cellular degeneration and dementia by joshua bower easter revision 2014 questions?...
TRANSCRIPT
Degeneration
• Describe the process of normal cellular aging• Explain the changes in function associated with
cellular aging• Use first principles to explain the changes you would
see with defects in cell aging• Use the neurodegenerative diseases to explain how
cellular stress can lead to accelerated degeneration of cells
• Outline the microscopic and ultrastructural changes you would see in degenerating cells
Give TWO examples of cellular processes which can lead to cellular aging [2]
• Reduced ATP• Mitochondrial damage• Ca2+ entry• Membrane damage• Protein misfolding• Reactive oxygen species
List THREE outcomes of cellular ageing [3]
• Reduced capacity to function
• Reduced capacity to respond to injury
• Cell death– Apoptosis vs necrosis
List THREE changes leading to cellular ageing [3]
• Decreased cellular replication– E.g. by p16INK4a, DNA damage
• Accumulation of genetic and metabolic changes– E.g. balance between metabolic damage and
repair
• Reactive oxygen species-induced damage
Reactive oxygen species injury cells by what THREE mechanisms? [3]
• Membrane lipid peroxidation• Interaction with proteins• DNA damage
What is Werner syndrome?
• Rare, autosomal recessive disorder causing premature ageing (progeria)
• Causes decreased cellular replication
What is Friedreich’s ataxia?
• Autosomal recessive disorder leading to spinocerebellar degeneration
• Leads to axon loss and gliosis
Where are the spinocerebellar tracts?
Mitochondrial dysfunction
Decreased ATP
Reactive oxygen species
DNA damage
Reduced frataxin protein
Neuro Flashback –Name FIVE types of glial cells [5]
• Astrocytes• Oligodendrocytes• Schwann cells• Ependymal cells• Microglia
Where is this?
What is ALS?
• Amylotrophic lateral sclerosis
• 1 of 5 MND subtypes• Reduced capacity to
detoxify cells OR misfolded proteins causes ER stress >> cell injury
• Affects the myelinated fibres of the corticospinal tracts
Motor Neurone Disease Subtypes
http://en.wikipedia.org/wiki/Motor_neuron_disease
• Explain the scientific basis for neurological and psychiatric presentations
• Explain the causes and investigation of neurological and psychiatric problems
• Describe how to do cognitive assessment in the context of undertaking a psychiatric mental state examination
• Distinguish delirium from dementia
Dementia
A 75 year old man is found wandering in the streets in his dressing gown in the middle of winter. He tells you
he got a bit lost on the way to the shops.
Differential diagnosis?
Dementia Delirium Substance misuse Hypoxia Head injury Electrolyte imbalance Pseudodementia
Distinguish delirium from dementia [5]
Delirium Dementia
Onset Rapid Gradual
Course Fluctuating Progressive
Consciousness Impaired Clear
Speech Dysarthria Normal
Memory and attention STM affected (recent change)Fluctuating attention
Poor memory (gradual loss)Inattention
Important to obtain a collateral history
List FOUR possible causes of delirium [4]
• Drugs• Electrolyte/fluid imbalance• Lack of drugs (withdrawal, delirium tremens)• Infection• Reduced sensory input (vision/hearing loss)• Intracranial (post-stroke)• Urinary difficulties (UTI, catheter)• MI
What are the clinical features of dementia?
• Cognitive impairment associated with a decline in self-care and an inability to perform ADLs
• Issues with:– Memory– Problem-solving– Judgement– Attention– Orientation– Language
How can dementia be investigated clinically?
• History• Mini-mental state exam (MMSE)– Score out of 30– <27 means cognitive impairment– Bad for fronto-temporal dementia
• Addenbrooke’s cognitive assessment– Incorporates MMSE and frontal lobe assessment
• GPCOG – GP cognitive assessment• CT scan
What is pseudodementia?
• Dementia caused by depression• Not caused by brain damage• Treated with anti-depressants
What is the commonest form of dementia?
• Alzheimer’s
What TWO pathological findings would confirm Alzheimer’s disease, and what is
the protein involved in each? [2+2]
• Plaques – beta-amyloid– Amyloid precursor proteins are directly neurotoxic
and cause inflammation• Tangles – tau-protein– Involved with microtubule stabilisation. When
hyperphosphorylated, prevent binding so microtubules degenerate affecting cellular function
What CT findings are suggestive of Alzheimer’s? [3]
• Shrinkage of cerebral hemispheres• Widened sulci• Enlarged ventricles
What class of drugs can be used to treat Alzheimer’s? Give an example [1+1]
• Acetylcholinesterase inhibitors– Donepezil– Rivastigmine– Neostigmine– Galantamine
• These stabilise the condition, slow decline and postpone onset of severe dementia
• Or NMDA-R antagonists if MMSE <12 e.g. memantine
Give TWO side effects of AChesterase inhibitors [2]
• Think dryness– Dry mouth– Blurred vision– Urinary retention– Constipation– Tachycardia– Confusion– N&V– Dizziness
What is vascular dementia?
• Aka multi-infarct dementia• Dementia following cerebral infarction –
patients can experience sudden decline, then plateau (step-wise deterioration)
• Emboli can cause sudden decline, with subsequent improvements in specific areas over time (e.g. speech)
• Treatment? Reduce risk factors!
What is mixed dementia?
• Alzheimer’s + vascular dementia
What are Lewy bodies?What THREE diseases are they associated with?
• Abnormal protein aggregates of alpha-synuclein which can form in neurones in the cerebral cortex
• Associated with Lewy Body Dementia, Alzheimer’s and Parkinson’s disease dementia
How can Lewy body dementia and Parkinson’s disease be distinguished?
• In PD dementia, motor symptoms present for ~1yr prior to dementia onset
• In LBD, memory symptoms occur first, or both occur together
Give an example of a frontotemporal dementia.How can it be distinguished from Alzheimer’s?
• Pick’s disease– Build up of tau-protein into Pick bodies
• In Pick’s disease, character and behaviour changes develop before memory loss. May also have speech problems
• There are 3 broad types of FTD for you to look up
Give an example of an organic dementia
• Creutzfeld-Jakob disease– Prion disease where abnormal folding of prions
leads to gliosis, synaptic and neuronal loss– Can be transmissible person-to-person– Sporadic (idiopathic), variant (bovine spongiform
encephalopathy) or familial (inherited)• HIV/AIDS–associated dementia– Can occur in up to 40%
• Neurosyphilis (Treponema pallidum)• Viral encephalitis (often HSV)
