Longitudinal Cognitive Decline in a Novel Rodent Model of Cerebral Amyloid Angiopathy Type-1.
脑淀粉样血管病 1 型新型啮齿类动物模型的纵向认知衰退。
- 作者列表："Popescu DL","Van Nostrand WE","Robinson JK
:Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by β-amyloid (Aβ) accumulation in and around the cerebral blood vessels and capillaries and is highly comorbid with Alzheimer's disease (AD). Familial forms of CAA result from mutations within the Aβ domain of the amyloid β precursor protein (AβPP). Numerous transgenic mouse models have been generated around expression of human AβPP mutants and used to study cerebral amyloid pathologies. While behavioral deficits have been observed in many AβPP transgenic mouse lines, relative to rats, mice are limited in behavioral expression within specific cognitive domains. Recently, we generated a novel rat model, rTg-DI, which expresses Dutch/Iowa familial CAA Aβ in brain, develops progressive and robust accumulation of cerebral microvascular fibrillar Aβ beginning at 3 months, and mimics many pathological features of the human disease. The novel rTg-DI model provides a unique opportunity to evaluate the severity and forms of cognitive deficits that develop over the emergence and progression of CAA pathology. Here, we present an in-depth, longitudinal study aimed to complete a comprehensive assessment detailing phenotypic disease expression through extensive and sophisticated operant testing. Cohorts of rTg-DI and wild-type (WT) rats underwent operant testing from 6 to 12 months of age. Non-operant behavior was assessed prior to operant training at 4 months and after completion of training at 12 months. By 6 months, rTg-DI animals demonstrated speed-accuracy tradeoffs that later manifested across multiple operant tasks. rTg-DI animals also demonstrated delayed reaction times beginning at 7 months. Although non-operant assessments at 4 and 12 months indicated comparable mobility and balance, rTg-DI showed evidence of slowed environmental interaction. Overall, this suggests a form of sensorimotor slowing is the likely core functional impairment in rTg-DI rats and reflects similar deficits observed in human CAA.
: 脑淀粉样血管病 (CAA) 是以 β-淀粉样蛋白 (a β) 为特征的小血管疾病在脑血管和毛细血管及其周围积聚，与阿尔茨海默病 (AD) 高度共病。家族性 CAA 形式是淀粉样 β 前体蛋白 (a β pp) a β 结构域内突变的结果。已经围绕人 a β pp 突变体的表达产生了许多转基因小鼠模型，并用于研究脑淀粉样蛋白病理。虽然在许多 a β pp 转基因小鼠系中观察到行为缺陷，但相对于大鼠，小鼠在特定认知领域内的行为表达受到限制。最近，我们建立了一种新的大鼠模型，rTg-DI，在大脑中表达荷兰/爱荷华州家族性 CAA a β，从 3 个月开始出现脑微血管纤维 a β 的进行性和健壮蓄积,并模仿了人类疾病的许多病理特征。新型 rTg-DI 模型提供了一个独特的机会来评估随着 CAA 病理的出现和进展而发展的认知缺陷的严重程度和形式。在此，我们提出了一项深入的纵向研究，旨在通过广泛而复杂的操作测试完成详细描述表型疾病表达的全面评估。RTg-DI 和野生型 (WT) 大鼠队列从 6 ~ 12 月龄进行操作试验。在 4 个月的操作训练之前和 12 个月的训练完成后评估非操作行为。到 6 个月时，rTg-DI 动物表现出速度-精度权衡，随后在多个操作任务中表现出来。RTg-DI 动物也表现出从 7 个月开始的延迟反应时间。虽然 4 个月和 12 个月的非操作评估表明具有相当的移动性和平衡性，但 rTg-DI 显示出环境相互作用减慢的证据。总体而言，这表明一种形式的感觉运动减慢是 rTg-DI 大鼠可能的核心功能障碍，反映了在人类 CAA 中观察到的类似缺陷。
METHODS:BACKGROUND:People with stroke are not meeting recommended levels of physical activity. The modifiable factors associated with post-stroke physical activity levels need to be identified to develop targeted interventions. OBJECTIVE:The objective of this study was to investigate the factors at discharge from inpatient rehabilitation that are associated with physical activity levels at 3 months following discharge. DESIGN:This was a prospective cohort study. METHODS:Sixty-four people with stroke completed baseline assessments at discharge from inpatient rehabilitation and 55 completed the follow-up 3 months later. The candidate factors (i.e. gait speed, balance, strength, cognition, mood and motivation) were measured at discharge. The primary outcome measure at follow-up was walking related activity (measured by wrist-worn accelerometer). Secondary outcome measures were physical activity participation (Activity Card Sort) and intensity of physical activity (International Physical Activity Questionnaire - Short 7 days). Adjusted separate multivariable linear regression models or proportional odds regression models were used to evaluate the associations between candidate factors and physical activity. RESULTS:Gait speed and balance were associated with all aspects of physical activity. Higher level of intrinsic motivation was also associated with higher physical activity participation. Anxiety demonstrated a significant non-linear relationship with physical activity participation. LIMITATIONS:Inclusion of fatigue and individual muscle strength could have provided further insights into associations with steps per day. CONCLUSION:The results demonstrated that better physical function at discharge from inpatient rehabilitation was associated with future increased levels of physical activity. Additionally, higher levels of motivation impacted on increased physical activity participation. The influence of anxiety on physical activity participation requires further exploration. Mixed-method study designs can be utilized to further understand the factors associated with post-stroke physical activity.
METHODS:Cerebral ischemia-reperfusion (I/R) is characterized by initial transient cerebral ischemia followed by reperfusion. Various pathophysiological processes are involved in brain injury and functional recovery during cerebral I/R. There are few studies on dynamic metabolic process after cerebral I/R. The present study was to observe dynamic alteration of brain injury, functional recovery, and metabolites after cerebral I/R in rats and discover potential metabolic markers. The cerebral I/R model was established by middle cerebral artery occlusion (MCAO) for 90 min, following reperfusion in rats. The results of cerebral infarction area, cerebral edema, and behavior test showed that there were dynamic changes in brain injury and functional recovery at different periods after cerebral I/R. Further analysis showed that the brain injury was severe on the first day of cerebral I/R, and there was a significant functional recovery from the 7th day of cerebral I/R, followed by an aggravation trend of brain injury from the days 7 to 28. Furthermore, Matrix-assisted laser desorption ionization mass spectrometry imaging analysis showed that the expression of ATP, glucose, and citric acid on 7th day was the highest during cerebral I/R, which indicated that energy metabolism and oxidative phosphorylation played important roles during cerebral I/R. In addition, the untargeted metabolomic results showed that the level of isocitric acid, the ratio of oxyglutaric acid/glutamic acid, and the level of pyruvic acid associated with the TCA cycle were also the highest on the 7th day during cerebral I/R, which indicated that the transient spontaneous recovery of ischemic brain on the 7th day after ischemia-reperfusion might be related to oxidative phosphorylation and energy metabolism in the brain in this period. In conclusion, the results suggest that some small molecule metabolites participate in the brain injury and functional recovery during cerebral I/R, which is of great significance to the development of therapeutic drugs and diagnostic markers.
METHODS:The aims of this study were to study the effects of miR-2 on cerebral ischemia–reperfusion rats and to explore its further mechanism. Rats were assigned into sham, model, miR-22 control and miR-22 groups. Observation of neurological behaviors at 24 h after operation found that neurological functions were severely damaged in the model and miR-22 control groups and these damages were improved by miR-22. RT-PCR indicated that miR-22 mRNA level in the brain tissue was significantly decreased in the model and miR-22 control groups, but increased in the miR-22 group. TTC staining showed increased percentage of cerebral infarction volume in the model and miR-22 control groups and this increase was reduced by miR-22. Immunohistochemistry showed increased densities of CD34^+ and VEGF^+ microvessels in the cortex in the model and miR-22 control groups, which were further increased in the miR-22 group. ELISA showed increased serum VEGF and Ang-1 levels in the model and miR-22 control groups, which were also further increased in the miR-22 group. Western blot analysis showed increased phosphorylation level of PI3K and Akt in brain tissue in the model and miR-22 control groups, which were further increased in the miR-22 group. Administration of LY294002, a specific PI3K pathway inhibitor, significantly reversed all the effects of miR-22 on rats in the model group. miR-22 exerts its neuroprotective and angiogenic functions via the PI3K/Akt signaling pathway, at least partly, in rats under cerebral ischemia–reperfusion.