Neuropathology (1)

Question 1

What are the subdivisions of primary and secondary events of head injuries?

Answer 1

Primary divided into neural and vascular

Secondary divided into ischaemia, oedema and infection

Question 2

What are common characteristics of a contusional injury?

Answer 2

focal symptoms
contre-coup injury = injury showing lesion opposite to impact
common in frontal and temporal lobes
Cause: burst lobe, intracerebral haemorrhage and post traumatic epilepsy

Question 3

What is TAI?

Answer 3

traumatic axonal injury
- Diffuse axonal injury is the most severe
- high velocity acceleration/deceleration with torsion are major causes of persistent vegetative state
Clinical effects are immediate but cellular effects evolve over hours
Axon bulbs form when axons rupture - 24 hours
Beta-APP present in 2-3 hours
Petechiae in corpus callosum, brainstem
Gliding contusions =haemorrhage in parasagittal WM, often bilateral but usually asymmetrical

Question 4

What are the 3 types of traumatic vascular damage?

Answer 4

1) diffuse vascular damage - widespread petechial haemorrhages - death soon after injury
2) damage to arteries -in neck or intra-cranially causing infarction or focal ischaemia
3) intracranial haemorrhage

Question 5

What are the different types of traumatic intracranial haemorrhage ?

Answer 5

1) Extradural - arterial, sometimes no associated cerebral damage, lucid interval
2) subdural - acute: from damage to underlying brain or bridging veins; chronic: from bridging veins; RF: cerebral atrophy, coagulation dysfunction, anticoagulation therapy, alcoholism
3) subarachnoid - damage to vertebral arteries in neck, or shearing of intracranial arteries
4) Intracerebral - often from contusions, may occur hours or even a day or 2 after injury

Question 6

What is a damaged brain more sensitive to?

Answer 6

more sensitive to hypoxia and hypercapnia/hypercarbia (co2 retention)
- hypoxia can occur due to compromised airway or chest injuries

Question 7

What are causes of an ischaemic brain?

Answer 7

reduced circulation due to:

• hypotension, hypovolemia, e.g. surgical shock
• raised intracranial pressure

Question 8

What are the different types of infarction in the brain due to ?

Answer 8

damage to an artery:

• intra-cranial compartment
• extracranially - carotid, vertebral arteries

Question 9

What are the causes of raised intracranial pressure?

Answer 9

1) Cerebral oedema - perfusions/circulatory problem, reaction to haemotoma, direct reaction to rapid deceleration
2) mass effect of haematoma

Question 10

What are the causes of infection?

Answer 10

1) meningitis - a) compound depressed fracture of the skull, b) fracture of base of skull, through air sinuses, middle ear
2) cerebral abscess - same routes

Question 11

When does head injury occur due to post traumatic epilepsy?

Answer 11

early (first week/mnth) = about 4-5%
Late = 40% within 6 mnths, 50% <1 year
early PTE gives rise to 25% risk of late pte
incidence relates to severity of injury therefore absence of intracranial haematoma, contusional damage or depressed fracture, risk of PTE is 1%

Question 12

What is chronic traumatic encephalopathy?

Answer 12

neurodegenerative disorder in people with repetitive brain trauma e.g. contact sports
delayed onset with progression over time
Tauopathy / dementia puglistica- distinct from AD as it is mainly frontotemporal atrophy and there is no beta-amyloid

Question 13

What occurs in protein misfolding?

Answer 13

involved in neurodegeneration

• incorrect folding into a tertiary structure is likely the cause of catalytic enzyme resistance- it is these molecules which form inert fibrils
• prefibrillar intermediate forms are also formed - cause toxicity e.g. in HD

Question 14

Why does protein misfolding occur?

Answer 14

Due to endoplasmic reticulum dysfunction - also plays a role in hypoxic damage

Question 15

What is the incidence of dementia?

Answer 15

5% @ 70-74 years
20% @ 75-80 years
40% > 90 years

Question 16

What are the causes of dementia?

Answer 16

vascular disease - mainly atheroma
alcohol
hydrocephalus
metabolic - hepatic and thyroid disease, b12 deficiency, poryphyria, anaemia, hypoxic
cerebral tumours and paraneoplastic syndrome
autoimmune limbic encephalitis
chronic traumatic encephalopathy
MS
infections: Herpes simplex encephalitis, HIV/AIDS, neurosyphilis, progressive multifocal leucoencephalopathy, subacute sclerosing pan encephalitis

Question 17

What are the common conditions that cause dementia?

Answer 17

AD - 65-70%
Vascular dementia - 15-20%
Lewy body dementia - 10%
Frontotemporal dementia - 5%
other <1%

Question 18

What are the key characteristics of AD?

Answer 18

Cerebral atrophy- mainly frontotemporal
neuritic plaques
neurofibrillary tangless
amyloid angiopathy - increases risk of haemorrhaging
basal nuclei affected - loss of cholinergic input to the cortex

Question 19

What is the pathogenesis of AD?

Answer 19

Similar features to normal ageing
NFT density correlates with severity - increased density = increased severity
Neuritic plaques only found in AD, LBD and ageing
- amyloid in these plaques - amyloid depositis are formed by beta-amyloid protein derived from beta amyloid precursor protein

Question 20

What are the risk factors for AD?

Answer 20

age, head injury, low educational status (but not socioeconomic status)

Question 21

What factors reduce risk of AD?

Answer 21

Cardioprotective lifestyle, statin therapy, active and socially integrated lifestyle, arthritis and IBD

Question 22

What are the genetic factors relating to AD?

Answer 22

Down’s syndrome - earlier onset (40s)
Autosomal dominant forms- mutations in:
- BAPP gene (chr21)
- presenillin-1 - onset 30-50 and is commonest form
- presenillin -2
common factor is they affect the processing of BAPP

Question 23

What are the treatments for AD?

Answer 23

arricept (Donezepil) - anticholinergic agents
Immunization against amyloid B peptide - reduced plaques but no clinical improvement and induced encephalitis in some pts

Question 24

What is the link between apolipoprotein E?

Answer 24

5 alleles, E4 has an increased risk of dementia (x3 increased risk with one E4 allele; homozygotes for e4 = x8 increased risk) +

• higher rate of fatal M
• poor outcome after head injury, cardiac bypass surgery, cerebral haemorrhage
• greater psychological impairment

Question 25

What is apolipoprotein E involved in?

Answer 25

processing of BAPP

Question 26

What are the clinical features of parkinson’s disease(-/+ dementia)?

Answer 26

pigmented cell loss in the substantia nigra with lewy bodies in some of the remaining cells - leads to loss of DA neurons input to basal ganglia

Question 27

What are the clinical features of lewy body dementia?

Answer 27

cortical lewy bodies - onset tends to be later
90% also have parkinsonism and they often have visual hallucinations, a fluctuating course, and relative memory preservation
Lewy bodies contain alpha-synuclein

Question 28

What are the clinical features of vascular dementia?

Answer 28

multi-infarct dementia
vol of grey matter lost
lesions in dominant hemisphere
lesions bilateral
small vessel disease associated with hypertensive changes - periventricular white matter damage
rarer causes of small vessel disease = vasculitis, beta-amyloid angiitis

Question 29

What are different variations of fronto-temporal dementias?

Answer 29

SEMANTIC VARIANT PRIMARY PROGRESSIVE ASPHASIA - disorder of semantic knowledge and naming

NON-FLUENT VARIANT PRIMARY PROGRESSIVE ASPHASIA - with language deficits

BEHAVIOURAL VARIANT - initial relative preservation of memory with deterioration in personality and behaviour, disinhibition, lack of insight, inflexibility, stereotypic behaviour, late onset alcoholism may occur

Question 30

What are common mutations found in fronto-temporal dementia?

Answer 30

Tau mutations (chr17)
progranulin genes

Question 31

What are the pathological classifications of fronto-temporal dementias?

Answer 31

Pick’s disease - pick bodies that are tau positive

Ubiquitin positive proteinopathies - includes dementia in MND and MND type inclusions

Question 32

What are the different types of MND?

Answer 32

primary lateral sclerosis - UMN
Progressive muscular atrophy - LMN
Progressive bulbar palsy

Question 33

What is the pathology of MND?

Answer 33

ubiquitinated inclusions in motor neuron nuclei, TDP43 inclusions in sporadic cases

Question 34

What are some of the gene mutations involved in MND?

Answer 34

SOD1, SQSTM1 (encodes p62 protein)

hexanucleotide repeat in the C90RF72 gen

Question 35

What is an examples of an exon trinucleotide repeat disorder and an intron trinucleotide repeat disorder?

Answer 35

Exon: HD
Intron: Friedereich’s ataxia

Question 36

What are the clinical features of HD?

Answer 36

Progressive dementia and choreiform movements, onset in adult hood

Question 37

What are examples of prion disorders?

Answer 37

Kuru
Creutzfeldt-jakob disease
fatal familial insomnia

Question 38

What is the pathology of prion disorders?

Answer 38

spongiform change, neuronal loss, gliosis, amyloid plaques in some cases, mostly in the cerebellum
numerous amyloid plaques in the cerebellum and also the cerebral cortex in variant CJD

Question 39

Define: prion

Answer 39

Proteinaceceous infective particle

• normal prion = part of the cell membrane
• abnromal = protease resistant form is agent causeing TSEs (PrPsc)

Question 40

What does PrPsc do?

Answer 40

induces cells to switch from PrPn to PrPsc productions - may form amyloid

Question 41

What is multiple sclerosis?

Answer 41

Relapsing/remitting neurological condition with gradual accumulation of neurological deficit
Sequential development of multiple lesions with demylelination - relative axonal sparing, inflammation, gliosis
Affects in particular optic nerves, perventricular white matter, cerebellum, brainstem and spinal cord
Can cause: depression, spinal cord syndrome, atacxia, optic neuritis, cogntiive problems

Question 42

What is the epidemiolgy/incidence of MS?

Answer 42

Onset is about 30 years
M:F = 1:1.5
little disability in 30% for 15 years 
overall reduction in life expectancy is a few years less than normal 
increased incidence further from equator
vitamin D appears to have a role in it

Question 43

What is the pathology of MS?

Answer 43

Loss of myelin sheath with relative axonal preservation
T cell mediated immune response to myelin antigen
now thought that oligodendrocyte apoposis may be a primary event