13-10-23 - Neuropathology 2 Flashcards
Learning outcomes
- Know the major causes of peripheral neuropathy
- Understand some classes of disease that affect muscle
- Understand the pathology of multiple sclerosis
- Be aware of some of the features of neurodegenerative disease pathology
What are 5 common neurodegenerative diseases?
- 5 common neurodegenerative diseases:
1) Motor neuron diseases
2) Dementia – Alzheimer’s disease
3) Parkinson’s disease
4) Spongiform encephalopathies
5) Multiple Sclerosis (inflammation)
What is a motor unit made from?
What does it form?
What is the motor unit a prominent target for?
What is the variation in motor unit disease presentation closely associated with?
What are 4 different types of motor unit disorders?
- A motor unit is made of motor neurons and a group of innervated muscle fibres
- They form the basic unit of a motor function
- The motor unit is the prominent target of disease
- The variation in motor unit disease presentation is closely associated with functional component primarily affected; (a) the cell body of the motor or sensory neuron (b) corresponding axon (c) neuromuscular junction (synapse between the motor axon and muscle) (d) muscle fibres innervated by the motor neuron.
- 4 different types of motor unit disorders:
1) Peripheral neuropathies
* Weakness linked with abnormal function of motor neurons or the axons.
2) Motor neuron diseases
* Motor neurons and motor tracts in spinal cord degenerate, but sensory nerve not affected.
3) Myopathies
* Weakness associated with muscle degeneration with no significant change to motor neurons.
4) Neuromuscular junction diseases
* Causes alteration in the neuromuscular synapse causing intermittent weakness.
What structures can motor neuron diseases attack?
What 4 different motor neuron diseases?
- Motor neuron diseases can attack:
1) Upper motor neurons (UMN)
* Orchestrate complex directed movements
* UMN cell bodies are in brain or brainstem and do not project outside the CNS
2) Interneurons
* Coordinate groups of muscles
3) Lower motor neurons (LMN)
* Single muscle innervation, cell bodies in the ventral horn of spinal cord or motor nuclei of the brainstem
* LMN cell bodies are in brainstem or spinal cord and project outside the CNS to muscle
- 4 different motor neuron diseases:
1) Amyotrophic lateral sclerosis (ALS) – brisk reflexes and fasciculations
2) Progressive bulbar atrophy (a variant of ALS)
3) Primary lateral sclerosis – affects Upper Motor Neurons (MNs) predominantly.
4) Spinal muscular atrophy – affects lower motor neurons predominantly
What is the meaning behind Amyotrophic Lateral Sclerosis (ALS)?
- Meaning behind Amyotrophic Lateral Sclerosis (ALS):
- Amyotrophic – from the Greek meaning without nourishment to the muscle or loss of signal to the muscle
- Lateral – where cell death was reported first in the spinal cord
- Sclerosis – hardened tissue or scar tissue
What is ALS? What UMN and LMN structures are damaged in ALS?
What % of cases are familial (genetic) and sporadic?
Which 2 genes are implicated in familial ALS?
How/when does ALS usually present?
What does this condition progress to?
- ALS is the most common type of motor neuron disease
- It is linked with UMN damage in the spinal cord, brainstem and the cortex, but less in the extra ocular area
- It is also linked with LMN damage in the bulbar and spinal cord
- About 10% of ALS cases are familiar (fALS) and 90% of ALS cases are sporadic
- In ALS, mutation in the C9orf72 gene account for about 20% and mutation in SOD1 gene (superoxidase dismutase) accounts for 25% of cases
- ALS usually begins between 50-60 y/old as cramps and weakness on one side followed by a progression to the same area on the other side.
- The condition will progress until motor centres for respiration become affected at which point the patient normally dies from respiratory complications.
Molecular Pathophysiology of ALS.
What is the most common cause of Fals?
Describe the pathophysiology of Fals.
- Molecular Pathophysiology of ALS
- The most common cause of fALS is the polymorphic hexanucleotide repeat expansion (HRE) in the non-coding region of C9of72 gene.
- The C9of72 mutation causes:
1) Reduction in C9OF72 protein – crucial in vesicle trafficking and stabilisation of molecules
* 1 is a loss of function mutation – Loss-of-function (LOF) mutations, also called inactivating mutations, result in a gene product that is partially or wholly inactivated
2) The HRE is transcribed bidirectionally (sense and antisense) resulting in nuclear and cytoplasmic accumulation of sense and antisense repeat-containing RNA
* Antisense transcribed HRE accumulates in toxic RNA foci, which sequesters RNA binding protein, such as splicing factors in nuclei, resulting in dysfunction of these proteins
* The sense transcription of HRE via a mechanism known as repeat associated non-AUG-dependent (RAN) produce dipeptide repeat protein toxicity (neurotoxic)
* 2 is a gain of function mutation - Examples of gain of function mutations include mutations that prevent clearance of protein from the cell surface via endocytosis
What are 6 common characteristics of ALS?
- 6 common characteristics of ALS:
1) Focal weakness and clumsiness which then spreads.
2) Painful fasciculation and cramping
3) Some patients present with dysarthria, dysphagia or respiratory issues.
4) Upper and lower motor neuron signs
5) Sensory examination and mental state usually normal
6) Electromyography (EMG) reveals evidence of denervation and re-innervation in two extremities or body segments (Arm and trunk or leg and head etc).
Mild and severe degeneration of corticospinal tracts in ALS (demyelination of white matter tracts) – in picture
What is dementia an umbrella term for?
Is dementia a syndrome or a diagnosis?
What is the definitive test/biomarker to diagnose dementia?
When does treatment tend to work better?
- Dementia is a general umbrella term used to describe many neurodegenerative diseases linked with a decline in cognitive ability severe enough to interfere with daily activities.
- 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
- Treatment tend to work better with early diagnosis
What are the 6 types of dementia?
Which are the most common?
- 6 Types of dementia:
1) Alzheimer’s disease (60-70%)
2) Vascular dementia (10-20%)
3) Frontotemporal dementia (10%)
4) Dementia with Lewy bodies (4%)
5) Younger onset Alzheimer’s (1-5%)
6) Others (including prions diseases and Huntington’s) (<1%)
What age group does Alzheimer’s disease occur in?
Where does neuron death start?
How is brain weight and thickness affected?
How does this affect the ventricles?
What is Alzheimer’s disease characterized by?
- Alzheimer’s occurs in persons over the age of 65 years
- Neuronal cell death starts in the entorhinal cortex and hippocampus.
- There is educed brain weight
- Cortical atrophy (reduced thickness)
- Enlarged ventricles
- Alzheimer’s is characterised by presence of amyloid plaques and hyperphosphorylated tau.
What is the cause of AD?
What are the 2 categories of AD?
What % of cases do they each make up?
Is fAD autosomal dominant or recessivwe?
What are 4 gene mutations linked to Fad?
What allele is also linked to Fad?
- The cause of AD is complex and multifactorial.
- AD is often categorised into sporadic AD (sAD) and familiar AD (fAD):
1) sAD accounts for 90 – 95% of AD cases and typical age of onset is 65 years or older
2) fAD account for 5 – 10% of AD cases - Fad is autosomal dominant
- 4 gene mutations linked to Fad:
1) APP gene on chromosome 21
2) Presenilin 1 (PSEN1) on chromosome 14
3) Presenilin 2 (PSEN2) on chromosome 1
4) MAPT on chromosome 17 - The E4 allele of apolipoprotein E (APOE) located on chromosome 19 is also associated with fAD
What is Braak staging used for in AD?
Describe the Braak staging for AD.
How long is the pre-clinical phase of AD?
- Braak staging is a pathological, post-mortem assessment of tau neurofibrillary and beta-amyloid progression based on brain anatomical distribution.
- In Stage A of the beta-amyloid plaque development, plaques are deposited below the frontal cortex and the occipital lobe
- In stage B and C, they spread throughout the entire brain
- Braak stages I and II are used when neurofibrillary tangle involvement is confined mainly to the transentorhinal region of the brain,
- Stages III and IV when there is also involvement of limbic regions such as the hippocampus,
- Stages V and VI when there is extensive neocortical involvement (severe)
- The pre-clinical phase of AD is 30 years, where patients will not have clinical symptoms
Microscopic Pathological Features of AD.
What Microscopic Pathological Features of AD predominantly composed of?
What is the normal role for tau?
How is tau protein affected in AD?
- Microscopic Pathological Features of AD
- Predominantly composed of tau protein.
- Normal tau stabilises microtubules in the axon.
- In AD Tau protein is hyperphosphorylated in tangles and forms paired helical filaments and finally neurofibrillary tangles (NFTs), which aren’t unique to AD
Practise question
Microscopic Pathological Features of AD.
What are Extracellular insoluble proteinaceous deposits composed of?
What do they form?
What are the 2 types of plaques in AD?
- Microscopic Pathological Features of AD
- Extracellular insoluble proteinaceous deposits are Largely composed of Amyloid β peptides (Aβ), which form amyloid plaques
- 2 types of plaques in AD:
1) Diffuse plaque
* Often found in older people with no dementia
2) Neuritic plaque
* Surrounded by Thick distorted neuronal processes. Strongly associated with cognitive decline
What are 3 clinical symptoms of Parkinson’s disease (PD)?
What are 3 pathological signs of PD?
What so surviving nigral neurons contain?
What are Lewy bodies?
How can they be stained?
What can this stain reveal?
- 3 pathological signs of PD:
1) Neuronal loss in the substantia nigra
2) Degeneration of the nigrostriatal tract
3) Profound loss of dopamine in the Basal nuclei (less than 20% of normal)
- Surviving nigral neurons contain Lewy bodies
- Lewy bodies are abnormal deposits of a protein called alpha-synuclein in the brain
- They can be stained with antibodies to alpha-synuclein
- This stain also reveals a widespread pathology through the brainstem, limbic lobes and neocortex in these patients on post-mortem and progression is described by Braak stage
Describe the 6 stages of Braak Lewy Body Staging in Parkinson’s Disease
- 6 stages of Braak Lewy Body Staging in Parkinson’s Disease:
1) Stage 1
* The disease begins in structures of the lower brainstem and the olfactory system. In particular, the dorsal motor nucleus of the vagus nerve in the medulla oblongata and anterior olfactory nucleus are affected.
* Lewy neurites, thread-like alpha-synuclein aggregates, are more prevalent than globular Lewy bodies in this stage.[4]
1) Stage 2
* In addition to the pathology observed in Stage 1, Stage 2 is characterized by additional lesions in the raphe nuclei and gigantocellular reticular nucleus of the medulla oblongata.
* The disease then moves up the brainstem, traveling from the medullary structures to the locus ceruleus in the pontine tegmentum.
* Similar to Stage 1, Lewy neurites outnumber Lewy bodies.[4]
2) Stage 3
* At the beginning of Stage 3, the disease has entered the substantia nigra and Lewy body lesions begin to form in the pars compacta.
* The latter half of this stage involves disease progression into the basal nucleus of Meynert, a cluster of acetylcholine-rich neurons in the basal forebrain.
* Further, structures affected in Stages 1 and 2 begin to develop more Lewy bodies.
3) Stage 4
* Stage 4 is characterized by severe dopaminergic cell destruction in the pars compacta. There is also mesocortex and allocortex involvement; the neocortex remains unaffected.
* In particular, pathology can be observed in the amygdala and in the subnuclei of the thalamus.
* There is significant damage done to the anterior olfactory nucleus.
4) Stage 5
* The disease has started to invade the neocortex and spreads into the structures of the temporal, parietal, and frontal lobes.
* Cell death can be observed in the substantia nigra, the dorsal motor nucleus of the vagus nerve, the gigantocellular reticular nucleus, and the locus ceruleus.
5) Stage 6
* The disease has fully invaded the neocortex, affecting the motor and sensory areas in the brain.
* The disease is at its most severe.
Pathology of prion diseases. What are PrPsc proteins?
What is scrapie?
How can PrPSc cause prion diseases?
- Pathology of prion diseases:
- PrPSc proteins are scrapie isoforms of prion proteins resulting from a posttranslational modification of the cellular prion protein (PrPc proteins)
- Scrapie is a prion disease of goats that can’t infect humans
- The beta-sheet of PrPSc can enter the host brain and turn the alpha helix of PrPc into PrPSc resulting in amplification of PrPSc
- This causes PrPSc aggregation in the brain resulting in prion disease (spongiform encephalopathy)
What is myelination of axons derived from?
What does the process of demyelination involve?
How is the autoimmunity in MS initiated?
What is the role of TH1 and TH17 cells in MS?
- Myelination of the axon is derived from two cell types, Oligodendrocytes (CNS) and Schwann cell (PNS).
- Demyelination involves the destruction of previously made myelin (leukodystrophy) or the disruption of the protein key in the formation of normal myelin sheaths (dysmyelination)
- Autoimmunity in MS is initiated by Th1 and Th17 T cells and B cells reacting against myelin antigens:
- Th1 secretes IFN-ϒ leading to macrophage activation.
- Th17 cells drives leukocytes recruitment, active leukocytes promote demyelination.
MS demyelination (in picture)
Myelinated and Demyelinated Axons in MS (in picture)
How are immune cells released in MS?
What are the immune cells released in MS?
- The migration of immune cells in and out of lymph nodes is via high endothelial venules and lymphatics
- In MS these cells are Th1 and Th17 T cells and B cells
What are Dawson’s fingers?
Where do they form?
How do they form?
- Dawson’s finger is a type of brain lesion common to people who have MS.
- These lesions develop on the ventricles, or fluid-filled spaces in the brain
- There are leaky venules that release super active B and T cells, which can lead to widening of the venules and the formation of Dawson’s fingers
What is remyelination?
What does it typically follow?
What is remyelination a function?
- Remyelination is the phenomenon by which new myelin sheaths are generated around axons in the adult central nervous system (CNS).
- This follows the pathological loss of myelin in diseases like multiple sclerosis (MS).
- Remyelination a function of disease progression and the level of astrocytic presence:
- Black stain shows overgrown astrocyte mats caused by recurrent inflammation
- The dense matting interferes eventually with oligodendrocytes re-myelinating axons
Demyelination in MS (in picture)
Normal vs disease brain in MS (in picture)
Describe the 4 types of MS.
Which is the most common?
How do symptoms differ between each type?
- 4 types of MS:
- Relapsing Remitting
* The most common type: 85% of cases
* Characterised by acute periods of relapse then recovery
* Symptoms do not worsen during recovery/ remitting phases, but patients may not return to original baseline after a relapse
* Can progress into secondary progressive MS - Secondary Progressive
* People with relapsing remitting MS can progress on to secondary progressive, where symptoms steadily worsen
* Thanks to newer therapies, less patients are progressing to secondary progressive - Primary Progressive
* The most severe type of MS
* Affects about 10-15% of patients
* Must never have had relapse/ remitting but have commenced with progressive symptoms from the beginning - Progressive Relapsing
* Steady progression of disease but with periods of acute relapse as well
When will clinical presentation occur in MS?
Describe the potential progression of MS (in picture)
- Clinical presentation in MS will occur when the inflammation threshold is crossed
- Potential progression of MS (in picture)
What are 2 types of causes of axonal degeneration in peripheral neuropathy?
What are 8 causes of axonal degeneration?
- Axonal degeneration in peripheral neuropathy can be hereditary or acquired
- 8 Causes of axonal degeneration:
1) Diabetes Mellitus
2) Idiopathic (cause unknown)
3) Toxic – alcohol, drugs
4) Vitamin Deficiency (B12)
5) Post-infectious (Guillain-Barre syndrome)
6) Paraneoplastic (T-cell autoimmune response)
7) Leprosy
8) Amyloid, other inflammation (e.g., vasculitis)
What is Charcot Marie-Tooth disease?
How does it present?
What area of the nervous system are affected by peripheral neuropathies?
Which gene is implicated?
- Charcot Marie-Tooth disease is an Inherited Peripheral Neuropathy
- Presents with loss of distal motor and sensation with associated muscle wasting and weakness
- Peripheral neuropathies are mostly demyelinating condition in the peripheral nervous system
- They are genetically linked to the ‘peripheral myelin P22’ gene
- This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system
Where is the sural nerve located?
What is its purpose?
How do patients with sural nerve neuropathy present?
What is peripheral neuropathy also associated with?
- Your sural nerve is just below your skin’s surface in the back of your lower leg (calf).
- It enables you to detect foot position and sensations, including touch, temperature and pain
- Patients with sural neuropathy often present with persistent pain, burning, aching, or numbness in the posterolateral leg, lateral ankle, or lateral foot,
- Aka loss of sensation and 30% pain.
What processes is peripheral neuropathy also associated with?
- Peripheral neuropathy also associated with inflammation of the vasculature (A-E) as well as demyelination (F-I)
What is dystrophin?
What is Duchenne Muscular Dystrophy?
What causes Duchenne’s Muscular Dsytrophy (DMD)?
How does DMD affect mobility?
What is used to treat DMD?
- Dystrophin is an adaptor protein that links integrin to the actin/intermediate filaments of the cytoskeleton.
- Duchenne’s muscular dystrophy (DMD) is an X-linked recessive trait that affect male in early childhood
- DMD is caused by a point gene mutation in the DMD gene (exon 48-50 deletion), which results in the absence of dystrophin in muscle cells due to premature termination of translation.
- This premature termination is causes by a premature stop signal during translation
- DMD results in muscle weakness and wasting, which causes the patient to be unable to walk by the time they are 12.
- PTC 124 (ataluren) is a drug that overrides the premature stop signal mutation to produce regular dystrophin
Clinical Presentation of DMD.
When does onset of DMD typically occur?
Where does muscle weakness begin?
How can the heart be affected?
How are serum creatine kinase levels affected?
What is the mean age for a DMD patient?
- Clinical Presentation of DMD
- Onset 3 – 5 years
- Muscle weakness begins in the pelvic girdle and progresses to shoulders.
- Cardiac muscle damage and fibrosis – heart failure and arrhythmias.
- High serum level of creatine kinase at birth and continues through the first decade of life owing to continuous muscle degeneration.
- However, over the next decade of life there is a decline in creatine kinase due to loss of muscle mass.
- The mean age for DMD patient is 25 – 30 years
Practice question 1
Practice question 2
