2. Cns Degenerative Diseases - Intro

Front 1

What is the current theory of why neurodegeneration occurs?

Back 1

A combination of events causes selective degeneration of some neurons; not just one single factor.

Front 2

What does Selective Vulnerability refer to?

Back 2

The increased vulnerability of some neurons to toxic insult than others.

Front 3

What is a clinical example of this selective vulnerability of neurons to toxic degeneration?

Back 3

Huntington's disease - all neurons HAVE the huntingtin gene, but not all neurons degenerate in this disease.

Front 4

What are 3 types of insults that can induce neurodegeneration?

Back 4

-Environmental toxins
-Neuronal metabolism
-Aging

Front 5

How do environmental toxins often induce neurodegeneration?

Back 5

By affecting mitochondrial function which results in low ATP and more oxidative stress.

Front 6

Why does neuronal metabolism cause neurodegeneration?

Back 6

Because it is an oxidative process, so oxidative stress on neurons is high - even normally.

Front 7

What are 3 ways that Aging contributes to neurodegeneration?

Back 7

-Affects mitochondrial function
-Loss in protective enzymes and molecules
-Progressive hits

Front 8

What are 3 major outcomes of the combined Environmental toxins, Neuronal metabolism, and Aging?

Back 8

-Free radical formation
-Oxidative stress
-Excitotoxicity

Front 9

What is excitotoxicity?

Back 9

Excessive intracellular calcium

Front 10

How do free radicals form?

Back 10

From dysfunctional, inefficient mitochondria which leak out electrons and oxygen radicals; caused by aging/environm. toxins

Front 11

What do the free radicals do?

Back 11

Cause lipid peroxidation

Front 12

What part of the mitochondria is particularly vulnerable to free radical injury?

Back 12

Complex 1

Front 13

What are 3 results of Complex 1 injury?

Back 13

-Loss of ATP synthesis
-Inability to extrude Ca2+ dt no energy
-Loss of ability for membrane to maintain resting potential

Front 14

What are the 2 main molecules that cause oxidative stress?

Back 14

-H2O2 and Superoxide

Front 15

What does oxidative stress precipitate?

Back 15

-Excitotoxicity
-Mitochondrial dysfunction

Front 16

And what is excitotoxicity?

Back 16

Excessive intracellular calcium

Front 17

What does Excitotoxicity result from?

Back 17

A vicious cycle:

Front 18

What are the 6 steps in the vicious cycle of excitotoxicity?

Back 18

1. Depletion of ATP for pumps
2. Cell death
3. Excessive glutamate release
4. Persistant activation of NMDA receptors
5. Excess intracellular Ca
6. More ATP depletion

Front 19

What is another factor that can cause persistant activation of NMDA receptors, other than excessive glutamate?

Back 19

Superoxide - so oxidative stress is linked to excitotoxicity too.

Front 20

What are 4 mechanisms that neuronal cells have for dealing with radicals?

Back 20

-Ascorbate (vit C)
-Glutathione
-Superoxide dismutase
-Catalase

Front 21

When does degeneration due to free radicals occur?

Back 21

-When too many radicals are produced
-When cells lose the ability detoxify

Front 22

What is the main thing to remember about neurodegeneration?

Back 22

There is SELECTIVE VULNERABILITY - not all neurons undergo degeneration even though the factors are present among them all

Front 23

What is Parkinson's disease?

Back 23

A movement disorder

Front 24

What is Parkinson's disease due to?

Back 24

Selective loss of the Dopaminergic neurons in Substantia nigra that project to the striatum

Front 25

What is the Striatum?

Back 25

Caudate + Putamen

Front 26

What are 4 pathologic findings in Parkinson's disease?

Back 26

-Neurodegeneration in basal ganglia and substantia nigra
-Lewy bodies
-Loss of nigrostriatal Dopamine neurons
-Decreased Dopamine levels in Substantia nigra

Front 27

What other level is decreased by decreased Dopamine in Substantia nigra?

Back 27

CSF levels of HVA - the DA metabolite

Front 28

What does the loss of Dopamine in nigrostriatal circuits result in overall?

Back 28

Dysregulation of the basal ganglia

Front 29

What does the dysregulation of the basal ganglia in Parkinson's disease result in?

Back 29

Not enough excitation of the motor cortex; decrease in movement.

Front 30

What are the 4 Major symptoms of Parkinsons disease?

Back 30

-Cogwheel rigidity
-Resting Tremor
-Bradykinesia
-Postural reflex loss

Front 31

What is the cogwheel rigidity in Parkinson's due to?

Back 31

Dysregulation of gamma motor neurons

Front 32

What does the loss of postural reflexes result in?

Back 32

Shuffling gait and unsteadiness

Front 33

What it the resting tremor seen in Parkinson's also called?

Back 33

Pill-rolling tremor

Front 34

What is Brady/Hypokinesia?

Back 34

Brady = slow movements
Hypo = fewer movements

Front 35

What are 4 physical manifestations of the brady/hypokinesia seen in Parkinson's?

Back 35

-Mask-like facial expression
-Muffled speech
-Sialorrhea (drool)
-Freezing

Front 36

What are the slower/fewer movements due to?

Back 36

The effect of decreased thalamic input to the cortex, so loss of alpha motor neuron stimulation.

Front 37

Is Parkinson's strictly a movement disorder?

Back 37

NO - there are also intellectual problems

Front 38

What are 3 intellectual changes in Parkinson's?

Back 38

-Changes in personality
-Loss of drive/curiosity
-Memory loss - ultimate dementia

Front 39

What are 2 more common personality changes seen in PD?

Back 39

-Irritibility
-Impulsivity

Front 40

What are the intellectual changes in PD due to?

Back 40

Effects on the ventral striatum - dopamine is part of several cerebral circuits

Front 41

What is the etiology of Parkinson's Disease?

Back 41

SELECTIVE VULNERABILITY of the dopaminergic cells of the substantia nigra

Front 42

Why are SN dopaminergic cells selectively vulnerable to degeneration?

Back 42

Because when MAO metabolizes Dopamine to DOPAC, H2O2 gets produced at the same time.

Front 43

What happens to the H2O2 product of Dopamine metabolism?

Back 43

It undergoes Fenton chemistry where Fe2+ reduces H2O2 to OH- and Hydroxy radicals + Fe3+

Front 44

What happens over the years as MAO and Fe2+ in dopaminergic neurons of SN continue to be produced?

Back 44

The accumulation of free radical damage over the years causes death and reduced # of DA cells

Front 45

Is the accumulation of free radicals and loss of DA neurons the same in everyone?

Back 45

No, the slope of DA loss down to a threshold where PD symptoms manifest varies btwn patients.

Front 46

What are 7 factors that can change the rate of how soon symptoms of Parkinson's disease will develop?

Back 46

ABCEING

Front 47

What is ABCEING?

Back 47

-Arteriosclerosis
-Brain trauma
-Chemicals
-Encephalitis
-Iatrogenic
-Neuroinflammation
-Genetic factors

Front 48

What are 6 chemicals that can increase the rate of development of parkinsons symptoms?

Back 48

-CO
-CN
-Methanol
-Manganese
-MPTP
-Insecticides

Front 49

Who developed PD due to brain injury?

Back 49

Muhammad ali

Front 50

What is an iatrogenic cause that has been linked to PD?

Back 50

Antipsychotics - block DA receptors

Front 51

What is a gene that may be related to the rate of PD manifestation?

Back 51

Parkin