Degenerative disorders in the central nervous system Flashcards
Dementia
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)
Degenerative Disorders in the Central nervous system
a group of unique disorders affecting mainly the CNS with secondary effects on the peripheral nervous system and the skeletal muscles.
Propensity of neurodegenerative diseases
Alzheimer disease mainly affects the cerebral cortex, Parkinson disease’s main pathology is in the substantia nigra, in the brainstem.
nerve loss and gliosis
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.
Aphasia
Language impairment
Apraxia
impairment in purposeful movement
Agnosia
impaired recognition & comprehension
The leading cause of dementia
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
Alzheimer Disease (cortex atrophy)
6th leading cause of death, (5th over age 65). No effective treatment. Cardinal failures: -RECENT memory loss -disorientation -confusion
Presentation of AD
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).
Senile or neuritic plaques in AD
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.
the neurofibrillary tangles (NFT)
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.
Mechanism of senile/neuritic plaque.
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.
Neurofibrilary tangle development mechanism
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.
1 risk factor of AD
- age (simple most important factor)
-other factors: - genetics, ~10% familial
Family History:
AD in 1st relative = 4 fold increase
trisomy 21/down syndrome
parkinson disease - APOE4 19, AD2
- Coronary artery disease
- Low education
- History of head trauma
- thyroid disease
AD1
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. **
AD2
asspcoated with Apo E allele located on CHROMOSOME 19
AD3
dur to presenilin-1 gene mutation located on CHROMOSOME 14
AD4
due to presenilin-2 gene mutation located on CHROMOSOME 1
Chronic traumatic brain injury
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
Parkinson Syndrome
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
Parkinson Disease
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.
Substantia Nigra
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.
cholinergic hypothesis and alzheimer disease
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.
