Demyelination and dementia Flashcards
What does the insulation of axons by oligodendrocytes achieve?
- locally confines neuronal depolarisation - protects axons - forms nodes of ranvier
What is the function of nodes of ranvier?
Precipitate rapid saltatory conduction
What is demyelination?
Preferential damage to myelin sheath
Relative preservation of axons
What are the causes of primary demyelination?
- multiple sclerosis
- acute haemorrhagic encephalomyelitis
- acute haemorrhagic leukoencephalitis
What are the causes of secondary demyelination?
Viral
Progressive multifocal leukoencephalopathy
Metabolic
Central pontine myelinosis
Toxic
CO, organic solvents, cyanide
What is the commonest demyelinating disease?
Multiple Sclerosis
Prevalence of 1/1000
Female:Male ratio is up to 2:1
Peak incidence in 20-30 years
Define multiple sclerosis?
Auto-immune demyelinating disorder characterised by distinct episodes of neurological deficits, separated in time, and which correspond to spatially separated foci of neurological injury
What criteria is there for the clinical diagnosis of MS?
- two distinct neurological defects occuring at different times
- a neurological deficit implicating one neuro-anatomical site, and a MRI appreciated defect at another neuro-anatomical site
- multiple distinct (usually white matter) CNS lesions on MRI
What is supportive of a diagnosis of MS?
Visual evoked potentials (evidence of slowed conduction)
IgG oligoclonal bands in CSF
Describe the presentation of MS
Optic nerve lesions (optic neuritis)
Unilateral visual impairment
Spinal cord lesions
Motor or sensory deficit in trunk and limbs
Spasticity
Bladder dysfunction
Brain stem lesions
Cranial nerve signs
Ataxia
Nystagmus
Internuclear opthalmoplegia
Describe the progression of MS
Acute or indisious onset
Relapsing and remiting
Later becomes progressive
Describe the morphology of multiple sclerosis?
Principally a white matter disease
The exterior of brain remains normal
Cut surface of the brain shows ‘plaques’
What are plaques?
Well circumscribed, well demarcated
Irregular shaped areas
Have a glassy, almost translucent appearance
Vary from very small to large lesions
Non-anatomical distribution
What locations are frequently affected by plaque?
- adjacent to lateral ventricles
- Corpus callosum
- Optic nerve and chiasm
- Brainstem
- Ascending and descending fibre tracts
- Cerebellum
- Spinal Cord
Describe the pathogenesis of plaques
Active Plaques
- perivascular inflammatory cells
- microglia
- ongoing demyelination
Inactive Plaques
- gliosis
- little remaining myelinated axons
- oligodendrocytes and axons reduced in number
What are shadow plaques?
May reflect a degree of demyelination
Demonstrate thinned out myelin sheaths at the edge of lesions
Result in a less well defined lesion
What is the macroscopic appearance of acute (Active lesions)
Demyelinating plaques are yellow/brown, with an ill-defined edge which blends into surrounding white matter
What is the macroscopic appearance of chronic (inactive) lesions
Well-demarcated grey/brown lesions in white matter, classically situated around lateral ventricles
What environmental factors are associated with MS?
Latitude
Relationship with Vitamin D deficiency. sunlight exposure?
A viral trigger remains hypothesised
What genetic factors are found in MS?
- 15 x risk if 1st degree relative has MS
- 150x risk with an affected monozygotic twin
- genetic linkage to HLA DRB1
- GWAS found association with polymorphism in IL-2 and IL-7
Why is MS an immune mediated disease?
- lymphocytic infiltration in histology
- oligoclonal IgG bands in CSF
- genetic linkage to HLA DRB1
What T- cell factors are thought to be associated with MS?
TH1 cells- IFN-g activating macrophages
TH17 cells- recruiting and activating damaging leukocytes
What are the humeral factors associated with MS?
- Oligoclonal IgG bands on CSF
- Anti B-cell (antibody producing lymphocytes) therapies reduce relapses and frequency of myelinating lesions
What are the degenerative diseases of the cerebral cortex?
Alzheimers disease, Pick disease, CJD
What are the degenerative diseases of the basal ganglia and brainstem?
Parkinsons disease, progressive supranuclear palsy, multiple system atrophy, huntington disease
What is the spinocerebellar degenerative disease?
Spinocerebellar ataxia (e.g. friedreich ataxia)
What is the degenerative disease of motor neurones?
Motor neuron disease
What are degenerative diseases pathologically classified by?
Simple neuronal atrophy and subsequent gliosis
Define dementia
An acquired persistent generalised disturbance of higher mental functions in an otherwise fully alert person
What are the causes of primary dementia?
- Alzheimer’s disease
- Lewy body dementia
- Pick’s disease (fronto-temporal dementia)
- Huntington’s disease
What are the causes of secondary dementia?
- multi-infarct (vascular) dementia
- infection (HIV, syphillis)
- Trauma
- Metabolic
- paraneoplastic syndromes
- intracranial SOL
- chronic hydrocephalus
- Drugs and toxins (alcohol)
- Vitamin deficiencies (vitamin B1 )
Who is affected by alzheimer’s disease?
F:M 2:1
40% prevalence in over 85s
How is dementia inherited?
Usually sporadic
May be familial (1%)
Implicated genes: amyloid precursor protein (APP), presenilin 1 &2)
Increased incidence in trisomy 21
What does alzheimers disease cause?
Initially- impairment of higher intellectual function, with alterations in mood and behaviour
Later- Progressive disortientation, memory loss and aphasia indicate severe cortical dysfunctino
Can result in profound disability, muteness and immobility
Describe the macroscopic pathology of dementia
- Decreased size and weight of brain (cortical atrophy)
- Location: frontal, temporal and parietal lobe atrophy
- widening of sulci
- Narrowing of gyri
- Compensatory dilatation ventricles, secondary hydrocephalus ex vacuo
- occipital lobe spared, brainstem and cerebellum normal
What are the microscopic features of alzheimers disease?
- extensive neuronal loss with associated astrocyte proliferation
- neurofibrillary tangles
- neuritic plaques
- amyloid angiopathy
Where are neurofibrillary tangles found?
In hippocampus and temporal lobe
Intracytoplasmic
Tau protein, associated with microtobules
What are neuritic plaques also called?
Aß amyloid plaques
Surrounding astrocytes and migroglia
How is Aß produced?
By cleavage of amyloid precursor protein (APP)
Where is APP found?
Chromosome 21
Where are presenilin 1 and presenilin 2 found?
Where is apolipoprotein E found?
Presenilin 1= chromosome 14
Presenilin 2= chromosome 1
Allele e4
What is amyloid angiopathy?
Extracellular eosinophillic accumulation
What is the structure of amyloid angiopathy
Polymerised beta pleated sheets formed by Aß
Amyloid angiopathy stains with what?
Congo red
What does amyloid angiopathy cause?
Disruption of BBB
- serum leaking
- oedema
- local hypoxia
Lewy body dementia makes up __-__% of dementias
Lewy body dementia makes up 10-15% of dementias
Lewy body demendia presents how?
Progressive dementia, along with hallucinations and fluctuating levels of attention/cognition
Fluctuation in severity on a day to day basis
Features of parkinsonism present at onset, or emerge shortly after
What is the clinical presentation of parkinsonism?
Loss of facial expression
Stooping
Shuffling gait
Slow initiation of movements
Stiffness
Pill rolling tremor
What conditions affect the nigro-striatal dopaminergic pathway and cause parkinsonism?
Idiopathic parkinsons diseae
Lewy body dementia
Drugs (phenothiazines)
Trauma (dementia puglistica)
Multi-system atrophy
Progressive supranuclear palsy
Cortico-basal degeneration
What are the pathological features of lewy body dementia?
Degeneration of the substantia nigra
What is seen macrospically in lewy body dementia?
Pallor in the substantia nigra, where pigmented dopaminergic neurones run
What is seen microscopically in lewy body dementia?
Loss of pigmented neurons
Reactive gliosis, microglial accumulation
Remaining neurons may show lewy bodies
Fewer cortical lewy bodies
What are lewy bodies?
- single/multuple intracytoplasmic, eosinophilic, round to elongated bodies that have a dense core and a surrounding pale halo
- Aggregates of a-synuclein and ubiquitin
Huntingtons disease is a relentlessly ______ neuropsychiatric disorder, onset most comminly between the ages of __-__ but can occur at any time
Huntingtons disease is a relentlessly progressive neuropsychiatric disorder, onset most comminly between the ages of 35-50 but can occur at any time
What are the clinical features of huntingtons disease?
Triad of emotional, cognitive and motor disturbance
Develop dementia later
What ar the symptoms of huntingtons disease?
- chorea
- myoclonus
- clumsiness
- slurred speech
- depression
- irritability
- apathy
Where is the hintintin gene?
On chromosone 4p
When is the huntingtin gene normal?
If < 28 repeats, disease penetrant if more than 34
What is the macroscopic pathology of huntingtons?
Atrophy of basal ganglia: caudate nucleus; putamen
Cortical atrophy occurs later
What is the microscopic pathology of huntingtons disease?
Simple neuronal atrophy of striatal neurones in the basal ganglia
Pronounced astrocytic gliosis
Pick’s disease is a ________ dementia commencing in ___ ____ (usually between __ and __ years) characterised by progressive changes in _______ and _____ deterioration leading on to impairment of _______, ______ and ________
Pick’s disease is a progressive dementia commencing in middle life (usually between 50 and 60 years) characterised by progressive changes in character and social deterioration leading on to impairment of intellect, memory and language
What are the symptoms of pick’s disease?
Personality and behavioural changes
speech and communication problems
changes in eating habits
reduced attention span
Picks disease may last between _ to __ years, the mean length of illness is around _ years.
Picks disease may last between 2 to 10 years, the mean length of illness is around 7 years.
What is the macroscopic pathology of pick’s disease?
Extreme atrophy of cerebral cortex and later in temporal lobes
Brain weight <1kg
Neuronal loss and gliosis
What are the histological hallmarks of FTD?
Pick’s cells (swollen neurons)
Intracytoplasmic filamentous inclusions known as pick’s bodies
Define multi-infarct dementia
Disorder involving a deterioration in mental functioning due to cumulative damage to the brain through hypoxia or anoxia (lack of oxygen) as a result of multiple blood clots within the blood vessels supplying the brain
Multi-infarct dementia is more common in ______ then in _____. It commonly occurs after the age of __, but also seen in middle aged ___________
Sufferers are aware of their mental deficits and are prone to ________ and ______
Multi-infarct dementia is more common in men then in women. It commonly occurs after the age of 60, but also seen in middle aged hypertensives
Sufferers are aware of their mental deficits and are prone to depression and anxiety
What clues help to differentiate MID from alzheimer’s disease?
- abrupt onset
- stepwise progression
- history of hypertension or stroke
- evidence of stroke will be seen on CT or MRI
What is the commonest morphological appearance of MID?
- Large vessel infarcts
- Scattered throughout hemispheres
- Atheroma of large cerebral arteries provoke thromboembolism
What is a rarer morphological appearance of MID?
Small vessel (lacunar) infarcts
Central, subcortical distribition
What are small vessel (lacunar) infarcts associated with?
Longstanding hypertension and arteriosclerosis of small vessels
