Liang Katharine J, Carlson Erik S
University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences, Seattle, WA, United States.
University of Washington School of Medicine, Seattle, WA, United States.
Neurobiol Learn Mem. 2020 Apr;170:106981. doi: 10.1016/j.nlm.2019.01.004. Epub 2019 Jan 7.
In the context of neurodegeneration and aging, the cerebellum is an enigma. Genetic markers of cellular aging in cerebellum accumulate more slowly than in the rest of the brain, and it generates unknown factors that may slow or even reverse neurodegenerative pathology in animal models of Alzheimer's Disease (AD). Cerebellum shows increased activity in early AD and Parkinson's disease (PD), suggesting a compensatory function that may mitigate early symptoms of neurodegenerative pathophysiology. Perhaps most notably, different parts of the brain accumulate neuropathological markers of AD in a recognized progression and generally, cerebellum is the last brain region to do so. Taken together, these data suggest that cerebellum may be resistant to certain neurodegenerative mechanisms. On the other hand, in some contexts of accelerated neurodegeneration, such as that seen in chronic traumatic encephalopathy (CTE) following repeated traumatic brain injury (TBI), the cerebellum appears to be one of the most susceptible brain regions to injury and one of the first to exhibit signs of pathology. Cerebellar pathology in neurodegenerative disorders is strongly associated with cognitive dysfunction. In neurodegenerative or neurological disorders associated with cerebellar pathology, such as spinocerebellar ataxia, cerebellar cortical atrophy, and essential tremor, rates of cognitive dysfunction, dementia and neuropsychiatric symptoms increase. When the cerebellum shows AD pathology, such as in familial AD, it is associated with earlier onset and greater severity of disease. These data suggest that when neurodegenerative processes are active in the cerebellum, it may contribute to pathological behavioral outcomes. The cerebellum is well known for comparing internal representations of information with observed outcomes and providing real-time feedback to cortical regions, a critical function that is disturbed in neuropsychiatric disorders such as intellectual disability, schizophrenia, dementia, and autism, and required for cognitive domains such as working memory. While cerebellum has reciprocal connections with non-motor brain regions and likely plays a role in complex, goal-directed behaviors, it has proven difficult to establish what it does mechanistically to modulate these behaviors. Due to this lack of understanding, it's not surprising to see the cerebellum reflexively dismissed or even ignored in basic and translational neuropsychiatric literature. The overarching goals of this review are to answer the following questions from primary literature: When the cerebellum is affected by pathology, is it associated with decreased cognitive function? When it is intact, does it play a compensatory or protective role in maintaining cognitive function? Are there theoretical frameworks for understanding the role of cerebellum in cognition, and perhaps, illnesses characterized by cognitive dysfunction? Understanding the role of the cognitive cerebellum in neurodegenerative diseases has the potential to offer insight into origins of cognitive deficits in other neuropsychiatric disorders, which are often underappreciated, poorly understood, and not often treated.
在神经退行性变和衰老的背景下，小脑是一个谜。小脑中细胞衰老的遗传标记积累速度比大脑其他部位慢，并且它会产生一些未知因素，这些因素可能会减缓甚至逆转阿尔茨海默病（AD）动物模型中的神经退行性病理变化。在早期AD和帕金森病（PD）中，小脑的活动增加，这表明其具有一种补偿功能，可能会减轻神经退行性病理生理学的早期症状。也许最值得注意的是，大脑的不同部位会按照公认的进程积累AD的神经病理标记，一般来说，小脑是最后一个出现这种情况的脑区。综合这些数据表明，小脑可能对某些神经退行性机制具有抗性。另一方面，在一些神经退行性变加速的情况下，比如在反复创伤性脑损伤（TBI）后的慢性创伤性脑病（CTE）中，小脑似乎是最易受损伤的脑区之一，也是最早出现病理迹象的脑区之一。神经退行性疾病中的小脑病理与认知功能障碍密切相关。在与小脑病理相关的神经退行性或神经系统疾病中，如脊髓小脑共济失调、小脑皮质萎缩和特发性震颤，认知功能障碍、痴呆和神经精神症状的发生率会增加。当小脑出现AD病理变化时，比如在家族性AD中，它与疾病的更早发病和更严重程度相关。这些数据表明，当神经退行性过程在小脑中活跃时，它可能会导致病理性行为结果。小脑以将信息的内部表征与观察到的结果进行比较并向皮质区域提供实时反馈而闻名，这一关键功能在诸如智力障碍、精神分裂症、痴呆和自闭症等神经精神疾病中受到干扰，并且是工作记忆等认知领域所必需的。虽然小脑与非运动脑区有相互连接，并且可能在复杂的目标导向行为中发挥作用，但事实证明，很难确定它在调节这些行为时的具体机制。由于缺乏这种理解，在基础和转化神经精神医学文献中，小脑被本能地忽视甚至忽略也就不足为奇了。本综述的总体目标是根据原始文献回答以下问题：当小脑受到病理影响时，它是否与认知功能下降有关？当它完好无损时，它在维持认知功能方面是否发挥补偿或保护作用？是否存在理解小脑在认知以及或许在以认知功能障碍为特征的疾病中作用的理论框架？了解认知性小脑在神经退行性疾病中的作用有可能为深入了解其他神经精神疾病中认知缺陷的起源提供线索，而这些疾病往往未得到充分重视、理解不足且治疗较少。
