WEEK 9 NEUROLOGICAL DISEASES CONTINUED Flashcards
What does the WHO define mental health as?
- A state of well-being in which an individual realises his or her own abilities, can cope with the normal stresses of life, can work productively and is able to make a contribution to his or her community.
On average, what proportion of men will have depression and anxiety in their lives respectfully?
- 1/8 men for depression and 1/5 men for anxiety
Which age group of Australian females report the highest % of mental illness conditions?
- 15-24 year olds
What are the 6 models of health?
- Biomedical
- Social
- Humanistic
- Existential
- Transpersonal
- Religious
What are 9 barriers to mental health services?
- Non-recognition- by patient and/or doctor
- Lack of “language” to describe symptoms
- Belief that it is not the domain of doctors
- Denial
- Stigma
- Distrust of doctors
- Poor medical advice
- Fear
- Failed first attempt at help seeking
Is there an association with mental disorders and homelessness, and also mental disorders and unemployment?
- Yes as of 484, 400 people that reported homelessness, 54% had a 12 month mental disorder
- For unemployment, there were 29% with a m12 month mental disorder
What are three main ways to manage mental illness that have been used?
- Pharmacological
- Psychological
- Electroconvulsive therapy
What are the three most common mental health issues managed by GPs and what is the form of management?
- Depression
- Anxiety
- Sleep
Form of management is medication (in 61.6% of cases)
What are 3 positive traits of someone with ASD?
- Attention to detail
- Honesty
- Conscientious
What are 4 negative traits of someone with ASD?
- Anxiety
- Sensitivity to light and sound
- Ned downtime
- Different “grow up” timeline
What are the unemplyoment rates of someone with autism?
- 58% of people in Aus
What are 6 things to know about someone with Autism?
- Social Anxiety
- Anxiety about unexpected changes
- Needing extra time
- Sensory sensitivities
- Stimming
- Meltdowns
Is it true that Autism affects more boys than girls?
- NO
- It is picked up in more boys than girls as it is missed in girls
What is the “medical model” of disability?
- That the problem belongs to the disabled person and we should focus on “fixing” that person’s diability
What is the “social model” of disability?
Select
Why is the brain very sensitive to oxidative damage during normal aging?
- Because of its high energy metabolism and relative low activity of anti-oxidative defense mechanisms (20% energy at rest).
What occurs with oxidative stress?
- DNA is damaged, proteins are oxidized, lipids are degraded and more are ROS produced = significant cell injury.
What are the three main sources for oxidative stress in terms of ageing?
- Endogenous sources
- Antioxidant defences
- Exogenous sources
What do endogenous sources include? (ageing context)
- Mitochondria
- Peroxisomes
- Lipoxygenases
- NADPH oxidase
- Cytochrome P450
What do exogenous sources include? (ageing context)
- UV light
- Ionising radiation
- Chemotherapeutics
- Inflammatory cytokines
- Environmental toxins
What do Antioxidant defences include? (ageing context)
- Enzymatic systems (CAT, SOD, GPx)
- Non – enzymatic systems (Glutathione, Vitamins- A C and E)
What can oxidants be good for?
- homeostasis e.g. Normal growth and metabolism
What can too much ROS lead to?
- Impaired physiological function e.g. Random cellular damage and specific signaling pathways leafing to ageing, disease and cell death**
What can not enough ROS lead to?
Impaired physiological function (just like too much ROS). This includes:
- Decreased proliferative response
- Defective host defences
What are the 9 hallmarks of ageing?
- Genomic instability
- Telomere attrition
- Epigenetic alterations
- Loss of proteostasis
- Dysregulated nutrient-sensing.
- Mitochondrial dysfunction
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
True or false: Mutations in mtDNA have been associated with the ageing process.
- True
Which complexes of the respiratory chain have been shown to have reduced efficiency in ageing?
- complexes I and IV
What does mtDNA encode?
- Proteins that are subunits of the ETC –] 13 proteins: I, III[ IV, B subunit complexes.
What does mitochondrial dysfunction involve in terms of ageing?
- There is reduced efficiency of complexes I and IV of the respiratory chain and mutations in mitochondrial DNA (mtDNA)
Which cells is telomerase found in?
- Germ cells
- Stem cells
- Cancer cells (continuous proliferation)
What does telomere attrition involve in terms of ageing?
- Telomeres Shorten with each round of cell division to limit the number of cycles of cell division.
- Difficult to repair telomreres as the cell cycle increases hence telomeres shortening.
During ageing, what occurs in terms of epigenetic modification?
- Histones are lost and global hypomethylation and focal hypermethylation occur.
- Abnormalities in function of histone-modifying enzymes and chromatin remodelling also occur leading to neurodegeneration.
What is an issue that can occur with damaged DNA and methylation?
- When the DNA is damaged, the methylation (or other epigenetic marking) is removed and DNA is repaired. Then the methylation must be re-added back on BUT this can occur in different places to the original
- histones lost in ageing process
During ageing, what occurs in terms of loss of proteostasis?
- There is reduced clearance of misfolded proteins due to defects in the proteasomal and autophagy pathways.
What usually detects misfolded proteins?
- Heat shock proteins (HSPs)
- They refold the protein via chaperones
- With increased environmental exposure, there can be more of the non-native proteins that are misfolded and the autophagy and proteosomal degradation systems are overwhelmed and hence this can lead to neurodegeneration.
- The autophagy or protosomal systems must then kick in to degrade the misfolded protein. HSP can also target to lysosome for degradation.
Which molecular pathways involved in nutrient sensing and growth also modulate ageing and senescence?
- Insulin/insulin like growth factor 1 (IGF-1) signalling pathway- attenuation (reduction) of which extends lifespan (blocking this in worms and mammals increases longevity)
- mTOR pathway- inhibition of which extends lifespan
Can caloric restriction improve longevity in terms of ageing?
- YES
What are the possible candidate longevity genes in humans?
- Sir 1, 2 and 3
- FOXO1 and 3 TF
- Akt 1 (possibly- still not known)
What are examples of nutrient and growth regulators?
- Insulin/IGFs–> IR and IGF-1R–> IRS-1, 2–> PI3K–> Akt/PKB–> mTOR/Forkhead –> growth/survival, Stress resistance/proteostasis
Is the mTOR pathway more upstream of downstream of the insulin receptor?
- Much more DOWNSTREAM of the insulin R
What are the changes that occur in terms of microglial cells and ageing?
- Increases in the number, size and activation markers of microglia
- Increase in reactivity and inflamm cytokines (neuroinflammation)
- Basal phagocytosis (protein aggregation)
- ROS (oxidative stress)
- Neurotoxic activation (neurodegen)
What is a MAJOR risk factor for neurodegenerative diseases?
- AGE IS A MAJOR RISK FACTOR WITH A DELAYED ONSET. Many symptoms are detected within the 8th or 9th decade of life.
What is a brief explanation of why neurons die for PD?
- Parkinsons neurons that are suceptible to misfolded protein= Dopaminergic nigral striatal neurons (accumulate alpha synuclein–> forms lewy bodies) this causes the neuronal population to die off.
What is a brief explanation of what occurs in Alzheimer’s disease with the protein aggregation?
- Aggregation of protein or peptide amyloid beta 1-42 misfolds. It accumulates OUTSIDE THE CELL.
What is still a major question asked in terms of Alzheimers disease cell mechanisms causing memory loss?
- How can Alzheimer’s cause a selective neuronal population (Ach neurons) to degenerate even though it is outside the cell to cause memory loss in the hippocampus?
What are the 5 principles of pathogenesis for neurodegenerative diseases?
- Accumulation of abberant or misfolded proteins- aggregating to form inclusion bodies – is a common feature of several neurodegenerative diseases.
- Defective protein handling-degradation (via Ubiquitin proteasome system and atophagy)
- Aberrant epigenetic mechanisms e.g. DNA methylation, histone modification.
- Metabolic dysfunction – mitochondrial, mTOR (ROS, ER stress)
- Neuroinflammation (although not sure on whether it is cause or effect)
What can be thought of as the garbage disposal system?
- Autophagy
What are the two hallmarks to Alzheimer’s?
- Amyloid proteins forming oligomers (these are taken up by the neurons and lead to neuronal cell death)
- Tau hyperphosphorylation (this causes degeneration of the axons hence no APs to conduct signals along axons. Thus leading to neuronal degeneration and cell death.)
What is the normal function of Tau?
- Helps neurons and axons maintain their structure
What is thought to contribute to AD (Alzheimer’s Disease)?
- Degeneration of the cholinergic neurones especially projections from the basal forebrain to the hippocampus and atrophy of the hippocampus.
What is thought to contribute to PD (Parkinson’s Disease)?
- Degeneration of the dopaminergic projections from the substantia nigra to the striatum. (Alpha synuclein)
What is thought to contribute to ALS (Amyotrophic Lateral Sclerosis (ALS)?
- Degeneration of the motor neurones in the spinal cord, brainstem and cortex
What causes Creutzfeldt-Jakob disease?
- Infectious agent, prions
Is HD (huntington’s disease) a genetic disorder, and if so, what is it characterized by?
- YES
- Characterised by loss of striatal neruones
What is SMA (Spinal Muscular Atrophy) characterised by?
- degeneration of motor neurons in the spinal cord and brain stem
What is the master regulator of cellular growth and metabolism in response to nutrient and hormonal cues?
- mTOR
Is Parkinson’s disease a progressive neurodegenerative disease?
- Yes
What is the mean age of onset for people with Parkinson’s disease?
- 55 and age is a risk factor
Gender risk factors for Parkinson’s disease and if so what is the male: female ratio?
- YES
- Male: female ratio= 3:2
What are 95% of Parkinson’s disease cases?
- Sporadic with no genetic linkage.
- There is no known cause if these
What is the environmental toxin hypothesis with regards to Parkinson’s disease?
- N-methyl-4-phenyl-1,2,3,6-tetrahydrop[yrimidine (MPTP) - induced parkinsonism
- The active metabolite, MPP+ is neurotoxic
What can MPTP be found in ?
- Synthetic heroin
What is the chemical reaction for MPTP?
- MPTP—-(MAOB enzyme)—> MPP+–> Dopamine neurons take up and neurotoxic (death of these neurons in the substantia nigra)
What does MPP+ interfere with in terms of PD and cellular processes?
- Complex I of the ETC (hallmarks of ageing)
What are the clinical features of Parkinson’s disease (what is the mnemonic)?
- TRAP
- T: Tremor at rest
- R: Musular rigidity
- A: Akinesia (slowing of voluntary movements)
- P : Postural gait/instability
What are two morphological features observed post mortem with someone who had PD?
- Degeneration of the substantia nigra pars compacta
- Lewy bodies and Lewy neurites
What are the 4 types of heterogenous motor symptoms found in PD?
- Bradykinesia-slowness of movement
- Akinesia- progressive decreased amplitude or speed.
- Tremor in a fully resting limb which is suppressed during movement initiation.
- Rigidity – velocity independent resistance to passive movements not solely reflecting failure to relax.
In terms of the motor symptoms, according to the international Parkinson and movement disorder society, what is parkinsonism defined as?
- Bradykinesia in combination with either at rest tremor or rigidity or both
What are the 6 types of non motor symptoms for Parkinson’s disease?
- Sleep dysfunction – sleep maintenance insomnia and excessive daytime somnolence (wanting to sleep during the day)
- Autonomic nervous system dysfunction – constipation, day time urinary urgency
- Olfactory dysfunction- hyposmia (loss of sense of smell
- Psychiatric symptoms – delusions, paranoia, hallucinations (most commonly visual).
- Cognitive impairment- dementia (memory loss).
- Pain (e.g. sharp nerve pain).
How far before the motor symptoms do the non-motor symptoms appear for PD, and why is this the case?
- They appear a decade before motor symptoms
- This is because there is no disorder to classify the non motor symptoms with- not characteristic of any disorder. Unfortunately after the motor symptoms have appeared, most of the dopaminergic neurons have been destroyed (degeneration). So very difficult to stop disease progression.
After the motor symptoms appear in PD, is there any chance to save the neurons?
- NO
- Unfortunately after the motor symptoms have appeared, most of the dopaminergic neurons have been destroyed (degeneration). So very difficult to stop disease progression.
What is a timeline example of symptoms occurring before motor symptoms for PD?
- 20 yrs before: Constipation
- 10 years before: REM sleep behaviour disorder
- 5 yrs before: daytime sleepiness, hyposmia, depression
- After 0 yrs (early): first motor symptoms- pain, fatigue, bradykinesia, tremor, rigidity
What are the symptoms of the late stages of PD?
- Orthostatic hypotension, Dementia, Urinary symptoms (Non-motor)
- Dysphagia, postural instability, freezing of gait, falls (motor)
- Psychosis (complication)
What is the pathological hallmark of parkinsons?
- Lewy bodies (with aggregated alpha-synuclein in the core) and Lewy neurites with alpha-synuclein stained processes
Which type of pathway is affected with PD?
- Susceptible pathway: nigo-striatal dopaminergic neurones, depletion
Where are Lewy bodies found prior to their appearance in the substantia nigra pars compacta (SNc)?
- Initially found in the olfactory bulb, enteric and autonomic nervous systems and brainstem.
PD is a disorder of protein ______-__-________.
- PD is a disorder of protein misfolding-alpha-synuclein
What are the three main autosomal dominant inherited causes of PD?
- Mutations in alpha-synuclein first gene link to familial PD, major constituent of lewy bodies and neurites
- Leucine-rich repeat kinase 2 (LRRK2) – mutations are the most frequent genetic cause of familiar PD, also account for 4% of sporadic PD.
- Vacuolar protein sorting-associated protein 35 (Vps35) – causal mutation with late-onset PD, subunit of the retromer complex involved in endosomal– lysosomal trafficking.
What are 4 major causes of PD that account of 5% of all parkinson’s patients?
- Parkin – autosomal recessive juvenile parkinsonism, major mutations for early onset PD (up to 50%), more than 100 mutations identified, deletions, insertions, duplications, Point mutations.
- DJ-1- 1 to 2% of early onset PD, positive regulator of PINK1 to modulate cell metabolism and proliferation
- Phosphatase and tensin homologue induced novel kinase-1 (PINK1)- 2- 4% of early onset PD with slow progression and often a typical features EG dystonia, sleep benefit, psychiatric comorbidities such as anxiety and depression.
- ATP13a2- lysosomal ATPase- mutations cause juvenile onset PD
Which gene mutation is known to be the largest risk factor for idiopathic PD?
- GBA mutation (glucocerebrosidase)- encodes a lysosomal enzyme (deficient in Gaucher’s disease)
- Risk OR>5
What is the gene that encodes the Tau protein?
- MAPT- common low risk gene mutation in PD
What are some examples of environmental risk factors that increase the risk (OR>1) of developing PD?
- Pesticide exposure (linked to living in rural areas)
- Well water drinking (also linked to pesticide exposure)
- Beta-blocker use
What are some examples of environmental factors that decrease the risk (OR<1) of developing PD?
- Tobacco smoking
- Coffee drinking
- NSAID use
- Alcohol consumption
- Ca2+ channel blocker use
What is a main possible cause of PD and how does this link with other processes in the dopaminergic neuron?
- increased formation of misfolded alpha-synuclein protein.
- The cell cannot deal with this increase
- Misfolded protein starts to accumulate in dopaminergic neuron (bc of defects in the ability of the cell to dispose of misfolded protein- via the lysosome dependent degradation or ubiquitin proteasome system)
- The aggregated misfolded protein aggregates in the cell to form Lewi bodies.
- Lewi bodies in neurons can undergo trans-synaptic transmission: It is transferred from an affected neuron to another- this is how it spreads and infects other neurons (new concept).
Are current therapies for PD treating the symptoms or causes?
- They can only treat the symptoms at this point
What are the three main treatments for motor symptoms of PD?
- Drugs designed to enhance Central dopamine content or stimulate dopamine receptors (levadopa, dopamine agonists e.g. apomorphine, rotigotine, bromocriptine or Monoamine oxidase B inhibitors)
- Anticholinergics- e.g. Trihexyphenidyl, for treatment of tremors
- Anti-psychotic Clozapine- for treatment of tremors
What are anticholinergics used for in terms of PD?
- Treatment of tremors
Which two classes of drugs are used for the treatment of tremors for PD?
- Anticholinergics and anti-psychotics (Chlozapine)
Why are some monoamine oxidase B inhibitors used in the treatment for motor symptoms of PD?
- more dopamine circulating so you want to INHIBIT this with inhibitors
What are the 4 main treatment areas of motor symptoms for PD with the corresponding treatments?
- Dementia - Cholesterase inhibitors (memory loss symptoms)
- Psychosis- Atypical antipsychotic
- Sleep disorders- benzodiazepines, melatonin
- Autonomic dysfunction - perihperal dopamine antagonist
What are 6 areas that are being targeted for the potential disease modifying treatment for parkinson’s?
- alpha-synuclein accumulation and aggregation
- Cell death – neutrophins (help to manitain the health of neuronal cells & prevent cell death)
- Neuroinflammation
- Mitochondrial dysfunction
- Oxidative stress
- Calcium channel activity.
What are neutrophic factors being trialled for in terms of mechanisms of PD progression and what are some examples of specific factors?
- Neurotrophic factors are being trialed to try and prevent the nigral striatal neurons from undergoing neurodegeneration.
- Examples include glial derived neurotrophic factor, brain derived neurotrophic factor, ciliary derived neurotrophic factor.
In terms of Parkinson’s disease what can be targeted in with neuro inflammation?
- Blocking pro-inflammatory cytokines and microglial activation
What is an example of a factor that prevents against oxidative stress in terms of parkinsons?
- urate
Which type of pathway are drugs that try to reverse mitochondrial dysfunction in terms of PD targeting?
- Drugs that act on the perisome proliferator activator receptor gamma pathway (NR1C3) is being trialled to see if they can reverse the mitochondrial dysfunction associated with parkinsons disease. This will increase the cell’s defense against ROS.
Are there more or less inhibitory outputs in a parkinsonian person compared to normal person?
- There are MORE PRONOUNCED inhibitory outputs to the thalamus and PPN (via the indirect pathway- less direct pathway)
- this contributes to slower gait
What specifically results in a more inhibitory output for the basal ganglia output strucutres (Gpi) to the thalamus and the PPN nucleus ot result in reduced amplitude of movements, including gait?
- Over activity for the indirect (striatum to the external part of the Globus Pallitus that has an inhibitory input to the subthalemic nucleus which then activates the internal globus pallitus)
- Underactivity for the direct pathways (stems from the striatum, inhibitory pathway is via GABA). What’s up Mum.
What is the PPN involved with?
- Voluntary limb movements and locomotion
What are the two main forms of surgical treatment for Parkinson’s Disease (PD) ?
- Deep brain stimulation- generally b/w 10-13 years after diagnosis
- Pallidotomy
What does deep brain stimulation for Parkinson’s Disease involve?
- It involves surgical implantation of a device that sends electrical impulses to specific brain regions.
Which areas of the brain does deep brain stimulation target for the treatment of Parkinson’s disease?
- The sub-thalamic nucleus, Globus pallidus and the thalamus.
Which types of patients is deep brain stimulation suitable for in terms of Parkinson’s disease?
- Suitable for patients with Parkinsonian symptoms that are still responsive to to levodopa but with motor fluctuations and dyskinesia that have become disabling.
Is the mechanism of action of deep brain stimulation well-known?
- No however thought to act by inhibiting neurons in the area of stimulation
What does a pallidotomy involve in terms of the treatment of Parkinson’s disease?
- Involves ablation of internal part of the Globus pallidus. (resects the input & output of striatum and can reverse the motor symptoms of PD)
Is a pallidotomy thought of is a really good treatment option for Parkinson’s disease?
- No because it’s quite invasive
- Popular in the 1950-60s and then popular again in the 1990s
What was the pallidotomy replaced by in terms of the treatment of Parkinson’s disease?
- Deep brain stimulation because it was less invasive.
Which type of stem cells have rich sources of dopamine that can prove is a potential treatment for Parkinson’s disease?
- Fetal stem cells
- BUT because of ethical issues with fetal stem cells and also limitations, alternative sources are being explored. So hence the stem cells above are being looked into to try and replace the dopaminergic neurons.
What is an alternative to replace the dopaminergic neurons that are lost in parkinsons disease (PD)?
- Stem cells (fetal are great but ethical issues, so other sources like mesenchymal etc are being looked into)
What is the gene based animal model for Parkinson’s disease?
- alpha synuclein transgenic mice- do NOT show progressive loss of DA neurones but form Lewy body like inclusions, display neuronal atrophy and neurite dystrophy
What is the toxin based model for Parkinson’s disease?
- The MPTP, Paraquat, Rotenone (pesticide. insecticide exposure) model
- 6-OHDA is injected into dopaminergic neuron to destroy it OR there is peripheral administration of the MPTP, Rotenone and Paraquat and they enter via BBB. They then study how they affect various processes in the neuron.
Dementia defined as?
- Significant loss of intellectual abilities severe enough to interfere with social or occupational functioning. (e.g. mild cognitive impairment and forgetfulness)
What are 7 criteria for the diagnosis of dementia?
Impairment of:
- Attention
- Orientation
- Memory.
- Judgement
- Language
- Motor and spatial skills.
- Function
What is mild cognitive impairment defined as?
- Significant memory loss without the loss of other cognitive functions.
What is a common symptom associated with aging?
- Forgetfulness
- This may or may not lead to mild cognitive impairment or dementia
How many Australians currently live with dementia?
- An estimated 459 000.
- 10% of individuals over 65 and 30% over 85 are affected
What is the second leading cause of death in Australia after heart disease, and who is more affected-males or females?
- Dementia with females being more vulnerable
- they contribute to 65% of all dementia related deaths
What is the most common form of dementia?
- The most common form of dementia is Alzheimer’s disease (AD)
What are the three other forms of dementia?
- Vascular dementia
- Frontotemporal dementia
- Lewy body dementia.
What is vascular dementia characterized by and caused by?
- second most common form of dementia caused by cerebrovascular pathologies
- Lacunes and infarcts caused by atherosclerosis, cardioembolic and small vessel diseases
What is frontotemporal dementia characterized caused by?
- Leading type of early onset dementia (under 65 years).
- Frontal and anterior temporal lobe atrophy.
- Pathologies caused by abnormal aggregation of tau, TAR DNA-binding protein 43 or fused in sarcoma protein.
What is lewy body dementia characterised and caused by (and what are the two types of it)?
- Pathological aggregates of alpha synuclein
1. Dementia with Lewy bodies (DLB)–> Global grey matter atrophy for DLB
2. Parkinson’s disease dementia (PDD) –>Temporal and frontal lobe atrophy for PDD
What is the most common neurodegenerative disease?
- Alzheimer’s, affecting more than 20 million people worldwide
What were the hallmark pathologies observed post mortem for Alzheimer’s in 1906?
- Neurofibrillary tangles
What is familiar AD (FAD) characterised by (what % of all AD cases does it account for, which mutations, how aggressive)?
- Approximately 5% of all AD cases
- 3 proteins mutated
- Associated with mutations in the amyloid Precursor protein APP as well as the processing enzymes presenilin 1 and 2.
- Very AGGRESSIVE form of the disease affecting individuals in their 40s and 50s- death within 10 yrs of diagnosis
What is late onset AD (LOAD) characterised by (what% of all AD cases does it account for, which pathway/or is there a pathway, which genes have increased risk)?
- > 95% of all cases, age-related (sporadic)
- NO strong links to any mutations of the amyloid beta processing pathway
- GWAS studies reveal at risk genes for AD: ApoE* (significantly increased risk), CLU, PICALM
What are the 4 symptoms that are the typical presentation of AD?
- Memory impairment – working memory, recently learnt information.
- Executive dysfunction – challenges with planning and problem solving.
- Confusion agitation – difficulty completing familiar tasks, confusion with time/place
- Mood and personality changes – withdrawal from social activities, suspicious, depressed, fearful and anxious.
What are 3 symptoms that are the atypical presentation of AD?
- Language impairment – problems with speaking sport / writing.
- Visual problems – trouble understanding visual images/spatial relationships.
- Motor dysfunction
What are the two main hallmarks of Alzheimer’s disease pathology and other two pathologies as well?
- Aggregation of amyloid protein (plaques) -extracellular (outside neurons)
- Hyperphosphorylation of tau protein (NFT-neurofibrillary tangles)- intracellular
OTHER TWO (NON HALLMARKS):
- Synaptic dysfunction and cell death
- Hippocampal atrophy and memory deficits
What is the main contributor for plaques, in terms of Alzheimers disease and the amyloid beta processing pathway?
- Ab1-42
What is AB1-42’s involvement in the Amyloid processing pathway in terms of Alzheimers?
- Produced in low quantities, more prone to form oligomers, protofibrils and fibrils, main form in amyloid plaques.
Which amyloid beta protein is pathogenic; AB1-40 or AB1-42? (AD)
- Ab1-42 is pathogenic
Where is the intracellular AB (Abeta) found in normal people? (In terms of AD)
- Normally found in the normal human brain and the highest in younger people
What is monomeric AB (Abeta) though to play a role in? (in terms of AD)
- Synaptic function
Which amyloid beta protein is the main form secreted as part of the amyloidogenic processing pathway?
- Ab1-40
- This is non pathogenic
- Lower tendency to aggregate
- Thought to have a neurotrophic tendency
Will all AP processing result in the formation of an amyloid plaque?
- NOOOO
- Ab1-40 is non pathogenic and is the major one produced
In the Amyloidogenic pathway, what results in neurotoxicity and the neural plaque formation?
The ratio of Ab40 and Ab42 that results in the neurotoxcitiy and leads to extracellular plaque formation.
Why do Ab40 and Ab42 accumulate outside the cell?
When beta secretase and gamma secretase cleaves APP that sits at the plasma membrane, the portion of Ab40 and Ab42 that is cleaved by gamma secretase then gets released into the Extracellular space.
What does APP stand for in terms of Alzheimers pathology?
- Amyloid Precursor Protein
Which type of protein is APP and what is it important for in terms of Alzheimer’s?
- It is a transmembrane protein
- Important for neural growth and repair
Which two types of pathways is the amyloid precursor protein (APP) processed via?
- Alpha-secretase pathway (Non-amyloidogenic)
- Amyloid forming Beta-secretase pathway (amyloidogenic)
What occurs in the alpha secretase (non-amyloidogenic) patwhay? (1st path hallmark of AD)
- Alpha secretase cleaves in the middle of the amyloid beta region to release a soluble fragment (alpha-APPs) . Then C83 metabolised to P3 by y-secretase
What occurs in the beta secretase (amyloidogenic) pathway? (1st path hallmark of AD)
- Beta secretase releases large soluble fragment , Beta-APPs. C99 is cleaved by y-secretase at SEVERAL positions which leads to the formation of amyloid-B40 (Ab40) and the pathogenic amyloid0B42 (AB42).
What can Beta-secretase inhibitors block? (1st path hallmark of AD)
- They can block the formation of B-APPs and C99 as well as AB42 (pathogenic)
What can gamma (y) secretase inhibitors block? (1st path hallmark of AD)
- AB42 (pathogenic)
- P3 and APP C. This leads to the accumulation of C99 and C83
What is the second pathological hallmark of AD?
- Tau hyperphosphorylation
How are neurofibrilary tangles formed in terms of AD?
- Tau protein hyperphosphorylation
How does tau hyperphosphorylation occur?
- Tau is bound to the microtubule normally
- BUT hyperphosphorylated tau detaches!
- This soluble form of tau aggregates
- These aggregations then form neurofibrillary tangles
- These tangles lead to synaptic dysfunction and an inflammatory response
Accumulation of amyloid plaque correlate with cognitive impairment?
- NO BUT mutations in amyloid precursor protein and in presenilin 1 and 2, which are essential in generating Abeta, cause familial, early onset AD
Which proteins that are essential in generating Abeta, cause familial, early onset AD?
- Amyloid precursor protein and presenilin 1 and 2
Do mutations in the Tau protein cause AD?
- NO they cause frontotemporal dmeentia
Do amyloid beta plaques still exist in a normal person?
- YES
In terms of FAD (Early onset Alzheimer’s disease):
- What type of mutations occur?
- In which pathway?
- Which proteins can be mutated?
- Roughly how many mutations have been identified?
- Dominantly inherited mutations in amyloid processing pathway.
- Amyloid precursor protein APP, presenilin-1 and to (components of gamma-secretase).
- Over 50 pathogenic mutations of APP identified, PSEN1 (250 mutations).
In terms of LOAD (Late Onset Alzheimer’s Disease):
- Which three main pathways are implicated and what are the corresponding mutations?
- Cholesterol metabolism – risk allele E4 clusterin, ABCA7 (ATP-binding cassette Transporter).
- Immune response – complement receptor 1, cd33, tram2 (receptor on microglia that stimulates phagocytosis).
- Endocytosis- BIN1, PICALM (PI binding clathrin assembly protein), CD2AP (scaffold protein), EPHA1 (ephrin tyrosine kinase), SORL1 (sortilin-related receptor)
- Rare variants of APP, presenilin 1 and 2
How many isoforms of the Tau protein are there?
- Different 3R/4R microtubule binding domain repeat
What is the role of Tau?
-To promote assembly of tubulin into microtubules and stabilise their structure.
How is the hyperphosphorylation of Tau neurotoxic?
- It is neuro toxic by inhibiting the microtubule assembly.
What do missense mutations f the MAPT gene (Tau) cause?
- Inherited cases of frontotemporal dementia (not AD)
What do silent mutations of the MAPT gene result in?
- This alters the ratio of 3R: 4R tau which results in hyperphosphorylation
Which gene variant confers the highest risk to developing AD?
- APOE4 gene variant
What are the two different theories for Alzheimer’s disease?
- The amyloid Cascade hypothesis
2. The Tau hypothesis.
What characterizes the amyloid Cascade hypothesis for AD?
- A buildup of Abeta and Tau drives AD pathogenesis possibly.
- In FAD – overproduction of ab42, alter propensities aggregate.
- In LOAD – not overproduction but DEFICITS in A-beta clearance.
What characterizes the Tau hypothesis for AD?
- Better correlation of phosphoTau with severity of disease.
- Tau is an important regulator of axonal Transport, postsynaptic scaffolding protein potentially.
- Human town mutations are associated with frontotemporal dementia not AD (so is it causal)?
What is the current debate for the role of Abeta in AD?
- There is poor correlation between Abeta load and clinical disease
- Toxic intermediates such as oligomers of Abeta peptide- artefact from isolation procedure??
What is a non modifiable risk factor for Alzheimer’s disease?
- Age
What are six risk factors for Alzheimer’s disease?
- Head trauma
- Vascular health – structural abnormalities in cerebrovascular leading to ischemic damage, cerebral amyloid angiopathy (metabolic disorders e.g. Obesity)
- Obesity and diabetes – AD is known as the diabetes of the brain where central insulin resistance has been suggested.
- Physical and mental inactivity – “use it or lose it.”
- Smoking
- Low education attainment (because not using the brain as much)
What are 4 major diagnostic tests for Alzheimer’s disease?
- Cognitive performance tests (detects dementia though not direct AD- that is only post mortem)
- No reliable biomarkers of diease in CSF (total Tau/phosphoTau and AB42)
- Neuroimaging (PIB-PET, amyloid pathology. 18FGD-PET, hypometabolism. MRI, hippicampal atrophy)
- Post mortem confirmation of pathology
What is the only way to 100% confirm AD diagnosis?
- Post mortem analysis- which isn’t helpful as the person is already deceased
With no symptoms (pre-symptomatic), are Amyloid plaques increased in level?
- YES
- By the time the symptoms have come the plaque levels have plateaued
What are the two types of treatment for Alzheimer’s disease?
- Symptomatic - cholersterase inhbitiors, NMDA receptor antagonist (FDA approved)
- Disease modifying- blocking the pathology
- Amyloid plaque formation – ABeta vaccine, gamma-secretase inhibitors.
- Tau hyperphosphorylation – kinase inhibitors, phosphatases.
- Synaptic dysfunction – neuroprotective agents.
- Hippocampal atrophy
What do Amyloid beta therapies include in terms of AD disease modifying treatments?
- Inhibitors of Abeta synthesis
- Anti-aggregation of Abeta
- these have NOT been effective in arresting alzheimers disease progression
What do Tau therapies include in terms of AD disease modifying treatments?
- Inhibitors of Tau phosphorylation
- Anti-aggregation of Tau
- these have NOT been effective in arresting alzheimers disease progression
What do neuroprotective agents include in terms of AD disease modifying treatments?
- Anti-inflammatory
- Anti-oxidants
- these have NOT been effective in arresting alzheimers disease progression
Have any of the AD disease modifying treatments been effective in arresting disease progression?
- NO
The different types of animal models for Alzheimer’s disease? (4 types)
- Expression of the human transgene in my start replication of some but not all characteristics of AD
1. Single transgenic (APP mutations- Sweedish, Indiana, London)
2. Double transgenic (Different PP and PS 1 mutations)
3. Triple Transgenic (APP, PS and Tau mutations)
4. Tau transgenic (Tau mutations)
Which of the characteristics listed below are common features of many newer developmental disorders?
A. NDDs are so named because the symptoms appear just after birth
B. The most debilitating symptoms of NDD are the cognitive and memory impairments
C. Most NDDs have a very strong monogenetic component and are highly heritable
D. Genetic and environmental factors contribute to the development of NDDs
D is correct: Genetic and environmental factors contribute to the development of NDDs
The excitatory/inhibitory theory for NDDs states that…..
A. All NDDs are caused by hyperactivity of the excitatory circuits in the developing brain.
B. All NDDs are caused by a shift in balance away from the inhibitory circuits.
C. All NDDs result from the failure of homeostatic mechanisms to regularize excitatory-inhibitory activity in the brain.
D. And it is a caused by the inability of GABAergic neurones to switch from being excitatory to inhibitory.
C is correct: All NDDs result from the failure of homeostatic mechanisms to regularize excitatory-inhibitory activity in the brain.
Case study:
The Pharmaceutical Company Mentalhealth Inc has decided to focus their drug development efforts on the drug therapies for schizophrenia. The company strongly believe in the “2-hit hypothesis for schizophrenia” and that this represents a new direction for the development of the novel drug candidates. They have been asked to prepare a business case for the board to persuade them to invest this new strategy.
Firstly, which of the following groups would be listed as the current front line treatment for schizophrenia?
A. Anti depressants and anti anxiety drugs
B. Cognitive enhancers and anti anxiety agents
C. Anti-psychotic agents and cognitive behavioural therapy
D. Anti-depressants and electroconvulsive therapy
The correct answer is C: Anti-psychotic agents and cognitive behavioural therapy
Case study:
The Pharmaceutical Company Mentalhealth Inc has decided to focus their drug development efforts on the drug therapies for schizophrenia. The company strongly believe in the “2-hit hypothesis for schizophrenia” and that this represents a new direction for the development of the novel drug candidates. They have been asked to prepare a business case for the board to persuade them to invest this new strategy.
Based on the two-hit theory for schizophrenia, which of the following groups of drugs could be explored as a potential preventative strategy for the second-wave hit?
A. Amphetamine and neuroleptic agents
B. Antibiotics and anti-anxiety agents
C. Anti-psychotic agents and cognitive behavioural therapy
D. Anti-depressants and anti-anxiety agents
- The correct answer is D: Anti-depressants and anti-anxiety agents
Case study:
The Pharmaceutical Company Mentalhealth Inc has decided to focus their drug development efforts on the drug therapies for schizophrenia. The company strongly believe in the “2-hit hypothesis for schizophrenia” and that this represents a new direction for the development of the novel drug candidates. They have been asked to prepare a business case for the board to persuade them to invest this new strategy.
Based on the two hit theory of schizophrenia, which of the animal models listed below would be best suited to test the novel preventative therapies in?
A. Phencyclidine (PCP) model
B. DISC 1 mutant mouse model
C. Lesion of the neonatal ventral hippocampus
D. Neuregulin overexpressing mouse model
The correct answer is A: Phencyclidine (PCP) model
What characteristics listed below are common features of many neurodegenerative disorders?
A. Many neurodegenerative disorders have defects in protein handling which results in accumulation and aggregation of the proteins.
B. The most readily detectable symptom of all neurodegenerative disorders is the cognitive impairment.
C. Most neurodegenerative disorders involving degeneration of a common neuronal pathway.
D. Causative gene mutations contribute to a significant proportion of most neurodegenerative disorders.
- The correect answer is A: Many neurodegenerative disorders have defects in protein handling which results in accumulation and aggregation of the proteins.
- D is INCORRECT as causative gene mutations contribute to only a small proportion of most neurodegenerative disorders
Caloric restriction has been shown to extend lifespan. Which of the following signalling pathways associated with nutrient-sensing, in your opinion, should be targeted to prevent the development age-associated disorders? A. Phosphatidylinositol 3-kinase (PI3K) B. Akt C. mTOR D. All 3
- Correct answer is mTOR
- All the other options are upstream of mTOR
CASE STUDY:
Family members of a 55 year old woman named Sara have noticed that her memory has deteriorated significantly over the past 3 months. They also observed that during her birthday celebration, she was confused and did not know what to do with her presents or with the birthday candles and cake. Moreover, Sara has been showing increasing signs of aggression and agitation and has been withdrawing from social events including cards and with her friends.
The family members expect that Sara is showing signs of Alzheimer’s dementia. What tests should be conducted to aid with the diagnosis?
A. Cognitive tests (MMSE), PET (using PiB) and MRI scans
B. Motor coordination tests, PET (using 18FDG) and MRI scans
C. Genetic tests to look for mutations in at-risk genes.
D. Alzheimer’s disease cannot be diagnosed
- The correct answer is A: Cognitive tests (MMSE), PET (using PiB) and MRI scans
CASE STUDY:
Family members of a 55 year old woman named Sara have noticed that her memory has deteriorated significantly over the past 3 months. They also observed that during her birthday celebration, she was confused and did not know what to do with her presents or with the birthday candles and cake. Moreover, Sara has been showing increasing signs of aggression and agitation and has been withdrawing from social events including cards and with her friends
Saras family knows that there is no cure for Alzheimer’s dementia but is aware of the promising drugs in the preclinical stages and development that have been shown to arrest the progression of the disease. If Sara does not have Alzheimer’s dementia, in your opinion what would be the best clinical trial to sign her up to?
A. Trials testing more effective cognitive-enhancing agents.
B. Trials on normal anti-inflammatory agents.
C. Trials testing amyloid intervention Therapies.
D. Trials on euro traffic agents such as nerve growth factor.
The correct answer is C: Trials testing amyloid intervention Therapies.
- This is because it is familial alzheimers (early onset)
CASE STUDY:
Family members of a 55 year old woman named Sara have noticed that her memory has deteriorated significantly over the past 3 months. They also observed that during her birthday celebration, she was confused and did not know what to do with her presents or with the birthday candles and cake. Moreover, Sara has been showing increasing signs of aggression and agitation and has been withdrawing from social events including cards and with her friends
. The early onset of dementia and Sarah’s case is highly indicative of The Familial form of Alzheimer’s dementia. Molly denes to be investigated to confirm this?
A. Microtubule-associated protein Tau (MAPT)
B. Amyloid precursor protein (APP)
C. ApoE
D. Both the MAPT and APP
- The correct answer is B: Amyloid precursor protein (APP)
