Demyelination and dementia Flashcards
What is demyelination?
Preferential damage to the myelin sheath
Relative preservation of the axons
What is the function of oligodendrocytes?
Locally confining neuronal depolarisation
Protecting axons
Forming nodes of ranvier
What are examples of primary demyelinating disorders?
MS
Acute disseminated encephalomyelitis
Acute haemorrhagic leukoencephalitis
What are examples of secondary demyelinating disorders?
Viral: PML
Metabolic: central pontine myelinolysis
Toxic: CO, organic solvents, cyanide
What is MS?
Auto-immune demyelination disorder characterised by distinct episodes of neurological deficits, separated in time and which correspond to spatially separated foci of neurological injury
What is required for the clinical diagnosis of MS?
Two distinct neurological deficits occurring at different times
A neurological deficit implicating one neuro-anatomical site and a MRI appreciated deficit at another neuro-anatomical site
Multiple distinct CNS lesions on MRI
What are tests that can be run in MS to support the diagnosis?
Visual evoked potentials; evidence of slowed conduction
IgG oligoclonal bands in CSF
What are the clinical features of MS?
Optic neuritis
Spinal cord lesions; motor or sensory deficit in trunk and limbs, spasticity, bladder dysfunction
Brain stem lesion: CN sign, ataxia, nystagmus, INO
Whatare the different types of MS?
Acute or insidious
Relapsing and remitting
What does MS look like morphologically?
White matter disease
Cut surface shows plaques
What are plaques in MS?
Well circumscribed, well demarcated Irregular shaped areas Glassy, translucent appearance Vary from small to large Non-anatomical distribution
What are frequently affected locations in MS?
Adjacent to lateral ventricles Corpus callosum Optic nerves and chiasm Brainstem Ascending and descending fibre tracts Cerebellum Spinal cord
What will active plaques show?
Perivascular inflammatory cells
Microglia
Ongoing demyelination
What will inactive plaques show?
Gliosis
Little remaining myelinated axons
Oligodendrocytes and axons reduced in number
Where are acute lesions commonly found?
Surrounding white matter
Where are chronic lesions commonly found?
Around lateral ventricles
What are the environmental factors of MS?
Assoc with latitude
Relationship with vit D deficiency
EBV viral trigger
What are the genetic risk factors for MS?
HLA DRB1
Why is MS classified as an immune mediated disease?
Lymphocytic infiltration in histology
Oligoclonal IgG bands in CSF
Genetic linkage to HLA DRb1
What are degenerative diseases of the cerebral cortex?
Alzheimer’s
Pick Disease
CJD
What are degenerative diseases of the basal ganglia and brain stem?
PD
Progressive supranuclear palsy
Multiple system atrophy
Huntington’s disease
What are degenerative diseases of the spinocerebellar system?
Friedreich Ataxia
What are degenerative diseases of the motor neurons?
MND
What is the pathogenesis of degenerative diseases?
Simple neuronal atrophy and subsequent gliosis
What is dementia?
An acquired and persistent generalised disturbance of higher mental functions in an otherwise fully alert person
What are the primary dementias?
Alzheimer’s
Lewy body
Pick’s disease
Huntington’s
What are the secondary dementias?
Vascular dementia Infection; HIV, syphilis Tauma, metabolic Alcohol B1 Paraneoplastic syndromes SOL Chronic hydrocephalus
What is the commonest dementia?
Alzheimer’s
What genes are implicated in alzheimer’s?
Amyloid precursor protein (APP) - chromosome 21
Presenilin 1 - chromosome 14
Presenilin 2 - chromosome 1
What are the clinical features of alzheimer’s disease?
Insidious impairment of higher intellectual function with alterations in mood and behaviour
Later: progressive disorientation, memory loss and aphasia
What can be seen macroscopically in alzheimer’s disease?
Cortical atrophy in frontal, temporal and parietal lobes
Widening of sulci and narrowing of gyri
Hydrocephalus ex vacuo
What areas of the brain tend to be spared in alzheimer’s disease?
Occipital
Brainstem
Cererbellum
What are the microscopic features of alzheimer’s disease?
Extensive neuronal loss with assoc astrocyte proliferation
Neurofibrillary tangles
Neuritic plaques
What are neurofibrillary tangles?
TAU protein, assoc with microtubules
Intracytoplasmotic
Where can neurofibrillary tangles be found?
Hippocampus and temporal lobes
Are neurofibrilary tangles a good indicator of disease severity?
No
What are neuritic plaques?
A-beta amyloid plaques
Where can neuritic plaques be found?
Surrounding astrocytes and microglia
How is A-beta amyloid produced?
Cleavage of amyloid precursor protein
What will amyloid stain with?
Congo red
What is the impact of amyloid angiopathy in the brain?
Serum leaking
Oedema
Local hypoxia
What is lewy body dementia?
Progressive dementia along with hallucinations and fluctuating levels of attention and cognition
PARKINSONISM
Is memory affected at the start of lewy body dementia?
No
What are the classical features of parkinson’s?
Loss of facial expression Stooping Shuffling Bradykinesia Stiffness Pill rolling tumour
What can cause parkinsonism?
Idiopatic PD Lewy body dementia Drugs; phenothiazines Trauma; dementia pugilistica Multi-system atrophy Progressive supranuclear palsy Cortio-basal degeneration
What is the pathogenesis of parkinson’s?
Loss of dopaminergic neurons in the substantia nigra
What is seen macroscopically in lewy body dementia?
Pallor in substantia nigra where the pigmented dopaminergic neurones should run
What is seen microscopically in lewy-body dementia?
Loss of pigmented neurones
Reactive gliosis
Microglial accumulation
Aggregates of alpha-synuclein and ubiquitin
What are the classical clinical features of huntington’s disease?
Emotional
Cognitive
Motor disturbance; chorea
What is the inheritance of huntington’s disease?
Chromosome 4
CAG repeats
Shows genetic anticipation
What is seen macroscopically in huntington’s disease?
Atrophy of striatum
Frontal and parietal atrophy occurs later
What is seen microscopically in huntington’s disease?
Simple neuronal atrophy of striatal neurones
Pronounced astrocytic gliosis
What is Pick’s disease (frontotemporal dementia)?
Progressive dementia commencing in middle life characterised by changes in character and social deterioration leading onto impairment of intellect, memory and language
What are the symptoms of frontotemporal dementia?
Personality and behavioural change
Speech and communication problems
Changes in eating habits
Reduced attention span
What can be seen macroscopically in frontotemporal dementia?
Extreme atrophy of cerebral cortex in frontal and later in temporal lobes
What is seen microscopically in frontotemporal dementia?
Neuronal loss and gliosis
Pick’s cells (swollen neurones)
Intracytoplasmic filamentous inclusions known as Pick’s bodies
What is multi-infarct dementia?
Disorder involving a deterioration in mental function due to cumulative damage to the brain through hypoxia or anoxia as a result of multiple blood clots within the blood vessels supplying the brain
Who is most likely affected by vascular dementia?
Men after age of 60
Middle-aged hypertensives
How can alzheimer’s and MID be differentiated?
Abrupt onset
Stepwise progression
History of hypertension or stroke
Evidence of stroke seen on CT or MRI
What is the morphological appearance of MID?
Large vessel infarcts
Atheroma of large cerebral arteries
Lacunar infarcts; related to longstanding hypertension and arteriosclerosis of small vessels
