2nd most common Neurodegenertaive disease

Affects 1.5 million in the US, 50000 new/yr

6:4 male to female (could be due to estorgen)

Rare under the age of 30

Economic impact = 25 billion $/yr

1. Degeneration of DA producing neurons in the SN

2. Depletion of DA in the ST

Early onset  = 5%

Late onset = 95 %

35 yrs old

>60 yrs of age

Less vivid facial expression = masked face

Cramped or small hand writting

a little shakiness and difficulty getting out of chair

1.Tremor ( like pill rolling, several beats/sec) that is worse at rest or when under stress.

2. Rigidity-- so emotionless face and cog-wheel arm movement.

3. Bradykinesia- is a slowing or loss of spontaneous and automatic movement

4. Posture instability that leads to shuffling and falling.

By having at least 2 of the 3 cardinal clinical signs:

Bradykinesia

Rigidity

Resting tremor

1. The movement disorders can affect daily activity, it only worsens over time.

2. Injury due to falling

3. Difficulty swallowing can lead to choking

4. Severe disability

1. Loss of neuromelannin rich DA neurons in the SN

2. Lewy Bodies

inhibitory  (GABA brake)

Stimulatory (Glutamate fuel)

The DA depletion in ST leads to

1. less stimulation on the striatal GABA releasing neurons . { the GABA brake is reduced, less inhibition)

2. Less inhibition via D2 ont he sTN Glut-releasing neurons. { Glut fuel on GABA releasing neurons is increased}

1. Sensory = pain, visual dysfunction

2. Sleep = insomnia, vivid dreaming

3. Psychiatric= Depression, anxiety, hallucinations, panic attack

4. GI = constipation

5. Bladder disturbance = frequent pee

6. fatigue

1. Mesolimibic: VTA to NAc = reward

2. Mesocortical: VTA to Nucleus Frontal Cortex= Motivation

3. Nigrostriatal: SN to ST = Movement

4. Tuberoinfundibular: Hypothalamus to pituitary gland = Prolactin secretion.

Aggregation-- leads to lewy bodys

loss of DA neurons

Alpha-synuclein

Synaptic vesicle recycling, storage and compartmentalizatio of NTs

Its accumulation is found in Lewy Bodies; the build up blocks normal protein trafficking in ER and Golgi.

Over expression induces toxicity to DA neurons

Mutated Park 1 causes mitochondrial damage

a 3 mis-sense mutation and genomic triplication

Parkin

E3 ubiquitin protein ligase

(It targets misfolded proteins to the ubiquitin proteasome pathway for degradation)

ligase activity

50%

Exists as a homodimer

Has an antioxidant protein

Is a transcriptional activator that upregulates the tyrosine hydroxylase expression

LRRK2

Leucine-rich-repeat-kinase 2

1. Elevated exposure to pesticides and certain heavy metals and infectious agents/viruses

2. Traumatic brain injury like in boxing or war veterans.

They have reduced anti-oxidant acitivy due to a lower content of glutathione

Have a high content of lipids, neuromelanin and iron which are all prone to free radicals.

2-80 years old

1-40 years

30-50 yrs old

2-20

1. Movement disorders

2. Cognition disorders

3. Psychiatric disorders

Involuntary= Chorea

Voluntary = trouble with movement coordination

Early stage = clumsiness, balance problems

Mid stage = prominent chorea, difficulties with voluntary movements

Late stage = severe chorea, akinetic, severe rigidity and bedridden

Death due to difficulty swallowing/choking.

Early stage= Deficits in cognitive speed, trouble retrieving memory, lack of concentration

Mid Stage = difficulty to use/ understand words, inability to recognize familiar objects

Late stage = global impairment affecting memory, judgement and nonverbal

Depression-

Irritability

Anxiety

Aggresive outbursts

Mood swing

social withdrawal

Loss of striatal medium spiny projection GABA neuron leads to:

1. reduced Glut released (indirect pathway) which leads to too little stimulation in next GABA neuron

2. The direct pathway becomes dominant so there is increased release of GABA which leads to too much inhibition on next GABA neuron.

in simpler words

Too little inhibitory output from basal ganglia to thalamus

and

too much stimulatory input into cortex/spinal cord/muscles

Htt gene (Huntingtin)

it is mapped on chromo. 4

autosomal dominant

50%

CAG (cytosine-adenine-guanine)

40 or more CAG repeats

9-29 (this is normal)

the average tho is around 10 CAG repeats

Adult HD = 40-55 CAG

Juvenile = >70 CAG

2 yo = 250 CAG

expansion

contraction

It is associated with spermatogenesis.

Sperm has more highly variable repeat lengths due to more cellular divisions.

16 million

112.6 million

65 yr old

Has a slow progression 8-25 yrs

Mild AD

Moderate AD

Severe AD

Passive mood

forget directions to familiar places

lose the concept of money

forget math

remembering recent events is hard

Daily activities are not that much interfered.

Degeneration of the hippocampal neurons

They lose their short term memory

the frontal lobe

Affects judgement, safety awareness, planning and other complex thinking

Medical history/status

Ability to carryout daily activities

Mini Mental State Exam that determines math/language ability

Lab tests for exclusions

Brain imaging via CT, MRI, PET

Exclusion of other disorders that affect memory and cognition.

The aim is to diagnose pre-clinical dementia. (~ 10 yrs before memory related symptoms appear)

Imaging for amyloid plaques and tangles in brain and imaging for amyloid peptides and tau proteins in the CSF.

Cortical atrophy

ventricular dilation

amyloid plaques

tangles

Narrowed gyrus

Widened sulcus

Extracellular

abudance

They are spherical and multi-cellular

There is a amyloid proteind deposit core

Degenerating neuronal processes

And reactive brain Ig's

1. Beta Amyloid peptides

2. Apolipoprotein E

3. Protease inhibitors

4. complement problems

5. metal irons

APP695, APP751, APP770

chromosome 21

N

C

May have growth factor like activity because it promtes progenitor cell proliferation in the brain.

Regulates Ca2+ levles

stimulates signal transduction.

Intracellular domain may act as an adaptor protein for G-protein

β-secretase- cuts at 671

γ-secretase - cuts at 711 and 713

Aβ (1-40) and Aβ (1-42)

they aggregate together to form insoluble fibers

Activate protein phsophorylation. (Tau)

inhibit neuritic outgrowth (Affects plasticity)

Are toxic to neurons

increases

AB 1-40 and AB 1-42

Gamma secretase

AB 1-42

decrease

AB 1-40 and AB 1-42

PS1 and PS2

gamma secretase

PS1

70%

PS2

5%

Trisomy 21 has 3 copies of APP gene.

There is increased APP expression so increased generation of AB 1-40 and 1-42.

By age of 12 a plaque forms and neuropathology of AD develops in the 40-50 yrs of age.

Paired helical filaments

PHF

E2, E3 and E4

E3 is the most abundant

E4 is associated with AD

it doesnt affect the APP expression, but instead enhances aggregation of AB.

It decreases the clearance of AB and increases GSK-3B activity.

1. Inhibitors for ACH esterase

2. NMDA antagonists

ACh

ACh esterase

choline