Neurodegenerative Diseases Flashcards
What are neurodegenerative diseases?
A range of conditions which primarily affect the neurons of the brain (sometimes spinal cord) resulting in a loss of structure and/or function
What is dementia?
▪️Multiple cognitive deficits (including memory)
▪️Decline form previous levels of functioning
▪️Severe enough to impair occupational and/or social functioning.
Do neurodegenerative diseases effect the brain symmetrically?
Not always
What functions may show impairment with degeneration in the frontal lobes?
▪️Behavioural problems, particularly disinhibition
▪️Judgement
▪️Abstract reasoning and strategic planning
▪️Emotional restraint
▪️Control of appetite and continence
What functions may show impairment with degeneration in the parietal lobes?
▪️Visuospatial skills
▪️Integration of sensory inputs ▪️This may lead to sensory agnosia and apraxias
Disorders of memory and hallucinations may suggest degeneration in which brain areas?
The medial temporal lobe, hippocampus, amygdala, and limbic system
What impairments may be apparent with degeneration in the temporal neocortex?
Receptive dysphasia (understanding language) and automatisms
What problem mignt be seen with occipital lobe degeneration?
Failure of visual sensory systems
What is the pathological classification of neurodegenerative diseases typically based on?
The accumulation of filamentous proteins
What are the two main categories of protein accumulation?
Intraneuronal and extracellular
What are the two main proteins associated with abnormal extracellular accumulation?
Amyloid beta and prion protein
What category of disease are associated with prion protein?
Human prion diseases such as Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI)
What conditions are associated with abnormal accumulation of amyloid beta?
Alzheimer’s and Down’s syndrome
What are the two main categories of abnormal intraneuronal accumulation?
Intranuclear and cytoplasmic/neuritic
What category of disorders is associated with abnormal intranuclear accumulations?
Polyglutamine disorders
What are three examples of polyglutamine disorders?
Huntington’s disease, spinocerebellar ataxia, and DRPLA
What are the four main proteins associated with abnormal cytoplasmic/neuritic accumulation?
▪️Tau
▪️Alpha synuclein
▪️TDP-43
▪️FUS
What is TDP-43?
A RNA/DNA-binding protein involved in RNA splicing, trafficking, and stabilisation, and thus regulating gene expression
What diseases are associated with TDP-43opathy?
Motor Neurone Disease (ALS-TDP), the FTLD-MND spectrum, and FTLD-TDP
What genetic mutation has been found in association with TDP-43opathy?
C9orf72 (a repeat insertion)
Why have C9orf72 mutations been found in individuals with what was thought to be sporadic ALS/FTD?
It has very low penetrance
What diseases are associated with FUSopathy?
ALS-FUS and FTLD-FUS (almost always familial and very rarely both)
What is alpha-synuclein?
A protein involved in the regulation of synaptic vesicles and subsequent neurotransmitter release
What three disease are primarily associated with an alpha-synucleinopathy?
Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy
In Parkinson’s, where are abnormal protein accumulations typically seen?
In the substantia nigra and parts of the brain stem
In dementia with Lewy bodies, where are abnormal protein accumulations typically seen?
In the cortex (may also be seen in the midbrain and brainstem hence parkinsonian features are also common)
Why is the alpha-synucleinopathy in multiple system atrophy unusual?
Because it is mainly deposited in oligodendrocytes (Papp-Lantos inclusions)
What are the two main categories of tauopathy?
Triplet and doublet band
Why is the proteinopathy seen in Alzheimer’s disease unusual?
It involves both intra and extracellular components
What gene is typically associated with tauopathy?
MAPT
What conditions are associated with triplet band 3 and 4 repeat tauopathy?
Alzheimer’s, Down’s syndrome and ALS-PDC
What diseases are associated with doublet band tauopathy with predominantly 4 repeats?
Parkinsonian disorders such as PSP, CBD, and GGT
What disease is associated with doublet band tauopathy with predominantly 3 repeats?
Pick’s disease (FTLD-Tau)
What is the most common dementing illness, particularly in the West?
Alzheimer’s disease
What is the average duratuion of Alzheimer’s from symptom onset to death?
9-12 years
What are the main symptoms of Alzheimer’s disease?
▪️Cognitive decline, particularly memory
▪️Decline in visuo-spatial skills
▪️Delusions and hallucinations
▪️Irritability
▪️Can be associated with movement disorders such as myoclonus
(Consciousness is not disturbed)
What are the two main pathologies associated with Alzheimer’s disease?
Abnormal amyloid beta deposition forming plaques, and hyperphosphorylated tau forming neurofibrillary tangles
What is myoclonus?
‘Jerking’ disodder
What are the four genetic mutations most commonly associated with familiar AD?
APOE e4 allele, APP, Presenilin 1 and Presenilin 2
What is the APP gene
The amyloid precursor protein gene - plays a role in the formation of amyloid beta
Why is there an association between familial AD and Down’s syndrome?
Because APP is located on chromosome 21
Heritable forms of AD present primarily as which type of AD?
Early onset
What are the main pathological brain changes seen in AD?
▪️Loss of cortical white matter
▪️Widened sulci
▪️Compensatory dilatoom of ventricles (enlarged)
What type of stain used to be used to make a histological diagnosis of AD?
Silver stain
What is now used to make a histological diagnosis of AD?
Antibodies
What is the main issue with using antibodies to diagnose AD?
Masses of hyperphosphorylated tau can make interpretation difficult
Which proteinopathy correlates best with cognitive decline in AD?
Tau and neurofibrillary tangles
Where are NFTs and NTs typically originally observed in Braak stages 1 and 2 of AD?
The transentorhinal cortex with small number in the CA1 region of the hippocampus
How does someone in AD Braak stages I and II typically present clinically?
Asymptomatic
Where do NFTs and NTs typically spread to in Braak stages III and IV of AD?
The limbic system - hippocampus, subiculum, fusiform gyrus, amygdala
Where do NFTs and NTs typically spread to in Braak stages V and VI of AD?
The cortex as well as the anterior cingulate cortex, thalamus, hypothalamus, claustrum, and substantia nigra
At what point during the Braak stages of AD do you see occipital lobe involvement?
At the highest stage (IV)
Which brain areas are relatively spared in AD?
The primary sensory and motor cortices
What staging is used to measure the progressive accumulation of amyloid plaques in AD?
Thal phase: phase 1-2 (A1), phase 3 (A2), phase 4-5 (A3)
What staging is used to measure the progressive accumulation of tau and NFTs in AD?
Braak staging: stage I-II (B1), stage III-IV (B2), stage V-VI (B3)
What structure is associated with the highest thal phase?
The cerebellum (although typically because it isn’t involved at all)
What is CERAD?
Another method of scoring neuritic plaque accumulation, rated mild (C1) moderate (C2) or severe (C3) (although not very meaningful)
What is an NIA/AA combined score?
A scoring system to classify neuropathological change in AD that combines Thal, CERAD, and Braak staging. It scores pathology as low, medium, high, or not AD
Which criteria for AD pathology is more important?
Braak staging (NFTs and tau) - can still be classified as low pathology in the present of high Thal and CERAD if tau is low
What is amyloid angiopathy?
The accumulatoln of amyloid beta peptide in the walls of blood vessels, making them more likely to leak and increasing risk of haemorrhage
What is APP?
A large transmembrane glycoprotein that sticks out from the membrane, involved in the production of amyloid-beta
What happens to amyloid precursor protein in healthy individuals?
It is cut apart at two locations firstly by alpha-secretase and secondly by gamma-secretase, producing extracellularly a P3 peptite from the middle
What happens to amyloid precursor protein in the amyloidogenic pathway?
Decreased alpha-secretase and increased beta-secretase causes beta-secretase to cut the APP higher up before the gamma-secretase, producing an extracellular longer amyloid-beta peptide/beta pleated sheets
Why does amyloid-beta form plaques?
Amyloid-beta is more hydrophobic than the peptide usually produced thus is harder for the brain to clear
What is the secondary mechanism of disease in the amyloid cascade model of AD?
hyperphosphorylation and NFT formation
What is the feedback mechanism in the amyloid cascade model of AD?
Microglia are activated around the plaques to clear them, which increases inflammation in turn triggering the production of more plaques
What are the two main arguments against the amyloid cascade hypothesis?
- Tau pathology correlates better with symptoms than AB, so why is tau only a secondary effect?
- Drug trials using anti-AB treatments are so far u effective
Why might drug trials addressing AB pathology not yet be effective?
- We are administering the drug too late (we need biomarkers!)
- Multiple pathologies may be present
What is tau?
A microtubule associated protein that binds and integrates into the microtubules to help stabilise them and give them structural integrity
What happens when tau becomes hyperphosphorylated?
Structural abnormalities appear in the microtubules, causing it to dissociate, disrupting transport in the cell
What happens to tau in tauopathies?
The switching on and off of the protein goes wronf and it becomes hyperphosphorylated in the wrong areas
What happens to tau when it detaches from the microtubule?
It forms paired helical filament which accumulate and stick to each other to form neurofibrillary tangles
What is the seeding and propagation model?
The hypothesis that proteinopathy is spread through the brain through the induction of structural changes to adjacent proteins. This is still an ongoing argument
What are the two most promising tau biomarkers for AD?
Blood p-tau 181 and 217
What does blood p-tau 181 predict?
AD 8 years prior to death
What does blood p-tau 217 predict?
AD up to 20 years prior to death
What are the three key features of parkinsonism?
Bradykinesia, rigidity, and tremor
How many of the three key features of parkinsonism are needed for a diagnosis of idiopathic Parkinson’s disease?
2
What is the mean age of PD onset?
61
What is the mean duration of PD?
13 years
What are the two key pathological signs of PD?
Neuronal loss in the substantia nigra and the presence of Lewy bodies
What proteinopathy is PD associated with?
Alpha-synucleinopathy
What are the dark patches in the substantia nigra and what do they indicate?
Neuromelanin - indicating healthy function
Why does someone with PD have less pigment in their substantia nigra?
Lewy bodies form and cause neuronal death here, leading to the loss of neuromelanin
What percentage of neurons in the substantia nigra are lost before the individual develops motor symptoms?
70%
What are Lewy bodies?
Abnormal deposits of alpha-synulcein in the cytoplasm, forming spherical inclusions (have halos under microscope)
Why might it be argued that vascular dementia is not a true dementia?
Due to its step-wise progression, as oppose to gradual
What are the main neuropathological signs of vascular dementia?
- Multiple infarcts - step-wise progression
- Diffuse white matter changes (degeneration) due to ischaemia/hypertension
- Strategic infarct - relatively small area wiped out (e.g., thalamus)
What symptoms might occur with vascular dementia affecting the subthalamic nucleus or basal ganglia?
Movement disturbances (e.g., throwing movements/jerks, parkisonism)
What macroscopic pathological changes can you see in Huntington’s disease?
Shrinkage of caudate nucleus and putamen
(loss of white matter and thinner cortex?)
What microscopic pathological changes can you see in Huntington’s disease?
▪️ Neuronal loss
▪️ Astrocytosis (increase)
▪️ Ubiquitin inclusions (intranuclear)
What are the two main pathologies typically seen with FTD?
▪️ Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) (more common)
▪️ Pick’s disease (FTLD-Tau) - behavioural!
What are the three types of ALS initiation?
▪️ Atrophy/weakness of muscles
▪️ Bulbar onset - tongue problems, dysphagia
▪️ Upper motor neurone signs - hyperreflexia
What are the main contributors to familial ALS?
▪️ C9orf72 repeat expansion - most common
▪️ SOD1 - very rare
▪️ TARDP (TDP-43)
▪️ FUS - very rare
Where is pathology most commonly seen in ALS?
▪️ Motor cortex
▪️ Brain stem (internal capsule, medulla)
▪️ Corticospinal tracts
▪️ Spinal cord - thinning of anterior nerve roots
What inclusions are typically seen in the spinal cord, medulla, and motor cortex of someone with ALS?
▪️ TDP-43
▪️ FUS (less commonly)
What is TDP-43?
▪️ RNA binding protein
▪️ Allows for translation of correct protein (stop translation of unwanted code)
What happens when something goes wrong with TDP-43?
▪️ Does not bind to unwanted sections
▪️ Protein does not get formed/defective protein made instead
▪️ TDP-43 accumulates in the cytoplasm
▪️ Binds instead to other proteins such as ubiquitin, clogging up the neuron
What cellular processes might be impaired with ALS-related genetic mutations, giving rise to disease?
▪️ RNA-processing abnormalities
▪️ ER dysfunction and stress
▪️ Mitochondrial dysfunction
▪️ Abnormal axonal transport and microtubule organisation
▪️ Endosomal dynamic dysfunctions
What is the most common pathological inclusion in ALS?
TDP-43 (97%)
(SOD1 = 2%, FUS <1%)
What are the most common pathological inclusions seen in FTD?
▪️ TDP-43 (45%) - spectrum with ALS?
▪️ Tau (45%)
(FUS = 9%, UPS = 1%)
What are the main types of Human Prion Disease?
▪️ Creutzfeldt-Jakob Disease (CJD)
▪️ Variant CJD
▪️ Familial Prion Diseases (e.g., fatal familial insomnia)
▪️ Iatrogenic CJD (e.g., historic treatment with growth hormone)
What is the protein only hypothesis?
Theory explaining how prion proteins replicate without nucleic acid
▪️ Prion propagates by inducing conformational changes in its normal counterpart - misfolded into beta pleated sheets
▪️ Positive feedback mechanism
▪️ Resulting in structural abnormalities in the brain
What are the four components of the prion disease cycle?
▪️ Inoculation
▪️ Interaction
▪️ Conversion
▪️ Accumulation
What two major histological changes do you see in CJD?
▪️ Prion protein deposition
▪️ Spongiform change (holes)
What pathology might you see in variant-CJD?
Florid plaques
