3301 - Clin Neuro Flashcards
What is dementia
Umbrella term for a disease that affect memory, thinking and reasoning - a deterioration in cognitive function.
Cognitive changes in dementia (8)
Memory loss, confusion, disorientation and difficulties with communicating, visual and spatial abilities, reasoning/problem-solving, complex tasks, planning/organising, coordination/motor functions.
Psychological changes in dementia (5)
Personality changes, depression, anxiety, agitation and hallucination
Types of dementia (10)
Alzheimers, Lewy-body disease, alcohol-related (Korsakoff’s), genetic (Huntington’s), vascular, fronto-temporal (Pick’s), Parkinson’s, younger-onset, infections (AIDS), Creutzfeldt-Jakob
Korsakoff’s disease cause
Thiamine (vit B1) deficiency from alcohol
Pick’s disease cause
Buildup of tau protein accumulate as Pick’s bodies
Lewy body dementia cause
Unknown. Changes in sleep, behaviour, movement and cognitive ability
Creutzfeldt-Jakob cause
Prion protein - contracted by consumption of infected tissue
Laws of dementia (2)
- Law of Disturbed Encoding - new memories not formed (no short > long)
- Law of Rollback - memory loss starts with most recent
What causes the reduction in brain mass in Alzheimers disease
A loss of communication between neurons causes them to die and brain shrinks
Causes of Alzheimers disease
Amyloid plaques, Neurofibrillary tangles, inflammation, degeneration of cholinergic neurons
What are amyloid plaques
Aggregates of amyloid beta generated by cleavage of amyloid beta precursor protein by β- and γ-secretase.
Stages of amyloid beta
small aggregates (oligomers - most toxic 42aa) > large aggregates (protofibrils) > fibrils > plaques
Effect of amyloid plaques
plaques on nerve endings stop messages getting out of neuron
What are neurofibrillary tangles
Hyperphosphorylated tau becomes paired-helical-filament (PHF) tau which form neurofibrillary tangles (NFTs)
Alternative splicing of gene MAPT produces
6 soluble isoforms of tau protein
Function of tau
stabilises microtubules in axons
Cholinergic hypothesis (AD)
loss of cholinergic (ACh) neurotransmission contributes to deterioration of cognitive function
How does inflammation contribute to AD
Amyloid beta may cause prolonged activation of microglia leading to neuron damage/death.
Familial Alzheimers mutations. % of cases?
APP, presenilin (PS1, PS2). 3% cases
Sporadic Alzheimers causes. % cases?
Risk factors (diabetes, female, age), life style, hormones, mutation in apolipoprotein E (APOE) (E4> 50%)
Down syndrome link to AD
Down syndrome patients have 3 copies of chromosome 21, 3 APP genes > amyloid-beta overproduction
Drugs for AD causes (3)
Cholinesterase inhibitors (mild/medium): Donepezil, Rivastigmine, Galantamine
NMDA receptor antagonist (moderate/severe): Memantine
Monoclonal antibody (severe) - Aducanumab
Drugs for AD symptoms (4)
antidepressants: specific serotonin reuptake inhibitors (citalopram, sertraline)
antipsychotics
typical antipsychotics (haloperidol)
atypical antipsychotics (risperidone)
mood stabilisers:
anticonvulsants (carbemazepine)
Aromatherapy with essential oils
melissa officinalis (lemon balm)
lavendula officinalis (lavender)
Function of (acetyl)cholinesterase
Acetylcholine (ACh) > acetate + choline
function of Acetyl-CoA Synthetase
Converts acetate to acetyl CoA
acetyl CoA + choline >
acetylcholine
Which cholinesterase inhibitor can be applied through transdermal patches
Rivastigmine
Side effects of cholinesterase inhibitors (6)
nausea, vomiting, diarrhoea, slow heartbeat, lack of appetite, weight loss
What is a combination drug for AD
Namzaric
Role of NMDA receptors in AD
Amyloid beta oligmers (and glutamate) stimulate NMDA receptors. NMDA receptors cause Ca influx, AMPA receptors move to membrane causing Na influx. Excess glutamate from drugs etc + Aβ > excess Ca > cell rupture and death
what is Remacemide
NMDA antagonist for epilepsy
what is Riluzole
NMDA antagonist for ASL
What is produced when APP gene is cleaved by a) a-secretase b) b-/y- secretase
a) soluble APP
b) amyloid beta protein
BACE 1 inhibitor MOA (+fun fact)
Target β- mainly and y- secretases to prevent amyloid-beta fragements forming (failed clinical trials)
Aducanumab is used to
Help clearance of amyloid beta oligomers
What is Ginkgo Biloba + SE?
Extract from Chinese plant has anti-inflammatory and anti-oxidant properties. Helps with memory and functions. SE: bleeding
What is Curcumin
Yellow pigment in turmeric. anti-oxidant, anti-inflammatory, cholesterol lowering, reducing amyloid accumulating
Biomarkers (tests) for ante-mortem AD diagnosis (6)
Brain scans (MRI, CT, PET- FDG, PiB), CSF, blood, genetic, ocular biomarkers, and cognitive tests. Blood and ocular not yet in clinical use.
What does a FDG-F18 PET show (fluorodeoxyglucose)
Shows active parts of the brain that use glucose
What does a PiB-PET show (Pittsburg compound)
PiB binds to amyloid-beta plaques to quantify levels in brain
Defining and staging AD uses
A (+/-) amyloid beta plaques
T (+/-) tau - neurofibrillary tangles
N (+/-) neurodegeneration
How does CSF biomarker work?
CSF is taken with a needle from lumbar region. In AD CSF is higher in tau and lower in amyloid beta
Why are blood tests not useful to diagnose AD?
Molecules of interest are in brain, low concentrations in systematic circulation
How can AD associated inflammation be detected?
Using a PET scan. C11 PBR28 binds to translocator protein (TSPO) on outer mitochondrial membrane of microglia. When microglia detect amyloid beta they release IL-3.
Cognitive test for dementia
Mini mental status examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog). Other tests for memory, attention, language, movement, mood
Limitation of cognitive tests for dementia
Doesn’t account for low education
What are ocular biomarkers? What tests are used?
Retina allows for viewing of nerves and blood vessels. AD can lead to a loss of retinal ganglion and macular ganglion cell complex. Viewing is done with OCT, ERG and VEP. Curcumin binds to amyloid beta aiding in imaging. Hyperspectral imaging can discriminate b/n high and low Aβ load on cerebral PET scanning.
Can neurofibrillary tangles be extracellular?
No
What can PET scans be used for?
To asses structural changes, metabolic differences, brain activity, correlates with progression and informs about inflammation processes
Does memantine inhibit generation of amyloid from glial cells with anti-inflammatory function
No
Which chromosome have genes a)PS1, b)PS2 and c)APP?
a) 14, b) 1, c) 21
Define: a) seizures b) epilepsy c) epileptogenesis
a) abnormal electrical signals in brain. b) a disorder of the brain state that supports seizures. c) process of which a normal brain is altered to allow seizures.
Seizure types (3)
Focal, generalised, unknown
Epilepsy syndrome types (3)
Onset in neonates/infants (<2yr), onset in childhood (<17), any age onset (>18)
Categories of epilepsy syndrome in neonates
Self-limited epilepsy, developmental and epileptic encephalopathies, and aetiology-specific
Which category of epilepsy is Dravet Syndrome
Developmental and epileptic encephalopathies in neonates/infants
categories of epilepsy in childhood onset
self-limited focal epilepsies, generalised epilepsies and developmental/epileptic encephalopathies
Categories of epilepsy in any age onset
focal, generalised, combined focal and generalised
Methods to diagnose epilepsy (4)
Medical history, physical examination, EEG, neuro-imaging (MRI, CT)
Physical and neurological indicators of epilepsy
Lateral tongue biting, dysmorphic features (indicate genetic pre-disposition e.g. downs), poor memory, behaviour and QOL
Treatments for epilepsy (4)
Anti-seizure drugs, surgery, neurostimulation (vagus n and deep brain - ant nucleus of thalamus), diet (keto - high fat, low protein, low carb / atkins)
anti-seizure drugs MOA
blockage of Na/Ca/NMDA (glutamate) channels, restore GABA A activity
Aetiology of epilepsy (6)
Genetic
Acquired - structural, metabolic, infections, immune
Unknown
What channel is affected in Dravets Syndrome
Na channels
Which GABA receptor is affected in epilepsy, explain
GABA A receptor has impaired function, loss of inhibitory signals leads to seizures
Epigenetics changes that can cause epilepsy (5)
DNA methylation, histone modification, chromatin remodelling, histone-DNA cross talk and non coding RNAs
Three phases of epileptogenesis
Trigger, latent phase, seizures
mTOR pathway and epilepsy
mTOR pathway responds to glutamate transmission to regulate neuronal structure, synapses, expression of ion channels and receptors. Mutations in parts of the mTOR pathway lead to epilepsy
What are the two GABAergic neurons affected in epilepsy
In hippocampus: Somatostatin +ve interneurons (SOM)
In cortex: parvalbumin +ve, fast spiking interneurons (PV)
What is status epilepticus
one seizure longer than 5min or more than 1 in 5 min w/o returning to normal consciousness in b/n. EMERGENCY!
Genetic cause of Dravets syndrome
mutation in SCN1A gene which encodes for alpha subunit of Na channel, Nav1.1. This reduces Na influx in inhibitory interneurons
What is glaucoma and cause
A group of diseases of the optic nerve usually caused by high intraocular pressure, otherwise caused by poor blood supply to optic nerve or structural issues with optic nerve.
Open angle glaucoma vs closed angle
Open angle is caused by fluid passing too slowly through trabecular meshwork, closed angle is obstruction of meshwork. Closed angle is fast onset and has many symptoms - redness, headache, halo, blurred vision.
Open angle is usually asymptomatic until severe.
Both have dilated pupil (mydriasis)
Treatment for closed-angle glaucoma
eyedrops, oral acetazolamide and laser
What are cataracts
Clouding of the lens caused by clumping of proteins
Three main types of cataracts
nuclear (occur in centre of lens), cortical (periphery of lens and move towards centre) and sub-capsular (beneath or w/n capsule of lens)
What is the difference between wet and dry macular degeneration
Dry: clumping of yellow drusen in retinal pigment epithelium (RPE) beneath photoreceptors. RPE cells may then die causing loss of function of the photoreceptors.
Wet/neovascular degeneration: new blood vessels grow under retina. Leaking and scarring from these vessels can damage photoreceptors.
> Leads to blurring of central vision and distortion of vision.
Dry has no treatment, wet is treated with intravitreal injections
Proliferative vs non-proliferative diabetic retinopathy. Pain?
Non-proliferative: Diabetes > poor glucose control > microaneurysms (swelling of vessel), retinal haemorrhages (leak blood), hard exudates (leak lipids) > spots/floaters and swelling/oedema > decreased vision.
Microvascular occlusion > ischaemia > retinal necrosis (cotton wool spots). Proliferative: ischaemia > VEGF > abnormal blood vessel growth > scarring > retinal detachment and glaucoma. No pain
What is retinitis pigmentosa
A group of genetic eye diseases that lead to damaged photoreceptors
What is a pterygium? Cause? Pain?
A non-cancerous growth of the conjunctiva. Cause is unknown but people working outdoors are more likely to develop. Painless.
Order of cells from vitreous humour to choroid plexus
ganglion cells, bipolar cells, photoreceptors (rods/cones), RPE (all in retina), choroid plexus
Where is the highest concentration of photoreceptors
The fovea
blood supply to eye - dual
internal carotid > ophthalmic > central retinal artery (retina) and ciliary arteries (choroid). Other parts of eye (cornea, photoreceptors..) supplied by diffusion
Extraocular muscles of eye (7)
Rectus (4) sup, inf, lat, med. Oblique (2) sup/inf. Levator palpebrae superioris
CN supply of extraocular eye muscles
3,4,6
CNIII: SR, IR, MR, IO, levator
CNIV: SO
CNVI: LR
what is visual acuity. What does 6/12 mean?
a measure of the eye to distinguish shapes at a certain distance. 6/12: normal person can read at 6m, pt read at 12m - cannot drive
Pupil size can be affected by (3)
Para/symp nerve pathology, horners syndrome (symp lesion - pupil constricts + ptosis), CN 3 palsy (para lesion - pupil dilated)
what does swinging torch test do
Tests for afferent pupillary defect - pupil not constricting with light shining in it
Mydriatic vs miotic pupil
dilated pupil vs constricted pupil
what is light-near dissociation? Cause?
Pupil does not constrict with light but does accomodate for near-sight (referred to as Argyll Robertson pupil) caused by neurosyphilis
Red reflex variants and causes
A darkened red reflex indicates obstruction preventing light from reflecting e.g cataracts. White reflex indicates cataract, retinoblastoma or retinal detachment
Anterior and posterior lesions respect which meridian? why?
Optic nerve axons before chiasm are organised into horizontal hemifields - anterior lesion respects horizontal meridian. Axons cross over in chiasm so posterior lesions respect vertical meridian and are bilateral
Types of refractive error (4)
Myopia (short sighted) - eyeball too long - corrected w concave lens
Hyperopia (long sighted) - eyeball too short - corrected w convex lens
Astigmatism (blurry) - irregular curved cornea - rays focus at different points
Presbyopia (loss of accomodation) - inflexible lens with age
Risk factors for cataracts
age, ocular trauma, ocular inflammation, steroids, systemic disease
Risk factors for macular degeneration
Smoking, age, poor diet
what systematic diseases can have ocular manifestations?
Diabetes, hypertension, thyroid disease, CN palsies, inflammatory disease (vasculitis, autoimmune)
What happens in hypertensive retinopathy
High blood pressure initially causes arteriovenous nicking and arteriosclerosis followed by retinal haemorrhages, cotton wool spots and hard exudates, followed by optic nerve swelling
Signs and symptoms of thyroid eye disease
lid swelling, bulging eyes (proptosis), exposure of eye can cause ulceration of cornea and irritation, eye swelling - can cause optic n compression and vision loss
Thyroid eye disease is mainly associated with what hyperthyroidism disease
Graves disease
Cranial nerve palsies - 3,4,6. Pain?
Affect movement of eye as CN3, 4 and 6 control extraocular muscles. Caused by aneurysms or tumours, sometimes diabetes or hypertension. Painful
What is iritis / uveitis
Inflammation inside the eye. Associated with autoimmune/inflammatory conditions (arthritis, Crohns, lupus)
Signs and symptoms of iritis/uveitis
Pain, blurred vision, keratic
precipitates, hypopyon (WBC accumulation), redness
Treatment of iritis/uveitis
steroids
What is giant cell arteritis/temporal arteritis. Signs/symptoms
Inflammation of arteries typically ext carotid branches but also aorta and vertebral arteries causes bad headaches, jaw pain, polymyalgia, anaemia, weight loss and transient vision loss
Treatment for giant cell arteritis
Steroids (IV administration), temporal artery biopsy for prescense of inflammatory cells
What are two blood biomarkers for inflammation
C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR)
Non-ocular causes of eye disorders (5)
Vitamin deficiencies: A-night vision, B-optic nerve
Drugs e.g corticosteroids > cataract, gluacoma
Emboli: from carotid plaques or calcification in heart
Tumours - often in choroid, melanoma in eye
Systemic infections - TB, HIV, syphilis
How is conjunctivitis and corneal ulcers treated with
antibiotics, antivirals, antifungals
How is glaucoma treated
intra-ocular pressure lowering drops: beta blockers, alpha agonists, carbonic anhydrase inhibitors (slow production of aqueous humour) and prostaglandins (help outflow)
What drugs dilate pupil and why
Atropine and mydriatic drops to examine back of eye
Treatment of proliferative diabetic retinopathy and wet macular degeneration
Anti-VEGF (-mab) injections to stop new vessel formation
Future research areas for eye disorders (5)
genetics (RPE65 gene), neuroprotection, stem cell regeneration, implants - restore accomodation, bionic eyes
What is the connection b/n AD and epilepsy
AD is associated caused by a buildup of tau. Tau binds to a post-synaptic complex that allows for excitotoxic signalling > seizures
What is excitotoxic signalling
Neuronal damage that results from excessive levels of neurotransmitters and results in toxic receptor down stream signalling.
What does P38-ɣ do?
Phosphorylates tau dissociating it from the complex and therefore blocking its excitotoxic effect. Can be used as gene therapy.
What do vigabatrin and sodium valproate do
maintain high GABA at synaptic cleft
In Dravets syndrome seizures are worsened by __ channel ___, such as carbamazepine, lamotrigine,
oxcarbazepine, and phenytoin
Na channel blockers
