Psychiatric Imaging Programme Transition

突触终末是允许信息从一个神经细胞流向下一个神经细胞的连接。突触末端蛋白，包括一种名为SV2A的蛋白，是这种信息流的关键，因此对整个大脑功能也是关键。突触末端蛋白的丢失被认为是导致包括精神分裂症在内的许多疾病的原因。这突出了了解突触末端蛋白丢失的潜在机制和影响的重要性。我们把重点放在精神分裂症上，尽管研究结果可能与其他大脑疾病、正常的神经发育和衰老有关。精神分裂症影响每100人中就有1人，以精神病和阴性症状以及认知障碍为特征。它是导致劳动年龄成年人残疾的十大原因之一。一个主要的假说提出，突触终末蛋白丢失是大脑功能受损的基础，从而导致精神分裂症的认知和其他症状。补体蛋白由脑细胞产生，通过标记它们被称为小胶质细胞的免疫细胞分解来调节突触终末的水平。一些补体蛋白在精神分裂症中升高，人们认为这会导致精神分裂症中SV2A和其他突触终端蛋白的丢失。然而，目前尚不清楚补体和SV2A的变化是否是精神分裂症症状和认知障碍的基础，或者是否在精神障碍的过程中发生进一步的SV2A丢失。此外，目前尚不清楚是否如预测的那样，调节SV2A会损害精神分裂症患者的大脑功能。最后，我们缺乏在多个时间点测量突触终末蛋白或测量突触后蛋白的方法。我们计划在三个相关的工作包中解决这些理解上的关键差距。第一项测试使用脑扫描测试精神分裂症患者的SV2A水平在发病时是否与对照组相比发生了变化，以及在精神分裂症过程中是否进一步下降。它还将测试出现时的补体水平是否预测随着时间的推移认知障碍和其他症状的增加&如果这与SV2A水平的变化有关。第二个测试是，减少SV2A的活动是否会损害大脑功能，从而导致精神分裂症的症状。这对于理解SV2A中减少的功能后果很重要。我们将使用一种名为左乙拉西坦的药物来降低SV2A的活性，并使用脑扫描将其对大脑功能的影响与安慰剂进行比较。第三项涉及开发新的突触蛋白成像方法。目前对SV2a成像的方法涉及少量辐射。这限制了一个人可以进行的扫描次数，特别是在青春期。有必要在多个时间点对青少年进行扫描，以充分了解大脑发育过程中突触终末发生了什么，许多大脑疾病通常始于青春期。为了克服这一限制，我们的目标是开发一种超低辐射方法，并将其与当前的标准扫描方法进行比较。这将涉及对健康志愿者的扫描。除了突触终末蛋白，突触后蛋白对大脑功能也很重要，并在精神分裂症和其他大脑疾病中受到影响。然而，目前还没有办法在活人身上进行研究，所以不可能测试突触后蛋白是否参与了这些疾病。为了解决这个问题，我们的目标是开发一种新的用于突触后标记的PET示踪剂。我们将评估潜在的配体，并选择最有希望的配体来推进。如果这项实验支持进展，我们将进行一项研究，以确定该配体在人类中的可靠性。这些研究有可能找到治疗精神分裂症和其他具有类似认知障碍和症状的疾病的新方法，包括阿尔茨海默病、情绪和自闭症。他们还有可能开发新的工具来进一步了解大脑疾病。

Synaptic terminals are the connections that allow information to flow from one nerve cell to the next. Synaptic terminal proteins, including one called SV2a, are key to this information flow & consequently for overall brain function. Loss of synaptic terminal proteins is thought to contribute to a number of illnesses, including schizophrenia. This highlights the importance of understanding potential mechanisms & effects of synaptic terminal protein loss. We focus on schizophrenia, although findings are likely to be relevant to other brain disorders, normal neurodevelopment & ageing as well.Schizophrenia affects 1 in 100 people & is characterized by psychotic & negative symptoms, & cognitive impairments. It is a top ten cause of disability in working-age adults. A leading hypothesis proposes that synaptic terminal protein loss underlies impaired brain function to lead to the cognitive & other symptoms of schizophrenia. Complement proteins are produced by brain cells & regulate levels of synaptic terminals by tagging them to be broken down by immune cells called microglia. Some complement proteins are elevated in schizophrenia, & it is thought this leads to loss of SV2a, & other synaptic terminal proteins, in schizophrenia. However, it remains unknown if the complement & SV2a changes underlie the symptoms & cognitive impairment in schizophrenia, or if further SV2a loss occurs during the course of the disorder. Moreover, it is not known if modulating SV2a impairs brain function in schizophrenia, as predicted. Finally, we lack approaches to measure synaptic terminal proteins at multiple time points, or to measure post-synaptic proteins.We plan to address these critical gaps in understanding in three related work-packages. The first tests whether SV2A levels are altered at illness onset in schizophrenia relative to controls and if they reduce further during the course of schizophrenia using brain scans. It will also test if complement levels at presentation predict increasing cognitive impairment & other symptoms over time & if this is linked to altered SV2a levels. The second tests if reducing SV2A activity impairs brain function & leads to symptoms in schizophrenia. This is important to understand the functional consequences of reductions in SV2A. We will use a drug called levetiracetam to reduce SV2A activity and compare its effects on brain function against a placebo using brain scans.The third involves developing new approaches to image synaptic proteins. The current approach to image SV2A involves a small amount of radiation. This limits the number of scans someone can have, particularly in adolescence. It is necessary to scan adolescents & at multiple time-points to fully understand what happens to synaptic terminals during brain development & many brain disorders, which often begin in adolescence. To overcome this limitation, we aim to develop an ultra-low radiation approach & compare it to the current standard scan approach. This will involve scans in healthy volunteers. In addition to synaptic terminal proteins, post-synaptic proteins are also important to brain function, and affected in schizophrenia & other brain disorders. However, there is currently no way of studying them in live humans, so it is not possible to test if post-synaptic proteins are involved in these disorders. To address this, we aim to develop a new PET tracer for post-synaptic markers. We will evaluate potential ligands & select the most promising ligand to take forward. If this experiment supports progression, we will then conduct a study to determine the reliability of the ligand in humans.These studies have the potential to identify new approaches to treat schizophrenia, & other disorders with similar cognitive impairments & symptoms, including Alzheimer's disease, mood & autistic disorders. They also have the potential to develop new tools to further understanding of brain disorders.