ICL 4.2: Neurodegenerative Disease

Question 1

what is a neurodegenerative disease?

Answer 1

although they have diverse clinical presentation, they all have ONE pathologic change = accumulation of protein aggregates aka proteinopathy

regardless how the proteins arise, the aggregates are resistant to degradation!!

Question 2

what are the 3 different reasons that could lead to protein aggregates?

Answer 2

1. mutation = altering the protein conformation
2. disruption of pathway involving the processing or clearance of the proteins
3. an imbalance between the synthesis and clearance of the proteins which leads to a gradual accumulation

Question 3

what are the 2 ways that the protein aggregates can effect neurons?

Answer 3

the preotiein aggregates seen in neurodegenerative diseases show aberrant localization within neurons

the neurons don’t want the proteins living in them so the neurons get stressed or the proteins can be directly toxic to the neurons

Question 4

what dictates the clinical manifestation of protein aggregates?

Answer 4

location and type of protein!

since protein aggregates can either cause neuron stress or direct toxic effect on the neurons, the clinical presentation is based on the location of the protein aggregates

Question 5

how do the protein aggregates spread in the brain?

Answer 5

aggregates can behave like prions

this means that aggregates derived from one cell can be taken up by another cell which then creates more aggregates = the proteins are multiplying indirectly

Question 6

what are the protein aggregates often called?

Answer 6

inclusions

Question 7

what is the clinical presentation of Alzheimer’s disease?

Answer 7

1. dementia in older adults
2. memory loss
3. language impairment
4. orientation impairment
5. personality changes
6. Slowly progressive
7. Loss of motor skills
8. Final stages includes incontinence, mute and cannot walk

Question 8

which proteins are in the inclusions involving Alzheimer’s disease? why do protein aggregates form?

Answer 8

1. amyloid beta
2. tau

AB and tau are deposited in specific brain regions as a result of excessive production and defective removal

Question 9

what are the 2 modalities that the proteins involved in alzheimer’s are deposited?

Answer 9

1. plaques

plaques are aggregated amyloid beta peptides in the neuropils

2. tangles

tangles are intercellular aggregates of the microtubule protein tau which lead to cell death –> after the cell dies, the tau leaves the cell and deposited in different parts of the brain

the interplay between the plaques and tangles is still being studied

Question 10

What initiates Alzheimer’s?

Answer 10

AB is one of the proteins that forms inclusions during Alzheimer’s

Amyloid beta generation is the critical initiating event in Alzheimer’s disease!!!!!!***

Question 11

How is amyloid beta produced?

Answer 11

APP = amyloid precursor protein is cleaved by protein phosphatase A to form amyloid beta

There are 2 pathways for PPA cleavage:
1. Alpha secretase site = soluble fragment so amyloid beta isn’t generated —> so we don’t worry about this pathway

2. Beta secretase site after endocytosis = amyloidogenic pathway —> so we worry about this pathway because it forms AB!

APP is a cell surface protein and it is usually present in the transmembrane domain and it functions as a receptor for a prion (prions extend from one cell to another and lead to increase in protein aggregates)

Question 12

What are the two modalities by which amyloid beta aggregates once it’s formed during Alzheimer’s?

Answer 12

Amyloid beta is formed when phosphatase A enzyme cleaves amyloid precursor protein at the beta secretase cleavage site

Once AB is generated it’s protein to aggregation and forms plaques via 2 modalities:

1. Small oligomers = the toxic form which is responsible for neuronal dysfunction
2. Large aggregated fibrils

Question 13

Why do Down Syndrome patients always develop Alzheimer’s?

Answer 13

The gene encoding amyloid precursor protein is on chromosome 21 in the Down syndrome region

This is why all downs patients get Alzheimer’s eventually and they get it a lot earlier than the general population because the APP gene and the Downs gene lie really close to each other on chromosome 21

DS patients will have histologic findings in their second and third decade with neurological decline 20 years later (in their 40s)

Question 14

What is tau?

Answer 14

One of the proteins that forms aggregates in Alzheimer’s —> specifically it forms tangles (not plaques, that’s amyloid beta)

Tau is a microtubules associated protein and it’s present in axons in association with the microtubules network

So it’s really important for neuron stability

Question 15

What causes tau to form tangles in Alzheimer’s?

Answer 15

Tau is a normal protein that helps support microtubules in neurons!

But in Alzheimer’s tau becomes phosphorylated and it loses its ability to bind to microtubules

Question 16

How do tau tangles in Alzheimer’s cause neuron injury?

Answer 16

1. Stress response by the neuron
2. The microtubules stabilizing function of the tau protein is lost when tau is phosphorylated

The more tangles the more cognitive impairment!

Question 17

How does inflammation play a role in Alzheimer’s?

Answer 17

Both small and large deposites of amyloid beta elicit an inflammatory response from the microglia and astrocytes in the brain

1. The inflammatory response happens because the neurons are trying to clear the aggregates!
2. Inflammation also stimulates the secretion of mediators — mediators are usually beneficial but sometimes they can cause damage; in this case, these mediators phosphorylate tau which is bad because they can’t stabilize the microtubules which causes oxidative injury to neurons

Question 18

What are the biomarkers that can be used to screen for Alzheimer’s?

Answer 18

Amyloid beta depositions that have been labeled with fluorescence can be seen during imaging

We can see these in asymptomatic patients so we can predict who will get Alzheimer’s (both good and bad)

Question 19

How can CSF analysis help screen for Alzheimer’s?

Answer 19

If there is increased phorphorylated tau and reduced amyloid beta in the CSF, this is a predictive marker and it identifies the preclinical stages of Alzheimer’s!!

Question 20

What gross anatomy changes do you see in the brain with Alzheimer’s?

Answer 20

1. Cortical atrophy —> the brain of patients with Alzheimer’s are much smaller and weigh less; the sulci will look very deep and the gyri will look very tin

The atrophy is mostly in the cortex because this is where the cognitive functions lie!

2. Ventricular enlargement = hydrocephalus ex vacuum

Because there is cortex atrophy, there is ventricular expansion = hydrocephalus ex vacuum

Question 21

What microscopic findings will you see in the brain tissue of an Alzheimer’s patient?

Answer 21

1. Neuritic plaques that have a central amyloid core and focal spherical collection of dilated neuritic processes
2. Neurofibrillary tangles in the cytoplasm of neurons encircling or displacing the nucleus

Slide 44 and 45

Question 22

What are tombstone ghost neurons?

Answer 22

They are a microscopic finding in Alzheimer’s that are the tangles! They got their name because the tangles are super damaging to the neurons

They are usually found in cortical neurons but they are not specific for AD

Slide 46

Question 23

What is an overall summary of Alzheimer’s?

Answer 23

1. Proteinopathy of amyloid beta and tau
2. AB is generated rom APP by cleavage of protein phosphatase A —> cleavage occurs through alpha and beta pathway but the beta is the one associated with AB production
3. Tau is a normal protein in the body but if it’s phosphorylated it loses its ability to stabilize microtubules and the patient develops cognitive problems

Question 24

What is frontotemporal lobar degeneration?

Answer 24

Aka Pick disease!

It’s a degeneration of the frontal and or temporal lobes that causes alternation in personality and language that is later followed by memory loss

Usually familial and incidence occurs at a much earlier age than Alzheimer’s (under 65)

Patient will have problems with language and personality BEFORE they lose their memory vs. the patients with AD will become recluse and quiet but people with Pick disease at the beginning become aggressive and arrogant before their memory loss

Question 25

Which proteins are found in the inclusions of Picks disease?`

Answer 25

1. Tau

2. TDP43

Question 26

What is TDP43? Which neurodegenerative disease is it associated with?

Answer 26

A nuclear protein that binds both DNA and RNA —> under normal circumstances it regulates transcription

But in Picks disease it forms aggregates!

Question 27

What are the characteristics of Picks disease?

Answer 27

1. Progressive neuronal loss
2. Tau containing inclusions in the cytoplasm of neurons —> Alzheimer’s also has tau inclusions but those are tangles while these are round inclusions = different configuration
3. Severe atrophy
4. Pick bodies = smooth contoured inclusions

Question 28

What causes Pick disease?

Answer 28

A missense AND point mutation in the tau gene

With Alzheimer’s it’s just a point mutation

Question 29

What gross anatomy changes do you see in the brain of a Pick patient?

Answer 29

Gross asymmetric atrophy of the frontal and temporal lobes

The parietal and occipital lobes are rarely involved

Question 30

What microscopic changes do you see in the brain of a Pick patient?

Answer 30

1. Neuronal loss
2. Swollen cells = Pick cells
3. Intracellular round to oval filamentous bodies = Pick bodies

Question 31

What is the clinical presentation of Pick disease?

Answer 31

1. Behavioral problems
2. Language problems
3. Sometimes the gene mutations are related to ALS so patients might have some muscle weakness too

Question 32

What is Párkinson disease?

Answer 32

A hypokinetic movement disorder due to loss of dopaminergic neurons from the substantia nigra in the midbrain

The diseases starts in the brainstem and basal ganglia and it eventually progresses to the cortex leading to dementia with Lewy bodies

Dementia is a very late development of Parkinson’s so it’s not part of the initial clinical presentation

Question 33

What is the clinical presentation of Parkinsons?

Answer 33

1. Masked face (can’t express emotion)
2. Shuffling gait
3. Rigidity
4. Pill rolling tremors

Dementia is a way later development

Question 34

What is acute parkinsonian syndrome?

Answer 34

Patient will be totally find and then will suddenly get Parkinson’s usually due to exposure to a certain substance such as MPTP or pesticides!

Caffeine and nicotine on the other hand are protective against acute parkinsonian syndrome

Question 35

Which protein forms aggregates in Parkinsons?

Answer 35

Alpha synuclein

This is the protein that is aggregating and seen inside the Lewy bodies

Alpha synuclein agregates are really toxic to the neurons and have a prion spread pattern

Question 36

What is the pathogenosis of Parkinson?

Answer 36

1. Protein aggregation of alpha synuclein
2. Mitochondrial abnormalities
3. Neuronal loss in the substantia nigra

The alpha synuclein is what is found in the Lewy bodies and these inclusions are very toxic to neurons —> they have a prion spread pattern ):

Question 37

What causes mitochondrial dysfunction in Parkinson patients?

Answer 37

Mutation of the genes encoding DJ1, alpha pink and Parkin

DJ1 is normally a transcription modulator while pink and Parkin normally clear dysfunctional mitochondria via phagocytosis so mutation of the genes regulating any of these proteins can lead to the mitochondrial dysfunction seen in Parkinson

Question 38

What morphological changes will you see in the brain of a Parkinson’s patient?

Answer 38

Pale substantia nigra due to neuron death

Question 39

What microscopic changes do you see in the brain tissue of Parkinson patients?

Answer 39

Lewy bodies made of alpha synuclein

They look like round dense inclusions in the neurons surrounded by a clear halo

Question 40

What are 3 atypical Parkinsonism syndromes?

Answer 40

Progressive supranuclear palsy and tauopathy:

1. Truncal rigidity
2. Frequent falls
3. Tau inclusions in the neurons and glia

Question 41

What is corticobasal degeneration?

Answer 41

Progressive tau aggregation but the location is in the cerebral cortex, NOT the substantia nigra like Parkinson’s

So there is tau in the basal ganglia like Parkinson’s AND the cortex

Question 42

What are the clinical symptoms of corticobasal degeneration?

Answer 42

1. Rigidity
2. Apraxia = inability to perform a skill when asked to do it even though the patient may be able to perform the skill and they have the desire to perform it but the just can’t when you ask them to do it
3. Cognitive decline

Question 43

What is multiple system atrophy?

Answer 43

MSA involves damage to 3 neuronal atomic circuits:

1. Striatonigral damage which leads to Parkinsonism
2. Olivocerebellar damage which leads to ataxia
3. Autonomic nervous system damage which leads to autonomic dysfunction

Question 44

What causes multiple system atrophy?

Answer 44

Glial cytoplasmic alpha-synuclein inclusions!

There is NO gene mutation involved but we have no idea where these inclusions come from

Question 45

What is the morphology involved with multiple system atrophy?

Answer 45

1. Cerebellum atrophy
2. Inferior medullary olive atrophy
3. Microscopic oligodendrocyte inclusions of alpha synuclein anddddd ubiquitin

Question 46

Which proteins are in the inclusions of multiple system atrophy?

Answer 46

1. Alpha synuclein

2. Ubiquitin

Question 47

What is Huntington disease?

Answer 47

An autosomal disease that causes dementia and progressive movement chorea = purposeless jerky movements

Question 48

What causes Huntington?

Answer 48

The HTT gene located on chromosome 4 provides instructions for making Huntingtin protein which plays an important role in the normal function of neurons

With Huntington’s disease, the HTT gene is mutated due to CAG repeats so Hungtintin isn’t produced and there’s neuronal dysfunction

Degeneration of striatal neurons results in a loss of GABA neurons = caudate + putamen

Neuronal death is believed to be from glutamate over-excitability which causes an excess of calcium influx into the neuron and somehow kills the cell; we aren’t really sure how this happens or if it’s even really the cause

Question 49

What is anticipation and which neurodegenerative disease is it associated with?

Answer 49

Anticipation is when grandpa has Huntington’s at 60 then dad starts to get it in his 40s and then you start to get symptoms in your 30s

Anticipation happens in Huntington’s because the CAG repeat occur is during spermatogenesis

Question 50

What is the gross and microscopic morphology associated with Hungtinton’s?

Answer 50

GROSS

1. Atrophy of the caudate nucleus
2. Atrophy of the globus pallidus
3. Dilated 3rd and lateral ventricles

MICROSCOPIC
1. Intranuclear ubiquitin inclusions

Question 51

What is the clinical presentation of Huntington’s?

Answer 51

1. Involuntary jerky movements
2. Progression to severe dementia
3. Aggression
4. Depression

Question 52

What is Freidreich ataxia?

Answer 52

An autosomal recessive disease that causes spinocerebellar degeneration

Onset is in the 1st decade of life and patients live till their 50s; they die of arrhythmia and heart failure

The dentate nucleus and Purkinje cells of the cerebellum are destroyed

Question 53

What are the clinical symptoms of Freidreich ataxia?

Answer 53

1. Spacticity
2. Ataxia
3. Cardiomyopathy
4. Dysarthria (speech problems)
5. Positive babinski
6. Impaired vibratory sense
7. Pez cavus
8. Kyphoscoliosis

Question 54

What causes Freidrich’s ataxia?

Answer 54

GAA repeat expansion on the gene that encodes Frataxin so patients have very LOW levels of frataxin

Frataxin is a mitochondrial protein that is found in high levels in the brain, heart and pancreas —> this explains why Freidrich’s patients have cerebellum problems, cardiomyopathy and high blood sugar

Question 55

What is ataxia telangiectasia?

Answer 55

An autosomal recessive disease that is due to lack of DNA nonhomologous repair from a mutated ATM gene

Without being able to do nonhomologous DNA end repair these patients are at very high risk for cancer!!

Question 56

What is the clinical presentation of ataxia telangiectasia?

Answer 56

1. Immune deficient
2. Ataxia
3. Telangiectasia in the eye and skin
4. Recurrent sinus infections
5. low IgA

Question 57

What is the morphology seen in ataxia telangiectasia?

Answer 57

1. Loss of Purkinje cells and granular cells in the cerebellum
2. Degeneration of the spinocerebellar tract
3. Large nuclei in the Schwann cells

Question 58

What is amyotrophic lateral sclerosis?

Answer 58

1. Loss of upper motor neurons in the cerebral cortex
2. Loss of lower motor neurons in the spinal cord and brain stem
3. Evidence of toxic protein accumulation

Question 59

What causes ALS?

Answer 59

There is a mutation in the superoxide dysmutase enzyme due to an expansion of a tetrachloride repeat (?)

SOD protects us from superoxide damage so when there’s an SOD mutation we get a lot of injury:

1. Autophagy where we eat our own neurons
2. Disruption of proteasome function
3. Apoptosis of neurons

Question 60

What is the morphology associated with ALS?

Answer 60

1. Thin anterior roots of spinal cord gliosis

2. Neurons contain PAS inclusion called Bunina bodies which are remnants of autophagic vacuoles

Question 61

What is the clinical presentation of ALS?

Answer 61

Global muscle weakness and atrophy

Patients can’t walk or use their arm and legs and what ends up killing them are their respiratory muscles are also eventually paralyzed and they can’t breathe

Question 62

What is Kennedy disease?

Answer 62

An X-linked disease caused by a polyglutamine repeat expansion that causes neuronal loss involving specific neuronal circuits and brain regions

It’s caused by a mutation in the AR gene that encodes for a protein known as the androgen receptor on the X chromosome; the androgen receptor is found in many parts of the body but the link between the AR mutation and the neuron impairment is impaired

It leads to a gradually progressive, wasting of the proximal muscles (those closer to the trunk) and bulbar muscles (those of the face and throat)

There is also problems in the exons of the androgen receptors in addition to the neurological manifestations that lead to:
1. Gynecomastia

2. Testicular atrophy
3. Oligospermia

Question 63

What are demyelinating diseases?

Answer 63

Disease that damage the myelin but preserve the axons

Question 64

What is multiple sclerosis?

Answer 64

An autoimmune demyelinating disorder that causes neurological deficits that are separated in space and time

The best theory on the cause is that it’s a type IV hypersensitivity reaction so it’s a T-cell mediated autoimmune reaction that uses INF-gamma to recruit macrophages and destroy myelin

what does separated in time and space mean? For example: 25 year old developed fatigue and pain in her right eye and some decreased vision in the right eye. She was seen by a doctor who thought she had thyroid problems and eventually fatigue went away and her eye recovered. This was M1 year. Then during M2 year she passed step exam and went onto clinical rotations and then she started to develop tiredness again and this time there was some motor weakness in one of her arms. So the first presentation was 2 years before = separated in time. Then she went on but the weakness progressed, she developed nystagmus and she was completely disabled and didn’t finish medical school. The space part is that it started with optic involvement then went to other sites of the brain ):

Question 65

What is the pathogenesis of multiple sclerosis?

Answer 65

It’s an autoimmune response of T cells directed against components of the myelin sheath (myelin basic protein) –> so it’s kind of a type IV hypersensitivity reaction

There is an HLA DR 2 association linked to MS; interestingly enough this HLA gene is also associated with RA which is another autoimmune disease

TH17 activates macrophages and the MS plaques contain mainly CD4 T cells and some CD8 macrophages which confirms that it’s an autoimmune problem

Question 66

What are the gross anatomy changes you see in the brain of an MS patient?

Answer 66

1. Firm lesions sclerosis
2. Tanned plaques
3. Irregularly shaped

Question 67

What are the microscopic changes you see in an MS patient brain?

Answer 67

1. Myelin breakdown
2. Macrophages containing lipid rich PAS positive debris (periodic acid-Schiff)
3. lymphocytes and monocytes surrounding blood vessels = perivascular cuffs

Question 68

What are the clinical symptoms of MS?

Answer 68

1. Optic neuritis = painful vision loss due to demyelination of CN 2
2. Ataxia
3. Nystagmus
4. Spasticity
5. Loss of bladder control
6. internuclear ophthalmoplegia = one eye can’t move laterally on lateral gaze due to destruction of medial longitudinal fasciculus pathway (CN 6 and 3)

Question 69

What does a CSF analysis of an MS patient show?

Answer 69

1. Mild elevation of protein
2. Increased IgG
3. Oligoclonal bands with immunoelectrophoresis

When there is CSF for analysis, we check the color, the consistency, we count how many cells are in the CSF, and then we measure protein and glucose levels. These are the routine tests that we run. If we suspect a patient has MS, we add tests = we check immunoglobulins and patients will have increased IgG. And if we do electrophoresis and try to separate the different bands of immunoglobulins we will find oligoclonal bands which are diagnostic and specific for MS

Question 70

What is the prognosis for people with MS?

Answer 70

People with MS can have different prognosis. Most of them go into prolonged remissions, others have remission and relapse while others are totally disabled. So another example of MS, is a resident who went on a jog and couldn’t feel his feet and by the time he got to the hospital he couldn’t breath because intercostal muscles were paralyzed. But he was treated and was fine, he just has to use a cane. Compare this to the M3 that was totally incapacitated

Question 71

What is the summary of MS?

Answer 71

1. Young people
2. Autoimmune disease
3. Lesions separated in time and space
4. Destruction of myelin sheath but axons are preserved
5. Clinical manifestations depend on which part of the brain is being involved in demyelination

Question 72

What are leukodystrophies?

Answer 72

Disorders caused by mutation of genes involved in the generation, turnover and maintenance of myelin

Patients will present with slow onset, chronic insidious loss of cerebral function at a young age

It’s usually due to a single enzyme defect that leads to myelin problems

Question 73

What is Krabbe disease?

Answer 73

A leukodystrophy that is a defect in the galactosyl ceramidase enzyme that normally breaks glucocerebroside into galactose and ceramide

When this gene is defective, there is an alternate pathway that shunts glucocerebroside into galactosoylsphingosine —> elevated levels of galactosoylsphingosine is extremely cytotoxic and leads to myelin loss (neurons and axons are spared)

Symptoms include stiffness and weakness that presents at 3-6 months of age followed by death before the age of 2

Question 74

What is metachromatic leukodystrophy?

Answer 74

An autosomal recessive defect in lysosomal arylsulfatase enzyme

This enzyme is responsible for degradation of sulfate containing lipids so when it’s defective there is sulfatide accumulation —> this causes white matter injury and an inflammatory response mediated by the microglia and astrocytes

This inflammatory response generates superoxides which are very toxic and cause demyelination

Question 75

What is the morphology of metachromatic leukodystrophy?

Answer 75

1. Demyelination
2. Vacuolated macrophages; the vacuoles contain sulfatides
3. To toluidine blue stains the sulfatides

Blue metachromasia stains young RBCs and similar metachromatic material can be detected in the peripheral nerves and urine

If there is metachromatic material in the urine, it can be used to diagnose the disease!!!

Question 76

What is adrenoleukodystrophy?

Answer 76

Lorenzo’s oil disease!! It’s x-linked recessive disease that is usually a peroxisomal inborn error of metabolism

It’s a mutation in the ABCDI gene which codes for ALD, an ATP binding casset transporter that normally transports molecules in the peroxisome

When the ABCDI protein is mutated, you are no longer able to catabolize very long chain fatty acids in the peroxizome so there are really elevated levels of VLCFA in the serum which lead to atrophy of the adrenal cortex, gliosis, and demyelination of axons

Question 77

What is the clinical presentation of adrenoleukodystrophy?

Answer 77

1. Young males
2. Behavioral changes; emotional instability, hyperactivity, disruptive behavior
3. Adrenal insufficiency
4. Seizures
5. Demyelination = problems speaking, listening and understanding verbal instructions, muscle stiffness, paraparesis and sexual dysfunction

Eventually leads to a vegetative state and then death