Page 1 of 18

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, Parkinsons
disease]
Secondary
1 - the main cause is Multi-infarct dementia; multiple infarcts all over the brain
in patients who are susceptible for infarction; for example those with
Page 2 of 18

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 in
the 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 <5% familial
cases]] on chromosomes 21, 19, 14, 12 & 1, with each chromosome there is an
abnormality.

Pathogenesis:

1- Chromosome 21: the first chromosome to be linked to AD, and since it is
where the gene encoding APP is located; Patients more than 40 years of age
with Trisomy 21 (Downs Syndrome) have higher risk of developing Alzheimer's
disease. They are mentally retarded, but live normally; they are happy and
friendly people, but may develop AD early in life.

Page 3 of 18

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 of fibrillar 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]].

Page 4 of 18

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 is
outspread 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]]

Page 5 of 18

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.


Page 6 of 18

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



Page 7 of 18





The next section is stained with a
special 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.




Page 8 of 18


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.
Page 9 of 18


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
Page 10 of 18


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 Diseases Dementia: the typical example is the PARKINSONS
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 6
th
decade.

+ Types :

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.

Page 11 of 18

Gross and microscopic findings:
Gross: there is loss 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 disease
in 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 the
cell (neuron), nucleus and in the cytoplasm there is a pink rounded
inclusions surrounded by a clear zone (halo)]]. And it Contains
Presynaptic Protein synuclein.
Lewy neurons: contain abnormal aggregates of synuclein


This is normal (pigmente)
This is decreased
(lost pigment)
This is the Lewy
bodies (inclusions)
and you can see the
clear zone [halo]
surrounding it
Page 12 of 18





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 of
repeats, 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
Page 13 of 18

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.

<Amyotrophictro Lateral Sclerosis:
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 the Babinski 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 that
it's uniformly fatal.



Page 14 of 18

+Pathology :
+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
roots
This is a section
through that area
(the figure above)
>> you can see the
neurons are very
much few in the
spinal cord

Page 15 of 18




This is the end result of
the muscle atrophy >>>
all the muscles are gone
in those two legs !






PERIPHERAL NEUROPATHIES

+Types according to etiology :
1- Nutritional & metabolic neuropathies: the main one is Diabetes.
2- Toxic neuropathies: could be alcohol or anybody working with metals as an
example.
3- Inflammatory neuropathies: some of these are autoimmune in nature
4- Hereditary neuropathies.
5- Miscellaneous neuropathies.
Note: Many of the above etiological factors may also affect the central nervous
system.




Page 16 of 18

<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 cell regeneration.
- 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... Etc
The typical e.g. is Guillain - Barre Syndrome.



Page 17 of 18

< Guillain-Barre Syndrome:
o It isnt uncommon.
o Its an acute, frequently severe, fulminant[[deadly, killing]]
polyradiculoneuropathy that is autoimmune in nature
o 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 paralysis rubbery 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).


Page 18 of 18




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: Noran Kofahi and Tasneem Masaadeh