Neurodegenerative Disorders

Front 1

Define Neurodegenerative disorders

Back 1

Progressive and irreversible loss of neurons from specific regions of the brain

Front 2

Neurodegenerative disorders are primarily disorders associated with what?

Back 2

aging

Front 3

What are the % of patients over age of 65 that have Parkinson's and Alzheimer's?

Back 3

1%
10%

Front 4

What % of each generation in families carrying gene have Huntington's?

Back 4

50%

Front 5

Define dementia?

Back 5

taken from Latin, from de- "without" + ment, the root of mens "mind") is a serious loss of cognitive function in a previously unimpaired person.

Front 6

How can dementia be induced?

Back 6

Drug induced
Depression induced
Stress induced
Head injury
Illnesses (kidney, heart failure)

Front 7

What are the striking feature of PD, HD, AZ & ALS

Back 7

selective vulnerability

Front 8

Pd is extensive destruction of what? But what regions are not effected?

Back 8

extensive destruction of Dopa neurons in substantia nigra but not cortex and other regions

Front 9

AZ is what kind of injury?

Back 9

neuronal injury most severe in hippocampus and neocortex (specific functional regions)

Front 10

HD is what kind of gene? How is it expressed? Where is it pronounced?

Back 10

mutant gene is expressed through out brain and other organs yet pathology pronounced in neostriatum

Front 11

ALS is the loss of what?

Back 11

loss of spinal motor neurons and cortical neurons

Front 12

PD creates mutations in what genes?

Back 12

mutations in alpha-synuclein, parkin, UCHL1 and DJ-1 genes lead to specific forms of the disease

Front 13

AZ creates mutations in genes for what two things?

Back 13

mutations in genes for amyloid precursor protein (APP) and presenilins (involved in APP processing)

Front 14

ALS creates mutations in what?

Back 14

mutations for SOD1 account for  2% of cases

Front 15

What are environmental triggers that play a role in neurodegenerative disorders?

Back 15

Infectious agents, environmental toxins and acquired brain injury play role in neurodegenerative disorders.

Front 16

What is Excitotoxicity?

Back 16

neural injury that results from the presence of excess glutamate in the brain.

Front 17

What is a major “excitatory” neurotransmitter

Back 17

Glutamate

Front 18

What is impaired during Excitotoxicity? What does this increase with?

Back 18

The brain’s ability to respond to excess synaptic glutamate levels is impaired


This increases with age, exposure to environmental toxins, stroke, head trauma

Front 19

During neuronal injury in neurodegenerative disease what happens to proteins?

Back 19

Proteins misfold, etc, causing dysfunction of normal cellular processes

Front 20

What is oxidative metabolism required for? What is a consequence of it?

Back 20

Oxidative metabolism required for survival but a consequence is the generation of reactive oxygen species (ROS) such as hydrogen peroxide and oxyradicals.

Front 21

What is Excitotoxicity?

Back 21

neural injury that results from the presence of excess glutamate in the brain.

Front 22

What is a major “excitatory” neurotransmitter

Back 22

Glutamate

Front 23

What is impaired during Excitotoxicity? What does this increase with?

Back 23

The brain’s ability to respond to excess synaptic glutamate levels is impaired


This increases with age, exposure to environmental toxins, stroke, head trauma

Front 24

During neuronal injury in neurodegenerative disease what happens to proteins?

Back 24

Proteins misfold, etc, causing dysfunction of normal cellular processes

Front 25

What is oxidative metabolism required for? What is a consequence of it?

Back 25

Oxidative metabolism required for survival but a consequence is the generation of reactive oxygen species (ROS) such as hydrogen peroxide and oxyradicals.

Front 26

Alterations in neuronal mitochondrial energy metabolism increases with what?

Back 26

age

Front 27

what increase the production of ROS?

Back 27

Environmental toxins

Front 28

What can ROs cause to break and what can it cause to reorganize?

Back 28

ROS cause DNA strand breaks, nucleotide reorganization

Front 29

What are 4 clinical features of Parkinson's disease?

Back 29

Bradykinesia (slow movement)
Muscle rigidity
Resting tremor
Impaired postural balance, altered gait, falling

Front 30

What are the 2 pathological hallmarks of PD?

Back 30

loss of the pigmented dopaminergic neurons of the substantia nigra (70-80% dopaminergic neurons)
↓ dopamine action in corpus striatum (Regions involved in motor control)

Front 31

Untreated PD progresses how long and to what state?

Back 31

progresses over 5-10 yr to akinetic state

Front 32

In PD, what does metabolism of Dopa via MAO yield? Hydrogen peroxide + Fe2+ (abundant in basal ganglia) yields what? Degeneration of dopa neurons could occur due to what?

Back 32

1. Metabolism of Dopa via MAO yields hydrogen peroxide
2. Hydrogen peroxide + Fe2+ (abundant in basal ganglia) yields free radicals
3. Degeneration of dopa neurons could occur due to deficiencies in protective mechanisms

Front 33

Levodopa is what kind of precursor and what is it a precursor for?

Back 33

metabolic precursor of dopa.

Front 34

What is the single most effective treatment of PD?

Back 34

Levodopa

Front 35

Levodopa is converted how?

Back 35

Levodopa is inert; conversion by decarboxylation to dopamine in presynaptic terminals of dopaminergic neurons of striatum

Front 36

Levodopa restores what signaling? How?

Back 36

Restores dopa signaling in corpus striatum by ↑dopa synthesis in surviving neurons of substantia nigra.

Front 37

What is Levodopa's half life? What can it result in>

Back 37

Short t1/2 (1-2 hr): can result in fluctuation in plasma [ drug] and response

Front 38

What is Carbidopa? What is used in combo with it?

Back 38

Dopa decarboxylase inhibitor that does not cross BBB. Used in combo w/levodopa

Front 39

When carbidopa is used with levodopa what is decreased and what is increased?

Back 39

↓ metabolism of levodopa in GI tract and periphery →↑ availability of levodopa to CNS (<1% levodopa reaches CNS if dosed alone)

Front 40

What kind of receptor is used to treat parkinson's? What are 4 drug examples of it?

Back 40

Dopamine Receptor Agonists: (bromocriptine, ropinirole, pramipexole, rotigotine)

Front 41

What are advantages of Dopamine Receptor Agonists compared to levodopa?

Back 41

Enzymatic conversion not required →don’t depend on functional capacity of nigrostriatal neurons.
Longer acting that levodopa; avoid fluctuations in motor activity.
MAY have neuroprotective effect via ↓ free radical formation from dopa metabolism (by reducing release of endogenous dopa and reducing need for levodopa)
Dopa agonists may delay levodopa treatment in early PD and may ↓ dose of levodopa in advanced PD
Ineffective in patients who have shown no therapeutic response to levodopa.

Front 42

What 2 components are involved with metabolism of dopamina and? levodopa

Back 42

Catechol-O-Methyltransferase (COMT) Inhibitors and MOA

Front 43

COMT inhibitors (selective, reversible) block what? What does this increase?

Back 43

the peripheral conversion of levodopa to 3-O-methylDOPA → increasing the plasma t½ of levodopa as well as the fraction of each dose that reaches the CNS.

Front 44

Catechol-O-Methyltransferase (COMT) Inhibitors are absorbed how? Bound how? what kind of vd?

Back 44

Readily absorbed, highly protein bound, limited Vd

Front 45

what drug crosses the BBB and inhibits COMT in the CNS (therapeutic effect in PERIPHERY)? What drug does not?

Back 45

Tolcapone, but not entacapone,

Front 46

What can tolcapone cause? When is it used? What is monitored?

Back 46

Tolcapone can cause fulminating hepatic necrosis→ only use when other Rx has failed and monitor liver function

Front 47

What are Selective MAO-B Inhibitors? Where are they expressed and what are they involved in?

Back 47

MAO-B is predominant isoform expressed in striatum and involved in dopa metabolism.

Front 48

What drug inhibitits MAO-B? At what dose levels? What does it increase?

Back 48

Selegiline (deprenyl) selective inhibits MAO-B (but not MAO-A) at low to moderate doses →↑ [dopa].

Front 49

Rasagline is what kind of inhibitor? What is its potenency compared to selegiline?

Back 49

Rasagline: irreversible, selective MAO-B inhibitor; 5X > potency than selegiline.

Front 50

What are 3 drugs that are Muscarinic Receptor Antagonists?

Back 50

Trihexyphenidyl, benztropine, biperiden

Front 51

What is amantadine?

Back 51

antiviral agent for influenza A. Modest efficacy for PD.

Front 52

amantadine increases release of what? What kind of blocker is it?What kind of weak receptor does it have? How is it compared to levodopa?

Back 52

Complex pharmacology; ↑ dopa release in the striatum, anticholinergic, weak NMDA glutamate receptor antagonist. Less efficacious than levodopa but fewer side effects.

Front 53

How many cases of Alzheimer’s Disease in the us is there?

Back 53

there are as many as 5.3 million Americans living with AZ

Front 54

What kind onset and progression is there for AZ?

Back 54

Gradual onset but “relentless progression”

Front 55

What is the first sign of AZ? What signs are there later?

Back 55

First sign: impaired short term memory
Later, other cognitive deficits appear:
Visual-spatial processing deficits
“Ideomotor apraxia” (loss of ability to use common tools)

Front 56

What 2 components remain normal until very late in the AZ disease?

Back 56

Arousal and motor function remain normal until very late in the disease

Front 57

AZ characterized by what two components? What neurons appear to be lost?

Back 57

AZ characterized by neuronal atrophy and a loss of cortical and subcortical neurons
In particular, cholinergic neurons in appear to be lost

Front 58

what kind of projections to the parietal lobe are less active during AZ?

Back 58

Serotonergic

Front 59

What plaques are common in az?

Back 59

Amyloid and senile plaques are common

Front 60

What are amyloid plaques caused by? What is it accompanied by?

Back 60

Amyloid plaques are caused by accumulation of the protein b-amyloid
Accompanied by neuronal degeneration

Front 61

What is b-amyloid? What is it the product of? Where is APP expressed? It maybe what kind of receptor? How is B-amloid hypothesized to be produced?

Back 61

1. b-amyloid is a short polypeptide (42-43 AA)
2.Product of the amyloid precursor protein (APP)
3.( APP is normally expressed in many neurons)
4. may be a membrane-bound receptor
5.b-amyloid is hypothesized to be produced via abnormal proteolytic cleavage of APP

Front 62

The probability of developing b-amyloid plaques is what? What may this be due to?

Back 62

1. Heritable
2.May be due to inheritance of abnormal genes involved in APP itself
May also be due to the inheritance of abnormal genes involved in processing APP

Front 63

What activity is altered in Alzheimer’s disease?

Back 63

Tau Protein

Front 64

What is tau protein associated with? What 2 places is it found in? What are microtubules important for?

Back 64

Tau protein is associated with microtubule stability
Found in both neuronal and non-neuronal tissue
Microtubules are important to neuronal architecture integrity, neurotransmitter transport

Front 65

Tau protein is though to by ___ in alzheimers?

Back 65

hyper-phosphorylated

Front 66

what does the hyper-phosphorylation of Tau protein leads to the development of? What 3 things does it lead to the loss of?

Back 66

1.The development of tangles
Loss of structural integrity of neurons
2.Loss of efficient neurotransmitter transport from the nucleus to the pre-synaptic area
Loss of efficient recycling of neurotransmitter metabolites

Front 67

In later stages of the disease, Neurofibrillary tangles are numerous in what?

Back 67

The hippocampus
Areas of cortex involved in abstract thinking, language, our general (not tactile) perception of the world and interaction in it

Front 68

In AZ, what happens to the neurotransmitter content of cerebral cortex?

Back 68

Neurotransmitter content of cerebral cortex ↓↓ consistent with neuronal loss

Front 69

In AZ there is Striking and disproportionate deficiency of what?

Back 69

acetylcholine (Ach)

Front 70

IN AZ acetylcholine neurons are though to degenerate in both what areas? What is thought to happen to Ach? What activity is also decreased?

Back 70

1.ACh neurons are thought to degenerate in both subcortical and cortical areas
2.ACh receptor levels are also thought to decrease
3.Choline acetyl transferase (CAT) activity is decreased
CAT is the final rate-limiting enzyme involved in ACh production

Front 71

What does reduced Choline acetyl transferase (CAT) activity = ?

Back 71

= reduced ACh in secretory vesicles

Front 72

What is the “Cholinergic hypothesis”?
What can Central cholinergic antagonists (atropine) induce?

Back 72

1.deficiency in Ach is critical in genesis of AZ
2.induce a state similar to dementia

Front 73

AZ pathology includes defects in what 3 things?

Back 73

includes defects in serotonin, glutamate and several neuropeptides

Front 74

IN AZ there are destruction of what 3 things?

Back 74

Destruction of not only cholinergic neurons but also cortical and hippocampal targets that receive cholinergic input

Front 75

Alzheimer’s patients exhibit what increased levels? What can these levels be measured in?

Back 75

1.Glutamate
2.Increased glutamate can be measured in the CSF

Front 76

In AZ patients, what does excessive glutamate result in? What does glutamate play major rules in? What can high levels of glutamate lead to?

Back 76

1. Excessive glutamate results in disrupted cognition
2.Glutamate plays a major role in learning and memory
3.High levels of glutamate ultimately can lead to excitotoxicity

Front 77

excitotoxicity in AZ patients lead to what?

Back 77

Toxicity is associated with the over-activation of NMDA (glutamate) receptors
Influx of Ca2+
Cell death

Front 78

What is the primary approach in tx of AZ?

Back 78

to attempt to augment cholinergic function

Front 79

ACh neurotransmission in AZ patients is intricately involved in multiple what?

Back 79

involved in multiple hippocampus, cortex functions

Front 80

What are 4 drugs Acetylcholinesterase (AChE) inhibitors (AChE)?

Back 80

Tacrine (Cognex
Donepezil(Aricept)
Rivastigmine (Excelon)
Galantamine (Razadyne)

Front 81

Tacrine is what kind of AChE inhibitor? What does it show effectiveness in improving?

Back 81

Centrally acting AChE inhibitor
Shows some effectiveness for improving memory

Front 82

Donepezil is what kind of inhibitor? What does it show moderate improvement in? What does its long t1/2 allow?

Back 82

Reversible, non-competitive central AChE inhibitor, Modest improvement in cognitive scores
Long t1/2 allows qd dosing

Front 83

Rivastigmine is what kind of inhibitor?

Back 83

Reversible, non-competitive AChE inhibitor

Front 84

Galantamine is what kind of inhibitor?

Back 84

Competitive inhibitor of AChE

Front 85

AZ rx memantin is hypothesized to be what? What does it block the flow of? What does it slow the rate of?

Back 85

1. hypothesized to be a non-competitive NMDA receptor antagonist
2.Blocks the flow of Na+ and Ca++ through the NMDA receptor channel
3.slow rate of memory los?

Front 86

What kind of disorder is Huntinton's Disease?

Back 86

HD is an autosomal dominant disorder with nearly complete penetrance.

Front 87

What gene does the HD mutation lie within? Equally heritable from both parents, however 80% of patients developing symptoms before age 20 inherit from which parent?

Back 87

1.IT15 gene
2. Father

Front 88

What is anticipation?

Back 88

tendency for the age of disease onset to ↓ w/each succeeding generation.

Front 89

What does tx of HD focus on?

Back 89

focuses on reducing symptoms, preventing complications, and providing support and assistance to the patient and family/caregivers.

Front 90

What is the only FDA-approved Rx for ALS?

Back 90

Riluzole

Front 91

Riluzole delays what? Has what kind of effects? Inhibits the release of?What does it block? Inhibits what channels?

Back 91

1.Delays onset of ventilator dependence or tracheotomy in some patients
2.Has both pre- and post-synaptic effects
3.Inhibits glutamine release
4. Blocks post-synaptic NMDA and kinate-type glutamate receptors
5. Inhibits voltage-dependent sodium channels

Front 92

What is spasticity?

Back 92

increase in muscle tone w/initial resistance to passive displacement of a limb at a joint, followed by sudden relaxation

Front 93

What are drug tx of spasticity?

Back 93

baclofen (GABA- B receptor agonist) and tizanidine (2 adrenergic receptor agonist in CNS)