Alzhiemer's Flashcards
What path does the discovery of degeneration follow?
failed organ - active disease - disease onset - risk factors
What are the symptoms of Shaking Palsy (Paralysis Agitans) as first described by James Parkinson in 1817?
- involuntary tremulous motion
- lessened muscular power in parts not in action and even when supported
- propensity to bend the trunk forward
- propensity to pass from walking to running pace
- sense and intellect uninjured (h/e we know this is false now)
What is the timeline of Parkinson’s in terms of discovery?
1817 - first described by Parkinson
1895 - Brissaud - Substantia Nigra cell loss (loss of dopamine)
*50-70% are lost when symptoms start
1912 - Lewy - Lewy bodies as pathological marker
1960’s - Dopamine & its use in PD
L-DOPA —-(L-AAAD)—->Dopamine
1997 - α-synuclein mutation in Greek family with autosomal dominant PD
1998 - α-synuclein = primary component of Lewy bodies
What are the key points for neurodegeneration?
- The single etiology model doesn’t work
- Risk & end stage are different entities
- What constitutes “X disease” is constantly changing
- Clinical signs can tell you the anatomical pathology
- Similar cells have similar disease susceptibilities
- Each neurodegeneration tends to have a specific “misbehaving” protein
- Each neurodegeneration affects a system of cells
- Neurodegenerations progress - WHY?
- How should we classify neurodegenerations?
Why do clinical signs (“phenotype”) matter?
Because they can tell you the anatomical pathology
Due to both:
- genetic cell type (biochemistry, cell morphology, energy demands)
- circuitry factors,
regional functions of the brain will be different and you can tell what brain region is injured by the clinical signs expressed.
What are the clinical signs of Amyotrophic Sclerosis/Motor Neurone Disease?
Upper Motor Neurones (cerebrum, cerebellum?: layer 5 of motor cortex)
- Weakness/paralyses
- Increased reflexes
Lower Motor Neurones (brainstem, spinal cord: anterior horn cells of the spinal cord)
- wasting
- weakness/paralyses
- fasciculations
No sensory features.
Similar neurones = similar risk to MND
In what ways are they similar?
- common embryology
- long axons (high energy needs)
- same transmitters
- similar morphology
- similar gene expression
SOD1 vs familial MND
- mutations in gene for superoxide dysmutase 1 are associated with familial MND
- Chesapeake Retriever dogs have SOD1 mutations with pathology in sensory spinal neurones
- Humans have MND pathology in motor neurones
What are the clinical signs of late PD?
sleep disorder autonomic failure motor signs dementia impulsivity neuro-psychiatry
- PD is more than motor symptoms
- other diseases can cause similar motor symptoms (parkinsonism)
What are the theories for the development of late PD clinical signs?
- Everything occurs at disease onset, just some cells are more susceptible than others.
- Cells have common susceptibilities (dopamine), disease spreads throughout the brain up the neural axis (progressive disease).
What are the relevant proteins of Alzheimer’s, Parkinsons & Dementia with Lewy Bodies?
AD: A-beta
PD & Dementia w LB: alpha-synuclein
What is the relevant protein of Progressive Supranuclear Palsy & Basal Ganglionic Degeneration?
Tau
What are the relevant proteins of Fronto-Temporal Dementia, MND & CJD
FTD: Tau, TDP43
MND: TDP43, FUS, SOD1, etc.
CJD: Prion protein
What are the 3 specific subsets of progressive neuronal death?
- Infantile - usually due to severe & generally a single genetic abnormality
- Young onset - less severe genetic abnormalities OR increased expression of late onset genes
- Late onset - post fertile: too late for genetic causality. Genetic influence less important, gene abnormalities related to longevity of neurones as they don’t propagate. Failing energetics.
What are the common mechanisms of progressive neuronal death?
- all neurodegenerations “spread” to neighbouring neurones
- all seem to have an energetics component
- all have inclusion formations: autophagy, midfolding, lysosome disturbance etc.
- all have axon transport problems & terminal dieback
