Cellular Degeneration and Ageing Susan Rutherford and Sarah Christie

What are the factors affecting cellular ageing and degeneration? (5)  Genetic factors  Diet  Social conditions  Age-related disease  Ageing-induced alterations in cells

What processes can lead to cellular ageing? (6)  Reduction in ATP production  Mitochondrial damage  Calcium entry  Increased Reactive Oxygen Species (ROS) production  Membrane damage  Protein misfolding and DNA damage

What are the potential outcomes of cellular ageing? (3)  Reduced capacity to function  Reduced capacity to respond to injury  Cell death  Apoptosis  Necrosis

What 3 changes can lead to cellular ageing?  Decreased cellular replication  Due to e.g. p16INK4a, DNA damage  Accumulation of metabolic and genetic changes  E.g. balance between metabolic damage and repair  Reactive Oxygen Species – injures cells by (3): 1.Membrane lipid peroxidation 2.Interaction with proteins 3.DNA damage

What is this condition called? What kind of inheritance?  Autosomal recessive What is it?  Rare genetic disease characterised by premature ageing (progeria) due to reduced cellular replication Werner’s Syndrome

Friedrich’s Ataxia Type of inheritance?  Autosomal recessive What happens?  Spinocerebellar degeneration -> axonal loss and gliosis What causes it?  GAA trinucleotide repeat leads to expression of frataxin (mitochondrial protein)  Leads to mitochondrial dysfunction -> decreased ATP -> ROS -> DNA damage

Friedrich’s Ataxia Signs/Symptoms  Muscle weakness in limbs  Loss of co-ordination  Cerebellar signs : nystagmus, fast saccadic eye movements, truncal ataxia, dysarthria. Dysmetria  LMN lesion : absent deep tendon reflexes  Pyramidal : extensor plantar reflexes (UMN symptom), distal weakness  Dorsal column : Loss of vibratory sensation and proprioception  Often get cardiac involvement e.g. cardiomegaly, hypertrophy, murmurs. Typical patient presentation:  20s-30s  Slow, progressive staggering/stumbling, frequent falls  Often associated with diabetes

Amylotrophic Lateral Sclerosis  Type of motor neuron disease Pathogenesis?  Genetic mutation – superoxide dismutase-1 enzyme (SOD1)  SOD1 = antioxidant. Protects cells against free radicals (superoxide)  Leads to reduced ability to detoxify cells OR  Misfolded proteins -> ER stress -> cell injury  Get loss of myelinated fibres in corticospinal tract

Amylotrophic Lateral Sclerosis Characteristic presentation?  Progressive disorder  Weakness and or muscle atrophy (UMN/LMN lesions)  Dysphagia, cramping, stiffness of muscles  Slurred/nasal speech

Recent diagnosis of motor neuron disease What should the patient be considering about their care? (3)  Power of attorney  Advanced care planning  Advanced decision to refuse care

Alzheimer’s disease  Most common form of dementia What might you see on CT? (3)  Cortical atrophy (especially temporal)  Widened sulci  Enlarged ventricles What are the histological changes seen in AD? (2)  Tau tangles (tau protein)  Beta-amyloid plaques

Dementia If you suspect dementia, what reversible causes would you want to rule out?  Substance abuse  Hypothyroidism  Space-occupying intracranial lesions  Normal pressure hydrocephalus  Syphilis  Vitamin B12 deficiency  Folate deficiency  Pellagra  Vitamin B3 deficiency  Causes 3Ds: Dementia, diarrhoea, dermatitis (+ death)

Thanks for listening!  Questions?  