基鸟嘌呤-DNA甲基转移酶）启动子甲基化状态。材料和方法：将26例LGG患者的治疗前ADC体积用于直方图分析。评估了WHO级，Ki-67表达，IDH突变和MGMT启动子甲基化状态。进行了比较和相关统计调查直方图分析和神经病理学之间的关联。结果：与I级神经胶质瘤相比，II级神经胶质瘤的几乎所有ADC谱（p25，p75，p90，平均值，中位数）均显着降低。作为ADC体积的二阶直方图参数，熵在II级神经胶质瘤中明显高于I级神经胶质瘤。 ADC直方图的平均值，最大值（ADCmax）和百分位数p10，p75和p90与Ki-67表达显着相关。此外，最小ADC值（ADCmin）与MGMT启动子甲基化状态以及IDH-1突变状态的ADC熵显着相关。结论：ADC直方图分析是一种有价值的放射学方法，可帮助区分肿瘤分级，估计生长动力学以及可能预后LGG的相关遗传以及后生遗传学改变。

BACKGROUND & AIMS: AIM:The pathogenesis of delayed encephalopathy induced by heavy-ion irradiation was investigated experimentally in cats. The left cerebral hemispheres were irradiated with 15-40 Gy of heavy ions (carbon), and histologically and morphometrically examined 12 months later. RESULTS:In the irradiated cerebral white matter the following occurred as the dose increased: astrocytic swelling, then the dilatation of small blood vessels with a fibrous thickening of the wall, and then loosening of the white matter with cavity formation and diffuse albumin deposition. Pathological features of these cavities suggested that they are induced by long-standing edema. Although the dilated vessels were arteries, veins, and capillaries, arteriovenous shunt and damage of the smooth muscle cells of the arterial media were absent. Changes of the cerebral cortex were scarce. Morphometrically, the irradiated cerebral white matter was swollen, and the capillary density tended to be reduced in the deep cortex and subcortical white matter, but this effect was not dose dependent. CONCLUSION:Heavy-ion irradiation induces delayed encephalopathy in cats, preferentially involving the white matter. The cardinal pathogenesis was long-standing edema of the white matter due to vascular hyperpermeability, and the vascular dilatation seemed to be caused by a reduction in the vascular bed and/or hemoconcentration due to hyperpermeability.

背景与目标： 目的：通过实验研究猫重离子辐照引起的迟发性脑病的发病机理。左脑半球用15-40 Gy重离子（碳）照射，并在12个月后进行组织学和形态学检查。
结果：在受辐照的脑白质中，随着剂量的增加，会发生以下情况：星形胶质细胞肿胀，然后扩张小血管，使纤维壁增厚，然后使白质变松，形成空腔并扩散白蛋白沉积。这些腔的病理特征表明它们是由长期浮肿引起的。尽管扩张的血管是动脉，静脉和毛细血管，但没有动静脉分流和动脉中枢平滑肌细胞的损伤。大脑皮层的变化很少。从形态学上讲，受辐照的脑白质肿胀，并且在深皮层和皮层下白质中毛细血管密度趋于降低，但这种作用与剂量无关。
结论：重离子辐射可诱发猫的迟发性脑病，优先涉及白质。主要的发病机制是由于血管通透性过高引起的白质的长期水肿，并且血管扩张似乎是由于通透性过高导致的血管床减少和/或血液浓缩引起的。

BACKGROUND & AIMS: :Sirtuins (SIRTs) are a family of regulatory proteins of genetic information with a high degree of conservation among species. The SIRTs are heavily involved in several physiological functions including control of gene expression, metabolism, and aging. SIRT1 has been the most studied sirtuin and plays important role in the prevention and progression of neurodegenerative diseases acting in different pathways of proteins involved in brain function. SIRT1 activation regulates important genes that also exert neuroprotective actions such as p53, nuclear factor kappa B, peroxisome proliferator-activated receptor-gamma (PPARγ), PPARγ coactivator-1α, liver X receptor, and forkhead box O. It is well established in literature that growing population aging, oxidative stress, inflammation, and genetic factors are important conditions to development of neurodegenerative disorders. However, the exact pathophysiological mechanisms leading to these diseases remain obscure. The sirtuins show strong potential to become valuable predictive and prognostic markers for diseases and as therapeutic targets for the treatment of a variety of neurodegenerative disorders. In this context, the aim of the current review is to present an actual view of the potential role of SIRT1 in modulating the interaction between target genes and neurodegenerative diseases on the brain.

背景与目标： ：Sirtuins（SIRTs）是遗传信息的调节蛋白家族，在物种间具有高度的保守性。 SIRTs大量参与多种生理功能，包括基因表达，代谢和衰老的控制。 SIRT1是研究最深入的sirtuin，在神经退行性疾病的预防和发展中起着重要作用，神经退行性疾病通过参与大脑功能的蛋白质的不同途径起作用。 SIRT1激活调节重要基因，这些重要基因也发挥神经保护作用，例如p53，核因子kappa B，过氧化物酶体增殖物激活受体-γ（PPARγ），PPARγcoactivator-1α，肝脏X受体和前叉箱O。不断增长的人口老龄化，氧化应激，炎症和遗传因素是神经退行性疾病发展的重要条件。但是，导致这些疾病的确切病理生理机制仍然不清楚。 sirtuins具有强大的潜力，可成为疾病的有价值的预测和预后标志物，并可作为治疗各种神经退行性疾病的治疗靶标。在这种情况下，本综述的目的是提出SIRT1在调节靶基因与大脑神经退行性疾病之间相互作用中的潜在作用的实际观点。

BACKGROUND & AIMS: :Missense mutations in UBQLN2 cause X-linked dominant inheritance of amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). UBQLN2 belongs to a family of four highly homologous proteins expressed in humans that play diverse roles in maintaining proteostasis, but whether one isoform can substitute for another is not known. Here, we tested whether overexpression of UBQLN1 can alleviate disease in the P497S UBQLN2 mouse model of ALS/FTD by crossing transgenic (Tg) mouse lines expressing the two proteins and characterizing the resulting genotypes using a battery of pathologic and behavioral tests. The pathologic findings revealed UBQLN1 overexpression dramatically reduced the burden of UBQLN2 inclusions, neuronal loss and disturbances in proteostasis in double Tg mice compared to single P497S Tg mice. The beneficial effects of UBQLN1 overexpression were primarily confirmed by behavioral improvements seen in rotarod performance and grip strength in male, but not female mice. Paradoxically, although UBQLN1 overexpression reduced pathologic signatures of disease in P497S Tg mice, female mice had larger percentage of body weight loss than males, and this correlated with a corresponding lack of behavioral improvements in the females. These findings lead us to speculate that methods to upregulate UBQLN1 expression may reduce pathogenicity caused by UBQLN2 mutations, but may also lead to gender-specific outcomes that will have to be carefully weighed with the therapeutic benefits of UBQLN1 upregulation.

背景与目标： ：UBQLN2中的缺失突变导致X连锁的肌萎缩性侧索硬化伴额颞痴呆（ALS / FTD）的显性遗传。 UBQLN2属于人类表达的四种高度同源蛋白家族，在维持蛋白稳态中发挥着多种作用，但尚不知道一种同工型是否可以替代另一种。在这里，我们测试了UBQLN1的过表达是否可以通过跨表达两种蛋白质的转基因（Tg）小鼠品系并使用一系列病理学和行为学测试来表征所产生的基因型，从而缓解ALS / FTD P497S UBQLN2小鼠模型中的疾病。病理结果表明，与单只P497S Tg小鼠相比，双Tg小鼠的UBQLN1过表达显着降低了UBQLN2内含物的负担，神经元丢失和蛋白稳态障碍。 UBQLN1过表达的有益作用主要由雄性小鼠的轮转表现和抓地力方面的行为改善所证实，而雌性小鼠却没有。矛盾的是，尽管UBQLN1过表达减少了P497S Tg小鼠的疾病病理特征，但雌性小鼠的体重减轻百分比高于雄性，这与雌性缺乏相应的行为改善有关。这些发现使我们推测，上调UBQLN1表达的方法可能会减少由UBQLN2突变​​引起的致病性，但也可能导致特定于性别的结局，因此必须仔细权衡UBQLN1上调的治疗益处。

BACKGROUND & AIMS: :Human prion diseases, in common with other neurodegenerative diseases, may be sporadic or inherited and are characterized by the accumulation of cellular proteins accompanied by neuronal death and synaptic loss. Prion diseases are, however, unique in being transmissible. Central to the pathogenesis of all forms of prion disease is the prion protein. This article provides a brief overview of the biology of human prion diseases followed by a more in-depth discussion of the neuropathology of these diseases, including features of neuroradiologic relevance.

背景与目标： 人pr病毒疾病与其他神经退行性疾病相同，可能是散发性或遗传性疾病，其特征是细胞蛋白蓄积，伴有神经元死亡和突触丧失。然而，病毒是可以传播的独特疾病。 forms病毒蛋白是所有形式的pr病毒病发病机制的核心。本文简要介绍了人类病毒疾病的生物学特性，然后更深入地讨论了这些疾病的神经病理学，包括神经放射学相关性的特征。

BACKGROUND & AIMS: :α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau. The identified neuropathological features closely resembled those in brains of p.A53T patients. Small molecules targeting αSyn reverted the degenerative phenotype under both basal and induced stress conditions, indicating a treatment strategy for PD and other synucleinopathies. Furthermore, mutant neurons showed disrupted synaptic connectivity and widespread transcriptional alterations in genes involved in synaptic signaling, a number of which have been previously linked to mental disorders, raising intriguing implications for potentially converging disease mechanisms.

背景与目标： ：-Synuclein（αSyn）是与散发性帕金森氏病（PD）相关的主要基因，而G209A（p.A53T）αSyn突变会导致家族性PD，其特征是早期发作和一般的严重表型，包括非运动表现。在这里，我们从具有p.A53T突变的患者中产生了从头诱导的多能干细胞（iPSC），并开发了一个强大的模型来捕获基础条件下的PD致病过程。 iPSC衍生的突变神经元显示出与疾病相关的新表型，包括蛋白质聚集，受损的神经营养增生以及轴突扭曲或破碎，曲张静脉曲张包含αSyn和Tau。所鉴定的神经病理学特征与p.A53T患者的大脑中的神经病理学特征极为相似。在基础和诱导应激条件下，靶向αSyn的小分子均能还原变性表型，这表明PD和其他突触核病的治疗策略。此外，突变的神经元在突触信号传导相关基因中显示出突触连通性受到破坏和广泛的转录改变，其中许多先前与精神障碍有关，对潜在的趋同疾病机制产生了有趣的影响。

BACKGROUND & AIMS: :Previously our study has demonstrated that long-term treadmill exercise improved cognitive deficit in APP/PS1 transgenic mice of Alzheimer's disease (AD) paralleled by enhanced long-term potentiation (LTP). The present study was undertaken to further investigate whether the treadmill running could inhibit the progression of Alzheimer's disease (AD)-like neuropathology in hippocampus of the APP/PS1 mouse models of AD, and to define a potential molecular mechanism underlying the exercise-induced reduction in AD-like neuropathology. Five months of treadmill exercise resulted in a robust reduction in β-amyloid (Aβ) deposition and tau phosphorylation in the hippocampus of APP/PS1 mice. This was accompanied by a significant decrease in APP phosphorylation and PS1 expression. We also observed GSK3, rather than CDK5, was inhibited by treadmill exercise. These results indicate that treadmill exercise is sufficient to inhibit the progression of AD-like neuropathology in the hippocampus of APP/PS1 transgenic mouse model, and may mediate APP processing in favor of reduced Aβ deposition. In addition, we demonstrate that treadmill exercise attenuates AD-like neuropathology in AD transgenic mice via a GSK3 dependent signaling pathway.

背景与目标： ：先前的研究表明，长期的跑步机锻炼可改善阿尔茨海默氏病（AD）的APP / PS1转基因小鼠的认知功能障碍，同时增强长期增强能力（LTP）。进行本研究以进一步调查跑步机是否可以抑制AD / APP1小鼠AD模型海马中的阿尔茨海默氏病（AD）样神经病理的进展，并确定运动诱导的降低的潜在分子机制在AD样神经病理学中。五个月的跑步机运动导致APP / PS1小鼠海马中β淀粉样蛋白（Aβ）沉积和tau磷酸化的明显降低。这伴随着APP磷酸化和PS1表达的显着降低。我们还观察到跑步机锻炼会抑制GSK3，而不是CDK5。这些结果表明，跑步机运动足以抑制APP / PS1转基因小鼠模型海马中AD样神经病理的进展，并可能介导APP的处理，从而减少Aβ的沉积。此外，我们证明了跑步机运动通过依赖GSK3的信号通路减弱了AD转基因小鼠的AD样神经病理。

BACKGROUND & AIMS: :Age and APOE are the most robust risk factors for dementia and cognitive decline, but the underlying neurobiology remains unclear. We examined the extent to which the hallmark pathologies of Alzheimer's disease, Lewy body disease, and cerebrovascular diseases account for the association of age and APOE with decline in episodic memory versus nonepisodic cognitive abilities. Up to 20 waves of longitudinal cognitive data were collected from 858 autopsied participants in 2 ongoing clinical-pathologic cohort studies of aging. Neuropathologic examinations quantified measures of beta amyloid (Aβ) plaque, mesial temporal and neocortical neurofibrillary tangles, macro- and microinfarcts, and neocortical Lewy bodies. Random coefficient models estimated person-specific slopes of decline in episodic memory and nonepisodic cognition. Path analysis examined the relation of age, APOE, and the 6 pathologic indices to the slopes of cognitive decline. The effect of age on decline in episodic memory was mediated by Aβ, mesial temporal and neocortical tau tangles, and macroscopic infarcts; age on decline in nonepisodic cognition was mediated by Aβ, neocortical tangles, and macroscopic infarcts. The effect of APOE on decline in episodic memory was mediated by Aβ, mesial temporal and neocortical tangles, and neocortical Lewy bodies; APOE on nonepisodic cognition was mediated by Aβ, neocortical tangles, and neocortical Lewy bodies. There were no direct effects of age and APOE on decline after accounting for these pathologic pathways.

背景与目标： ：年龄和APOE是痴呆和认知功能减退的最强危险因素，但潜在的神经生物学仍不清楚。我们检查了阿尔茨海默氏病，路易体病和脑血管疾病的标志性病理在多大程度上解释了年龄和APOE与发作性记忆与非间歇性认知能力下降之间的关系。在2项正在进行的衰老临床病理队列研究中，从858名接受尸检的参与者中收集了多达20个纵向认知数据。神经病理学检查量化了β淀粉样蛋白（Aβ）斑块，颞内侧和新皮质神经原纤维缠结，大和微梗塞以及新皮质路易体的测量值。随机系数模型估计了情景记忆和非间歇性认知下降的人特定斜率。路径分析检查了年龄，APOE和6种病理学指标与认知能力下降的关系。年龄对发作性记忆下降的影响是由Aβ，颞内侧和新皮质tau缠结以及宏观梗死介导的。非间歇性认知下降的年龄是由Aβ，新皮层缠结和宏观梗死介导的。 APOE对发作性记忆下降的影响是由Aβ，颞内侧和新皮质缠结以及新皮质路易体介导的。 APE，新皮质缠结和新皮质路易体介导了关于非短时认知的APOE。在考虑了这些病理路径后，年龄和APOE对下降没有直接影响。

BACKGROUND & AIMS: AIMS:Among the putative mechanisms proposed to be common factors in Down syndrome (DS) and Alzheimer's disease (AD) neuropathology, deficits in protein quality control (PQC) have emerged as a unifying mechanism of neurodegeneration. Considering that disturbance of protein degradation systems is present in DS and that oxidized/misfolded proteins require polyubiquitinylation for degradation via the ubiquitin proteasome system, this study investigated if dysregulation of protein polyubiquitinylation is associated with AD neurodegeneration in DS. RESULTS:Postmortem brains from DS cases before and after development of AD neuropathology and age-matched controls were analyzed. By selectively isolating polyubiquitinated proteins, we were able to identify specific proteins with an altered pattern of polyubiquitinylation as a function of age. Interestingly, we found that oxidation is coupled with polyubiquitinylation for most proteins mainly involved in PQC and energy metabolism. INNOVATION:This is the first study showing alteration of the polyubiquitinylation profile as a function of aging in DS brain compared with healthy controls. Understanding the onset of the altered ubiquitome profile in DS brain may contribute to identification of key molecular regulators of age-associated cognitive decline. CONCLUSIONS:Disturbance of the polyubiquitinylation machinery may be a key feature of aging and neurodegeneration. In DS, age-associated deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins, which is not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology. Antioxid. Redox Signal. 26, 280-298.

背景与目标： 目的：在被认为是唐氏综合症（DS）和阿尔茨海默氏病（AD）神经病理学的常见因素的推测机制中，蛋白质质量控​​制（PQC）的缺陷已成为神经退行性变的统一机制。考虑到DS中存在蛋白质降解系统的紊乱，并且氧化/错折叠的蛋白质需要通过泛素蛋白酶体系统降解才能进行多泛素化，因此本研究调查了蛋白质多泛素化的失调是否与DS中的AD神经变性有关。
结果：分析了AD患者在AD神经病理学发展之前和之后以及年龄匹配的对照组的死后大脑。通过选择性分离多聚泛素化蛋白，我们能够鉴定出随年龄变化而改变的多聚泛素化模式的特定蛋白。有趣的是，我们发现对于大多数主要参与PQC和能量代谢的蛋白质，氧化与聚泛素化作用有关。
创新：这是第一项研究，表明与健康对照组相比，DS大脑中多泛素化的变化与衰老有关。了解DS脑中遍在基因组谱改变的发作可能有助于识别与年龄相关的认知功能下降的关键分子调节剂。
结论：泛泛素化机制的紊乱可能是衰老和神经退行性变的关键特征。在DS中，与年龄相关的蛋白水解系统缺陷可能会进一步加剧氧化/错折叠/多泛素化蛋白的积累，这种蛋白不能有效降解并且可能对神经元有害并有助于AD神经病理学。抗氧化。氧化还原信号。 26，280-298。