13-10-23 - Neuropathology 2 Flashcards
(45 cards)
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.
What are prion diseases?
What is it caused by?
What is the most common human form of prion disease?
What are the 2 different forms?
How can cVJD be obtained?
What is another example of a prion disease?
- Prion disease are TSEs (Transmissible spongiform encephalopathies)
- Prions disease is caused by a misfolded cell surface protein – causes cells and proteins to clump together resulting in cell death.
- The most common human form is CJD (Creutzfeldt-Jakob disease).
- Prion diseases can be heritable (Familial CJD or spontaneously arising (Sporadic CJD) or acquired (Acquired CJD) from medical procedure.
- Variant CJD (vCJD) communicable by ingestion of meat infected with ‘mad cow disease’ – BSE (Bovine spongiform encephalopathies).
- Kuru is another example of a human prion disease
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 are 4 symptoms of CJD?
What are 2 later-stage symptoms of CJD?
- 4 symptoms of CJD:
1) Rapidly developing dementia – key trigger for investigation (MRI, Biopsy).
2) Difficulty walking – needing a cane or frame
3) Muscle stiffness and fatigue
4) Speech problems - 2 later-stage symptoms of CJD:
1) Hallucinations
2) Confusion
What is Multiple Sclerosis (MS)?
What are 4 common characteristics of MS?
How do immune cells affect myelin in MS?
How does this affect signal transmission in these areas?
How does this affect synchronisation of sensory and motor output?
How does this affect patients mobility?
- Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS)
- 4 common characteristics of MS:
1) Chronic inflammation
2) Demyelination
3) Gliosis
* Fibrous proliferation of glial cells in injured areas of the CNS.
4) Neuronal loss
- Immune cells are stimulated to phagocytose the Myelin normally found insulating the axons of nerve cells.
- Where axon insulation is removed, the signal transmission along the fibre 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.
