Week 9 part 1 Flashcards
What are neurodegenerative disorder characterised by?
Progressive loss of neuronal structure and function
What are neurodegenerative disorders?
Diverse in their pathophysiology
What is an example of pathophysiology?
Heterogenous clinical and pathological expression affect specific subset of neurons in specific-functional anatomic systems
What are parkinson’s disease characterised by?
- Resting Tremor
- Slowness of movement (bradykinesia)
- Muscular rigidity
- Postural instability
What are defects in motor function due to?
loss of dopaminergic neurons in the substantia nigra pars compacta
What is substantia nigra?
Strips of cells which contain neuromelanin
Very dark pigment
dopaminergic cells
What do neurodegenerative disorder rise dramatically with?
Age
Numbers are expected to increase due to increasing life expectancy
What are Huntington disease characterised by?
- Involuntary movements
- Mood alterations e.g. depression
- Personality alterations e.g. irritability, impulsive or eccentric behavioyr
- Defect in memory and attention
What is the pathology of Huntington disease?
- striatal atrophy: loss of medium spiny neurons
2. Cortical atrophy: loss of cortical pyramidal neurons (CPNs) in motor and premotor area
What are defects in motor function of HD pathology?
- loss of GABAergic neurons in corpus stratium
2. Enlargement of ventricles and shrinkage of basal ganglia
What are limitations to brain bank material?
- Pathological changes are only revealed post-mortem
- Earliest changes in neurodegenerative disorders are missed
- End-stage tissue is depleted of neurons
- Post-mortem delay affects protein e.g. stability
What can biomarkers reflecting different types of pathophysiology be viewed as?
- Clinical diagnosis
- Predict and monitor disease progression
- Monitoring effects of novel drug candidates in clinical trials
- Clinical research into the pathogenesis of disease
What are biomarkers that allow for pre-symptomatic detection crucial for
Faciliate the development of an efficient and rapid treatment as early as possible
What are Alzheimer’s disease characterised by?
- Defects in memory
- Cognitive decline
- Confusion and disorientation
- Changes in mood and personality
What are 2 two pathological hallmark of AD?
- Amyloid plaques
2. Tau - Neurofibril tangles
What do amyloid plaque and Tau have?
Specific pattern of deposition
Where are amyloid plaques in?
Medial and frontal temporal lobe before the burden increases
Area which amyloid deposits increases in the cortex
Where is Tau located in?
Hippocampus
Before spreading to the frontal love and over the cortex
What are Amyloid plaques?
Extracellular accumulations prinicipally composed of abnormally folded amylod beta with 40-42 amino acids
What are two by-products of APP metabolism?
- Ab40
2. Ab42
What is more abundant within plaques?
Ab40
Due to higher rate of fibrillisation and insolubility
What is APP cleaved by?
beta-gamma secretase which leads to formation of ab peptide
What is Tau?
- Microtubule-associated protein
What does Tau have a role in?
- Microtubule stabilisation
2. Axonal transport
What does hyperphosphorylation of Tau result in?
Formation of neurofibrillary tangles
which are composed of paired helical filaments (PHF) of Tau
What are the 3 areas where most biomarkers are focused on?
- Plaques
- Tangles of Tau
- Neuronal degeneration
When is clinical diagnosis of dementia made?
Biomarkers follow this time pattern and when enough change in brain structure happens
What is considered in terms of gene base biomarkers?
target amyloid and tau progression early on or even better trying to target before
What does the cerebrospinal fluid occupy?
- Ventricular system
2. Cranial and spinal subarachnoid space
What does CSF acts as?
Liquid cushion providing basic mechanical and immunological protection
What is CSF?
most informative fluid in biomarker discovery for neurodegenerative disorders.
What does CSF have?
more physical contact with brain than any other fluid, as it is not separated from the brain by the blood brain barrier (BBB)
What most likely diffuse into CSF than into any other bodily fluid?
proteins or peptides that may be directly reflective of brain specific activities as well as disease pathology
How can we categorise CSF biomarkers?
- the core csf biomarkers and theres 3 of them
2. theres more novel biomarkers that need more verification and validation
What it is total Tau?
Not AD specific
What is counter intuitive?
♣ ab42 and ab42/40 ratio
What us lowered ub CSF?
increase in CSF of amyloid ab42 and ab42/40 ratio
What is the main test for CSF amyloid 42 and the ratio of 42-40?
Elisa
What is a problem with Elisa?
variation between research groups and organizations
What are core CSF biomarkers ?
Well-validated for neurodegeneration as well as amyloid plaque and tau tangle pathology
What are there no validated biomarkers for?
Synaptic dysfunction
What is biomarkers for synaptic dysfunction?
Best pathoanatomical correlates of cognitive deficit and predicts disease better than amyloid plaque load
What would be a valuable addition to Alzheimer’s disease diagnostic biomarker toolbox?
reliable biomarkers to monitor synaptic and dendritic function and loss directly
What is Neurogranin?
dendritic protein expressed in the cortex and hippocampus with an important role in long‐term potentiation.
Where is Neurogranin expression markedly reduced?
- Hippocampus
- Frontal cortex in AD
indicating loss of post-synaptic element
in AD
What does measurement of neurogranin in CSF serve?
Biomarker for dendritic instability and synaptic degeneration
What does meta analyses studies look at?
various AD cohorts and collate all the data that’s been found correlating the biomarker to AD
What are biomarkers with the best performance?
Core CSF biomarkers
What is strongly associated with AD?
Neurofilament light chain (NFL)
What was moderately associated with AD?
- neuron specific enolase (NSE),
- visinin-like protein 1 (VLP-1),
- heart fatty acid binding protein (HFABP)
- glial activation protein YKL-40
What should be used in clinical practice and clinical research?
- T-tau, P-tau, Aβ42 and NFL
2. Due to their consistency
What is the most validated of AD?
CSF biomarkers
What are advantages to CSF?
- Highly sensitive and specific - Not separated from the brain via BBB
- Can correlate with Alzheimer’s disease directly
- Can detect Alzheimer’s disease progression
What are disadvantage to CSF?
- Invasive and painful procedure via lumbar puncture
2. Irreproducible diagnosis due to sample storage and transportation
What makes an ideal for biomarker investigation?
Easier sampling of the blood plasma
What has met with little success?
Plasma biomarkers
What makes plasma biomarkers a much easier biomarker method?
Easier collection
Whatmight occur due to different analytical methodologies utilised in various laboratories, different choice of anticoagulant and depletion strategy and storage related problems in blood-based biomarker?
- Irreproducibility
What are biomarkers for Blood-based biomarkers for AD?
- CDH
2. a-2m
What is the most popular plasma peptide utilised for biomarker reseacher?
AB
the fundamental element of senile plaques in brain of Alzheimer’s disease patients
What are Ambiguous results probably explained by?
that plasma Aβis derived from peripheral tissues and may not reflect brain Aβproduction
What can result in epitope masking?
the hydrophobic nature of Aβ makes the peptide bind to plasma proteins
What did blood tests find?
Toxic Alzheimer’s proteins
What did they term ab40, ab42 and APP fragment?
- app699-711
2. Based on its amino acid composition
What are advantages for blood?
- Non-invasive
- Samples are easily accessible
- Cost effective and routine
- ~500ml of CSF absorbed into blood each day
What are disadvantage of Blood?
- Less sensitive and specific than CSF (e.g. epitope masking)
- Less correlation with Alzheimer’s disease than CSF
