Degeneration and Dementia Flashcards
What are the three main forms of neuronal degeneration?
1) Wallerian –> distal degeneration of both the axon and myelin, usually trauma induced.
2) Axonal –> degeneration of the axon towards the cell body (some regeneration is possible)
3) Demyelination –> loss of oligodendrocytes or schwann cells, affecting conduction velocity. Central form –> multiple sclerosis Peripheral form –> Guillian Barre
What are some of the common causes of Wallerian degeneration?
Generally head trauma, causing diffuse axonal injury - where you get widespread shearing of axons from their cell bodies, damage to white matter tracts and grey matter.
Shaken baby syndrome (coup- contre coup injury), and nerve compression.
What are the three classes of wallerian degeneration?
Neuropraxia –> least severe, stretching injury rather than shearing, neuronal cell body and axon remain intact. (praxia = inaction)
Axontmesis –> moderate damage to neuronal axon/ myelin, but remain intact (tmesis = to cut)
Neurotmesis –> most severe, partial or complete severing/ shearing of neuronal cell body and axon. (tmesis = to cut)
After a wallerian degenerative injury is regeneration possible?
Regeneration is possible but depends on the type of cut, clean cut better than twisting/ ripping.
Depends exactly on GF’s, proteins and amount of electrical activity of the injured neuron.
Peripheral NS is better than the CNS at regeneration as Schwann cells are better at releasing GF’s than oligodendrocytes.
What is transneural degeneration and why might it occur?
Transneural degeneration is degeneration of the neurons that synapse with the primarily injured neuron.
It occurs as injury to 1 neuron means loss of communication to the other neurons which die by the “use it or lose it” principle.
What are amyloid plaques?
What proteins are involved and what conditions are these proteins associated with?
Amyloid plaques are aggregrates of misfolded protein or fragmented protein.
Proteins involved: Beta amyloid –> alzheimers
Alpha synuclein –> in parkinsons
prions –> CJD
Tau proteins –> alzheimers and parkinsons
How might amyloid plaques be caused?
- Amyloid plaques are caused by misfolded or fragmented proteins
- this can be caused by a change in phsophorylation or changes in protein folding
- Leads to increased Beta sheet formation
What are neurofibrilary tangles?
What protein is involved?
What is the normal function of this protein and how is this changed in disease?
- Neurofibrilary tangles are formed by misfolded Tau protein that forms long strips and fibrils that group together to become a tangle.
- Tau is a microtubule associated protein that normally functions to stabilised the structure of MT’s and is involved in the transport of vesicles down microtubules to the synapse, where Tau stabilises vesicles being held there.
- In disease, hyperphosphorylation of Tau proteins leads to misfolding of the Tau protein. Misfolding of the Tau protein leads to:
- Get loss of structural integrity of microtubules/ breakdown
- loss of vesicle transport and neuronal signalling
- leading to cell death.
What are inclusions? What is included under this term?
What are the proteins normally involved?
What other proteins can be involved?
What is the characteristic appearance of inclusions?
- Inclusions are intracellular protein aggregations formed of misfolded proteins
- Includes both Lewy bodies and Pick cells (also pick bodies- formed of large, dark protein aggregations).
- Protein involved is mainly alpha synuclein
- other proteins that can be involved = ubiquitin, crystallin, neurofilament
- Characteristic appearance = dense core and halo of surrounding filaments
What is diabetic neuropathy?
How does it present?
What is the cause?
- Diabetic neuropathy is where you get degeneration in neurones due to microvascular disease. Insufficient blood supply to neurons leading to axonal degeneration that heads towards the cell body.
- Primarily axonal –> dying back
- It can affect peripheral, autonomic or central nerves
- If peripheral it is often symmetrical and has a glove and stocking appearance –> starts in peripheries first, affecting feet, knees then fingers.
- Affects regions with poorest circulation first.
- Presents with pain both neurological and nociceptive (ulcer formation).
- Neurological pain presents with tingling and poor balance.
What is motor neurone disease?
How can it present?
Who does it affect more?
What is the mean survival?
- Motor neurone disease is a rare neurological condition that causes the degeneration of the motor system, leading to muscle weakness and wasting. There are no sensory signs, bladder or ocular involvement.
- Regions of degeneration affects the presentation of the disease which can present with both UMN and LMN symptoms, bulbar and pseudobulbar features and muscle weakness/ atrophy. Degeneration can occur in:
- Corticospinal and pyramidal tracts –> primary lateral sclerosis = progressive muscle weakness in voluntary muscles, affecting UMN
- Motor cortex itself
- Corticobulbar pathways (pseudobulbar palsy)
- Cranial nerve nuclei (progressive bulbar palsy)
- Anterior horn cell (progressive muscle atrophy)
- Unknown cause but affects men > women
- Mean survival is only 3 years
What is amyotrophic lateral sclerosis?
What is the cause? Where does degneration occur?
How may it present/ what are its particular features?
what is the life expectancy?
Amyotrophic lateral sclerosis (also known as Lou gehrig’s disease), describes a progressive neurological degenerative condition that affects the motor pathways specifically involved in the control of voluntary muscles.
- Caused by change in SOD1 - superoxide dismutase that breaks down ROS that cause neuronal damage.
- Leads to degeneration of motor neurons in corticospinal tract (Betz cells) and neurons in anterior horn. Thinning of anterior roots and fibres pathways.
- Characterised by:
- Gliosis –> increase in glial / supporting cells following damage
- Astrocytosis –> increase in astrocytes following neuronal damage
- degeneration of corticospinal tract
- muscle atrophy
- Presents with Tonic atrophy –> muscle atrophy, fasiculations, hypereflexia
- Life expectancy only 2-6 years.
What is Friedrich’s ataxia?
What is the inheritance pattern? What is the cause?
How does it present?
- Friedrich’s ataxia is an autosomal recessive inherited disorder that affects the Frataxin gene, affecting Iron metabolism.
- This leads to degeneration of large myelinated neurons, spinocerebellar tracts, dorsal columns, dorsal root ganglia and eventually loss of cerebellar mass and corticospinal tracts.
- Presents with:
- Progressive limb and gait ataxia
- Sensory ataxia
- Loss of proprioception, joint position and vibration senses
- Loss of tendon reflexes lower limb
- muscle weakness
- cardiomyopathy
- Dysmetria –> over or undershoot of movement
- Dysarthria –> difficult/ unclear articulation of speech
What is Guillain Barre syndrome?
What is the trigger?
How may it present?
What forms are there?
How is it treated?
- Guillian Barre syndrome is a progressive demyelinating autoimmune disorder triggered by an acute bacterial or viral infection.
- Presents with:
- rapid onset weakness and tingling that spread through the body
- prickling, pins and needles in peripheries
- Weakness in legs that spreads up body, unsteady walking
- difficulty with eye/ facial movements
- Generally starts in feet/legs and spreads upwards
- Peak symptoms 2-4 weeks after onset
- Can lead to paralysis
- Three forms:
- AIDP - acute inflammatory demyelinating polyradiculoneuropathy - most common
- miller fisher syndrome - ocular form
- Acute motor axonal neuropathy –> aggressive and nondemyelinating
- Treatment:
- Immunoglobulins
- Plasmapheresis (like dialysis but removes harmful antibodies).
- Good prognosis
What is multiple sclerosis?
How does it normally present?
How is MS diagnosed?
- Multiple sclerosis is a primary inflammatory, autoimmune disease causing CNS demyelination.
- Presents with neuropathy —> usually 1 feature initially , either blindness, weakness or numbness
Often presents with optic neuritis, may present similar to stroke.
- MS normally diagnosed via symptoms, there has to multiple systems of the CNS involved in the symptoms.
If there is only 1 symptom could infer it is only a lacunar infarct, if there are multiple areas affected (visual/ weakness/ numbness) likely to be MS.
Also take CSF sample —> looking for oligoclonal bands (immunoglobulins against oligodendrocytes). However not all MS patients will present with this —> 70%.
How can Multiple Sclerosis present differently?
- There are multiple types of MS (8 forms). The relapsing/ remitting course is the most likely.
- The benign form presents with its initial symptoms for a certain but then returns back to their normal function.
- Relapsing/ remitting—> patients start at a baseline level of disability and may have an episode/ attack in which symptoms worsen. They then return to this new baseline level of disability inbetween, worsening at next attack.
- Progressive forms:
- Secondary progressive —> No new disability in between attacks but then followed by a steady increase in disability.
- Primary progressive —> steady increase in disability without attacks.
How might MS present on a CT/MRI?
Outline the gross pathological changes of MS?
- Presents as loss of deep white matter
- Plaques which are the product of inflammation accumulate in demyelinated areas, seen as flares in white matter regions of the CNS.
How might Lewy Body dementia present differently to Parkinson’s disease histologically?
- Lewy body dementia presents with Lewy bodies within the neocortex, and subcortical regions (thalamus and basal ganglia) , rather than just the substantia nigra of the basal ganglia.
What are the gross pathological changes that would show in a Huntingtons brain?
—> Expanded ventricles (ex vacuo dilatation)
—> loss of basala ganglia, thalamus and shrunken head of caudate nucleus
—> cortical structural changes —-> widened sulci
Describe the clinical course of dementia: Time frame
What conditions fit into which type of time frame?
- Acute (Weeks): infective (viral encephalitis), paraneoplastic - inflammatory reaction to neoplasm
- Subacute (months): CJD, inflammatory ( vasculitis), thiamine deficiency wernickers encephalopathy ( lack of thiamine- B1)
- Chronic: Alzheimer’s, parkinsons/huntingtons/ multi infarct/ picks
What is cortical and subcortical dementia?
How can they present differently?
Link this to the anatomical regions that are affected.
- Cortical dementia describes dementia that occurs mainly via degeneration of the cortex, affecting higher cognitive functions - problem solving, reasoning, memory, language.
- Link to anatomy: affects lobes of brain:
- frontal lobe with motor cortex, personality and judgement
- parietal lobe with sensory cortex and visuospatial integration
- temporal lobe with auditory, olfactory, wernickes, memory, emotion
- Occipital with primary visual cortex
- Presents with dysphasia/aphasia (impaired production/ understanding speech) , agnosia (inability to interpret sensation and recognise objects), apraxia (difficulty planning and performing motor tasks, affects purposeful movement) and amnesia (total or partial loss of memory).
- Subcortical dementia describes degeneration that occurs mainly in subcortical structures - thalamus, basal ganglia, limbic system and generally spares higher cortical functions.
- Presents with apathetic depressed personality, impaired visuospatial reasoning, forgetful slow memory and reduced speech.
Give examples of subcortical, cortical and then mixed dementias
- Subcortical: Parkinsons, huntingtons, normal pressure hydrocephalus
- Cortical: alzheimer’s, frontotemporal/ picks disease, CJD
- Subcortical and cortical: Vascular dementia - multi infarct dementia, cortical lewy body dementia
Define alzheimer’s disease/ What is alzheimer’s disease?
- Alzheimer’s disease is a progressive neurodegenerative disorder, the most common form of dementia (62%).
- Normally presents during late middle age or old age –> rarely genetic early onset form presents under 45 yrs
- Characterised by progressive mental deterioration, with impaired cognition, memory, behavioural and personality changes, disorientation.
- Histologically characterised by neuronal cell death in the cerebral cortex, neurofibrillary tangles and beta amyloid plaques.
Describe the stages of development of alzheimer’s disease
- Mild cognitive impairment:
- Impairment episodic memory (episodic - autobiographical events, time place who what etc..)
- anterograde amnesia
- Mild - moderate dementia:
- Problems with short and long term memory
- poor semantic memory, poor naming ability (semantic memory - factual recall, general world knowledge).
- loss of general knowledge
- visuo-spatial problems
- apathy, irritability and low mood
- Advanced dementia:
- Global intellectual loss
- Disintegration of personality
- myoclonus and extrapyramidal motor signs
- myoclonus –> spasmodic jerky contractions groups of muscles
- Extrapyramidal symptoms –> due to loss of DA neurons, dyskinesia, bradykinesia, parkinsonism, dystonia (sustained muscle contraction).
What are some possible causes of alzheimer’s disease?
What would be shown histologically during a post-mortem of an alzheimer’s brain?
What is the normal cause of death in an alzheimer’s patient?
- Causes: environmental, genetic, loss of cholinergic neurons
- Histological: Post mortem changes:
- Neurofibrillary tangles
- Beta amyloid plaques
- Gross morphology:
- Cerebral atrophy –> temporal, hippocampal, cortical
- ex-vacuo dilation
- Alzheimers can only be confirmed post mortem
- Normal cause of death –> pneumonia
What is vascular dementia? How does the deterioration occur?
What conditions does this include?
What are some of the risk factors for one of the subtypes of vascular dementia?
Vascular dementia, also known as multi infarct dementia is the 2nd most common form of demetia (17%), caused by a lack of blood supply to the brain that leads to neuronal cell damage and death.
Can be caused by:
Stroke related dementia: multiple infarcts (Multiple TIA’s) or by a single large infarct (Stroke).
Small vessel dementia: Binswager’s disease
-Affects small deep penentrating vessels of the brain that go to the thalamus and basal ganglia, often presents with extrapyramidal symptoms (dyskinesia/ akinesia/ parkinsonism/ dystonia).
Watch out for risk factors for binswager’s disease such as hyoercholesterolaemia and hypertension.
What is dementia with Lewy Bodies?
What are lewy bodies also linked to?
How does dementia with lewy bodies present?
- Dementia with Lewy bodies is the 3rd most common type of dementia, accounting for 4% of dementia in UK.
- Linked to Alzheimer’s and loss of Ach and Parkinsons and loss of DA neurons
- Degeneration of neurons due to the presence of Lewy bodies: protein aggregations of alpha synuclein.
- Characteristics/ presentation:
- Parkinsonsim- shuffling gait, balance issues, rigidity, dyskinesia
- Visual hallucinations and inability to interpret visual information, unable to identify known persons
- Delusions
- fluctations in cognition - decline thinking, reasoning and memory
- REM sleep disorder (Acting out dreams)
What is fronto temporal dementia?
What is it also known as?
what type of patients is it more common in?
Describe the pathology, what proteins are involved?
Frontotemporal dementia accounts for 2% of dementias in the UK. Due to focal atrophy of the frontal or temporal lobes. Also known as pick’s disease, however this is now a subtype of frontotemporal dementia which includes other subtypes.
More common in younger patients (under 65), those with a family history of dementia, parkinsons or motor neurone disease (1/3 patients with FTD have family history).
Pathology:
Subgroup of FTD due to Tau protein aggregation forming Pick’s cells, leading to death of neurons in frontal/ temporal lobes. Also due to neuronal inclusions (protein aggregation within the cell) –> known as Pick body.
Other group due to Ubiquitin protein aggregation.
Others are Tau negative and ubiquitin negative.
What is normal pressure hydrocephalus?
What are the causes?
What will you see on imaging?
- Normal pressure hydrocephalus is a clinical symptom complex caused by the build up of CSF.
- Condition is characterised by abnormal gait, urinary incontinence and reversible dementia/ cognitive decline with subcortical pattern
- Abnormal gait –> bradykinesia, broad shuffing gait (due to compression of periventricular sacral motor fibres)
- Urinary incontinence –> frequency, urgency or incontinence (due to compression of periventricular sacral motor fibres)
- Dementia –> memory loss, decreased attention
- Causes:
- Known –> injury/ bleeding/ infection/ trauma.
- Often idiopathic –> unknown cause
- Imaging: ventriculomegaly
What are some of the pharmacological treatments of Dementia?
- Mild to moderate dementia: Reversible Cholinesterase inhibitors –> donepezil, galantamine, rivastigmine
- Treats mild to moderate dementia by preventing the breakdown of acetylcholine the most affected NT in alzheimers.
- “Acetylcholinesterase, you’re DONE GALAvanting down the RIVA”
- Moderate to severe dementia: Glutamate receptor NMDA anatagonist: Memantine “NoMoreDementiA with memory and tea”
- alter disease progression by interfering with glutamate mediated cell death.
