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CNSLF Path Neurodegeneration (i) (Pathogenesis (known proteins (Alpha…
CNSLF Path Neurodegeneration (i)
Intro
progressive dysfunction + death of neurons (neuronal loss)
disease with known vasc/toxic/metabolic/infective/AI aetiology are excluded
gliosis
intracellular accumulation
Pathogenesis
abnormal accumulation of (usually intracellular protein underlies this group of diseases)
abnormal protein production
abnormal protein folding (protein couldve been produced normally just folded abnormally)
failure to eliminate protein (not digested)
defective neuronal +/- glial functioning + cell death due to...
oxidative stress
excitotoxicity (cell Rs overactivated by glutamate)
programmed cell death
CK-mediated
known proteins
Tau - stabilises microtubules (part of cytoskeleton in neurons - "tauopathy"
Alpha-synuclein
not fully understood
abundant in brain esp synapses
thought to play role in maintaining supply of synaptic vesicles in axonal terminal of neurons
"synucleinopathy"
amyloid
only one that is extracellular
role of APP not fully understood
TDP-43
FUS
Huntingtin
Ubiquitin - helps regulate processes of other proteins in body
selective neuronal vulnerability
phenomenon whereby specific groups of neurons/systems are targeted by disease process
this is what determines clinical phenotype
hence to dx, find what disease the phenotype fits
e.g. memory loss always part of Alz
considerable clinical + pathological overlap
distinct clinical phenotypes a/w several different types of pathology
the same neurodegenerative disease process can have several different clinical phenotypes
2 main clinical groups
movement disorders
akinetic/rigid e.g. PD (can be alpha-synuclein or tau but not both)
affects substantia nigra + basal ganglia
extra-pyramidal: rigidity, bradykinesia, tremor, falls
hyperkinetic e.g. Huntington's chorea
dysregulation of movement
affects basal ganglia
ataxic e.g. spinocerebellar ataxia
affects cerebellum + its connecting tracts
alpha-synuclein
motor neuron disorders e.g. MND
TDP43
dementia syndromes
temporo-parietal degeneration e.g. Alz
affects hippocampus (memory) + cortical neurons
frontotemporal degeneration (FTLD)
apathy, disinhibition, depression, memory
TDP43, ubiquitin, FUS
multifocal degeneration (all cortical function)
Manifestation of disease depends on part of brain affected
Parietal lobe: visuospatial, sensory deficits
Occipital lobe: visual sensory deficit
Temporal neocortex: receptive (Wernicke's aphasia + automatisms
Limbic system: memory + hallucinations
Frontal lobe: changed behaviour, judgement, reasonings, planning, emotions, appetite + continence
Aetiology
historically infective/toxic/environmental factors were explored without causative links identified
majority are sporadic
some have multiple susceptibility factors e.g. Alz has @ least 10 genes with environmental factors (e.g. head injury) implicated
those with hereditary bases (minority) have lead to major understanding in pathogenesis
single mutation e.g. MAPT (provides instructions for making tau)
trinucleotide repeat (polyglutamine disorders) e.g. HD
Prion disease
like all neurodegeneration
neuronal loss
gliosis
abnormal protein accumulation
selective neuronal vulnerability
Unique transmissible protein
within 1 brain, + from 1 brain to another e.g. via neurosurgery, cannibalism
no DNA/RA
exact function unknown, highly concentrated in neurons
spongiform encephalopathy
Creutzfeldt Jacob disease
Gerstmann Straussler Scheinker
fatal familial insomnia
Kuru (from cannibalism)
rapidly progressive dementia often with behavioural symptoms, hallucinations, myoclonus