Patho- Neurodegeneration Flashcards
Give some examples of neurodegenerative diseases?
Parkinson’s Disease
MND
Spinal muscular atrophy
Dementia
What are the four main forms of dementia?
Alzheimer’s Disease
Dementia with Lewy Bodies
Vascular dementia
Pick’s disease
What are some general symptoms of dementia?
Loss of memory
Lack of emotional control
Loss of motivation
Changes in social behavior
What are the two forms of AD?
Late Onset AD (LOAD)
Early Onset AD (EOAD)
What genetics are EOAD inked with?
Autosomal dominant
What is the patho of AD?
Neuron loss
ACh transmission deficiency
What causes neuron loss in AD?
Ab/senile plaques
Tau/neurofibrillary tangles
What are some symptoms of AD?
Gradual onset Loss of ability to take in info and form new memories Decline in language Failure to recognise objects Impaired ability to carry out skilled motor activities Behavioral changes Loss of insight Depression Secondary hydrocephalus
What kind of behavioural changes are seen in AD?
Agitation
Aggression
Wandering
Persecution delusions
How do you diagnose AD?
No test as such
Clinical
Psychometric tests
Rule out vascular dementia etc- History of hypertension suggests VD
What are some symptoms of dementia with Lewy bodies?
Progressive dementia
Daily fluctuations in consciousness
Less memory loss in early stages
Prominent loss of attention and visuospacal skills
Parkinsonism- Falls
Delusions
Very sensitive to haloperidol- causes Parkinsonism
Give some symptoms of vascular dementia
Stepwise progression
History of hypertension of AF or diabetes etc
Brisk reflexes
Up going plantar
How can vascular dementia present on CT?
Can show areas of damage
Describe Pick’s disease
Progressive dementia in midlife
What is the patho of Pick’s disease
Neuron loss
Neuronal swelling- Pick’s bodies
Astrocyte proliferation
What are some symptoms of Pick’s disease?
Slow progressive changes in character- Impaired memory, intellect and language Personality and behavioural change Speech and communication problems Changes in eating habits Lower attention span
What are some differentials of dementia?
Pseudodementia
Delirium
Learning difficulties
How do you treat dementia?
Treat underlying cause if possible
Support
What are some symptoms of spinal muscular atrophy?
Slow progressive symmetrical muscle wasting
What are the three forms of spinal muscular atrophy?
Acute infantile
Chronic childhood
Adult
What is the differential for spinal muscular atrophy?
Muscular dystrophies
MND
What is MND?
Degenerative disease of upper and lower MN
What is the patho of MND?
Progressive deterioration of lower and upper motor neurons in the spinal cord, in cranial nerve motor nuclei and within the cortex
What is the cause of MND?
Generally unknown
Maybe genetic- Rare familial form
What are the four forms of MND?
Amyotrophic lateral sclerosis (ALS)
Progressive bulbar palsy
Progressive muscular atrophy
Primary lateral sclerosis
What is the most common form of MND?
ALS
Describe ALS
Disease of lateral corticospinal tracts causing muscle atrophy
What are some symptoms of ALS?
Evolve over weeks to months
Muscle weakness and spacticity
No sensory loss
How do you diagnose ALS?
Neurophysiology (EMG with evidence of fasciculations)
MRI brain and spine to exclude alternative causes
CK to exclude myopathy
If confirmed – overnight pulse oximetry and ABG
How do you treat ALS?
No cure
Palliative
Riluzole (NMDA blocker and sodium channel blocker)
Describe progressive bulbar palsy
Involves lower cranial nerve nuclei
What are some symptoms of progressive bulbar palsy?
Dysarthria Dysphagia Chocking Nasal regurgitation Wasting of tongue
What is the patho of progressive muscular atrophy?
Spontaneous firing of abnormally large motor units due to loss of other nerve fibres resulting in one nerve fibre taking over many muscle fibres.
What are some symptoms of progressive muscular atrophy?
Muscle wasting- Wasting beginning in the small muscles of hand
Fasciculation
Late sphincter control loss
What are some symptoms of primary lateral sclerosis?
Progressive tetraplegia
What are some general symptoms of MND?
Any sensory signs rule out the diagnosis of MND
Eye movement unaffected in all
Consciousness preserved
Sometimes develop dementia
How do you diagnose MND?
Clinical
EMG
How do you treat MND?
No cure- Death in 3 years
Riluzole slows progress
Symptomatic treatment
What symptomatic treatment can used for MND?
Baclofen for spacticity
Amitriptyline for drooling
Ventilation and feeding etc
What is the pathology of Parkinson’s?
Eosinophilic inclusion bodies (Lewy bodies) develop Substantia nigra (in basal ganglia) undergoes progressive neuronal degeneration- Loss of dopamine
What are some symptoms of Parkinson’s?
Resting tremor- Pill rolling tremor Rigidity Bradykinesia- Delayed initiation of movement Restlessness Shuffling gait Constipation Loss of facial expression Flexed back Monotone then slurring Cognitive changes- Depression Brisk reflexes
What symptom is not seen in Parkinson’s?
No power or sensory loss
How do you treat Parkinson’s?
Clinical: Must have bradykinesis + tremor/disorder of posture balance or gait
Dopamine brain imaging
Symptoms improve with levodopa
Rule out Parkinsonism
How do you rule out Parkinsonism?
Bloods for: TSH, Copper, U+E
CT for vascular
What is the differential for Parkinson’s?
Parkinsonism
What is Parkinsonism?
Symptoms of Parkinson’s without Lewy Bodies
What can cause Parkinsonism?
Drug induced
Vascular
What are some symptoms of drug induced Parkinsonism?
Symmetrical
Coarse postural tremor
What are the symptoms of Parkinsonism?
Tremor, bradykinesia, rigidity, and postural instability
What drugs can cause Parkinsonism?
Haloperidol
TCAs
How do you treat drug induced Parkinsonism?
Stop offending drug
What are some of the symptoms of vascular induced Parkinsonism?
Affects lower limb
No tremour
Poor levodopa response
Brain vascular lesions
How do you treat Parkinson’s?
Dopamine agonists
Levodopa
MAO-B inhibitors
Symptom treatment
Give an example of a dopamine agonist used in Parkinson’s?
Ropinerol
What are some side effects of Ropinerol?
N+V
Postural hypotension
Confusion
Psychosis
Why are dopamine agonists used before levodopa?
Less effective but less side effects
What are some side effects of levodopa?
N+V
Postural hypotension
Confusion
Movement disorders- Freezing
What should you always give with levodopa?
Aromatic amino acid decarboxylase inhibitor
What does MOA-B do?
Break down dopamine
WHen should you prescribe MOA-B inhibitor?
With levodopa
Give an example of a MOA-B inhibitor?
Selegiline
What are some side effects of MOA-B inhibitors?
Hypertension
AF
Sudden uncontrolled movements
Hallucinations
What symptoms do you treat in Parkinson’s?
Tremour
What treatment do you give for tremor in Parkinson’s?
Antimuscarinics and anticholinergics
What protein is LOAD associated with?
ApoE
What genes is EOAD associated with?
APP, PSEN1/2
Physiologically what does ApoE do?
Forms a major part of VLDLP
What are the three major forms of ApoE?
ApoE2
ApoE3
ApoE4
Which form of ApoE is associated with AD?
ApoE4
What is the benefit of ApoE2?
Protective from AD
What is ApoE4 associated with in AD?
More extensive plaques and tangles Higher CSF concentrations of soluble Aβ Impaired synaptic plasticity Increased hypocampal atrophy Reduced cerebral metabolism More brain inflammation
What is the relationship between ApoE and Abeta?
ApoE in VLDLP can uptake and remove Abeta
What does ApoE4 in VLDLP cause?
Abeta uptake into neurons (toxic) instead of glial cells (protective)
What does the APP gene code for?
Amyloid Precursor Protein
What does APP do?
Cell adhesion and signalling
What are the three main forms of APP?
APP695, APP751 and APP770
What enzymes can first cleave APP extracellularly?
α-secretase (ADAM10/17) or β- secretases (BACE1/2)
What happens to ADAM cleaved APP?
Non-amyloidogenic sAPPα and an 83 amino acid C-terminal domain (C83) are produced,
What happens to BACE cleaved APP?
Amyloidogenic sAPPβ and a 99 amino acid C-terminal (C99) are produced
What do the PSEN genes code for?
Presenilin
What does presenilin do?
Forms part of y-secretase which cleaves the C-terminal end of APP
What happens to C83 when cleaved by y-secretase?
Splits into P3 and APP intracellular domain (AICD).
What happens to C99 when cleaved by y-secretase?
Splits into Abeta and APP intracellular domain (AICD).
How does Abeta plaques and Tau tangles cause AD patho?
Increased inflammation
Decreased antioxidants
Calcium toxicity
WHich drugs can help treat ACh loss in AD?
Donepezil- AChE blocker
Galantamine- AChE blocker
Rivastigmine- AChE- blocker
What drug can be used to help treat Ca toxicity in AD?
Memantine- Blocks NMDAR
