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The ageing brain

The ageing brain. Volume reduction: begins around 50 with a loss of brain weight of around 2-3% per decade Changes in nerve cell numbers and size - various studies with various results ( 10-25%), although some structures seem resistent

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The ageing brain

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  1. The ageing brain • Volume reduction: begins around 50 with a loss of brain weight of around 2-3% per decade • Changes in nerve cell numbers and size - various studies with various results ( 10-25%), although some structures seem resistent - dendritic and synaptic changes may be compensated by sprouting

  2. Microscopy of the ageing brain • Increase in lipofuscin • Senile plaques • Neurofibrillary tangles • Granulovacuolar degeneration • Hirano bodies • Leukoaraiosis • Amyloid (congophilic) angiopathy

  3. Neurodegenerations • Damage to lysosomes, nuclear DNA, mitochondria leads to release of caspases, initiating apoptosis. • In many if not most neurodegenerations this damage is triggered by abnormal protein-protein interactions leading to protein storage. • Examples: • Ubiquinopathies • Tauopathies • Synucleinopathies • Prion diseases

  4. Agrégation des protéines : voie commune finale menant à la neurodégénérescence

  5. Ubiquinopathies: Alzheimer’s disease Pre-senile and senile forms Onset before or after 65 years of age Progression slow (often > 1 decade) Pathological changes are similar to aging, but more severe

  6. Senile plaque Heterogeneous structure Amyloid core surrounded by a clear zone Crown of filamentous or granular material made up of neuronal projections filled with argyrophilic filaments and debris Macrophages and astrocytes

  7. De: Ellison D., Love S., Chimelli L., Harding B., Lowe., Roberts G., Vinters H. (Eds.) Neuropathology. A Reference Text of CNS Pathology. Mosby. 1998

  8. ABeta generation

  9. Protein folding diseases Protein-normal folded + Mutation in protein Chaperones/Ubiquitin/ Clipping mechanisms - Hydrophobic interactions + - age Protein-abnormal folded – small aggregates (toxic) lipid raft: synapse dysf H2O2 Protein aggregated (non toxic?) amyloid membrane damage

  10. Movement Disorders • Protein storage diseases: • Tau protein storage: Progressive Supranuclear Palsy • Synuclein: Parkinson’s disease • Huntingtin: Huntington’s disease • Ubiquitin/TDP-43: Amyotrophic Lateral Sclerosis

  11. Synucleinopathies • Parkinson’s disease • Dementia with Lewy bodies • etc

  12. Parkinson’s Disease

  13. Parkinson’s disease • Onset 30-80 • Rest tremor mostly starting with hands (like counting money) • Stooped posture, walking with small steps • Depigmentation of substantianigra and locus coeruleus • Lewy bodies and loss of pigmented neurons • Loss of dopaminergic innervation to the striatum

  14. Lewy bodies

  15. Synuclein

  16. Dementia with Lewy bodies

  17. Tauopathies • Pick’s disease • Progressive Supranuclear Palsy • Cortico basal degeneration • etc

  18. Pick’s disease • Dementia with relative rapid progression with frontal symptoms (aggressive behavior often, or problems with initiation of tasks), onset from 50 years of age, frequently hereditary. • Gross findings are characterized by a lobar atrophy affecting the frontal lobe and the anterior temporal lobe (mostly the anterior 1/3 of the superior temporal gyrus) • Histology:Pick’s cells (swollen neurons ), Pick’s bodies ( argyrophilic intracytoplasmic inclusions), neuronal loss and gliosis

  19. Progressive supranuclear palsy • Dementia combined with vertical gaze paralysis, and parkinsonism • Abnormal tau accumulation in neurons and glial cells, neuronal loss and gliosis • Characteristic topography: in the midbrain and striatum (substantianigra, red nucleus,colliculi, globuspallidus, subthalamic nucleus, periaqueductal grey matter, dorsal and medial raphe, locus coeruleus)

  20. PSP • Tauopathy—leads to tangles with tau protein storage • Both taupoathy of neurons and gliacells (oligodendrocytes and astocytes) • Multiple systems neurodegeneration • Locations: • periaqueductal grey matter • Substantia nigra • Locus coeruleus • Subthalamic Nucleus • Globus pallidus • White matter surrounding these structures

  21. Clinical signs and symptoms • Parkinsonism: • Slowing of movement • shuffeling gait • resting tremor • But anti parkinson medication does not help • Vertical gaze paralysis (leading to falls on stairs) • Dementia • Slurred speech

  22. Amyotrophic Lateral Sclerosis

  23. Clinical Symptoms/Lab results • Mainly sporadic condition, 1% autosomal dominant • Middle aged individuals • Muscle weakness of distal extremities with fasciculations and atrophy (neurogenic) • Spasticity (with Babinski reflexes) • Incontinence (often later) • Ultimately respiratory insufficiency and death • EMG: giant motor potentials and fasciculations (spontaneous activity) • Location of abnormalities: • Motor cortex (Betz cells) • Spinal cord (Pyramidal tract, Anterior horn cells, anterior rootlets of spinal nerve) • Muscle (secondary: neurogenic atrophy)

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