Lecture 17 - CNS 3 Flashcards
What are the challenges of diagnosis and treatment of CNS injury?
- The brain has limited regenerative capacity
- Clinical symptoms reflect neuronal dysfunction/injury/loss
- Deficits caused by neuronal injury/loss are difficult to replace
- Early diagnosis is key to good outcome
- BBB limits entry of plasma components to the brain
- Access to brain is limited/expensive
o Invasive procedures e.g., brain biopsy, lumbar
o PET/MRI
What are the aims for diagnosis of CNS injury?
- Early
- Non-invasive
- Accurate-specificity and sensitivity
o Biopsy-Histology, IHC
o EEG-records, electrical patterns
o PET-measures blood flow, energy consumption, specific tracers
o MRI-identifies structural changes
o Biomarkers
CSF
Blood
What is the difference between sensitivity and specificity?
- Sensitivity: Proportion of positive samples that are correctly identified
- Specificity: Proportion of negative samples that are correctly identified
What is the specificity of PET imaging for Alzheimer’s Disease?
- Detects quantity of protein aggregates but does not differentiate between the types of protein
- Whereabouts the protein aggregates are identified is very diagnostic of the disease
- PET imaging can provide diagnostic and prognostic biomarkers for AD
How are CSF biomarkers used for Creutzfeldt-Jakob disease (CJD)?
- CSF 14-3-3 protein in CJD
- As a single biomarker overall sensitivity 85%
- The main limitation is that it has low specificity
- Generally used to exclude treatable inflammatory conditions
What are the objectives for treatment for CNS injury?
- Early-before symptomatic and unrecoverable degeneration
o Extended survival vs. quality of life - Able to cross the BBB
o PPS has prophylactic effects against peripherally acquired prion disease but the drug cannot penetrate the BBB and requires intraventricular administration to affect disease in the CNS - Not associated with too much collateral damage
o Anti-amyloid-beta immunotherapy has been shown to reduce amyloid burden in both mouse models and in humans, immunotherapy also exacerbates vascular pathologies
How is neurogenesis a type of repair mechanism for CNS injury?
- Neurons are terminally differentiated cells that are incapable of cell division
- Brain is thought to have limited regenerative capacity
- Neurogenesis is the process of generating functional neurons from precursors
- Adult neural stem cells (neural progenitor cells)
o Discrete regions of the brain (neurogenic niche)
o Have the potential to differentiate into neurons, astrocytes and oligodendrocytes
Neurons, astrocytes, oligodendrocytes and ependyma and arise from the neuroectoderm
Microglia-arise from the mesoderm
What are neural progenitor cells?
- Neural stem cells isolated from adult mouse brain
- Form neural sphere (fast dividing neural progenitor cells)
- Induced to differentiate into astrocytes, oligodendrocytes and neurons
How are adult neural stem cells a potential for CNS injury repair?
- In vitro:
o Stem cell potential
o Self-renewing neural spheres
o Neurons, astrocytes and oligodendrocytes - In vivo:
o Low frequency of division
o Generates neurons - NG2 glia:
o Dispersed throughout adult
o Generate differentiate into myelinating oligodendrocytes - Found in subventricular zone (SVZ)
What is NSC treatment of MPTP-lesion?
NSC stands for neural stem cell, and MPTP is a toxin that is commonly used to model Parkinson’s disease in animal models. The MPTP lesion model results in the selective loss of dopamine-producing neurons in the substantia nigra region of the brain, leading to motor deficits that are characteristic of Parkinson’s disease.
NSCs are typically derived from fetal or embryonic tissues and are transplanted into the brains of animals with MPTP-induced lesions.
NSCs have the potential to differentiate into various types of neural cells, including dopamine-producing neurons, and can therefore potentially replace the lost neurons in the substantia nigra. Additionally, NSCs have been shown to promote the survival and regeneration of endogenous neurons and to modulate the immune response, potentially providing further neuroprotective benefits.
What types of secondary cell death results from TBI?
Mitochondrial dysfunction
Neuroinflammation
Excitotoxicity
BBB dysfunction
Oxidative stress
What results from mitochondrial dysfunction?
- Mitochondria impaired
o Damage to mitochondrial membrane
o Increased ROS
o Increased calcium - Activation of mitochondrial permeability transition pore
- Loss of membrane potential
- Decreased ATP production
- Activation of caspases
What results from oxidative stress?
- Accumulation of ROS and RON
- Increased production and impairment of antioxidants
- Lipoperoxidation of the cell membranes
- Fragmentation/mutation of DNA
- Infiltration of neutrophil-inflammation
What results from excitotoxicity?
- Injured nerve cells secrete glutamate into the extracellular space
- Overstimulates the AMPA and NMDA receptors
- Activated receptors allows influx of sodium and calcium ions into the cell
- Cytosolic calcium ions activate enzymes
- DNA fragmentation, lipid membrane degradation
- Increased production of ROS, RON
What results from BBB dysfunction?
- Primary injury disrupts tight junctions, allowing an influx of peripheral immune cells and circulating factors that increases osmotic force
- Affects the interaction between BBB endothelial cells and astrocytic glial cells, further contributing to the effects of BBB dysfunction by increasing its permeability
