Figure 6-1
Pathway of cerebral ischemia
Reduction in blood flow:
Cerebral ischemia develops when CBF is reduced to <22 ml/100 g/min
<10 ml/100 g/min leads to infarct
Energy failure:
Diminished CBF leads to metabolic stress and depletion of energy stores (ATP, phosphocreatine)
Leads to breakdown of ion gradients, lipolysis, proteolysis, lactic acidosis in infarct core, accumulation of oxygen free radicals
Cell membrane depolarization and Na+/K+ pump dysfunction
Large Na, Cl influx leads to passive water influx into cell leads to development of cytotoxic edema
Cell membranes are unable to counteract cell swelling due to pump failure
Increased signal can be seen on early MRI scans representing restricted diffusion of water due to edema
Increased efflux of intracellular K
Increased release of Glu from presynaptic terminals into synaptic cleft and failure of Glu re-uptake from synaptic cleft (concentrations increased 150x)
Glu → Excessive stimulation of NMDA receptors → excessive Ca++ influx
Glu → ++inward fluxes of Na + and Ca++ → cell swelling
Increased intracellular calcium activates phospholipases and proteases (matrix metalloproteinases), degrading basal lamina, leading to BBB breakdown and triggering excitotoxic cell death
Cell Death
Occurs either via necrosis or apoptosis
Necrosis : cell death when energy stores (ATP) are depleted
More often found at infarct core due to lower ATP levels compared to periphery (or penumbra)
Causes cell swelling and rupture of membranes, leading to cellular material being deposited into surrounding environment, triggering an inflammatory cascade
Apoptosis : regulated, energy-dependent, programmed cell death, usually occurs in periphery (where ATP levels are higher)
Occurs by increased mitochondrial permeability, “death receptor” Fas pathway, systematic cellular degradation and phagocytosis
The longer the duration of ischemia, the higher the likelihood of cell death by neuronal necrosis than apoptosis
Excessive amounts of zinc released from excitatory neurons also contributes to cell death
Cortical spreading depression
Cells at core of lesion remain depolarized and can propagate sustained waves of depressed electrical activity (cortical spreading depression) in nearby tissue
Leads to further release of glutamate → excitotoxicity
Cerebral Autoregulation
Mechanism of responding to changes in cerebral perfusion pressure (CPP) by altering vascular tone, with a goal of maintaining a consistent level of CBF (Fig. 6-2)
Figure 6-2
Cerebral autoregulation
Low BP (low CPP) → vasodilation
High BP (high CPP) → vasoconstriction
Cerebral Perfusion Pressure (CPP): An estimate of mean arterial pressure (MAP) under normal intracranial pressure (ICP) conditions
CPP = MAP – ICP
Normal range is 50–150 mmHg in nonhypertensive person
Mean Arterial Pressure (MAP): an estimate of cerebral perfusion pressure
Increased MAP → vasoconstriction and increased vascular resistance to maintain CBF over a wide range
When MAP is beyond the upper limit of autoregulation , this leads to increased vessel permeability → forced dilation, autoregulatory breakthrough
Hypertensive encephalopathy, hemorrhage, cerebral edema, raised intracranial pressure (ICP)
When MAP falls below the lower limit of autoregulation , this leads to impaired dilation and arterial collapse
Cerebral Blood Flow (CBF ): Rate of blood flow through brain parenchyma at a given time
CBF = Cerebral Blood Volume (CBV )/Mean Transit Time (MTT )
CBF rates (in ml/100g/min):
As CBF decreases, oxygen extraction increases to maintain normal metabolic rate
50–55 ml/100 g/min: normal CBF
35–25 ml/100 g/min: oligemia, protein synthesis decreased, glycolysis increasedRelated posts:
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