PBD Active Learning 3 - Parkinson's Disease

In the US, are there are more cases of Parkinson's disease than Alzheimer's disease?
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Parkinson's incidence is higher in men or women?Men (6:4 ratio).Parkinson's is rare in people under what age?30.Countries around the world with similar life expectancies have ______________ prevalence of PD.Similar.What is the current economic impact of Parkinson's in terms of dollars/year?$25 billion dollars per year.A 2007 study shows that between 2005 and 2030, Parkinson's rates are expected to...Nearly double. Going from 4.1 million (2005) -> 8.7 million (2030).In the beginning, motor symptoms of Parkinson's progress very ________.very slowly.Early symptoms of Parkinson's can be difficult or easy to identify?DIFFICULT.Early symptoms of PD are...- Less vivid facial expression (masked face/flat affect) - Cramped, small handwriting (starts big and gets smaller and smaller). - Shakiness and difficulty getting out of a chair (difficulty initiating movement). Basically - flat affect, cramped handwriting, difficulty starting movement.What are the later stage symptoms of PD?- Tremors (pill-rolling) at rest/under stress. - Rigidity (emotionless face), clock-like arm movement. - Bradykinesia (slowed movement and difficulty starting and stoping movement). - Posture instability (shuffling and falling). "*T*he *R*ye *B*read is *P*ote" - The mind of Phil NettleParkinson's tremors decrease with _______ ________, and go away with _________.intentional movement (decrease), sleep (goes away).What are the impacts of PD on patients?- Movement disorders hamper daily activities - Injury due to falling at later stage - Difficulty swallowing (choking hazard and pneumonia) - Dementia or AD symptoms in a portion of PD patients.There is a __% overlap of Dementia and Alzheimer's in patients with Parkinson's.30%.How many dopamine producing/releasing pathways are there in the brain?four.Which Dopamine (DA) pathway handles reward?The Mesolimbic DA pathway.Where does the Mesolimbic DA pathway run?Ventral Tagmental area to Nucleus Accumbens and the Amygdala.Which Dopamine (DA) pathway handles motivation?Mesocortical DA pathway.Where does the Mesocortical DA pathway run?Ventral tagmental to frontal cortex.Which Dopamine (DA) pathway handles movement?The Nigrostriatal DA pathway.Where does the Nigrostriatal DA pathway run?Substantia Nigra to striatum (caudate nucleus and putamen).Which Dopamine (DA) pathway handles prolactin secretion?The Tuberoinfundibular DA pathway.Where does the Tuberoinfundibular DA pathway run?Hypothalamus to pituitary gland.The degeneration of DA-producing neurons in the substantia nigra causes a reduction of DA release by the same neuron in the ____________ which causes ________ _________.Striatum Movement Disorders.How much striatal DA releasing capacity needs to be lost to produce PD movement disorders?At *LEAST* 60%.After losing 60% of Striatal DA releasing neurons, there is a _________ __________ of loss.Rapid progression (prior to this, there was a fairly steady decrease).Parkinson's has both _________ and __________ forms.Genetic and sporadic (idiopathic) forms.Early onset PD is usually due to which form?Genetic formEarly onset PD usually occurs around what age?around 35 years.The genetic form of PD represents ____% of total PD cases.(less than) 5%Late onset PD is usually due to which form?Sporadic/idiopathic.Late onset PD usually occurs around what age?60 years and over.Late onset PD represents ___% of total PD cases.(over) 95%Is there currently a bio-marker for PD?Nope.Clinical diagnosis of PD is based on at least two of the the cardinal signs/behavioral characteristics. What are they?- Bradykinesia - Rigidity - Resting tremorWhy is posture instability not included in the cardinal signs of PD diagnosis?Because it is commonly observed in the elderly.In addition to movement abnormalities, additional routine diagnostic tools for PD include... - High powered imaging - Specific proteins in blood - Cognitive capacity - Specific gene mutations - All of these - None of theseNone of these!What are the hallmarks of a postmortem diagnosis of PD?1) Loss of neuromelanin-rich DA neurons in Substantia Nigra (SN) 2) Lewy bodies.What are Lewy bodies?Intracellular inclusions that contain neurofilament proteins, lipids, ubiquitin and alpha-synuclein. PATHOLOGICAL HALLMARK OF PD.Lewy bodies are present in approximately __% of PD cases.85%Can Lewy bodies be used in pre-symptomatic diagnosis?Nope! Can't see them in live patients yet.Are Lewy bodies known causes of neurodegeneration in PD?Nope.Why are the nigral DA neurons so vulnerable to insult?*Long explanation* 1) Defect in mitochondrial complex I which increases generation of superoxides (O2) and hydrogen peroxides (H2O2) via superoxide dismutase. 2) Nigra is rich in iron (sequestered in neuromelanin), this is compromised in PD brains and free divalent iron is released. 3) Free iron converts H2O2 to HO- which is MUCH more reactive than H2O2 *shorter explanation* A defect in Mitochondrial complex 1 increases free radical (O2 and H2O2) generation. In PD brains, the iron than should normally be sequestered in the neuromelanin gets released as free divalent irons. These two things combine and the free irons convert H2O2 to HO- which is much more reactive.Dopamine and it's metabolites are prone to ____________ which generates what?Oxidation (which generates) H2O2.Why are free radicals (O2, H2O2) dangerous in large amounts in the Substantia Nigra?The free radicals overwhelm intracellular antioxidant capacity. Modifies proteins to make them inactive, forms adducts with nucleic acid to alter gene expression. All of these cause neuronal injury and eventual death of DA neurons.How do brain immune cells respond to neuronal injury?Sustained glial activation leads to more free radicals and pro-inflammatory cytokine production which exacerbates neuronal degeneration and *forms a self-feeding vicous cycle of neuronal damage and glial activation.*Muscle contraction is the result of...Abstract thoughts of movement in the cortex which becomes voluntary action in the neuromuscular junction.In the *basal ganglia loop*, GABA is __________.Inhibitory.In the *basal ganglia loop*, Glutamate is _________.stimulatory/excitatory.In the *basal ganglia loop*, DA is __________.Can be both. Depends on different factors.Cortical neurons send activating signals (____________) to activate both the _________ and ____________ pathways.Glutamate (activating signals), direct and indirect (pathways).The *direct pathway* releases _____ to inhibit _______ release from GPi resulting in *less inhibition* on thalamic glutamate releasing neurons hence ____ glutamate release and ___________ of motor activity.GABA (to inhibit) GABA (release), more (glutamate), stimulation (of motor activity).Stimulation of motor activity is referred to as...HyperkeneticThe *indirect pathway* releases ___________ to stimulate ______ release from GPi resulting in *more inhibition* on thalamic glutamate releasing neurons hence _____ glutamate and _________ of motor activity.Glutamate (to stimulate) GABA (release), less (glutamate), inhibition (of motor activity)Inhibition of motor activity is referred to as...Hypokenetic.__________, produced by nigral _________ neurons and released in striatum works on and regulates the activity of both the direct and indirect pathways.Dopamine (for both).The balance of direct and indirect pathways controls the amount of ____ release critical to movement regulation.GABASo basically, Dopamine regulates the _________ of the direct and indirect pathway.balanceIt is known that the first GABA neurons in the direct and indirect pathways respond differently to Dopamine, the difference is due to their differences in...Dopamine receptors expressed.THROWBACK Gi inhibits...Adenylyl Cyclase (AC) which decreases cAMP.THROWBACK X 2 BONUS ROUND Gs stimulates...Adenylyl Cyclase (AC) which increases cAMP.Depletion of DA in the striatum leads to less stimulation of the...Striatal GABA-releasing neurons innervating to Gpi, so the inhibitory action on them is reduced.Depletion of DA in the striatum leads to less inhibition on the...STN glutamate-releasing neurons innervating to the Gpi, thus the stimulatory action on the GABA-releasing neurons in Gpi is increased.What is the overall effect of depletion of DA in the striatum?GABA-releasing neurons in Gpi become overly active, so the totally inhibitory output is excessive which results in inhibition of movement.Basal ganglial output of GABA is regulated by...?The balance of the direct and indirect pathways.What are the major non-motor *sensory* symptoms of PD?Olfactory deficit, pain, visual dysfunction.What are the major non-motor *sleep* symptoms of PD?insomnia and vivid dreams.What are the major non-motor *psychiatric* symptoms of PD?depression, apathy, anxiety, hallucination, panic attacks.What are the major non-motor *GI* symptoms of PD?constipation.What are the major non-motor *bladder* symptoms of PD?urgency, nocturia, and increased frequency.True or false... Fatigue is a major non-motor symptom of PD.TrueCertain non-motor symptoms such as olfactory defect, depression, sleep disorder, and constipation may precede expression of motor symptoms by ___ years.12 (years).These non-motor symptoms may signal that Parkinson's...Just doesn't impact the nigrostriatal (motor) DA pathway. Other DA pathways that are non-motor may be impacted as well. As well as non-DA neurons.Outside of GABA, striatal D1 neurons also release what? What about D2?D1: Dynorphins and substance P D2: enkephalins ... which impact other brain functions.Are there different genes associated with familiar Parkinson's?YesIs Parkinson's autosomal recessive or dominant?Both!In many genes, several encoded proteins that deal with ___________ of cellular proteins have been proposed to play a role in Parkinson's.folding (normal processing).Mutation in folding proteins alter their functions which can lead to...mis-folding, aggregation (Lewy bodies), and cell damage (loss of DA neurons).In Familial PD, the age of onset is much earlier because...The mutated genes greatly accelerate degeneration.Misfolded proteins can be _______ to the body.Toxic (causes response from body which can cause a vicious cycle).True or false... Exposure to certain pesticides and head injuries are proven causes of PD.False (Only PROVEN cause of PD are gene mutations, which make up 5% of PD cases).However, elevated exposure to pesticides and certain heavy metals as well as traumatic brain injury are _________ _______ _________.Potential risk factors (but we're not completely positive yet).Lower incidence of PD is found in people who are...coffee drinkers and cigarette smokers.Injection of MPTP can induce Parkinson's in a matter of...days.How does MPTP induced PD work?Mimics DA transporters and fits in their place even though they're nothing alike. Causes DA neuron death due to running out of energy (ATP).