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)