Demyelination & Dementia Flashcards
What does it mean to have a rise in lymphocytes in CSF?
-indicates INFECTION or INFLAMMATION in the intracranial cavity
What are the 3 roles of Oligodendrocytes?
MYELIN production:
- locally confining neuronal DEPOLARIZATION
- protecting axons
- forming NODES of RANVIER
What are the nodes resp. for?
Precipitating RAPID saltatory conduction
Most likely group to have MULTIPLE SCLEORSIS?
- Female in 20-30yr gr.
- a/w Latitude
Describe Multiple SCELORSIS.
- demyelinating d.o characterized by distinct NEUROLOGICAL deficits, seperated in TIME
How to clinically dx MS?
- two DISTINCT neuro deficits occurring at diff. times
- neuro defect implicating site A on brain, but MRI appreciates a site B defect
- multiple, distinct CNS lesions on MRI
What is seen in the CSF of MS?
IgG oligoclonal bands in CSF
What are the clinical fts of MS?
- OPTIC nerve lesions (neuritis) –unilateral
- spinal cord lesions (MOTOR/SENSORY deficit in TRUNK or LIMBS; spasticity; bladder dysfxn)
- brain stem lesions (CN signs; ataxia; nystagmus; internuclear ophthalmoplegia
Describe in 3 points the course of MS.
- Acute or Insidious onset
- relapsing and remitting course
- neurological deficits may mount and become progressive
Describe plaques on cut surface.
- well circumscribed/demarcated
- irregular shape
- glassy appearance
- v.small to LARGE
Which sites are commonly affected by Plaques? (7)
- CN 2
- periventricular white matter
- corpus callosum
- brainstem
- ascending and descending tracts.
- spinal cord and cerebellum
What is seen Microscopically in Active plaques? (2)
- active inflammation (perivascular)
- ongoing DEMYELINATION
What is seen in Inactive plaques?
- gliosis
- little myelinated axons
- oligodendrocytes and axons REDUCE in no.
What cells are predominantly present in an Active Plaque?
Microglia
Distinguish grossly an Active plaque from an Inactive plaque.
Active plaque - appears YELLO/BROWN
Inactive- appears Grey-brown
What could be environmental factors causing MS to occurs?
- latitude association
- vit.D deficiency (inadequate sunlight exposure at high latitudes)
- probable viral trigger (EBV)
Are genes a possible cause for MS?
- genetic a/w HLA DRB1
- 15x risk if first degree relative has MS
- 150x risk if you have a Monozygotic twin
- a/w polymorphisms in IL-2 and IL-7
Why is MS said to be an immune mediated disease?
- histologically: lymphocytic infiltration in csf
- oligoclonal IgG bands in csf
- genetic linkage to HLA DRB1
What have animal studies proven in terms of the immune pathogenesis of MS?
- T-helper 1 and 17 are actively involved in the demyelinating disease
What is one form of immune therapy for MS?
Anti B-cells therapies reduce relapses and frequencies of myelinating lesions
—-b-cells are the Ab-producing lymphocytes
Define Dementia
ACQUIRED and PERSISTENT, generalized disturbance of higher mental functions, in an otherwise alert person.
PATHOLOGICAL! —not part of ageing
Apart from IIary dementia; what other factors may contribute to the manifestation of dementia?
- Drugs and Toxins (ALCOHOL)
- Vit. B1 deficiency
- paraneoplastic syndromes
- intracranial space occupying lesions
- chronic hydrocephalus
Why is the age of onset for Alzheimer’s dementia relevant?
- the LATER, the age of onset; the more rapid and severe the changes tend to be.
What are demographics of Alzheimer’s like?
female, 85+y.o
What is Alzheimer’s genetically a/w?
- increased incidence with TRISOMY 21 (APP)
- Familial incidence (1%)
What mutations are implicated in familial AD?
- Presenilin 1 (Chr.14) &2 (Chr.1)
- point mutations in amyloid precursor protein (APP)
What is the initial presentation of Alzheimer’s?
- insidious impairment of HIGHER INTELLECTUAL fxn
- alterations in MOOD and BEHAVIOUR
What occurs later on in Alzheimer’s?
- progressive disorientation
- MEMORY LOSS
- aphasia (d/t severe cortical DYSFXN)
- results in muteness, profound disability, immobility
Which areas of the brain is primarily affected and how?
- the frontal, parietal and temporal lobes will ATROPHY
- widening of sulci and narrowing of gyri
- ->DECREASED size and weight of the brain
What may occur IIary to cortical loss of the brain?
-hydrocephalus Ex Vacuo (dilatation of the ventricles)
What are 2 major microscopic fts of Alzheimer’s?
- Neuritic Plaques
2. Neurofibrillary tangles
What are neurofibrillary tangles?
- accumulation of INSOLUBLE microtubules in the cytoplasm of neurones
- TAU protein is disregulated in AD and other dementias
- microscopic changes, specifically seen in HIPPOCAMPUS and TEMPORAL lobe
What is seen in and around the plaques?
- tortuous neuritic fibres surrounding an A-beta amyloid core
- also surrounded by astrocytes and microglia
What is a vascular ft of AD?
-AMYLOID ANGIOPATHY
Why are Down $ pts most likely to get early onset Alzheimer’s ?
because the APP gene is located on Chromosome 21 —extra quantity of the gene
What is Presenilin resp. for?
- metabolism of APP
what is a/w pathological severity of AD and why?
-the quantity of A-beta OLIGOMERS
What does A-Beta Oligomers do pathologically?
- known to promote hyper-phosphorylation and mislocalisation of TAU (accumulation)==> neuronal dysfxn and cell death
- brings about POST-SYNAPTIC activation of NMDA receptors==> EXCITOTOXICITY ==> NEURONAL DAMAGE
How does Amyloid angiopathy come about?
occurs due to accumulation of A-beta amyloid proteins within the walls of the vessels.
What occurs as a result of amyloid angiopathy?
-disruption of BBB
>serum leaking
>edema
>local hypoxia ==>excititoxicity
What is the presentation of Lewis Bodies Dementia?
- progressive dementia, with Hallucinations and FLUCTUATING levels of attention/cognition
- memory is affect later (contrast to AD)
- fts of Parkinsonism at onset
What is the relation between Parkinson’s and Lewis Body Dementia?
- only a small portion of those with Parkinson’s will develop Lewis Body Dementia
- ALL with Lewis body dementia get Parkinson’s fts
What other conditions affect the Substantia Nigra ?
- idiopathic parkinson disease
- Drugs (phenothiazines)–chlorpromazine
- trauma …dementia Pugilistica (boxer’s dementia)
- Multi-system Atrophy
- progressive SUPRANUCLEAR PALSY
- cortico-basal degeneration
What macroscopic change is seen in the Mid brain in Lewis Body dementia?
pallor of the substantia Nigra
What is seen microscopically in Lewis Body Dementia at the Substantia Nigra?
- loss of pigmented neurons
- reactive gliosis
- remaining neurons contain Lewis Bodies ( eosinophilic bodies with a DENSE core and pale halo)
- aggreagates of alpha-synuclein and ubiquitin
What demographics for Huntington’s disease? 1
ages 35-60
What are the clinical fts. of Huntington’s Disease?
- triad of Emotional, Cognitive and Motor Disturbance >chorea, myoclonus >clumsiness, slurred speech > depressed. irritable and apathetic LATER DEVELOPS DEMENTIA
Why is genetic counselling important in Huntington’s Disease?
- because it is an AUTOSOMAL DOMINANT inherited disease, which has a late disease onset at about 35-50y.o
- by the time, most people would have already have kids
Explain the genetic pathogenesis in Huntington’s Disease.
- mutation of the Huntingtin gene on Chromosome 4p
- mutant gene of CAG repeats form
- DISEASE occurs when >35 repeats occur!
What is seen macroscopically in Huntington’s?
- atrophy of the BASAL ganglia (Caudate-esp. , and Putamen nuclei)
- cortical atrophy occurs later on
What is seen microscopically in Huntington’s?
- neuronal atrophy of striatal neurones in basal ganglia ==> loss of INHIBITORY inhibition of motor activity> CHOREA
- Pronounced astrocytic gliosis
What is Fronto-Temporal Dementia?
- aka Pick’s Disease
- progressive dementia beginning MID-LIFE (between 50-60s)
- progressive change in CHARACTER and SOCIALdeterioration
>impairment of INTELLECT, MEMORY and LANGUAGE
What are the symptoms of Pick’s Disease?
- a/w frontal and temporal lobes
- speech and comm. problems
- personality and behavioural changes
- change in EATING habits
- reduced attention span
Describe the progress of FTD?
- rapidly progressive illness
- may last between 2-10years
- mean length of illness (7years)
How diff. is the degree of Atrophy in Pick’s?
- MUCH BIGGER than AD
- extreme atrophy of cerebral cortex in the F AND T lobes
- so severe that the brain weighs <1 kg
What is seen Microscopically in Picks?
- pick’s cells (Swollen Neurones)
- intracytoplasmic filamentous INCLUSIONS known as PICK’S
- pick’s cells are enriched with TAU, Ubiquitin and TDP-43
How does Multi-infarct (VASCULAR) dementia come about?
- deteriotration in mental functioning d/t CUMULATIVE damage to the BRAIN through hypoxia/anoxia as a result of MULTIPLE BLOOD CLOTS in blood vessels. > large areas of cell death and damage = DEMENTIA (need 50-100ml of brain loss for dementia to occur)
What are the demographic in this disease?
- 60y.o Men
- also in middle-aged hypertensives
- –note: those aware of THEIR mental deficits are prone to DEPRESSION and ANXIETY
How to distinguish Vascular dementia from AD?
- MID has an ABRUPT onset
- stepwise progression—as further strokes occur down the line
- hx of HTN or STROKE
- evidence seen on CT or MRI
What is seen morphologically with Vascular Dementia ?
- large vessel infarcts
- scattered throughout hemispheres
- atheroma of large vessel arteries
- small vessel infarcts (rarer) —d/t longstnding HTN
Which genes are involved in the early onset of AD?
- Presinilin 1, 2
- APP
What gene prediposes you rrisk of AD in general?
- Apoprotein E allele E4
