Dementia & Degeneration Flashcards
Which diseases are characterised by central degeneration?
- Alzheimer’s - Multiple Sclerosis - Parkinson’s - Huntington’s
Which diseases are characterised by peripheral degeneration?
-Diabetic Neuropathy -Motorneuron disease -ALS -Guillain Barre Sydrome
Name 3 types of neurodegeneration
-Wallerian -Axonal -Myelin
Describe Wallerian degeneration
- Distal degeneration of axon and myelin, generally trauma induced. -Rupture - cuts transmission completely
Describe Axonal degeneration
-Dying back of the axon proximal to cell body -Some regeneration is possible -progressive
Describe myelin degeneration
-Loss of oligodendroglial (central)/Schwann (peripheral) cells affecting conduction velocity -Seen in MS (central) -Seen in Guillain Barre (peripheral)
Name 2 causes of Wallerian Degeneration
-Head trauma (shaken baby syndrome, diffuse axonal injury) -Nerve compression
Why is regeneration more likely in the periphery rather than central nervous system?
-Schwann cells in the periphery are better than oligodendroglial cells at releasing growth factors
What are the 3 classifications of Wallerian degeneration?
- Neuropraxia 2. Axonotmesis 3. Neurotmesis
What are amyloid plaques?
-Aggregations of misfolded/fragmented proteins -Caused by changes in phosphorylation or protein folding -Lead to increased Beta sheet formation
What are beta-amyloid plaques associated with?
Alzheimers disease
what are alpha-synuclein associated with
Parkinson’s disease
What are prion proteins associated with?
CJD
What are Tau proteins?
Maintain the structural composition of microtubules, allowing transport through the neuron.
What are neurofibrillary Tangles?
- Hyperphosphorylation of tau proteins leads to misfolding -misfolding causes breakdown of tubules, B-sheet and fibril formation -Fibrils aggregate to form tangles. -This occurs OUTSIDE the cell
What are inclusions?
-Intracellular protein aggregations including LEWY BODIES and PICK CELLS -Generally alpha-synuclein -Inclusions are INTRACELLULAR
How does diabetic neuropathy present and what is it caused by?
Presentation: Pain, ulcers, tingling, poor balance Caused by: microvascular disease, activated PKC, polyols (secondary to high glucose)
How does Motor Neuron Disease (MND) present?
- UMN and LMN features -Bulbar or pseudobulbar features -muscle weakness and atrophy -no sensory signs, bladder involvement or ocular involvement
What is MND caused by?
-Degeneration of the motor pathways, affecting outflow from the anterior horn cells
What is Guillain-Barre Syndrome?
- Autoimmune reaction triggered by preceding viral/bacterial infection -Rapid onset weakness and tingling that spreads through the body. Normally starts in the feet/legs and spreads upwards -Demyelinating disorder -Treated with IV immunoglobulins and plasmapheresis
What is Multiple Sclerosis?
-Primary inflammatory, autoimmune disease causing CNS demyelination (oligodendroglial cells)
How does multiple sclerosis present?
-Neuropathy -Blindness -Weakness -Numbness Diagnosis is based on demonstration of multiple levels of CNS involvement and CSF sample immunoglobulin bands. MRI: Plaques of products of inflammation accumulate in demyelinated areas, seen as flares in white matter regions of CNS on
What are the different types of MS?
-Benign = No disability, return to normal between attacks, least impact on quality of life - Relapsing-Remitting = Episode + slight deterioration which becomes new baseline = most common - Secondary Progressive = no new disability between attacks, followed by steady increase in disability - Primary progressive = Steady increase in disability without attacks - worst case and the fastest decline
What would be seen in Histology for a patient with Parkinson’s Disease?
-Loss of Dopamine neurons in substantia nigra -Presence of Lewy Bodies -Raised alpha-synuclein/parkin levels -Also get inclusions
What are the characteristics of Huntington’s disease?
- Choreiform movements - Character alteration - Psychotic behaviour - Presentation between 20-50yrs
What causes Huntington’s disease?
- Genetic - Autosomal dominant - Loss of GABA neurons - Loss of cholinergic function - Astrocytosis -Loss of substance P
What pathologies would be seen in the brain of a Huntington’s disease patient?
- Loss of caudate nucleus - Expansion of sulci - Ex vacuo dilatation (Brain produces more CSF to compensate for degeneration, in order to still support the brain) = ventricles get bigger
What causes Creutzfeld-Jakob disease? Presentation?
- Prion protein alteration from PrPc to PrPs - Genetic component - Transmissable Presentation: Behaviour + personality changes, then coordination and myoclonic twitches, incontinence and gradually motor symptoms get worse. - Visbile amyloid plaques and vacuolisation give spongiform appearance
What is a prion?
- Proteinaceous infectious particle - Normal function is presynaptic transport and cell signalling, like alpha-synuclein - Confirmation changes lead to formation of B-sheets and fibrils
Explain the presentation of Variant Creutzfeld-Jakob Disease or “Mad Cow disease”
- Cerebellar presentation (ataxias, stammers, slurred speech) - Cerebellar spongiform - Plaques in cerebral and cerebellar regions - Psychiatric symptoms - PrP in GI tract Notifiable disease! - Local teams + National CJD surveillance unit + National Prion clinic
What is dementia?
A progressive global deterioration in: - Cognition - Memory - Orientation - Concentration - Speech - Behaviour - Personality Deterioration must be sufficient to affect work, social function or relationships It is common, about 1 in 100 people over 60 years old have dementia
Name the 4 broad causes of dementia
- Neurodegenerative - Cerebrovascular - Infection - Normal Pressure Hydrocephalus
Give examples of neurodegenerative conditions which may lead to dementia
Alzheimer’s disease Huntington’s disease Parkinson’s disease Pick’s disease Progressive supranuclear palsy Frontal lobe dementia Dementia with lewy bodies
Give examples of cerebrovascular causes of dementia
Multi-infarct dementia Binswanger’s dementia
Give examples of infection causing dementia
Prion dementias - CJD/ variant CJD AIDs dementia complex Viral Encephalitis
Give examples of acute dementia causes (weeks)
Infective e.g. encephalitis Paraneoplastic
Give examples of subacute (months) dementia?
Thiamine deficiency e.g. Wernicke’s Creutzfeld-Jakob (variant CJD quicker) Inflammatory e.g. vasculitis, sarcoidosis
Give examples of chronic (years) dementia?
Alzheimer’s Pick’s disease Multi-infarct dementia Huntington’s disease
How do we test for dementia?
History from patient and family/friend/carer Cognitive tests Bloods (rule out other causes): FBC, ESR, CRP, B12, LFT, Ca2+, TFT, VDRL/TPHA (rule out syphilis as stomping gait due to dorsal column loss) Neuroimaging - CT/MRI/fMRI For rapidly progressing dementia, may need CSF sample
Which types of dementia are subcortical?
Normal pressure hydrocephalus Parkinson’s disease (BG) Huntington’s disease (BG)
Which types of dementia are cortical?
Frontotemporal dementia Creutzfeld-Jakob disease Alzeheimer’s disease
name some subcortical features of dementia
Apathetic Forgetful & slow impaired visuospatial ability depression of mood
Name some cortical features of dementia
Dysphasia Agnosia Apraxia
Which types of dementia show subcortical and cortical features?
Lewy Body dementia Multi-infarct dementia
What is the commonest cause of dementia? (62%)
Alzheimer’s Disease
Describe the stages of Alzheimer’s disease
Mild cognitive impairment:
- Impairment of episodic memory (hippocampus degeneration)
- Anterograde memory loss
Mild-Moderate dementia:
- poor short-term and longer term memory
- poor semantic memory with poor naming ability
- loss of general knowledge
- visuo-spatial defects
- apathy, irritability, low mood
Advanced dementia:
- global intellectual loss with aphasia, amnesia, apraxia
- Disintegration of personality
- Myoclonus and extrapyramidal motor signs
What can be seen on imaging an adult with Alzheimer’s disease?
How is it truly diagnosed?
- early imaging normal
- Later see neocortical/hippocampal atrophy and medial temporal lobe atrophy
- Functional imaging shows hypometabolism in the posterior cingulate and bilateral parieto-temporal regions
Only confirmed 100% post mortem by histology:
- Plaques
- Neurofibrillary tangles
- Cerebral atrophy- hippocampal/temporal/cortical
- Ex-vacuo dilatation
Normal cause of death is pneumonia
Describe Vascular dementia
- Second most common of dementias (17%)
- Stroke-related
- Step-wise deterioration due to multiple successive events –> multi-infarct dementia
- Pyramidal signs are common
Where there are lots of damaged areas over time e.g. TIAs
Describe Dementia with Lewy Bodies
- Linked to Alzheimer’s and Parkinson’s
- Lewy bodies: protein deposits - alpha-synuclein
- Dopamine & Acetylcholine neurons lose (as in Parkinsons)
- Characteristics are parkonsonisms, visual hallucinations and fluctuations in cognition
Differentiate via DAT scan which is hard on the patient so not often worth it as can easily be distinguished from history, symptoms and exam
Treatments for mild to moderate dementia
Cholinesterase inhibitors: Donepezil, galantamine, rivastigmine Prevents breakdown of acetylcholine, most affected neurotransmitter system in Alzheimer’s disease)
Glutamate receptor (NMDA) antagonist: memantine
May alter disease progression by interfering with glutamate mediated cell death - modest effect (Amantadine and Talampanel also used in Parkinson’s)
