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Cellular Degeneration and Dementia

Cellular Degeneration and Dementia. By Joshua Bower Easter Revision 2014 Questions? J.Bower@warwick.ac.uk. Degeneration. Describe the process of normal cellular aging Explain the changes in function associated with cellular aging

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Cellular Degeneration and Dementia

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  1. Cellular Degeneration and Dementia By Joshua BowerEaster Revision 2014Questions? J.Bower@warwick.ac.uk

  2. 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

  3. 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

  4. List THREE outcomes of cellular ageing [3] • Reduced capacity to function • Reduced capacity to respond to injury • Cell death • Apoptosis vs necrosis

  5. 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

  6. Reactive oxygen species injury cells by what THREE mechanisms? [3] • Membrane lipid peroxidation • Interaction with proteins • DNA damage

  7. What is Werner syndrome? • Rare, autosomal recessive disorder causing premature ageing (progeria) • Causes decreased cellular replication

  8. What is Friedreich’s ataxia? • Autosomal recessive disorder leading to spinocerebellar degeneration • Leads to axon loss and gliosis Reduced frataxin protein Where are the spinocerebellar tracts?

  9. Neuro Flashback –Name FIVE types of glial cells [5] • Astrocytes • Oligodendrocytes • Schwann cells • Ependymal cells • Microglia Where is this?

  10. 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

  11. Motor Neurone Disease Subtypes http://en.wikipedia.org/wiki/Motor_neuron_disease

  12. Dementia • 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

  13. 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

  14. Distinguish delirium from dementia [5] Important to obtain a collateral history

  15. 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

  16. 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

  17. 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

  18. What is pseudodementia? • Dementia caused by depression • Not caused by brain damage • Treated with anti-depressants

  19. What is the commonest form of dementia? • Alzheimer’s

  20. 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

  21. What CT findings are suggestive of Alzheimer’s? [3] • Shrinkage of cerebral hemispheres • Widened sulci • Enlarged ventricles

  22. 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

  23. Give TWO side effects of AChesterase inhibitors [2] • Think dryness • Dry mouth • Blurred vision • Urinary retention • Constipation • Tachycardia • Confusion • N&V • Dizziness

  24. 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!

  25. What is mixed dementia? • Alzheimer’s + vascular dementia

  26. 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

  27. 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

  28. 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

  29. 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(Treponemapallidum) • Viral encephalitis (often HSV)

  30. Thank you J.Bower@warwick.ac.uk

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