CNS 1 : Neurogenerative Disorders: (Alzheimers + Parkinsons + Huningtons)

what are the four neurogenerative diseases?

1. huntington’s

2. alzheimer’s

3. parkinsons

4. ataxias

which region of the brain deals with

• memory

• learning

• behavior

• language

which disease is associated with its loss of function?

Hippocampus + Neocortex = alzeheimers

which part of the brain deals with

• voluntary movement

loss of function is associated with:

basal ganglia = parkinson’s + huntingston’s

which part of the brain deals with

• coordination and balance

loss of function of this region would lead to?

Cerebellum

Ataxia

what are the the common pathological processes of neurogenerative diseases?

1. AMYLODIOSIS

mutated accumulated protein aggregates

mutations due to oxidative stress

2. NUEROINFLAMATION

Which proteins aggregate in Alzheimers disease?

what do mutations in these aggregates lead to?

• AB (plaques) and Tau (tangles)

• dementia

Which proteins aggregate in Parkinson’s Disease?

what do mutations in these aggregates lead to?

• a-synuclein

• hypOkinetic movement disorder

Which proteins aggregate in Huntington’s Disease?

what do mutations in these aggregates lead to?

• polyglutamine repeat expansions (huntingtons) — trinucleotide

• hypERkinetic movement disorder

which neurogenerative disease leads to HYPERkinetic movement and which leads to HYPOkinetic movement?

hyper= huntington’s

hypo = parkinson’s

________ is an umbrella term for impaired ability to remember, think, or make decisions that interferes with everyday activities

under this umbrella are

• _________

• vascular

• lewy body

• frontotemporal

dimentia

under = allzheimers

Epidemiology of Alzheimer’s:

• more common in males or females?

• what age is considered early onset/ late onset?

• females

• early= less than 65 years late = greater than 65 years

does familiar or sporadic alzheimers have early onset?

what is considered early?

which is more common, familial or sporadic?

• familiar = early

• early = younger than 65

• more common is sporadic = late onset= 65 or elder

is familial alzheimer’s monogenic? what does that mean?

familial alzheimers has high ___________

yes

monogenic = autosomal dominant (only need one mutated gene)

penetrance (ALOT of people experience symptoms)

what three genes, if mutated lead to familial alzheimers?

PSEN1 (presenilin 1)

PSEN2 (presenilin 2)

APP (amyloid precursor protein)

what is a risk allele for late-onet SPORADIC alzheimers?

APOE (Apolipoprotein) and TAU related genes

Can sporadic alzheimer’s be familial?

what mutation is the common cause of sporadic alzheimers?

YES

SNPs (single nucleotide point mutations)

do

• NSAIDS

• statins

• estrogens

• Vitamen C or E intake

• mediteranian dier

• moderate alcohol intake

• cognitive reserve (crosswords)

increase or decrease risk of Alzheimers

DECREASE

what 5 environmental factors can increase your risk of alzheimer’s?

• hypertension

• diabetes

• obesity

• hypercholesteremia

• smoking

what is the differnce between alzheimers and expected forgetfulness that comes with age?

alzheimer’s is frequent and is PROGRESSIVE (gets signicantly worse)

Alzheimers GROSS ANATOMY:

• decrease in the brain’s ___________

• widening of ________ and narrowing of _______

• degeneration of neurons in the __________ and __________ , loss of ____________

• loss of pigment in the locus ________

• weight

• sulcus gyri

• hippocampus, neocortex, acetylcholine

• coeruleus (blue spot)

ALZHEIMERS deals with the

narrowing of _________

widening of ___________

is this the same or opposite for HYPOXIC ISCHEMIA ENCEPHALOPATHY

narrow GYRI (folds)

widen SULCUS (space between folds)

OPPOSITE FOR HYPOXIC ISCHEMIA ENCEPHALOPATHY

what areas are preserved in alzheimer’s

1. pigmented neurons in the substantia nigra

2. occipital lobe

3. cerebellum

BLUE SPOT appears due to loss of pigmented neurons in the _________ __________ of ALZHEIMERS patients

locus coeruleus

what are the two hallmarks of ALZHEIMERS disease required for diagnosis?

which are internal and which are external to neurons?

1. amyloid plaques (external AB protein fibers)

2. neurofibrillary tangles (hyperphosphorylated tau protein INSIDE neuron —- disrupt microtubules (tracts for neurons)

HALLMARKS OF ALZHEIMERS (NUERONAL LOSS):

1. glutamatergic ______________ neurons in the entorhinal cortex and hippocampus

2. __________ receptors in the basal forebrain

3. _______________ neurons in the locus coeruleus (blue spot)
   

1. PYRAMIDAL

2. cholinergic (Ach and Nicotine)

3. noradrenergic (epinephrine, norepinephrine, dopamine)

Alzheimer’s Disease: Amyloid Precursor Protein Cleavage

• How is APP normally cleaved?

• how is APP cleaved in patients with Alzheimer’s?

• a-secretase (cut into two peices)

• cut by BOTH B-secretase and G-secretase leaving AB peptide which makes up amyloid plaque

what stimulates b- and g- secretase to cleave APP instead of a- secretase?

what is the fragment cut up by b- and g- secretase called?

why is that fragment so dangerous?

b stimulated by APP mutation

g stimulated by PSEN 1 and PSEN 2

AB peptide

AB peptide MAKES UP amyloid plaque

Alzheimers deals with not only the inappropriate cleavage of APP stimulated by mutated APP and PSEN1 and 2 but also complications with Tau

What does Tau normally do?

tau stabilizes microtubules which acts as tracks for neuronal signaling

Alzheimers = crack in the track of neuronal signaling

how is Tau tangled in alzheimer’s?

phosphorylation

Alzheimers Disease Neuroinflammation:

protein aggregates can activate ____________ and ________ which can lead to further aggregation

• microglia and astrocytes

Alzheimers Disease Neuroinflammation:

dysregulated neuroinflammation is bad for neurons!

what can it lead to?

1. tau phosphorylation (break in track!)

2. oxidative stress

3. abnormal PRUNING of synapses

Current alzheimer’s treatments can do 2 things:

1. PREVENT FURTHER LOSS OF NEUROTRANSMITTERS —> SYMPTOMATIC

   • Inhibit esterases AchE

   • noradrenergic (epinephrine, norepinephrine, dopamine)— lost from locus coeruleus— missing blue spot

   • cholinergic (Ach)— lost from basal forebrain

2. AGAINST AB —> DISEASE-MODIFYING

   • monoclonal antibodies against AB peptides that make up amyloid plaque (inappropriately cleaved APP)

PARKINSONS EPIDEMIOLOGY:

What age group is typically affected?

What is considered early onset?

Which gender is mostly impacted?

• typically 60-70s

• early is less than 50 years

• males

what is the fastest growing neurological disease?

PARKINSONS (hypokinetic movement)

• pesticides and toxicants

• heavy metals

• physical activity

do the following increase or decrease the risk of Parkinson’s Disease?

INCREASE RISK

• smoking

• caffeine consumption

• physical activity

do the following increase or decrease your risk of getting Parkinson?

NEXT LECTURE:

the symptoms of WHAT disease can decrease due to pregnancy?

MULTIPLE SCLEROSIS

Is familial Parkinsons monogenetic?

Is it autosomal dominant?

monogenetic (only takes one gene) but not necessarily autosomal dominant

what is responsible for the protein aggregates of FAMILIAL PARKINSONS

SNCA (a-synuclein)

LRRK2

GBA1

which protein aggregate is seen in SPORADIC Parkinson's? where is it found?

what other genes are present?

SNCA (a-synuclein)—found in Lewy bodies

LRRK2

GBA1

HLA

which genetic mutations are specific to SPORADIC PARKINSONS'

HLA genes

LRRK2, GBA1, and HLA are all genes that if mutated lead to PARKINSONS

what info do you know about them

LRRK2 = lysosome kinase — repairs lysosome membrane BAD IF MUTATED

GBA1= glycogen storage disease —> Gaucher

HLA = MHC mutation in sporadic Parkinsons

is SPORATIC or FAMILIAL parkinsons more common?

is SPORATIC or FAMILIAL alzheimers more common?

SPORATIC PARKINSONS

SPORATIC ALZHEIMERS

• REM sleep disorder (awake in dreams)

• hypersomnia

• depression

• constipation

• excessive daytime sleepiness

• diabetes

• high plasma urate (decreased risk)

are the following medical risk factors of PARKINSONS or ALZHEIMERS?

PARKINSONS

** remember parkinsons is HYPOkinetic movement *

what are the cardinal motor symptoms of parkinsons?

• ____________ (slow movement)

• _________ (stiffness)

• ______________( at rest)

• __________ instability

• bradykinesia

• rigidity

• tremor

• postural

what are non-motor symptoms of Parkinsons?

• constipation

• REM (Rapid Eye Movement)

• EDS (excessive daytime sleep)

• loss of sense of smell

• mood disorders

• sexual dysfunction

Name the 2 HALLMARKS OF PARKINSONS

1. Nigrostriatal Degeneration

2. Lewy Bodies

HALLMARKS OF PARKINSONS:

1. Nigrostriatal Degeneration:

   Degeneration of _________ _________ neurons in the nigrostriatal pathway

2. Lewy Bodies:

   aggregates of __________ protein and other cellular components inside the neurons of the _____________

1. pigmented dopaminergic

2. a-synuclein substancia

What are the regions of the brain affected by PARKINSONS patients?

• substantia nigra

• enteric nervous system (ENS)

• olfactory bulb (smell)

• brain stem

• Neocortex

Basal Ganglia ROLE in PARKISONS

what does it usually do? how?

what blocks its function?

basal ganglia controls VOLUNTARY movement by sending OUTPUT to MOTOR CORTEX which sends info to muscles via the corticospinal tract

decreased dopaminergic neurons in the substantia nigra

does high plasma urate increase of decrease the risk of parkinson’s?

DECREASE

By the time you have been diagnosed with PD by motor symptoms, 80% of dopamine in the _____________and 50% of ___________ _______________dopaminergic cell bodies are lost.

striatum (basal ganglia)

Substantia Nigra

Which gene mutation causes

• Mitochondrial damage

• Autophagic and lysosomal dysfunction

• Neuroinflammation

  IN PARKINSONS DISEASE

mitochondria = MPTP

lysosome = LRRK2 + GBA

neutroinflamatin = NLRP3 inflammasome

What are the current FDA treatments for PARKINSONS?

1. DEEP BRAIN STIMULATION

2. SYMPTOMATIC (motor symtoms)

   1. levodopa/carbidopa INCREASE DOPAMINE

what do treatments for Parkinsons do?

1. REPLACE DOPAMINE

2. PREVENT FURTHER BREAKDOWN OF DOPAMINE

3. MIMIC DOPAMINE

dopamine neurons decreased in substantia nigra and striatum (basal ganglia)

How do the following help increase/maintain dopamine levels in Parkinson’s patients?

• COMT and MAO-B inhibitors

• DA agonists

• Levidopa/ Carbidopa

Can any of the following end progression?

• prevent the breakdown of Dopamine (catecholamine)

• mimic dopamine

• replace dopamine (allow dopamine to get through the blood-brain barrier)

NO

Which neurogenerative disease involves TOO MUCH dopamine?

Which involves TOO LITTLE dopamine?

too much dopamine = huntiningt’s = hyperkinetic movement

too little dopamine = parkinson’s = hypokinetic movement

is Hunington’s disease autosomal dominant?

does it effect one gender more than the other?

since Hunnington’s is trinucleotide what is true about offspring?

YES

NO

Genetic Anticipation - higher chance of children having disease early on bc/ number of repeats INCREASES

Hunington’’s disease is a trinucleotide repeat of what nucleotides in what genes?

what does the nucleotide sequence encode for

CAG repeat in Htt

CAG = glutamine

EXCESS GLUTAMINE IN Htt

how is Hunigton’s’s a polyglutamine expansion in Huntingtin

CAG is overexpressed in Htt gene

CAG expresses glutamine

EXCESS GLUTAMINE IN Htt GENE

is trinucleotide repeats a copy number variant?

NO

HUNTINGTON: CAG REPEAT CHART

• what are normal levels of CAG repeats (neither child nor parent will get if they have this many repeats)

• what is considered higher than normal CAG repeats? (do parents or kids get huntingtons)?

• what is considered reduced penetration levels in Huntingtons? (do parents or kids get Huntingtons)

• what is considered high penetrance levels in Hunigtons? (do parents or kids get huningtons)?

• 26

• 27-35 (kids possible parents no)

• 36-39 (kids yes parents possible) — genetic anticipation more likely to affect kids

• greater than 40 (kids yes parents yes)

how much CAG is needed for a parent and child to both DEFINETLY have huntingtons?

more than 40 repeats

Huningtons’s: Clinical Progression

• Age of motor symptom onset

• what age is considered juvenile onset?

• how long does one usually go without being diagnosed (PRODOMAL)

• 30-50

• less than 20

• 10-15 years LONG

what is a hallmark of Huntington’s disease (ALL PATIENTS HAVE IT)

chorea

involuntary dance-like movements

what are some symptoms of Hunigtons?

1. chorea- uncontrollable dance

2. difficulty with voluntary motor behavior

3. motor persistence

4. variability of pace of walking

HUNNINGTON”S : GROSS ANATOMY

Striatal (Caudate) Atrophy

• atrophy of ________ _______ and _____ ________

_________ Thinning

• degeneration and reduced volume of the __________

LEADING TO ENLARGEMENT OF ___________________

• basal ganglia and brain stem

• cortical

• cerebellum

• ventricles (bigger gaps—sulci)

DESCRIBE SULCI AND GYRI CONDITIONS IN

• Alzheimer’s

• Huntington’s

• Hypoxic- Ischemic Encephalopathy (HIE)

Alzheimers AND Huntingtons: wide sulci + narrow gyri

HIE: widened gyri + narrowed sulci

which protein aggregates in HUNINGTONS?

which protein aggregates in

• HUNNINGTONS

• PARKINSONS

• ALZHEIMERS

• protein encoded by Htt

• SNCA (a-synuclein) in lewy bodies

• AB peptides due to APP mutated cleavage (APP mutation-b and PSEN1 and PSEN2—y) instead of a- cleavage

which protein aggregates in Huntingtons ?

where is it found? is the amyloid outside or inside neuron?

HTT protein amyloid is inside nueron in NUCLEOUS or CYTOPLASM

pathological hallmarks of huntingtons:

1. ________ inclusions

_________(motor)

loss of __________ medium spiny neurons (MSNs) in the _____________: specific degeneration of MSNs in the striatum, the target of nigrostriatal DA neurons

1. HTT

2. Chorea - involuntary dance

3. GABAergic Caudate

HUNTINGTON’S DISEASE: BASAL GANGLIA

• Basal Ganglia controls ________ movement

  • sends output to _________ ________

  • ______ _______ sends info to muscles via the corticospinal tract

• LOSS of _______ergic nuerons in _________ INCCREASES activity of motor cortex

• voluntary

• motor cortex

• motor cortex

• GABA in STRIATIUM (in basal ganglia)

How to treat symptomatic (motor symptoms) of Hunnington’s Disease:

• Decrease ________ signaling (Xenazine + Austed)

• Reduce ___________ as a side effect (antipsychotics)

DECREASE DOPAMINE SIGNALLING

REDUCE MOVEMENT