Degeneration And Dementia Flashcards
Give examples of conditions caused by central degeneration of the nervous system
Alzheimer’s
Multiple Sclerosis
Parkinson’s
Huntingdon’s
Give examples of conditions caused by peripheral degeneration of the nervous system
Diabetic Neuropathy
Motor Neurone Disease
Guillain Barre syndrome
What are the 3 main types of neurodegeneration?
Wallerian
Axonal
Myelin
What is Wallerian neurodegeneration?
Distal degeneration of axon and myelin
Generally trauma induced
What are the 3 classifications of Wallerian neurodegeneration (according to Seddon’s classification)?
Neuropraxia (often stretching with no actual damage to fibres of sheathing)
Axonotmesis (damage to axon but not sheathing)
Neurotmesis (partial or complete severance of axon and sheathing)
What is axonal neurodegeneration?
Loss of axon proximal to cell body
Some regeneration can occur
What is myelin neurodegeneration?
Loss of Schwann cells/ ogliodendrogial cells affecting conduction velocity
What are amyloid plaques?
Aggregations of misfolded/ fragmented proteins
What causes amyloid plaque build up?
Changes in phosphorylation and protein folding leading to increased beta-sheet formation
What type of amyloid plaques are found in Alzheimer’s Disease?
Beta-amyloid
What type of amyloid plaques are found in Parkinson’s Disease?
Alpha-synuclein
What is the normal function of tau?
Structural composition of microtubules for transport in the neuron
What causes neurofibrillary tangles?
- Hyperphosphorylation leads to misfolding
- Misfolding leads to breakdown of tubules and beta-sheet/ fibrils formation
- Fibrils aggregate to form tangles
What are inclusions?
Aggregation of intracellular proteins (including Lewy bodies and Pick cells)
What is diabetic neuropathy?
Axonal degeneration
Can be peripheral, autonomic or central
Presentation is often symmetrical ‘glove and stocking’
Presents with pain, ulcers, tingling or poor balance
What causes diabetic neuropathy?
Mixture or microvascular disease and glycolated end products, activated Protein Kinase C and polyols (secondary to high glucose)
What causes the symptoms of motor neuron disease?
Degeneration of the motor pathways, affecting outflow from the anterior horn cells
Aetiology is unknown
What are the symptoms of MND?
UMN and LMN features
Muscle weakness
Atrophy
Bulbar/ pseudobulbar features
What is Guillain-Barre syndrome?
An autoimmune reaction triggered by preceding viral or bacterial infection.
Demyelinating disorder.
What are the symptoms of Guillain-Barre syndrome?
Rapid onset weakness/ tingling spreading from legs to rest of body Paralysis (in some cases) Autonomic dysfunction Difficulty with bladder/ bowel control Severe pain
How is Guillain-Barre Syndrome treated?
IV immunoglobins
Plasmapheresis (filtering of blood)
What is multiple sclerosis?
A primary inflammatory, autoimmune disease causing CNS demyelination
How can MS be seen on MRI?
‘Plaques’ of products of inflammation accumulate in demyelinated areas are seen as flares in white matter regions of CNS
What is the histology of Parkinson’s Disease?
Loss of dopamine neurons in the Substantia Nigra
Presence of Lewy bodies
Raised alpha-synuclein/ parkin levels
Loss of pigmented cells in Substantia Nigra
Where are Lewy Bodies seen in Dementia with Lewy Bodies?
Neocortex
Basal ganglia
Diencephalon
What are the characteristics of Huntingdon’s Disease?
Choreiform movements
Character alteration
Psychotic behaviour
What are the causes of Huntingdon’s Disease?
Genetic (autosomal dominant) Loss of GABA neurons Loss of cholinergic function Astrocytosis (increased astrocytes) Loss of Substance P
What are the causes of Creutzfeld-Jakob disease?
Genetic
Transmittable
Prion protein alteration [PrPc to PrPsc]
What are the different forms of CJD?
Sporadic
Inherited
Iatrogenic
Varient (e.g. GSS)
What is a prion?
Proteinaceous infectious particle
What is the normal function of a prion?
Pre-synaptic transport and cell signalling
How do prions contribute to CJD?
Conformation changes lead to formation of beta sheets and fibrils
Which form of CJD is a notifiable disease?
Variant CJD
What are the stages of the clinical course of dementia?
Acute (weeks) e.g. Infective
Subacute (months) e.g. Inflammatory, Thiamine deficiency or CJD
Chronic (years) e.g. Alzheimer’s, Pick’s, Huntingdon’s
How can dementia be tested for?
History (from patient and others)
Cognitive tests
Bloods (FBC, ESR, CRP, B12, LFT, TFT, VDRL)
Neuroimaging
CSF (sometimes used in rapidly progressing cases)
What types of Dementia are classified as subcortical?
Normal pressure hydrocephalus
Parkinson’s Disease
Huntingdon’s Disease
What types of Dementia are classified as cortical?
Frontotemporal dementia
Creutzfeld-Jakob Disease
Alzheimer’s Disease
What are the features of a subcortical form of dementia?
Apathetic
Forgetful/ slow
Impaired visuospatial abilities
Depression of mood
What are the features of a cortical form of dementia?
Higher cortical abnormalities
Dysphasia
Agnosia
Apraxia
What types of Dementia are classified as both cortical and subcortical?
Multi-infarct Dementia
Dementia with Lewy Bodies
What are the pathological features of Alzheimer’s Disease?
Neurofibrillary tangles (tau) Neuritic plaque (beta-amyloid) Increase diffuse plaque
What characterises a ‘mild cognitive impairment’ stage of Alzheimer’s Disease?
Impairment of episodic memory
Anterograde memory loss
What characterises a ‘mild to moderate’ form of Alzheimer’s Disease?
Poor short and longer-term memory Poor semantic memory (e.g. poor naming ability) Loss of general knowledge Visuo-spatial deficits Apathy/ irritability/ low mood
What characterises an ‘advanced’ form of Alzheimer’s Disease?
Global intellectual loss (e.g. aphasia, amnesia, apraxia)
Disintegration of personality
Myoclonus and extrapyramidal motor signs
How can Alzheimer’s Disease be identified on MRI/ fMRI?
Atrophy of medial temporal and hippocampal regions
Functional imaging may show hypometabolism in the posterior cingulate and bilateral parieto-temporal regions (less activity seen so dark areas on fMRI)
Nb. early imaging may be normal!
When can an Alzheimer’s Disease diagnosis be confirmed?
Through a post-mortem
Identification of plaques, neurofibrillary tangles, cerebral atrophy
What causes Vascular Dementia?
Stroke-related (can be multi-infarct or single-infarct)
Small vessel damage (e.g. Binswanger’s disease)
What are the most common forms of Dementia?
- Alzheimer’s (62%)
- Vascular Dementia (17%)
- Mixed Dementia
What is the pathology of Dementia with Lewy Bodies?
Lewy body deposits (alpha-synuclein)
Loss of Dopamine and ACh neurons
What characteristics are indicative of Dementia with Lewy Bodies?
Hallucinations
Parkinsonism
Fluctuations in cognition
What is the pathology of fronto-temporal dementia?
Atrophy of frontal and temporal lobes
Tau positive
Pick cells (ballooned cells)
Neuronal inclusions (Pick bodies)
What are the 3 cardinal features of normal pressure hydrocephalus?
- Gait disturbance
- Cognitive decline (subcortical pattern)
- Urinary incontinence
How can normal pressure hydrocephalus be identified on MRI?
Enlarged ventricles
What are the pharmacological treatment options for Dementia?
- Cholinesterase inhibitors (prevent breakdown of ACh)
2. Glutamate receptor antagonists (used in more severe forms of dementia)
What are the key cholinesterase inhibitors used in the treatment of Dementia?
Donepezil
Galantamine
Rivastagmine
What is the key glutamate receptor (NMDA) antagonist used in the treatment of Dementia?
Memantine
Which form of Dementia is generally not treated pharmacologically?
Vascular Dementia (as damage affects localised areas not NTs so drugs generally ineffective) Should instead focus on improving QoL and background problems (e.g. BP and cholesterol)
What is the treatment for normal pressure hydrocephalus?
CSF shunt inserted
Third ventriculostomy
What abnormalities on imaging would you expect to see in a patient with Alzheimer’s?
Cortical atrophy (enlarged sulci post mortem) Enlarged ventricles
What is Freidreich’s Ataxia?
Autosomal recessive disorder caused by GAA triplet repeats in the FXN gene (Frataxin) leading to problems with iron metabolism - this results in loss of large myelinated fibres and affects the spinocerebellar tracts, dorsal root ganglia, posterior column and loss of cerebellar mass and corticospinal tracts
What are the key features of Freidreich’s Ataxia?
Progressive limb and gait ataxia
Dysmetria (loss of coordination)
Dysarthria (difficulty articulating speech)
Poor balance (sensory ataxia)
Loss of joint position and vibration senses
Absent tendon reflexes in lower limbs (extensor plantar)
Muscle weakness
Cardiomyopathy
What causes ALS?
Mutation of the SOD1 gene which leads to protein misfolding and reduced removal of Reactive Oxygen Species (ROS) leading to loss of motor neurons predominantly in the corticospinal tract and anterior horn cells
What pathological features characterise ALS?
Gliosis (nonspecific reactive change of glial cells e.g. ogliodendrocytes)
Astrocytosis
Lateral column degeneration
What are the typical features of ALS?
TONIC ATROPHY:
muscle wasting
fasciculations
brisk reflexes
