《基础医学各论3》资料：CNS病理生理

1、Brain dysfunction脑功能障碍,Zhihua Gao Neuroscience Institute,Outline,Biology of the brain Cognitive disorders认知功能障碍 Conscious disorders Summary,4,Biology of the brain,inside the skull skull provides protection but confines the brain,Basics on human adult brain: Weight: 3 pounds Size: a medium cauliflowe

2、r,Brain nutrition,Blood supply from twin vertebral arteries (椎底动脉) and carotis internal artery (颈内动脉) provides the brain nutrition.,However, nutrients have to pass through the blood brain barrier (血脑屏障) to get into the brain.,Blood brain barrier (血脑屏障),BBB consists of: tight junctions around the cap

3、illaries endothelial cells a thick basement membrane astrocyte endfeets,7,Blood brain barrier (BBB) provides a selective filter for the brain,BBB allows essential metabolites, e.g. oxygen and glucose to diffuse from the blood to the brain, but blocks most molecules (500 Dalton).,Protects the brain f

4、rom foreign pathogens, e.g. viruses and bacteria Shields the brain from hormones and neurotransmitters Maintains brain homeostasis,8,Brain metabolism,Brain is the most active organ in energy metabolism (high demand for blood and oxygen supply). Glucose is the primary energy source for brain; however

5、, the storage of glucose in the brain is very limited.,Take home message:Brain is highly sensitive to hypoxia and ischemia.,9,Brain components,100 billions of neurons: They are executors of brain function. 1000 billions of glial cells: They are supporters and sponsors.,Neurons and glial cells form a

6、 complex network to ensure normal brain function.,Cell communication in the brain,Functional unit in the brain-synapse,11,Electrical current travels down the axon. Vesicles move towards and fuse into the membrane. Chemicals are released, diffusing into the cleft. The chemicals bind to the receptor o

7、n the neighbour cell, opens up channels and relays the signal.,Pre-synaptic membrane,Post-synaptic membrane,Synaptic transmission,12,Brain function,Central control of the human body Maintain cognition Maintain consciousness,Lesion size correlates with symptoms. Diffusive or localized lesion? In gene

8、ral, the degree of dysfunction is in proportion to the extent of the damage and the size of the lesion area. However, there is a region-dependent consequence to brain injuries. When the injury occurs in the brain stem, a small damage can cause complete loss of consciousness and even death.,Brain les

9、ions: some principles,Location determines the symptom Cerebral cortex damage: cognitive or conscious disorder Brain stem damage: conscious disorder Phase determines the symptom Acute: conscious disorder Chronic： cognitive disorder Brain has very limited capacity for self-repair-neurons do not regene

10、rate.,Brain lesions: some principles,15,Brain responses to lesions,Cellular level: Cell death of neurons Degeneration of axons/dendrites Inflammation triggered by microglia, astrocytes Demyelination of oligodentrocytes Systemic level: Cognitive disorder (认知障碍) Conscious disorder (意识障碍),16,Outline,Bi

11、ology of the brain Cognitive disorder (认知障碍) Conscious disorder (意识障碍) Summary,17,Cognition and cognitive disorder,Cognition-the process of the brain to sense, handle and acquire information Involves a series of voluntary psychological and social behaviors, such as study, memory, thinking, judgment

12、and emotion. Relies on the normal function of the cerebral cortex. Cognitive disorders-the disturbance of the process related to cognition. usually caused by damages in the cerebral cortex.,Structural Basis of Cognition,Brodmann Mapping (52 areas),Cerebral cortex,Structural Basis of Cognition,Cognit

13、ive disorder,Major manifestations of cognitive disorder,Learning and memory defects Aphasia (失语) Hemiplegia (偏瘫) Agraphia (失写) Apraxia (失用) Alexia (失读) Agnosia (失认) Dementia (痴呆),Frontal lobe,Controls voluntary movement, memory, writing, thinking, creative thoughts, judgment, understanding and socia

14、l responsibility and personal morals. When damaged: Loss of simple movement Loss of flexibility in thinking Changes in social behavior Changes in personality Inability to express language,23,When frontal lobe is damaged: Hemiplegia (偏瘫): paralysis of one side of the body Aphasia (失语): partial or tot

15、al loss of the ability to communicate verbally or using written words Brocas aphasia: inability to express language (areas 44&45) Agraphia (失写): A form of aphasia characterized by loss of the ability to write. Dementia (痴呆): loss of mental ability that interferes with normal activities of daily livi

16、ng ( 6 months), without a loss or alteration of consciousness.,24,Processes and discriminates between different sensory inputs When damaged: Agraphia (失写): inability to locate the words for writing Alexia (失读): Problems with reading Agnosia (失认): Inability to recognize objects Contralateral sensory

17、deficits,Parietal lobe,25,Is involved in processing sensory (auditory and visual) input, language comprehension and new memories When damaged Wernickes aphasia (感觉性失语) (area 22， can speak, but meaningless) Spatial or emotional memory impairment caused by hippocampal lesion (空间与情感记忆障碍),Temporal lobe,

18、Differential diagnosis (DD),Brocas vs Wernickies aphasia,Aphasia is a disturbance of the comprehension and formulation of language caused by dysfunction in specific brain regions. This class of language disorder ranges from having difficulty remembering words to losing the ability to speak, read, or

19、 write. This also affects visual language such as sign language. Wiki definition,Brocas aphrasia:expressive aphrasia (运动性失语) loss of the ability to produce language (spoken or written) Wernickies aphrasia: receptive aphrasia (感觉性失语) inability to comprehend language or speak with appropriately meanin

20、gful words,27,Visual sensing and processing Lesions in the primary visual cortex result in defects in visual fields. Lesions in the visual association cortex result in loss of objective recognition and of distinguishing the differences between animals cat or dog? Deer or horse?,Occipital lobe,28,Eti

21、ology and Pathogenesis,Chronic brain damage Chronic systemic diseases Mental and psychic disorder Other factors,Pathogenesis of cognitive disorder,Pathogenic factors,Changes in neurotransmitters, receptors, neuropeptides and neurotrophic factors,Genetic abnormalities,Chronic viral infection,Chronic

22、ischemia,Metabolic abnormalities,Protein aggregation,Abnormal protein modifications,Reduced ATP production, acidosis, elevation of calcium, free radicals and inflammatory factors,Chronic brain damage,brain dysfunction,Cognitive disorder,30,Chronic Brain Damage,Alterations in regulatory molecules Abe

23、rrant protein aggregation Chronic cerebral ischemic injury Environmental and metabolic toxins Cerebral trauma Brain aging,Alterations in regulatory molecules,Abnormal levels in Neurotransmitters and receptors Dopamine Norepinephrine Acetylcholine (Ach) Glutamate Neuropeptides Neurotrophic factors,Do

24、pamine Pathway,Dopamine,Distribution：Dopamine pathway,Parkinson Disease,Abnormal protein aggregation,Generally seen in a range of neurodegenerative diseases, e.g. Alzheimers disease, Parkinsons disease, Huntingtons disease, Prion disease Caused by Gene mutations Abnormal post-translational modificat

25、ions Infection of prion protein in the brain,Cleaved to generate N-terminal polyQ fragments Aggregates form in cytoplasm and in nucleus-amyloid-like conformation Controversy over whether aggregates are toxic or protective Gain of toxic function and/or loss of protective function,Q,Q,Q,Q,Q,Q,Q,Q,Q,Mu

26、tant Huntingtin in Huntingtons disease,Q,Q,Q,Q,Q,Q,Q,Q,Q,Mutant a-synuclein in Parkinsons disease,Alzheimers Disease,Alzheimers Disease,Gradual memory loss Decline in the ability to perform routine tasks Disorientation Difficulty in learning Loss of language skills Impairment of judgment and plannin

27、g Personality changes,Senile plaques,Neurofibrillary tangles,Chronic Cerebral Ischemic Injury,Brain has low energy reserve. Brain is highly sensitive to ischemia and hypoxia. Neurons die upon complete ischemia for 5 min. Ischemia causes cognitive disorder likely by the following mechanisms: Energy e

28、xhaustion and acidosis Intracellular calcium overload Free radical injury Excitatory toxicity Cytokines induced inflammatory reactions,Excitatory toxicity,Deficits in energy production, caused by ischemia and hypoxia, inhibits the activity of the Na+-K+-ATPase in plasma membrane, resulting in substa

29、ntial elevation of extracellular K+ , depolarization of neurons, accompanied by overdosed release of EAA (excitatory amino acids). This leads to the over activation of EAA receptors and neuronal over excitement and death. EAA: glutamate and aspartate IAA: GABA and glycine,Principles for Treatment of

30、 Cognitive Disorders,General neuroprotective treatments Restore and maintain the normal levels of neurotransmitters and regulatory molecules Surgery,Case studies of cognitive disorder,Phineas Gage (18231860),Henry Molaison (1926-2008),Phineas Gage- a case of frontal lobe damage,Left frontal lobe dam

31、age caused by a mental rod intrusion,He survived after the trauma but his personality had a dramatic change afterwords.,47,Learning and memory defects,Henry Molaison (HM) Patient,An epileptic patient,48,HMs lesion includes medial temporal lope structures in addition to hippocampus (amygdala, entorhi

32、nal cortex),Surgery removal of the temporal lobe,49,HMs meomory defects,The surgery had a profound effect on declarative memory Severe anterograde amnesia (非常严重的顺行性健忘) Moderate retrograde amnesia (轻微的逆行性健忘) Intact short memory (完好的瞬时记忆) unable to commit new short-term memory into long-term memory Bu

33、t there was no effect on: Personality Attention Intelligence (normal IQ) Motor skill learning,Outline,Biology of the brain Cognitive disorders Conscious disorders Summary,51,Consciousness and conscious disorder,Consciousness refers to individual awareness of self thoughts, memories, feelings, sensat

34、ions and environment Two aspects: State of arousal (by subcortical regions) Responsiveness (controlled by cortex) Conscious disorder refers to the impairments in maintaining awareness of self and environment and responding to environmental stimuli,Structural Basis for Consciousness,cerebral cortex,B

35、rain stem reticular formation,thalamus,Brain stem reticular formation,上行激动系统(ARAS) 上行抑制系统(ARIS) ARAS的投射纤维终止于大脑皮层广泛区域 主要维持大脑皮层兴奋性，维持觉醒状态和产生意识活动 ARIS发出的上行纤维行走于ARAS大体一致 主要对大脑皮层兴奋性起抑制作用,Hypothalamus,由多个核团组成 特异性核团: 向大脑皮层传递各种特异性感觉信息 非特异性核团: 接受脑干 网状结构上行纤维并向 大脑皮层广泛部位投射， 参与维持大脑皮层觉醒状态 损害可致长期昏睡。,Major manifest

36、ations of conscious disorder,Delirium,Confusion,Stupor,Coma,谵妄,精神错乱,昏睡,昏迷,Delirium：意识内容异常为主的急性精神失常状态 常有睡眠-觉醒周期紊乱及错觉、幻觉、兴奋性增高为主的精神运动性改变等。 Confusion：觉醒与意识内容均出现异常，一种似睡似醒的状态，常伴有睡眠-觉醒周期颠倒。 Stupor：觉醒状态与意识内容均降至最低水平，强烈疼痛刺激可出现睁眼、眼球活动等反应，但很快又陷入昏睡状态，病人几乎无随意运动，但腱反射尚存。 Coma：觉醒状态、意识内容随意运动持续丧失（6h）或完全丧失的严重意识障碍。可出现病理反射，强烈疼痛刺激可引出简单的防御性肢体运动，但不能觉醒。,Etiology and Pa