Degenerative disorders in the central nervous system

Question 1

Dementia

Answer 1

a decline in intellectual or cognitive function to a degree where the person can no longer care for his or her own needs. It is usually accompanied by loss of memory.
DSM-IV diagnostic criteria: Memory impairment plus one or more of the following: Aphasia (language impairment), Apraxia (impairment in purposeful movement), Agnosia (impaired recognition & comprehension), impaired executive function (higher functions such as problem solving and control of self-actions)

Question 2

Degenerative Disorders in the Central nervous system

Answer 2

a group of unique disorders affecting mainly the CNS with secondary effects on the peripheral nervous system and the skeletal muscles.

Question 3

Propensity of neurodegenerative diseases

Answer 3

Alzheimer disease mainly affects the cerebral cortex, Parkinson disease’s main pathology is in the substantia nigra, in the brainstem.

Question 4

nerve loss and gliosis

Answer 4

loss of neurons and scarring/gliosis by astrocytes develops in areas most affected by the disease and result in grossly evident atrophy.
Almost all neurodegenerative diseases have specific microscopic lesions/inclusions that represent pathology affecting a specific protein aka “proteinopathy”.
Senile plaques and neurofibrillary tangles in AD
Lewi bodies in PD.

Question 5

Aphasia

Answer 5

Language impairment

Question 6

Apraxia

Answer 6

impairment in purposeful movement

Question 7

Agnosia

Answer 7

impaired recognition & comprehension

Question 8

The leading cause of dementia

Answer 8

Alzheimer’s disease. In the developed countries of the western world, Alzheimer accounts for 50-60% of all cases of dementia. There are between 5 million to 6 million persons in the U.S. with AD.
Other causes: vascular, lewy body, AD/lewy, AD/Vasc, other

Question 9

Alzheimer Disease (cortex atrophy)

Answer 9

6th leading cause of death, (5th over age 65). No effective treatment. 
Cardinal failures: 
-RECENT memory loss
-disorientation
-confusion

Question 10

Presentation of AD

Answer 10

widened sulk and strophic, narrowed gyri.
-Note widened sulci representing cerebral cortical atrophy.
Atrophy is most severe in FRONTAL and TEMPORAL lobes.
Severe reduction in brain weight.

Two characteristic features:
Senile or neuritic plaque (extracellular) and neurofibrillary tangles (intracellular).

Question 11

Senile or neuritic plaques in AD

Answer 11

appear as extracellular mats or networks of fibrillary material in a loose disjointed arrangement. they are composed of swollen, degenerated neuronal processes (neurites) arranged around a central deposit of amyloid protein in close association with small vessels.
Glial cells such as astrocytes are often seen in and around sniffle plaques. amyloid is deposited in the walls of parenchymal and extraparenchymal blood vessels (in the subarachnoid spaces) in 90% of pateints with AD, ultimately leading to vascular wall injury and weakness. Rupture of these vessels is a common cause of spontaneous cerebral hemorrhage in the elderly.
* it is due to amyloid precursor protein, which is named by where amyloid is come from.

Question 12

the neurofibrillary tangles (NFT)

Answer 12

consist of accumulations of large numbers of filaments which stain with silver in the cytoplasm of neurons. INTRACELLULAR inclusion. they are most commonly found in cerebral cortical pyramidal neurons and especially in the temporal lobe. the filaments forming NFT are in form of paired helical filament. They are formed through hyperphosphorylation of tau protein (which makes them insoluble and accumulate), which is associated with microtubules in the cytoplasm of neurons.

Question 13

Mechanism of senile/neuritic plaque.

Answer 13

APP is a transmembrane protein. originally one cleavage by a-secretase at the middle to make a soluble segment ==> two cuts by beta and gamma-secretase and make a insoluble segment of amyloid precursor protein, which is then deposited in the cerebral cortex and around blood vessels (b-amyloid proteins) ==> toxic to neurons, can cause neuronal death and gliosis and plaque.

Question 14

Neurofibrilary tangle development mechanism

Answer 14

tau proteins are microtubules associated with neural conduction. In normal turn over of tau, it breaks off and is recycled (soluble). however, in hyperphosphorylated condition (homozygous APOE 4 expression) it becomes insoluble and form helical filaments which accumulates and present as neurofibrillary tangles.

Question 15

1 risk factor of AD

Answer 15

1. age (simple most important factor)
   -other factors:
2. genetics, ~10% familial
   Family History:
   AD in 1st relative = 4 fold increase
   trisomy 21/down syndrome
   parkinson disease
3. APOE4 19, AD2
4. Coronary artery disease
5. Low education
6. History of head trauma
7. thyroid disease

Question 16

AD1

Answer 16

due to amyloid precursor protein gene mutation on CHROMOSOME 21
**indivuduals with Down syndrome, which is trisomy 21, develop beta-amyloid deposits at a relatively early age. **

Question 17

AD2

Answer 17

asspcoated with Apo E allele located on CHROMOSOME 19

Question 18

AD3

Answer 18

dur to presenilin-1 gene mutation located on CHROMOSOME 14

Question 19

AD4

Answer 19

due to presenilin-2 gene mutation located on CHROMOSOME 1

Question 20

Chronic traumatic brain injury

Answer 20

Gross: thickened and discolored dura dur to bouts of head trauma leading to repeated subdural hemorrhages. Brain atrophy, Torn septum pellucidum, degeneration of hypothalamus, substantial nigra and cerebellar tonsils.

Microscopic: there are similarities with changes in AD. neurofibrilary tangles are present mostly in SUPERFACIAL layers of the cerebral cortex. a {subtype of b-amyloid plaque} is deposited in the cerebral cortex.

** a single injury won’t cause chronic traumatic brain injury **
ex-boxer
Parkinson Syndrome/disease

Question 21

Parkinson Syndrome

Answer 21

Relatively common group of sporadic degenerative diseases with onset in middle life or later.
Mask-like facial expression
shuffling gate
pill-rolling tremor
can’t call it parkinson disease unless levy bodies are found in nigral neurons. And loss of pigmentation in substantial nigra

Question 22

Parkinson Disease

Answer 22

Basic types: idiopathic (parkinson disease, no specified cause, the most common), post-infectious, and toxic (CO poisoning manganese intoxication, phenothiazine toxicity, or the use of MPP). rarely, it may be associated with neoplasm or infarct.

DEPIGMENTATION OF SUBSTANTIA NIGRA AND LOCUS CERULEUS
these nuclei are composed of neurons which utilize dopamine in neuronal transmission.
Microscopically there is loss of neurons and melanin pigment in these nuclei.

characterized y degeneration and loss (atrophy) of pigmented neurons in the subtantia nigra (in the midbrain). In addition, a specific type of intracellular inclusion, known as levy bodies, are found in the nigral neurons.

20% of patients have some degree of dementia. often these individuals display loss of neurons in the cerebral cortex and various other nuclei in the brain, especially the thalamus.

Question 23

Substantia Nigra

Answer 23

contains neurons which produce dopamine and is the major dopaminergic source for the entire brain.
the neurons in substantial nigra may be divided into two major groups:
1. supply dopamine for caudate nucleus and putamen. These are involved in motor activity and are severely degenerated in parkinson disease.
2. supply dopamine for other centers in the brain under the mesolimbic dopamine system. (reward center, degeneration causes loss of cholinergic input). convey signals from the basal ganglia to numerous other brain structures.

Question 24

cholinergic hypothesis and alzheimer disease

Answer 24

much research implicates Ach in memory functions. drugs which increase Ach function enhance memory. Drugs which decrease Ach function lead to impaired memory.
the enzyme choline acetyl transferase (CAT) can be measured to post mortem brain tissue. CAT is an enzyme which is a marker for Ach. in AD, there is a profound decrease in cortical and hippocampal CAT.
treatments unsuccessful. most trails focus on drugs which enhance cholinergic function.
physostigmine inhibits an enzyme which breaks down Ach.
can have side effects.

Question 25

Amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND)

Answer 25

affects individuals between 20-70.
clinical manifestation:
-weakness of muscles in distal limbs and later the entire body
-resulting in movement loss including ambulation
-Swallowing difficulties
-Atrophy of muscles including the tongue
-Fasciculations (wormlike muscle twitching under the skin)

Pathology:
degeneration and loss of motor neurons (upper and/or lower motor neurons) with gliosis, atrophy of motor peripheral nerves due to loss of lower motor neurons, skeletal muscle atrophy, and denervation changes microscopically.
Peripheral nerve sensory neurons are intact but much thinner than normal, number of drops lower motor neurons ==> denervation atrophy/neurogenic atrophy
These individuals don’t have dementias.
MFB stain for myelinated fibers show that the lateral cortical spinal tracts (upper motor neurons) are paler. while the dorsal columns (sensory tracts are normal and blue). The lower motor neuron is also degenerated.

In microscopic view of muscle fibers, there are severe group atrophies.