L24-26: CNS Flashcards
1
Q
Brain requires what percentage of cardiac output?
A
20%
2
Q
Spinal injuries
A
C1-C2 - loss of involuntary function-breathing
Cervical region - quadraplegia
Thoracic nerves - paraplegia
3
Q
CSF is produced by
A
choroid plexus of ventricle cavities
4
Q
CSF flows through which layer of membrane
A
Arachnoid mater
5
Q
Flow of CSF
A
CSF enters subarachnoid space, flows between meningeal layers of brains and spinal cord, reabsorbed into the blood
6
Q
CSF functions
A
Shock-absorbing to prevent brain from bumping against
the skull
Contributes to the composition of interstitial fluid
7
Q
Blood brain barrier
A
Highly specialised brain endothelial structure of the fully differentiated neurovascular system which separates components of blood from neurones
Maintains chemical composition of interstitial space by limiting entry of plasma components, RBC and leukocytes
Regulated active transport of ions and carrier mediated
transport of glucose and amino acids
8
Q
Pericytes
A
Adjacent to endothelial cells, share common basement
membrane
Contribute to microvascular stability
Release growth factors + angiogenic molecules
Microvascular permeability, remodelling, angiogenesis
Smooth muscle cell lineage
Contractile – regulate blood flow
9
Q
Blood brain barrier allows diffusion of
A
small lipid soluble molecules (400Da)
10
Q
Grey matter contains
A
Cell bodies and dendrites
Glia
Blood vessels
11
Q
White matter contains
A
Myelinated axons
Glia
Blood vessels
12
Q
Glial cells
A
Oligodendrocytes (myelin forming) Astrocytes (homeostasis) Microglia (immune surveillance), Ependymal cells (lining of ventricles and central canal) Adult progenitor cells
13
Q
Glia: oligodendrocyte function
A
synthesises myelin
14
Q
1 oligodendrocyte myelinates how many axons?
A
4-40 depending on axon size and position
15
Q
Function of myelin
A
- Enables saltatory conduction - node to node
- Acts as insulator, reduces current leakage across internodal axonal membrane
- Increases conduction velocity
- Miniaturisation of nervous system - large fibre
diameter, high conduction velocity
Saves space, metabolic and synthetic energy
Very metabolically active - eg. proteins continually
phosphorylating
16
Q
Glia: Astrocytes
A
Support and maintain the CNS
Two major types:
1. Protoplasmic (grey matter) - processes spread radially
2. Fibrous (white matter) - arranged in rows between axon bundles, send processes to nodes of adjacent myelinated axons
17
Q
Astrocytes endfeet
A
Endfeet – at the end of processes-
- Contact blood vessels
- Interact with ependymal cells (CSF-brain barrier)
- Associated with the Node of Ranvier
- Ensheath synapses
- Associated with nerve cell bodies
- Communicate with other astrocytes
- Communicate with oligodendrocytes and microglia
18
Q
Astrocytes and homeostasis
A
- CNS development: neuronal path finding oligodendrocyte maturation (growth factors)
- Maintenance of environment at the synapse (removal and recycling of neurotransmitters)
- Synthesis of precursors for transmitters (glutamate and GABA)
- Maintenance of the environment at the Node of Ranvier
- Supply of energy to neurons
- Brain water homeostasis
- Maintenance of blood brain barrier integrity (glia limitans)
- Regulation of extracellular pH
- Modulation of synaptogenesis/synaptic activity
- Regulation/modulation of neurogenesis
- Modulation of post-injury repair
- Modulation of memory formation
19
Q
Glia: microglia
A
Resident macrophages
- 10 - 20% glial cell population
- From mesoderm - mononuclear phagocyte precursors
- Enter brain during early development, before the formation of the blood brain barrier
- Distributed equally in grey and white matter - but there are regional differences, reason/mechanism not known
- In adult brain - low turnover, down-regulated phenotype
20
Q
Microglia function
A
- Homeostasis, first-line of defence against viruses, bacteria, parasitic CNS infections
- Present at the blood brain barrier
- Remove debris
21
Q
4 different phenotypes of microglia
A
- Ameboid microglia – during development & perinatal period
- Ramified, under normal conditions - in mature CNS
- Reactive, non-phagocytic microglia - sublethal injury
- Phagocytic microglia
22
Q
Acute neuronal injury sequence of events
A
- Damaging event - hypoxia/ ischemia, acute insult
- Nuclear pyknosis, shrinkage of cell body, loss of Nissl substance, disappearance of nucleolus, eosinophilia of cytoplasm
- Dissolution of cell, phagocytosis of debris
23
Q
Transynaptic degeneration
A
The neurons that input or synapse the damaged neuron may also die, e.g. effect of eye enucleation on cells of lateral genticulate neurons
24
Q
Axonal morphological reaction in cell body following damage to axon
A
Enlargement and rounding of cell body
Displacement of nucleolus
Dispersion of Nissl substance (chromatolyis)
25
Neuronal inclusions
Ageing (complex lipids; lipofuscin, proteins and carbohydrates)
Viral infection
26
Intracytoplasmic inclusions
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Neurofibrillary tangles (Alzheimer disease)
Lewy bodies (Parkinson disease)
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27
When directly injured as a result of ischaemia, toxicity or acute inflammation cytoplasmic swelling occurs as a result of
failure of cellular and organelle membrane pumps
28
Astrocyte activity in response to injury
Gliosis:
- Hypertrophy & hyperplasia
- Up-regulation of GFAP synthesis
- Extension of processes
- Stimulated by TNF-α, IL-β, IL-6 from activated microglia
- Release byproducts of increased biological activity (nitric oxide, glutamate): toxic to the environment
- May contribute to further injury
29
Rosenthal fibre
Observed in regions of chronic gliosis
Cytoplasmic inclusions of heat shock proteins and ubiquitin within the astrocyte
Contain brightly eosinophilic inclusions
30
Most important histological indicator of CNS injury
Gliosis (hypertrophy and hyperplasia of astrocytes) - detected with GFAP
31
Oligodendrocytes and injury
Do not respond to injury but can be injured
If myelin is damaged, it can be replaced provided that oligodendrocytes survive
Remyelination: thinner than normal, shorter internodes
If oligodendrocytes are lost, they can be replaced from the pool of oligodendrocyte progenitors; however this pool will eventually be depleted.
32
Activated microglia become rounded phagocytic cells when...
```
ONLY when neuronal death occurs
Destructive (Th1: IFN-γ, TNF-α, IL-2, IL-12) and
Repair promoting (Th2: IL-4, IL-5, IL-6, IL-10, IL-13)
```
33
Microglia
Activated in response to injury, the more severe the injury, the greater the activation
Not phagocytic unless in death of neurons
Express CD4, MHC I and II Ag, cell adhesion molecules, produce cytokines e.g. IL-6, TGF-beta
34
Inflammation in the brain
Limited penetration of the BBB by immune system from the systemic circulation;
- A lack of lymphatic vessels in the brain parenchyma;
- Inability of microglial and astroglial cells to sustain immune responses, lack of dendritic cells (DCs) in the parenchyma;
- Low levels of major histocompatibility complex expression in the brain
35
Following injury in the brain:
Activation endothelial cells and associated cells (astrocytes)
- Reduced tight junction integrity
- Formation of transendothelial channels
- Migration of leukocyte
36
Inflammation in the CNS: sequence of events
12-24 hours: Diffuse eosinophilia and shrinkage of neurons “red neurons’.
3-10 days: Infiltration by neutrophils at edge of lesion where vascular supply is intact
10-14 days: Macrophages and reactive gliosis
2-3+ weeks: Small infarcts-tissue loss with residual gliosis
37
Raised intercranial pressure
Injury may increase the volume of the brain due to:
- Brain edema
- Increased CSF volume (hydrocephalus)
- Focally expanding lesion (tumour or hemorrhage)
Absence of lymphatic drainage
Volume initially compensated by compression of veins and displacement of CSF
Raised intracranial pressure
Herniation
38
Trauma-Contusions and lacerations
A blow to the surface of the brain resulting in lesion at
point of contact, diametrically opposed or both.
Evidence of acute neuronal injury:
- Axonal swelling close to or distant from site of damage
- Hemorrhage, edema
- Inflammatory response
Crest of gyri are most vulnerable
39
Epidural haematoma
Bleed between skull and the dura (arterial)
40
Subdural haematoma
Dura still attached to skull. Venous blood pooling between dura and pia mater
41
Cerebrovascular disease
Consequence of altered blood flow - stroke
1. Hypoxia, ischemia, infarction - impairment of blood supply and oxygenation of CNS due to cardiac arrest/ hypotension or thrombosis/ Embolism
2. Hemorrhage - rupture of CNS blood vessels due to hypertension or aneurysm
42
Global cerebral ischemia
Generalized loss of cerebral perfusion
Cardiac arrest, shock, severe hypotension
Selective vulnerability: Neurons >> oligodendrocytes, & astrocytes.
Pyramidal cells CA1 region of hippocampus, Purkinje cells of cerebellum, Cortical pyramidal cells particularly vulnerable.
43
Bacterial infection of meninges
Evasion of host defense systems/ invasion and pathogenesis in CNS:
1. Binds epithelial cells of nasopharynx
2. Penetrates mucosa and gains access to blood stream (avoids recognition and destruction by immune response)
3. Crosses the BBB
Proinflammatory mediators in the subarachnoid space leads to an
•inflammatory response in the central nervous system
•increased permeability of the blood–brain barrier,
•cerebral edema, and
•increased intracranial pressure
44
Multiple Sclerosis
- Autoimmune response to myelin sheath - self-reactive T cells: CD4+ TH1 and TH17 cells react to self myelin antigen. TH1 cell secrete IFNγ, which activates macrophages and TH17 and causes leukocyte recruitment
- Breach in integrity of blood brain barrier (of genetically predisposed) allow infiltration of T-lymphocytes that recognize myelin, causing acute inflammatory demyelinating lesions.
- Associated with white matter lesions
- Genetic and environmental factors: GWAS show association with HLA haplotype and genes encoding immune response proteins (ie IL-2 and IL-7R’s)
45
Neuronal storage disease
Deficiency of enzyme involved in catabolism of sphingolipids, mucopolysaccharides and mucolipids.
Accumulation of substrate within lysosomes causes neuronal death
46
Leukodystrophies
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Myelin abnormalities (synthesis or turnover)
Diffuse involvement of white matter
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47
Tay-Sachs disease
Lysosomal storage disease
Hexosamindase A deficiency
GM2 ganglioside accumulates in many tissues (heart, liver spleen and brain)
GM2 gangliosides - lipid essential for neuronal function
Neurological defects predominant clinical feature
48
Degenerative disorders affect ___ matter
grey
49
Parkinson’s disease
Characterised by motor dysfunction typical of disturbance of nigostiatal dopaminergic system - tremor, rigidity, bradykinesia
Typified by the loss of dopaminergic neurons of the substantia nigra and presence of Lewy bodies in neurons - accumulation of α-synuclein which correlates with symptoms.
Progressive disease that begins in the brain stem and spreads to cerebral cortex eventually leading to cognitive impairment
Mutations in α-synuclein and genes associated with mitochondrial function
50
PET imaging for AD
Radioactive tracer binds to amyloid
51
Neural progenitor cells
Form neural spheres.
| Adult neural stem cell (NSC)
52
NG2 glia
Dispersed throughout adult brain parenchyma
| Generate differentiate into myelinating oligodendrocytes
53
NSC treatment of MPTP-lesion
hNSCs implanted into the striatum showed a remarkable migratory ability and were found in the substantia nigra, where a small number appeared to differentiate into dopamine neurons
54
Excitoxicty
Injured nerve cells secrete glutamate into the extracellular space
Overstimulates the AMPA and NMDA receptors
Activated receptors allow influx of sodium and calcium ions into the cell
Cytosolic calcium ions activates enzymes
55
CNS secondary injury
BBB dysfunction
Oxidative stress
Excitotoxicity
Mitochondrial dysfunction
56
Secondary injury: BBB dysfunction
Primary injury disrupts the tight junctions, allowing an influx of peripheral immune cells and circulating factors that increase osmotic force
Affect the interaction between BBB endothelial cells and astrocytic glial cells, further contributing to the effects of BBB dysfunction by increasing its permeability
57
Oxidative stress
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Accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RON).
Impairment of antioxidants
Lipoperoxidation of the cell membrane,
Fragment DNA
Infiltration of neutrophil
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58
Beneficial outcomes of neuroinflammation
Neuroprotection
Axonal regeneration
Neurogenesis
Remyelination
59
Detrimental outcomes of neuroinflammation
Injury to neural elements
Death to neurons and oligodendrocytes
Inhibition of regenerative processes
