Neurodegenerative and cognitive disorders Flashcards
Definition of neurodegenerative disorders
Degenerative, progressive disease of the CNS that is sporadic.
- Characterised by misfolding of proteins that aggregated into oligomers then insoluble deposits, causing neuronal death.
Includes
- Alzheimer’s
- Parkinson’s/ LBD
- Motor neurone disease
Protein misfolded in AD
Tau protein
- leads to accumulation of neurofibrillary tangles
Beta-amyloid
- Aggregates outside cells
- This precedes tau aggregation inside cells and the walls of blood vessels (amyloidangiopathie)
Regions affected
- Typically temporal/ parietal regions
Parkinson’s disease
- Protein misfolded + lesions
- Regions affected
- Cell type affected
Protein misfolded
- alpha-synuclein
- Forms lewy bodies, leading to neuronal loss
Region affected
- Substantial nigra
Neurones affected
- Dopaminergic neurones, substantia nigra neurones.
Motor neurone disease
- Protein misfolded + lesions
- Regions affected
- Cell type affected
Protein misfolding
- TDP-43, forms inclusions, leading to neuronal loss
Regions
- Primary motor cortex
Neurones affected
- Layer 5 pyramidal neurones
Presentation of PD
- Cognitive
- Motor
- Sleep
- Autonomic
- Behavioural
- Psychiatric
Cognitive
- Memory
- Executive function
- Visuospatial
Motor
- Parkinsonism
- Tremors
- Dystonia
Sleep
- Insomnia
- Shorter REM sleep/ REM sleep disorder
- Periodic limb movements
Autonomic dysfunction
- Erectile dysfunction
- Constipation
- Postural hypotension
- Hypersalivation
Behavioural
- Apathy
- Stereotypy
Psychiatric
- depression
- Hallucination
- Paranoia
- Compulsions
Presentation of MND
- Cognitive
- Motor
- Behavioural
- Psychiatry
- Autonomic
Cognitive
- Language
- Executive
- Social dysfunction
Motor
- UMN and LMN disease
Behavioural
- Apathy
- Disinhibition
- Stereotypy
- Eating
Psychiatry
- Depression
- Paranoia
Autonomic
- Hypersalivation
Imaging for NDD
Brain MRI
- Shows loss of brain volume but this signifies later stages, when condition becomes symptomatic
- Not specific: FTLD can show hippocampal atrophy and AD can show frontal atophy
Brain PET
- Able to show dysfunction of regions that may not show up on MRI, allows earlier detection than MRI
- Regions that have neuronal dysfunction appear cold.
- Example, AD: cold parietal-temporal regions, fronto-occipital sparing.
Genetics and NDD
Minority of cases are directly linked to genetic mutations, specifically of the misfolded protein aetiology.
AD
- MAPT–> Tau
- GRN–> TDP-43
- C9ORF72, most common mutation–> TDP-43
Genetics that predispose to early-onset AD
Autosomal dominance
- APP= amyloid precursor protein
- PSEN1,2= presenilin, involved in generation of amyloid beta
Progressive pathology of AD
- where does it start
Typically starts in hippocampus
- Has a predictive spread of pathology, superior
Different classifications of AD (6)
Determined by the primary symptoms presenting.
- AD
- Presenting first with memory problems.
- The most common and is due to AD. - Primary progressive aphasia
- Presenting first with language problems, before memory dysfunction. - Posterior cortical atrophy
- Presenting with visuospatial dysfunction. - Frontal Alzheimer’s
- Presenting with behavioural/ social symptoms before memory= apathy, disinhibition, social dysfunction. - Presenting initially with psychiatric dysfuntion before memory symptoms
- Corticobasal syndrome
- Presenting primarily with movement disorder.
APOE and AD
Mutation causing at least 1 copy of epsilon 4, predisposes to developing AD
- But not early onset
Compare AD to other NDD
- Similarities
- Differences
Similarities
- All caused by protein misfolding and aggregation
- Can all present with wide variety of symptoms in different domains.
Differences
- Has two protein pathology (beta-amyloid, tau patholohy)
- More common than other NDD.
Inhertiance of ADD
Very few minority have single gene dominance inheritance
- i.e. PSEN-1
Young-onset with strong family history has strong predisposition
- Esp. with FTLD
Inheritance is unlikely.
Uncommon AD initial symptoms
PCA
- Visuospatial
Primary progresisve aphasia
- language
Frontal AD
- Behavioural
