Pathology Lec # 3

7/29/2019 Pathology Lec # 3

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Degenerative Diseases

Degenerative diseases are Progressive and there is no treatment. There are different

types involving different structures:

CORTEX (Alzheimers & dementias " ")

BASAL GANGLIA and BRAIN STEM (Parkinsonism, Huntingtons [ less

common])

SPINOCEREBELLAR (ataxias e.g. Friedreichs ataxia)

MOTOR NEURONS Amyotrophic Lateral Sclerosis (ALS )

Degenerative diseases share the following:

Gradual loss of neurological function affecting selective populations of neurons;in each disease one group of neurons is affected.

Unknown causes, only a small percentage are familial. No effective treatment.

And they are Classified according to neurological manifestation into:

Dementia. Postural / Movement disorders. Combined; dementia and postural.

Dementia

Definition: Global impairment of intellect, reason and personality but without

loss of consciousness. These patients differ from patients in vegetative state [[in

vegetative state patients are unconscious]].

[[ extra: The vegetative state is a chronic or long-term condition in which patients have awakened from

coma, but still have not regained awareness. In the vegetative state patients can open their eyelids

occasionally and demonstrate sleep-wake cycles. They also completely lack cognitive function]]

Classified into :

Primary degenerative diseases [Alzheimers Disease, Picks disease, Parkinsonsdisease]

Secondary1 - the main cause is Multi-infarct dementia; multiple infarcts all over the brainin patients who are susceptible for infarction; for example those with


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hypercoagulative state or severe atherosclerosis with ischemic changes, they

end up by loss of neurons in multiple infarcts and gradually they develop

dementia.

2 - Infections [mad cow disease, Creutzfeldt-Jakob disease].

3 - Chronic subdural hematoma [when you have gradual collection of blood inthe subdural space, the pressure produced causes localized atrophy in the

underlying brain.]

[[1]] ALZHEIMERS DISEASE

It is the commonest cause of dementia in the west, but occurs here as well. There

is insidious progressive neurological disorder showing gradual loss of Cognitive

function; [memory, speech, movement and intellect].

It could be Sporadic or familial (10-15%), and the Incidence rises with increasing

age. it is very slow initially, we dont know it Is happening, and it can occur 20 years

before actual symptoms arise. as the patient becomes older, in late 80s or 90s,

these patients have almost 15% higher chance to develop Alzheimer. While those in

60s are less susceptible.

Familial type has earlier age of onset than sporadic; and is called [[Presenile

dementia]]

Basic pathogenesis of the disease is linked to deposition of-amyloid in the brain

by, this results from the splitting of the precursor protein APP [[Amyloid precursor

Protein]] by certain enzymes. And this will lead to abnormal neurotransmission.

There are several Genetic defects identified in the familial group [[in


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2- Presenelin Mutations:Alzheimer's disease (AD) patients with an inherited form of the disease carry

mutations in the Presenilin proteins or the amyloid precursor protein (APP)

Two types of Presenilin gene:

Presenilin 1 (PS-1) on chromosome 14 Presenilin 2 (PS-2) on chromosome 1

These genes are involved in processing cleavages of Amyloid Precursor

Protein (APP):

>> If the APP is cleaved by -secretase; it produces a soluble type of amyloid

which is harmless.

>> If it is cleaved -secretase or-secretase, it produces an insoluble type of

amyloid [[-amyloid]]; this is the bad one. If we have mutations in these genes,

the enzymes will be overactive and there will be overproduction of -amyloid

which damages when accumulates.

Defects result in the accumulation offibrillar aggregates of beta-amyloid that

are toxic to neurons and interfere with their function.

3- Tau protein:

abnormalities can be seen on

several degenerative diseases, not

only in AD, and Tau is a normal

protein involved in the assembly of

axonal microtubules & their

stability. These microtubules are

usually parallel.

Mutations in the tau gene which

codes for tau protein, will lead to

Hyperphosphorylation of tau

protein, and end up with filaments

that are not parallel, rather they

become tangled leading to what is

very typical to AD which is

[[neurofibrillary tangles]].


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4- Apolipoprotein E ( Apo E):

patients with Apo E have increased deposition of fibrillar beta-amyloid, it is

present in 30- 40% of AD cases but is not necessarily present for the

development of AD.

Previously, the test for the presence of ApoE was used to identify patients

who are at higher risk; it was thought to be a marker. But nowadays it is not

really important.

Diagnosis

diagnosis depends on:

1- Clinical Picture, in which there is Progressive memory loss with increasing

inability to participate in daily living. First starts with forgetfulness, speech

difficulty. Later on swallowing and movements difficulty, then gradually

everything related to previous events disappears, very little memory of the past,

they forget how to eat and to use a pencil. Anything that is acquired by learning

is lost.

2- Radiological methods.

3- Brain biopsy.

>> The final diagnosis is made pathologically by examining the brain at autopsy. But

overall you can take MRI and you can do a stereotactic biopsy [[extra:neurosurgery

involves mapping the brain in a three dimensional coordinate system]]

Pathology

Macroscopically: Cerebral atrophy; because of the loss of neurons, it isoutspread throughout the brain, mainly in frontal, temporal, and parietal region

rather than occipital. hippocampus is very much affected.

Because of the atrophy there will be dilatation of the ventricles; [[ex vacuo

ventricular dilation]].although it is sometimes linked to hydrocephalus but no

evidence for increased ICP. [[extra: Hydrocephalus ex vacuo refers to an enlargement of

cerebral ventricles and subarachnoid spaces, and is usually due to brain atrophy (as it occurs

in dementias), post-traumatic brain injuries and even in some psychiatric disorders, such

as schizophrenia.As opposed to hydrocephalus, this is a compensatory enlargement of the CSF-

spaces in response to brain parenchyma loss - it is not the result of increased CSF pressure]]
http://en.wikipedia.org/wiki/Atrophyhttp://en.wikipedia.org/wiki/Dementiahttp://en.wikipedia.org/wiki/Traumatic_brain_injuryhttp://en.wikipedia.org/wiki/Schizophreniahttp://en.wikipedia.org/wiki/Parenchymahttp://en.wikipedia.org/wiki/Parenchymahttp://en.wikipedia.org/wiki/Schizophreniahttp://en.wikipedia.org/wiki/Traumatic_brain_injuryhttp://en.wikipedia.org/wiki/Dementiahttp://en.wikipedia.org/wiki/Atrophy


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Notice here the Thinner gyri and deeper sulci in the atrophied brain compared

to normal one.

You can see in the brain at the

bottom how it is shrunken compared

to the size of the skull .

Notice how the gray matter, becomes

atrophic and is lost gradually, and you

know that all of the cognitive functions are

in the gray rather than the white matter.


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As we said AD is progressive, note that it is limited to a small area at the beginning,

which leads to memory loss, then it gradually increases until it involves the whole

brain. This takes several years. the last stage may be developed 20 years ago.

Microscopically:1. Neuritic (Senile) plaques:

Intercellular plaques, Composed of tortuous neuritic processes

surrounding a central amyloid core of-amyloid. Around it are Reactive

astrocytes and microglia at the periphery.

Later on, these may minimally end up with gliosis.

They can be found in normal brain, but they are not as dense as in AD; their

numbers are less and their location is not severe. So it is not diagnostic, you

have to find the full clinical picture with other findings


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The next section is stained with aspecial stain for brain tissue; the

center is full of amyloid surrounded

by neuritis, in addition to the reactive

cells around it. Remember that they

are between the cells [[intercellular]].

As its number increases, the

condition is considered more serious.

Here is a section with an

immunohistochemical stain for the -

amyloid [[anti- beta amyloid

immunostain]]

You have an antigen-antibody

reaction for any component, if I have

an antibody for beta-amyloid, I link it to

anti beta-amyloid on a section and it

stains in a certain way. here all of this is

positive for -amyloid.

2. Neurofibrillary tangles :Intracellular location. They are Insoluble filaments of tau protein mainly in

pyramidal cells of hippocampus.


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If you compare the two areas in this electron microscopy; the healthy one is very

organized; parallel and straight. But in the abnormal one the microtubules are

tangled up

The figure shows a neuron with tangles that pushes the nucleus to one side.


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3. Amyloid angiopathy: deposition of amyloid in blood vessels of the brain.

[[2]] VASCULAR DEMENTIA

Associated with multiple infarcts

that's why it's called [[multiple infract

Dementia]].

You get all sorts of infarcts: Lacunar

infarcts, Cortical microinfarcts and

Multiple embolic infarcts.

In MRI you see Grey matter lesions

[[different patches in grey matte]]

rather than white as in MS.

It is the SECOND commonest form of

dementia after Alzheimer, and

certain people are more likely to get

it.

In this picture u

can see different

areas of infarcts


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OTHER DEGENERATIVE DISEASES:

1. You have some diseases which are located only in the Frontal temporal area,

and the typical example for this is Picks disease and others [[you can read

about them from the book]].

2. Lewy body DiseasesDementia: the typical example is thePARKINSONS

DISEASE and some of these are also related to abnormal tau protein.

PARKINSON DISEASE:o A Disturbance of motor function with rigidity, slow movements [[first of all it's a

difficulty in initiating movements and they are jerky]] it ends up in expressionless

face and there is resting tremor.

Actually if you meet a patient with Parkinson: usually he/she is in 60s and it's very

difficult to him/her to enter a car (one of the very typical symptoms).

o It's a common disease. Caused by damaged Dopaminergic neurons in Substantia

Nigra.o Most commonly in Adults in the 6th decade.

:

Idiopathic [[primary]]: the typical idiopathic could be Sporadic (commoner)

or familial (linked to synuclein gene which is involved in neuronal

synapses).

- Several other genetic abnormalities found, some related to Tau protien.

If you look to the book there are many other genetic lesions some of them still in

the experimental phase but there is a lot f research in this field.

Secondary: it could be related to Trauma (the typical example of that is the

boxer Muhammad Ali), some vascular disorders after viral encephalitis,

neurotoxic agents and drugs.

the majority are idiopathic, but from these idiopathic a minority is familiar.


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Gross and microscopic findings: Gross: there isloss of pigment in the substantia nigra.

Microscopic : Loss of pigmented neurons with gliosis in the substantia

nigra.

In the residual uninvolved neurons [[not the ones that have already been lost]] we

find Lewy bodies which contain synuclein.

Cortical Lewy bodies may be present in small numbers all over the brain (not just in

substantia nigra) in 80% or more of PD cases.

Lewy bodies can occur anywhere in the cortex & may be very numerous.

When it is very numerous the patient will get what is called Diffuse Lewy diseasein this disease there is an Overlap with Alzheimer and this patient will get Dementia

as well, and it's found that many patients with Prkinson D who live long enough,

they go into Demintia and this is progressive.

Lewy bodies :

Concentric eosinophilic inclusions in the cytoplasm [[you have thecell (neuron), nucleus and in the cytoplasm there is a pink rounded

inclusions surrounded by a clear zone (halo)]]. And itContains

Presynaptic Protein synuclein.

Lewy neurons: contain abnormal aggregates of synuclein

This is normal (pigmente)

This is decreased

(lost pigment)


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HUNTINGTONS DISEASE

A Hereditary progressive disease. AD (autosomal dominant) with a defect on

chromosome 4 at which Huntingtin gene is located, this gene contains

increased trinucleotide CAG repeat sequences. The greater the number ofrepeats, the earlier the onset of the disease.

Age 30 and 50 years, with average course of 15 years before death.

Symptoms usually appear in middle age.

Clinical Presentation:

Involuntary jerky movements & dementia

Pathology :

Severe loss of small neurons in the caudate and putamen with subsequent

astrocytosis [[gliosis]].

The Head of caudate becomes shrunken

There is "ex vacuo" dilatation of the anterior horns of the lateral ventricles.

This is the Lewy

bodies (inclusions)

and you can see the

clear zone [halo]

surrounding it


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MOTOR NEURON DISEASES

Amyotrophic Lateral Sclerosis (ALS).

It's also called Lou Gehrigs disease

because it was 1.st described in an

American baseball player and he

developed the typical symptoms, of

course he died but he was one of

the champions of the state!

Most cases are sporadic, 5-10% are

familial AD

There are several gene mutations

implicated [[again you can go to the book :D]] BUT the most frequent is

superoxide dismutase(SOD1) on chromosome 21.

Several things happen here:

Death of motor neurons in spinal cord & brain stem, the result of this is

painful fasciculation of muscles [[the muscles flatter and they are very

painful with weakness of the muscle, this is the initial symptom]] and it will

end up with neurogenic atrophy of the muscles because there is

denervation.

Death of the upper motor neurons in motor cortex this will lead later on

to paresis & spasticity so theBabinski sign will be positive.

Degeneration of corticospinal tracts in lateral part of spinal cord. Later on the patient cant speech, cant swallow, finally there will be very

difficult breathing because it will also involve the respiratory muscles, and

he will die usually of intercurrent pneumonia and things like thatit's uniformly fatal.


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Loss of motor neurons in:

1- Ant. horn cells of spinal cord.2- Brain stem nuclei.3- Upper motor neurons in cerebral cortex.

Later, there will be gliosis, axonal degeneration and loss of myelinated fibres in

lateral corticospinal tracts then muscle atrophy.

Atrophy of

anterior Spinal

motor nerve

This is a section

through that area

(the figure above)

>> you can see the

neurons are very

much few in the

spinal cord


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Types of lesions neuropathy -they are of several types - :

1- Wallerian Degeneration:

o its seen mainly in Trauma & ischemia

o Axonal & myelin sheath degeneration distal to transaction [[ if a nerve is

cut, below that cut there will be Wallerian Degeneration]], wounds distal to

that area will show:

Myelin disintegration

Phagocytosis.

Axonal & Schwann cellregeneration.

sometimes if the nerve recovers you may have Remyelination >> if you do

a stain for the mylein you can see the breakdown and disappearance.

2-Distal axonal degeneration:

it is different and seen in the Nutritional deficiency & toxic causes there is

Metabolic distrubances within the axon; there will be:

Peripheral distal symmetrical degeneration

Dying back of cell body- Chromatolysis

Dying back of axon with demyelination

Regeneration of schwann cells can occure, but it is very limited.

BTW this is in the chapter of the muscles not from the CNS >> this is if you have

EXTRA TIME and want to read this subject from the book :D

3- Segmental demyelination:

Axon remains intact but myelin sheath is broken you end up in bare axon

without myelin and without Schwann cells and then there may be

myelination this may lead to proliferation of the nerve end which is called

onion bulb

there is Leukodystrophies , hereditary, metabolic diseases..Inflammation may follow some viral infections, mycoplasma, allergic... EtcThe typical e.g. is Guillain - Barre Syndrome.


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Guillain-Barre Syndrome:

o It isnt uncommon.

o Its an acute, frequently severe, fulminant[[deadly, killing]]

polyradiculoneuropathy that is autoimmune in natureo There is Acute inflammatory demyelinating polyneuropathy (AIDP) is the most

common type of GBS but it is really autoimmune due to many causes [[virus for

example]]

o M=F

o Adults > children

o In 75% of cases it is preceded 1 to 3 weeks by a respiratory or gastrointestinal

infection.

Clinical Presentation:

There is Motor paralysis with or without sensory disturbances

Then there is Ascending paralysisrubbery legs>>the legs are very weak;

the patient falls down because of paralysis .

The Weakness may be very rapid evolves over hours to days, and it goes up

Then Paraesthesia of the extremities

Legs more than arms

Autonomic involvement is common in severe cases >> Bladder dysfunction,

loss of vasomotor control then infection.

Question by a student:

could the patient develop bilateral facial palsy?

The Dr: it's not typical for it!

Pathology :

Segmental demylinization; different areas in segments.

Findings include infiltration of nerve by lymphocytes & macrophages CSF :

Protein (100-1000 mg/L) without pleocytosis (after 48 hours)

Occasionally transient WCC (10-100/L).


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THE END

..

And after 17 years of teaching, this lecture was the last for Dr. Huda, as she is leaving

Techno.

May Allah bless her, making Duaa for her may be the best way to thank.

Done By and

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Pathology Lec # 3