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Dynamic Neuropathology of Cerebral Injury

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Presentation on theme: "Dynamic Neuropathology of Cerebral Injury"— Presentation transcript:

1 Dynamic Neuropathology of Cerebral Injury

2 Cerebral Energy A continuous supply of energy is important for maintaining several aspect of brain functioning, including: membrane potentials and electrochemical gradients; neurochemical processes responsible for synaptic transmission; and integrity of intracellular structures and membranes. Energy is produced in the brain almost entirely from oxidative metabolism of glucose. Oxidative metabolism of glucose yields energy in the form of phosphate bonds, the most important of which is ATP (adenosine triphosphate).

3 Cerebral Energy Under conditions of aerobic metabolism, not only is ATP produced, but CO2 is a resulting metabolite that facilitates vasodilation of cerebral vessels and increases cerebral blood flow. The energy status of any part of the brain is reflected by its content of ATP which demands more O2. Thus, increasing function results in increasing O2 requirements, while decreasing function reduces O2 demands. The brain can only store O2 for a few seconds and cannot store glucose.

4 Cerebral Energy Therefore, an incessant supply of both glucose and O2 is essential for the continuing function of the brain. If the energy supply fails completely, rapid and dramatic events occur. After a few seconds neuronal function fails; After a few minutes, permanent structural damage occurs.

5 Hypoxemia Hypoxemia is an abnormal deficiency of O2 in the arterial blood. Hypoxemia can result from a variety of pulmonary conditions, such as chronic obstructive pulmonary disease (COPD), in which an inadequate amount of O2 makes it into the arterial blood. With inadequate arterial O2, the brain experiences a consequent inadequate level of cellular O2, a condition known as hypoxia.

6 Hypoxemia With hypoxia at the cellular level of the brain, glucose can only be metabolized by less efficient anaerobic means. Anaerobic metabolism of glucose produces less ATP as well as metabolites other than CO2. Glucose only partially oxidized results in lactic acid, which accumulates in the blood and reduces the cell’s electron transport system. Lysosomes within the neuron cell bodies are sensitive to decreases in O2.

7 Ischemia Ischemia refers to a reduced blood supply to the brain that deprives the neuronal tissue not only of O2 but of glucose as well. The effects of low O2 have been discussed (anaerobic metabolism), but low glucose levels (hypoglycemia) can contribute to mental confusion, dizziness, convulsions, and loss of consciousness. Tissue ischemia can damage the blood-brain barrier— the special mechanism that permits differential passage of certain materials from the blood into most parts of the brain.

8 Ischemia This may result in brain edema and a rise in intracranial pressure (ICP). Ischemia may also cause a rapid depletion of ATP, paralyzing the membrane transport system, and allowing accumulation of toxic molecules. Increased tissue toxicity can also disrupt the blood-brain barrier, causing the capillary lumens to swell shut, further compounding tissue ischemia.

9 Cerebral Blood Flow Blood flow, or perfusion, refers to the amount of blood that passes through a blood vessel in a given period of time. Blood flow is determined by (1) blood pressure and (2) resistance, the force of friction as the blood travels through blood vessels. The flow of blood through the vessels of the circulatory system is a function of the pressure in the system and the resistance to flow caused by the blood vessels.

10 Cerebral Blood Flow Blood flow is directly proportional to pressure and inversely proportional to resistance. If the pressure in a vessel increases then the blood flow will increase. However, if the resistance in a vessel increases then the blood flow will decrease. Resistance in the blood vessels is effected by three parameters: Length of the vessel-the longer the vessel the greater the resistance. Viscosity of the blood-the greater the viscosity the greater the resistance. Radius of the vessel--the smaller the radius the greater the resistance.

11 Cerebral Blood Flow Dehydration causes increased blood viscosity.
If viscosity increases, blood pressure must increase to maintain flow. Decreased plasma protein levels or decreased red blood count due to anemia or hemorrhage contributes to decreased viscosity. This "thin" blood flows more easily, so blood pressure can drop and still deliver the same flow of blood to tissues. Of all of the factors that affect blood flow, the radius of the blood vessel is the most potent.

12 Cerebral Blood Flow If the radius of a blood vessel doubles (by vasodilation) then the flow will increase 16 fold. If, however, the radius of a vessel is reduce in half (by vasoconstriction), then the blood flow will be reduced 16 fold. Because small changes in vessel radius make very large changes in blood flow, it is no surprise that the body controls blood flow to specific areas of the body by controlling the radius of arterioles servicing those areas.

13 Cerebral Blood Flow The level of blood flow throughout the brain is carefully regulated to the metabolic needs of different parts of the brain. Although the brain receives about 15% of the heart’s total output, or about 800 ml/min of blood, the level of flow through the grey matter is much greater than that of the white matter. The difference in the level of flow reflects the greater metabolic activity and greater vascularity of the grey matter.

14 Cerebral Blood Flow Moreover, the level of flow also varies between different parts of the cerebral cortex, depending upon functional demands. Chemoreceptors in the arterial walls cause the vessels to constrict or dilate in response to changes in gas levels. If PaO2 falls below 50 mm Hg, a distinct increase in cerebral blood flow takes place. If PaO2 falls to 30 mm Hg, cerebral blood flow is more than doubled. Raising PaO2 above 100 mm Hg causes only slight changes in cerebral blood flow.

15 Cerebral Blood Flow CO2 is a very potent stimulus of cerebral vasodilation as well, so variations in PaCO2 can cause profound changes in cerebral blood flow. Cerebral blood flow doubles when PaCO2 is increased from 40 to 80 mm Hg. Cerebral blood flow is halved when PaCO2 drops to 20 mm Hg. Below 20 mm Hg, PaCO2 has very little effect on cerebral blood flow. The flow is probably so low because of tissue hypoxia.

16 Cerebral Blood Flow In a variety of pathological situations, the response of cerebral blood flow circulation to either changes in PaO2 or PaCO2 levels may be profoundly altered. When there is a focal disorder, cerebral blood flow may fail to increase during low O2. Indeed, blood flow may be increased to the surrounding normal area at the expense of the fall in flow in the affected area. This is referred to as “steal,” where the normal surrounding areas of the brain are “hyperperfused” while the area in which there is some focal damage is actually “hypoperfused.”

17 Pressure Regulation Blood pressure is controlled on a minute-to-minute basis by baroreceptor reflexes. Baroreceptors, located in the walls of arteries, veins, and the heart, are specialized stretch receptors that detect changes in blood pressure. They constantly monitor blood pressure and communicate with the cardiovascular control center (CCC) found in the medulla. The most important baroreceptors are found in the carotid sinus and the aorta.

18 Pressure Regulation Changes in blood pressure affect the frequency of action potentials sent to the CCC from the baroreceptors. The CCC responds to changes in baroreceptor input by initiating compensatory mechanisms that restore blood pressure back to normal. An increase in blood pressure causes an increase in action potentials sent to the CCC. The CCC responds by decreasing sympathetic input to the blood vessels. This results in vasodilation and lowered resistance which causes blood pressure to drop and return to normal.

19 Pressure Regulation Conversely, a decrease in blood pressure causes a decrease in action potentials sent to the CCC. The CCC responds by increasing sympathetic input to the blood vessels. This results in vasoconstriction and increased cardiac output, which causes a rise in blood pressure, thus restoring blood pressure back to normal. In addition to changes in the systemic blood pressure, blood flow in a particular area of the body, such as the brain, can also be regulated.

20 Pressure Regulation The brain’s mechanism for maintaining a constant flow of blood despite wide changes in arterial pressure is referred to as autoregulation. Physical changes such as warming or cooling a particular body part will cause changes in blood flow—warming causes vasodilation, cooling causes vasoconstriction. Chemical changes such as low O2 levels, high CO2 levels, or stretch of tissue can cause cells in the area to release chemicals called vasoactive factors and these influence the diameter of blood vessels just in the affected area.

21 Pressure Regulation However, any factor which alters the ability of the cerebral vessels to constrict or dilate interferes with the autoregulator. The autoregulator can be impaired or even abolished by a wide variety of insults, such as ischemia, hypoxia, hypercapnia (CO2), and brain trauma. At arterial systolic (top) pressures below 60 mm Hg, as in the case of hemorrhage, vasoconstriction still occurs but the mechanism is no longer sufficient to prevent blood flow from falling.

22 Pressure Regulation When arterial pressure and blood flow decrease beyond a certain point, the perfusion of the brain becomes critically decreased (i.e., the blood supply is not sufficient), causing lightheadedness, dizziness, weakness or fainting. At acute extreme rises in diastolic (bottom) blood pressure over 160 mm Hg, vasodilation fails and instead vasoconstriction occurs which increases cerebral blood flow and resistance. All levels of arterial pressure put mechanical stress on the arterial walls.

23 Pressure Regulation The higher the pressure, the more stress that is present and the more likely that atheroma—a mass or plaque of degenerated thickened arterial intima—will form within the walls of the arteries. Initially the atheroma contributes to a thickening of the inner lumen, but over time, the arterial lumen weakens and the vessels become distended. In the areas of vessel distension, there may be breakdown of the blood-brain barrier with foci of cerebral edema.

24 Reduced Blood Flow When cerebral blood flow is reduced, a progressive sequence of events can be demonstrated. Initially, electrical function and metabolism continue but impaired. From impairment of function follows complete failure of electrical activity. At certain “critical” reductions in blood flow, loss of cell homeostasis occurs. When blood flow is reduced to about 30-35% of normal values, responses to somatosensory information and cortical directives fail.

25 Reduced Blood Flow Cell death becomes inevitable only at even lower levels of blood flow. At least in the short term, ischemic neurological dysfunction can be reversed by restoring blood flow.

26 Intracranial Pressure
There are four intracranial constituents contained within the noncompliant skull. These are the brain (neurons and neuroglia), cerebrospinal fluid (CSF), cerebral blood, and extracellular fluid. Glial and neural tissues account for about 70% of intracranial contents. CSF, cerebral blood, and extracellular fluid each account for another 10% of the total volume. Increased intracranial pressure (ICP) results from an addition to the volume of these intracranial constituents in excess of compensatory capacity.

27 Intracranial Pressure
CSF may be squeezed from the cranial subarachnoid space and ventricles into the spinal subarachnoid space. Cerebral venous blood may be expelled into the jugular veins or into the scalp via emissary veins. However, past these compensatory mechanisms, any increase in blood (e.g., hematoma), extracellular fluid (e.g., edema), brain tissue (e.g., tumor), or CSF (e.g., hydrocephalus) may induce an increase in ICP. The brain can handle some changes in ICP without affecting cerebral blood flow if the autoregulator is not impaired.

28 Intracranial Pressure
However, if the autoregulator is impaired because of some pathological condition (see slide 21), much smaller increases in ICP can be tolerated before the sufficient reduction in cerebral blood flow may produce neurological dysfunction. In multiple trauma, hypotension from other organ injuries may further narrow the difference between mean arterial pressure and ICP. In other words, since raised ICP is common in brain trauma and since trauma impairs the autoregulator, it should not be surprising that ischemic brain damage is also found.

29 Brain and Water Edema The brain has a high water content: 80% in grey matter and 70% in white matter, where the fat content is higher. The majority of brain water is intracellular, but extracellular fluid volume makes up as much as 10% of the intracranial space. Brain water is derived from the blood and ultimately returns to it by reentry at the venous ends of the capillaries. Relatively little brain water passes through the CSF, but this route may be more important when edema is present.

30 Brain and Water Edema Edema refers to an increase in tissue fluid content that results in increased tissue volume. Two different forms of cerebral edema are recognized: vasogenic and cytotoxic edema. Vasogenic edema is the most common cause of brain edema and results from disruption of the blood-brain barrier. Fluid is allowed to flow out of the cerebral vessels into the extracellular space. In other words, the origin or genesis of the edema is in the vessel (vaso). This form of edema largely affects the white matter and is the most common kind of edema encountered after HI.

31 Brain and Water Edema Cytotoxic edema, on the other hand, is intracellular swelling of neurons and glia in grey matter, with a concomitant reduction of brain extracellular space. It occurs in hypoxia, after cardiac arrest, or asphyxia because the ATP dependent sodium-potassium pump allows sodium and water to accumulate within the cells. In other words, the cell (cyto) becomes toxic from the accumulation of sodium and water within the cell.

32 Morphological and Neurochemical Changes
The most characteristic morphological change in the brains of persons with Alzheimer’s disease is the formation of neurofibrillary tangles. Neurofibrillary tangles (NFTs) are an intracellular abnormality, involving the cytoplasm of nerve cells. They consist of paired filaments twisted around one another in a helical fashion that course throughout the cytoplasm.

33 Neurofibrillary Tangles
In Alzheimer's disease, NFTs are generally found in the neurons of the cerebral cortex and are most common in the temporal lobe structures, such as the hippocampus and amygdala. Spared cortical areas are seen in dark blue.

34 Neuritic Plaques Neuritic or senile plaques are extracellular abnormalities. They consist of a dense central core of amyloid, surrounded by a halo and a ring of abnormal neurites (degenerated axon terminals and preterminals). They are found in the same brain centers as NFTs, especially in the outer half the cortex where the number of neuronal connections is greatest.

35 Neuritic Plaques & Neurofibrillary Tangles
This stain shows NFTs (in black) and neuritic (senile) plaques (in brown). Neurons containing NFTs eventually die.

36 Granulovacular Degeneration (GVD)
GVD is a descriptive term that refers to the presence of fluid-filled space and granular debris within nerve cells. Like NFTs and neuritic plaques, GVD has a predilection for the hippocampal formation, and are significantly related to the presence of dementia

37 Lewy Bodies Lewy bodies are structures located within the cytoplasm of neurons that characteristically have a circular and dense protein core surrounded by a peripheral halo. They have often been likened to a sunflower--a dense central core of circular shaped structures with a rim of radiating filaments.

38 Lewy Bodies F. H. Lewy first described Lewy bodies in 1912.
They are distinctive neuronal inclusions, thought to be the result of altered neurofilament metabolism and/or transport due to neuronal damage and subsequent degeneration, causing an accumulation of altered cytoskeletal elements. Lewy bodies with the circular and dense protein core surrounded by a peripheral halo are usually found in brainstem locations, such as the substantia nigra and the locus ceruleus, and may appear singlely or multiply within a neuron. In other locations, such as the cerebral cortex, they are often more elongated, and usually lack the peripheral halo around the central core.

39 Lewy Bodies They were first linked to idiopathic Parkinson's disease.
More recently it has been noted that Lewy bodies may be seen in several different neurodegenerative processes, including diffuse Lewy body disease, Alzheimer's disease, and idiopathic Parkinson's disease.

40 Pick’s Bodies (PBs) Ultrastructurally, Pick bodies consist mostly of bundles of disorganized straight filaments, which may be mixed with coiled fibrils. PBs are homogeneous and smooth-edged, and the large majority are round or ovoid, although some are occasionally flame-shaped. Some authorities believe Pick cells represent deafferented neurons.

41 Pick’s Bodies In Pick’s disease, there is extensive neuron loss and gliosis concentrated in the outer third of the cerebral cortex. The frontal and temporal lobes are most affected with brain cells in these areas found to be abnormal and swollen. The neurons have distended cytoplasm called “ballooned cells or “Pick cells.”

42 Pick’s Bodies When these typical features are not seen on post mortem examination but the same areas of the brain are affected by cell death, the case may be described as Pick’s syndrome or frontotemporal dementia.

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