Trauma, Demyelination + Neurodegenerative Disease Flashcards
How can head injury mechanisms be divided?
Primary events
- neural
- vascular
Secondary events
- ischaemia
- raised ICP
- infection
- post-traumatic epilepsy
- chronic traumatic encephalopathy
What are the different types of neural damage associated with trauma?
Contusional damage
Traumatic axonal injury
What causes contusional damage and what are the consequences?
Causes: (leads to swelling around brain)
- burst lobe due to parenchymal breath through
- intracerebral haemorrhage
Consequences:
- Focal symptoms= specific to site of injury
- Contre-coup injury i.e. injury to opposite side to origin of trauma
- post traumatic epilepsy
What is a TAI and what causes it? What are the clinical and histological consequences of TAI?
Traumatic axonal injury occurs when injury causes stretching and damage to axons
Cause:
-high velocity acceleration and deceleration with torsion
Clinical consequences:
- post-traumatic PSV
Histological
- Axonal bulbs form w/i 24hrs i.e. appears very eosinophilic
- beta-APP i.e. released from damaged axons w/i 2-3 hrs
- Petechiae in WM tracts in corpus callosum and brainstem
- Gliding contusions= haemorrhage in parasagittal WM
What type of brain injury is a diffuse axonal injury? What is the prognosis?
Traumatic axonal injury
Not compatible with life
What are the 3 different causes of traumatic vascular damage?
Diffuse vascular damage= Petechial haemorrhages
Damage to arteries (neck or intracranial)
Intracranial haemorrhage
What are the 4 types of traumatic intracranial haemorrhage? Which vessels are they associated with?
Extradural
- arterial
- lucid interval present
Subdural
- acute =damage to underlying brain or bridging veins
- chronic= bridging veins
Subarachnoid
-damage to vertebral arteries
-shearing of intracranial arteries
NOTE: associated with thunderclap headache
Intracerebral:
-delayed intracranial haemorrhage often due to contusions
What is the role of protein misfolding in neurodegenerative disease? Why do inert fibrils form?
- Intra or extracellular insoluble fibrils form inclusions
- Incorrect polypeptide folding leads to loss of tertiary structure which means that the protein will be resistant to catalytic enzyme which means these proteins are inert
- prefibrillar intermediate forms also form which cause toxicity associated with Huntington’s
Why does protein misfolding occur?
Endoplasmic reticulum dysfunction which can occur due to ER stress
What are the common causes of dementia?
Neurodegenerative disease (Alzheimer’s disease) i.e. neurone is primary factor
Vascular disease i.e atheroma, vasculitis or small vessel disease
Alcohol
Hydrocephalus
Metabolic i.e. hepatic or thyroid disease or B12 deficiency, anaemia and hypoxia
Cerebra tumours
AI limbic encephalitis
Chronic traumatic encephalopathy
MS
Infections i.e. Herpes Simplex Encephalitis, HIV/AIDs, Neurosyphilis
What is the pathological process behind Alzheimer’s disease?
Cerebral atrophy due to reduced dendritic branching:
Atrophy occurs due to:
-neuritic plaques (NPs)
-Neurofibrillary tangles (NFTs)
-Amyloid angioplasty (AA)
-Basal nuclei affected= loss of cholinerfgic input to cortex
Which parts of the cerebral cortex are most commonly effected by Alzheimers?
Front and temporal lobes
Sometimes parietal
How are the ventricles affected in Alzheimers and why?
Ventricles become dilated
Due to shrinkage and death of surrounding brain tissue which leads to ventricles appearing enlarged
What proteins are associated with Alzheimer’s disease? Can these proteins be used to definitively diagnose AD?
Neurofibrillary tangles (NFT)= correlate to degree of dementia
Neuritic plaques (NP)
Amyloid angiopathy (AA)
No because NFT are associated with other disorders and NPs are also associated with normal ageing and Lewy body dementia (LBD)
What are risk factors for alzheimers?
Age
Head injury
Low educational status
What factors reduce the risk of Alzheimer’s?
Cardioprotective lifestyle Statin therapy Active and socially integrated lifestyle Arthritis IBD
What are the risk factors for a subdural haemorrhage?
Cerebral atrophy i.e age or dementia
Coagulation dysfunction
Anticoagulation therapy
Alcoholism
What are the secondary events which can lead to head injury?
Ischaemia
Raised ICP
Infection
Post-traumatic epilepsy
Chronic traumatic encephalopathy
What 4 factors can lead to development of cerebral ischaemia and therefore act to cause brain injury?
- Damage brain more sensitive to hypoxia and hypercapnia
- Reduced circulation due to hypotension/hypovolaemia/RICP
- Hypoxia due to obstructed airways or chest injuries
- Infarction due to damage to intracranial or extracranial arteries
What are the 2 main causes of raised intracranial pressure?
Cerebral oedema due to:
- perfusion problems
- reaction to haematoma
- direct reaction to rapid deceleration
Mass effect of haematoma
What are the 2 major causes of infections causing brain injury and by what route can they occur?
Meningitis
Cerebral abscess
Routes: i.e. enables passage of bacteria into intra-cranial cavity
- compound depressed fracture of skull
- fracture of base of skull i.e. air sinuses or middle ear
What types of brain injury increase the risk of post traumatic epilepsy occurring? How can post-traumatic epilepsy lead to TBI?
Intracranial haematomas
Contusional damage
Depressed fractures
PTE can lead to further damage of brain occurring further down the line to original trauma which brought about the PTE
What is chronic traumatic encephalopathy? How is it distinct from Alzheimer’s disease?
Neurodegenerative disease associate with repetitive brain trauma which occurs during contact sports and has a delayed onset
Associated with tau proteins rather than beta-amyloid
Associated with frontotemporal atrophy where as Alzheimers associated with entorhinal cortex and hippocampus damage
What are the histological features associated with Alzheimer’s disease?
Neuritic plaques
Amyloid angiopathy
Neurofibrillary tangle i.e. filament accumulation
What is considered the possible primary event for AD?
Production of beta amyloid protein from beta amyloid precusor protein (BAPP) which is then involved in the production of NPs and AAs
What genetic factors can increase the risk of developing Alzheimer’s disease?
Down’s syndrome
AD mutations in genes affecting processing of BAPP
- BAPP gene
- presenilin 1 gene
- Presenilin 2 gene
What protein aggregates in Alzheimer’s disease and what causes this accumulation?
Beta-amyloid polypeptide
Beta secretase is pathologically active which leads to aggregation of protein
What are the possible treatment options for Alzheimer’s disease?
Donezepil (anticholinergic agent)
Immunisation against amyloid beta peptide but only acts to reduce the plaques rather than having clinical influence
What conditions can apolipoprotein E be a risk factor for?
Increased risk of dementia i.e 3x for those with 1 E4 allele and 8x for homozygotes
-associated with AD because apolipoprotein is involved in the processing of BAPP
MI
Poorer outcomes after heart surgery and head injury etc
What are the 2 main examples of Lewy body disorders? Where are the Lewy bodies located in each of the disorders?
Parkinson’s
-substantia nigra= leads to loss of dopaminergic input to basal ganglia which presents as pallor in the substania nigra
Lewy body dementia or Dementia with Lewy body
-cortical Lewy bodies
-lewy bodies contain alpha-synuclein
NOTE: 90% of people also have Parkinson’s
What is the aetiology of vascular dementia? Where is the damage seen?
Small vessel disease associated with hypertensive changes
Multiple infarcts leads to accumulation of damage
Dominant hemisphere or bilaterally
What is the difference between small and large vessel disease in terms of which part of the brain it preferentially affects?
Small= periventricular white matter
Large= grey matter
What are examples of small vessel disease which can lead to development of vascular dementia?
Vasculitis= associated with vasculitis
Beta-amyloid angiitis
Arteriolosclerosis
What are the different types of dementia?
Alzheimers
Vascular
Lewy body
Fronto-temporal dementias
What are the 3 different variants of fronto-temporal dementia (FTDs)? What is the difference between them?
Semantic-variant primary progressive aphasia
-disorder of semantic knowledge and naming i.e. loss of meanings of words
Non-fluent variant primary progressive aphasia
-gradual loss of ability to speak (i.e. pronounce), understand, read and write
Behavioural variant
-changes in personality, behaviour, insight, disinhibition, inflexibility
What are the pathological classifications of fronts-temporal dementia?
Pick’s disease
-pick bodies found in neurones
Ubiquitin positive proteinopathies
- i.e dementia in MND
- due to depositions
Frontotemporal degeneration w/o specific histology
What structural effect does FTD have on the brain?
Causes knife edge gyri and increased depth of sulci
What are the 3 different types of MND?
Primary lateral sclerosis
Progressive muscular atrophy
Progressive bulbar palsy
What is the pathology associated with MND?
Ubiquitinated inclusions in MN nuclei which can be TDP43 in some cases
I.e. damage to the anterior horn leading to anterior horn atrophy
What type of dementia can motor neurone disease be associated with?
FTD (non-picks disease type)
What are 2 examples of trinucleotide repeat disorders and where are the repeat expansion found?
Huntington’s disease: (AD)
-CAG repeats in EXON= causes abnormal variant protein to form
Friedereichs Ataxia: (AR)
-INTRON= leads to reduced level of protein forming
What are the 3 main forms of human prion disease?
Kuru
Creutzfeldt-Jakob disease
- sporadic (main type)
- iatrogenic
- variant
Fatal familial insomnia (affects the thalamus)
What pathological changes occur in prion disease?
Spongiform changes
Neuronal loss
Gliosis= reactive astrocytic response to brain injury
Amyloid plaque formation in cerebellum mostly
NOTE: vCJD has amyloid plaques in the cerebral cortex
Which type of prion is associated with TSEs?
Protease resistant form of prions which leads to switch from PrP form to PrPsc production
PrPsc are resistant to sterilisation and may form amyloid
What is another way of classifying prion disorders?
Transmissible spongiform encephalopathies (TSEs)
What is MS and what is the pathology behind the disease?
Relapsing condition with gradual accumulation of neurological deficit
Loss of myelin sheaths with relative preservation of axons
Inflammation and gliosis
What structures are affected in MS and what are the commonly associated signs?
Optic nerves Periventricular white matter= leads to formation of periventricular plaques Cerebellum Brainstem Spinal cord
Symptoms:
- optic neuritis
- spinal cord syndrome
- ataxia
- depression
- cognitive problems
What is thought to be the cause of MS?
T-cell mediated immune response to myelin antigens
OR
Oligondendrocyte apoptosis
What is the cause of neuromyelitis optics?
Aquaporin 4 IgG antibodies which leads to damage to the spinal cord and optic nerve
I.e. optic neuritis and transverse myelitis (inflammation of both sides of one part of spinal cord)
