Patho- Neurodegeneration Flashcards by Finlay Strivens

Give some examples of neurodegenerative diseases?

Parkinson’s Disease
MND
Spinal muscular atrophy
Dementia

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What are the four main forms of dementia?

Alzheimer’s Disease
Dementia with Lewy Bodies
Vascular dementia
Pick’s disease

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What are some general symptoms of dementia?

Loss of memory
Lack of emotional control
Loss of motivation
Changes in social behavior

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What are the two forms of AD?

Late Onset AD (LOAD)

Early Onset AD (EOAD)

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What genetics are EOAD inked with?

Autosomal dominant

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What is the patho of AD?

Neuron loss

ACh transmission deficiency

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What causes neuron loss in AD?

Ab/senile plaques

Tau/neurofibrillary tangles

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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

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What kind of behavioural changes are seen in AD?

Agitation
Aggression
Wandering
Persecution delusions

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How do you diagnose AD?

No test as such
Clinical
Psychometric tests
Rule out vascular dementia etc- History of hypertension suggests VD

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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

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Give some symptoms of vascular dementia

Stepwise progression
History of hypertension of AF or diabetes etc
Brisk reflexes
Up going plantar

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How can vascular dementia present on CT?

Can show areas of damage

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Describe Pick’s disease

Progressive dementia in midlife

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What is the patho of Pick’s disease

Neuron loss
Neuronal swelling- Pick’s bodies
Astrocyte proliferation

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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

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What are some differentials of dementia?

Pseudodementia
Delirium
Learning difficulties

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How do you treat dementia?

Treat underlying cause if possible

Support

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What are some symptoms of spinal muscular atrophy?

Slow progressive symmetrical muscle wasting

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What are the three forms of spinal muscular atrophy?

Acute infantile
Chronic childhood
Adult

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What is the differential for spinal muscular atrophy?

Muscular dystrophies

MND

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What is MND?

Degenerative disease of upper and lower MN

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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

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What is the cause of MND?

Generally unknown

Maybe genetic- Rare familial form

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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