Neuropathology 2 Flashcards
What issues to we face in pathology ?
- Sampling error
- Accessibility of tissue
- Often tissue only available late in disease process (i.e post mortem)
What are some Common Neurodegenerative diseases ?
Common Neurodegenerative diseases;
- Motor neuron diseases - ALS (amyotrophic lateral sclerosis)
- Dementia - Alzehimers
- Parkinson’s disease
- Spongiform encephalopathies
- Multiple Sclerosis (inflammation)
What are the main types of Motor Neuron Disease ?
Amyotrophic lateral sclerosis (ALS);
- brisk reflexes and fasciculations
Progressive bulbar atrophy (a variant of AS)
Primary lateral sclerosis;
- affects Upper MN’s predominantly
Spinal muscular atrophy;
- affects Lower MN’s predominantly
What occurs in motor neuron disease ?
Can attack upper, inter or lower motoneurons
UMN’s orchestrate complex directed movement and their cell bodies are in the brainstem and do not project outside the CNS
Interneurons co-ordinate groups of muscles
LMN’s do single muscle innervation, cell bodies in the ventral horn of the spinal cord or motor nuclei of the brainstem
What is ALS and where does the word come from?
Amyotrophic Lateral Sclerosis;
Amyotrophic - from the Greek meaning without nourishment to the muscle loss of signal to muscle
Lateral - where cell death was reported first in the spinal cord
Sclerosis - hardened tissue or scar tissue
What is it;
- ALS has become a general term for Motor Neuron Disease - by far the most common condition of its type (between 1 - 3 : 100,000)
- It usually begins between 50 - 60 years old as cramps and weakness on one side followed by a progression to the same area on the other side (e.g hand first)
- Lower MN’s are affected in both Bulbar and spinal locations
- UMN’s are affected all through the brain, brainstem and spinal cord but less so in the extra ocular area (eye movement spared)
- Research is underway to see if UMN and LMN die from the same causes or not
- The condition will progress until motor centres for respiration become affected at which point the patient normally dies from respiratory complications
- Most cases are sporadic, although about 10% are linked to a genetic mutation in Super Oxide Dismutase which prevents it from working properly. The resultant increase ion reactive O2 species can cause cell death
What are the common characterisation in those with ALS?
ALS Common Characterisation;
- Focal weakness and clumsiness which then spreads
- Painful fasciculation and cramping
- Some patients present with dysarthria, dysphagia or respiratory issues
- Upper and lower motor neuron signs
- Sensory exam and mental state usually normal
- EMG reveals evidence of denervation and re-innervation in two extremities or body segments (Arm and trunk or leg and head etc)
- Issue with 1 arm, then other, then issue with leg and arms get better - have to show synchronous denervation
- See degeneration of corticospinal tracts and degradation of brainstem nuclei (e.g hypogloassal)
What are the key points of Dementia?
- Dementia is a syndrome, not a specific diagnosis
- Ultimately the only definitive diagnostic test is pathology, usually post-mortem
- There is no single diagnostic test
- There is no single reliable biomarker
- Treatments tend to work better the longer they are used
What are the percentages of the different subtypes of dementia ?
Types of dementia;
- Alzheimers (65% of all)
- Dementia with Lewy bodies (20% of all)
- Vascular Dementia (10% of all)
- Frontotemporal Dementias (5% of all)
What is seen in the Alzheimer’s disease pathology?
- Reduced brain weight
- Cortical atrophy (reduced thickness)
- Enlarged ventricles
- Cell loss evident in medial temporal lobes and hippocampi
What are the Microscopic pathological features of Alzheimer’s disease?
Tau, Neurofibrially tangles (NFTs) and Amyloid plaques
- Predominantly composed of Tau
- Normal Tau stabilises axons
- In AD Tau is hyperphosphorylated in tangles and forms paid helical filaments in cytoplasm (Destabilises cells stop from working properly and ultimately kills cell)
- See Neurofibrially tangles (NFTs) - Not unique to AD
- Also see extracellular insoluble proteinaceous deposits, largely composed of Amyloid B peptides (AB peptides) called Amyloid Plaques
- See Diffuse plaques in all older patients, doesn’t mean dementia but when see Neuritic plaque which is surrounded by Thick distorted neuronal processes, strongly associated with cognitive decline !
How does the Tau tangle progress?
Usually starts early on mainly in the Transentorhinal cortex in the inferior part of the temporal lobe then spreads and eventually affects the majority of the brain in late stages
What does this image show?
Tau - seen in Alzheimers !
What does this image show ?
Neurofibrillary Tangles (NFT’s)
What does this image show?
Amyloid plaque (AB plaque) - Surrounded by thick distorted neuronal processes. Strongly associated with cognitive decline and will most definitely cause neuronal cell death !
What does this image show?
Diffuse plaque - often see in older people WITHOUT dementia!
What are the key signs of Parkinson’s disease?
- Repetitive “pill rolling” movement
- Persistent tremors
- Shuffling gait, taking small steps
What is the Pathology of Parkinson’s disease?
PD characterised by;
- Neuronal loss in Substantia Nigra
- Degradation of the Nigrostriatal tract
- Profound loss of dopamine in the Basal nuclei (less than 20% of normal)
Surviving nigral neurons contain Lewy bodies
They can be stained with antibodies to alpha-synuclein (a protein that forms lewy bodies)
This stain also reveals a widespread pathology through brainstem, limbic lobes and neocortex in these patients on post mortem and progression is described by Braaks stages (see image)
Braaks stages starts at;
- Peripheral and enteric nervous system
- Medulla oblongata
- Pontine tegmenjtum
- Basal mid- and forebrain, hypothalamus and thalamus
- Mesocortex, allocortex
- Neocortex
Basically starts at periphery and works way up brainstem into brain
What is the Pathology of Prion diseases?
Cells cluster together to form vacuole like structure and sponge like appearance, cells die and leaves holes in cell
Get a prion disease called KURU that was due to cannibalism
What is Multiple Sclerosis and its features?
MS is an Autoimmune disease of the CNS
- Immune cells are stimulated to phargoctyose the Myelin normally found insulating the axons of nerve cells (will affect saltatory conduction)
- Where axon insulation is removed, the signal transmission along fibres slows, and within a pathway can become delayed
- Proprioceptive and other feedback systems do not then synchronise well with motor output
- Muscles fatigue and patients find it difficult to control movement properly
In the pathologies you will see;
Aggregation for T Lymphocytes, oblique cut through venule. Cell walls that comprise venule become leaky and super charged T cells come out and destroy myelin in that area. When wall is repaired these cells fuse away and back to normal, get relapsing remitting part for MS, cycle of rupturing and repairing
Axons at bottom demyelinated, myelinated at top, can be specific area - Depends on how far away from venules they go
What are Dawson’s Fingers?
Seen on MRI
Have a venule and outside is zone demyelinated where all lymphocytes come out and destroy myelin. With repeated episodes get more of space around venule broken down and area gets larger. Where you have venules that are predominantly more leaky have more damage so look like Dawsons fingers pointing out
Can we get repair of Myelin and what issues may we face?
If oligodendrocytes haven’t been damaged can start to remyelinate
Can see transacted axons in this cut, can see ones with small myelin which have been repaired by oligodendrocytes, can get some repair which adds into boom bust nature of this condition
However Astrocytes can overgrow and make an ‘astrocyte mat’ caused by recurrent inflammation and this dense matting interferes eventually with oligodendrocytes re-myelinating axons
When can ‘Transection’ occur and what does it cause?
When demyelinating axons Transection can occur cutting through the axon causing neuronal death and tissue shrinkage
E.g Reduction in spinal cord, cervical section through patient in MRI
How can demyelination affect bigger structures like the cortex?
Demyelination can cause punched out areas of the brain (pons in image attached)
Lose neurons and mass of brain
How does the progression of demyelination look?
Early stages;
Initially damage is being done when patient is normal and before presenting to the clinic as their inflammation is below clinical threshold.
- Important to note that early diagnosis or findings of inflammation is important to reduce the episodes and prevent damage to axons over time, preventing patient deterioration
Patient will present with more episodes which will be destroying more axons, progressing the growth along dawsons fingers
Cellular occurrences;
- Frequency inflammation
- Demyelination
- Axonal transection
- Plasticity and demyelination (as not complete loss yet)
Patients symptoms go back to normal
Relapsing and remitting stage;
Patients enter the Relapsing and Remitting stage where less cases of inflammation are occurring because increased axonal loss stops spiking with inflammation and starts to steadily rise. Patients clinical presentations will get worse but still spike in their visits
Cellular occurrences;
- Continuing inflammation
- Persistent demyelination
Patients symptoms go back to normal at start of this stage but eventually will stop going back to normal as get into early stages of secondary progression
Secondary progression stage;
Clinical episodes gradually just get worse from here until patient dies. Patients have even less inflammatory responses because of so much ongoing increasing axonal loss.
Cellular occurrences;
- Infrequent inflammation
- Chronic axonal degradation
- Gliosis (fibrous proliferation of glial cells in injured areas of the CNS)
What are the 2 types of axonal demyelination ?
- Distal Axonal Degeneration (multiple segments of axon breaks down in a line closer to muscle)
- Segmental Demyelination (a segment of axon breaks down)
How do we recruit motor units?
Size Principle - Motor neurons are recruited in order of size
Smallest is alpha motor neurones a2 which belong to slow twitch and are recruited first
Largest alpha motor neurones are a1 which being to fast twitch and are recruited last
What are muscle fibre staining properties ?
Slow twitch fibres (type 1) have myosin isoforms with low ATPase activities
Fast twitch fibres (type 2) have myosin isoforms with high ATPase activity that promotes the rapid breakdown of ATP for energy of high-speed muscle shortening (due to strength)
What causes dystrophies ?
Caused by mutations in structural dystrophian proteins
Without anchoring proteins muscles cannot contract properly and produce enough energy to work properly
X-linked recessive inheritance (more common to affect males, and daughter carriers)
Different types affecting different combinations of arms, legs, face, eyes, etc
Will see symptoms and different types in attached images
