Cellular Degeneration and DementiaBy 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• 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)

Thank you

J.Bower@warwick.ac.uk