Degenerative Disorders in the CNS Flashcards
Degenerative Diseases- General Considerations
Some first manifest as deficits in higher CNS function such as memory and/or cognition.
Others will present peripherally such as skeletal muscle weakness.
Most have BOTH CNS AND PNS manifestations as the disease progresses.
Have propensity for certain parts of the CNS.
AD mostly affects the cerebral cortex
PD affects the substrata nigra, in the brainstem.
Morphologic Changes
- Atrophy: seen grossly in areas most prominently affected by the disease.
Frontal and temporal cortices in AD
Substantia nigra in PD
Peripheral Nerves in ALS/MND - Nerve cell loss and gliosis: loss of neurons and scaring/gliosis by astrocytes develops in areas most affected by the disease and resulting grossly evident atrophy.
- Specific hallmark lesions/inclusions: pathology representing a specific protein=proteinopathy inside and outside of nerve cell bodies
Senile plaques and neurofibrillary tangles in AD; amyloid=outside cells.
Lewi Bodies in PD (inside cells).
Dementia
Decline in intellectual or cognitive function to a degree where the person can no longer care for themselves; usually accompanied by loss of memory.
DSM 4 diagnostic criteria:
Memore impairment PLUS one or more of:
-Aphasia; language problems
-Apraxia- problems with purposeful movement
-Agnosia- impaired recognition and comprehension
-Impaired executive function.
Some causes:
AD, Lewy Bodies, CJD Prion, vascular
Alzheimer’s Disease
Most common form of dementia in the elderly, 50-60% of all dementia.
Typically starts in the 50s or later.
Cardinal features: failure of recent memory, disorientation, confusion; depression, emotional, personality changes are common.
Course averages 2-5 years or more and patients usually get so debilitated that they die of an infectious disease such has pneumonia.
No effective treatment.
Widened sulci representing cerebral coritcal atrophy; decreased brain weight.
Nerve cell loss and gliosis, girl atrophic; interrupted tissue: senile (amyloid plaques); astrocytes causing gliosis.
Atrophic, narrowed gyri; atrophy most severe in frontal and temporal lobes.
AD brain-low levels of metabolic glucose activity, decreased number of neurons.
Progressive involvement of different cortical areas with time.
Risk factors: age (single most important risk factor), genetics (10% familial), family history (AD in 1st relative=4 fold increase, trisomy 21 down Syndrome, PD), female, head trauma, coronary artery disease/MI, lack of education, thyroid disease.
Gene mutations in chromosomes 1, 14, 19, and 21 have been associated with AD (four main genes):
AD1, due to APP gene mutation located on chromosome 21
AD2, associated with Apo E allele located on chromosome 19
AP3, due to presenilin-1 gene located on chromosome 14
AD4, due to presenilin-2 gene mutation located on chromosome 1.
Senile plaques in AD
Senile or neuritic plaques appear as EXTRACELLULAR mats or networks of fibrillary material in a loose, disjointed arrangement.
Composed of swollen, degenerated neuronal processes (neurites) arranged around a central deposit of amyloid protein in close association with small vessels. Glial cells (astrocytes) are also seen in and around senile plaques.
Amyloid is deposited in the walls of parenchymal and extraparenchymal blood vessels (in subarachnoid spaces) in 90% patients with AD, leading to vascular wall injury and weakness.
Rupture of these vessels is a common cause of spontaneous cerebral hemorrhage in the elderly.
MECHANISM:
Beta Amyloid Precursor Protein spend the neuronal membrane.
Normal situation: part of the normal turnover of the precursor protein, alpha secretase shows up and makes one cut in the protein; fragments are soluble.
In people who are destined to develop AD: beta and gamma secretase instead both cut this enzyme; the fragments produced by these enzymes are insoluble and deposit in the cerebral cortex and around blood vessels; these are the beta amyloid proteins that are toxic to neurons and cause neuronal death.
Neurofibrillary Tangles (NFT)
Consist of accumulations of large numbers of filaments which stain with silver IN THE CYTOPLASM of neurons.
INTRACELLULAR INCLUSIONS.
Most commonly found in cerebral cortical pyramidal neurons and especially in the temporal lobe.
Filaments forming NFT are in form of paired helical filament; formed through hyperphosphorylation of tau protein (microtubule associated protein), which is a microtubule associated protein in the cytoplasm of neurons.
Need tau for moving synaptic vesicles along microtubules.
In a normal cell, there is a normal turnover of this protein tau.
When people have homozygous APOE e 4 gene and the tau protein breaks down, it becomes hyperphosphorylated and becomes insoluble and it accumulates in the cell in fibrillar material as paired helical filaments; and this accumulation shows up as a NFT within the cell.
Under APOE 2 and 3, tau can breakdown normally and there is no NFT formation.
Simplified: not everyone is APOE 4 homozygous when develop AD.
Abnormal tau protein may be seen in processes of locus caeruleus neurons as early as teenage years.
The locus caeruleus is a pigmented brainstem nucleus similar to the substantia nigra, but instead it resides in the pons and produces neuepinephrin.
It is thought that diffuse synapses of locus caeruleus neurons with cerebral cortical and subcortical neurons may provide means by which the abnormal tau protein may spread to these regions.
Chronic Traumatic Brain Injury
Seen in sporting activities.
Many ex-boxerse develop a form of dementia known as dementia pugilistica (punched drunk) which has distinct pathologic findings.
frequent concussive brain injuries
football, boxing.
Pathology:
Groos observations: thickened and discolored dura due to bouts of head trauma leading to repeated subdural hemorrhages.
Brain atrophy, torn septum pellucidum (between lateral ventricles), degeneration of hypothalamus, substantia nigra, and cerebellar tonsils.
Microscopic observations: similarities with changes in Alzheimers disease, NFT present mostly in superficial layers of the cerebral cortex.
A subtype of beta amyloid plaque is deposited in the cerebral cortex.
Dementia
Parksinson Syndrome
Relatively common group of sporadic degenerative diseases with onset in middle life or later.
Clinical features: mask-like facial expressions, shuffling gait, pill-rolling tremor in the hands (shaking at rest and may abate with onset of purposeful movement)
Motor disorder
Autonomic dysfunction and dementia may also be associated with PS.
Most common form of the syndrome is of unknown etiology and called Parkinson’s Disease (also post-infectious and toxic types)
Characterized by degeneration and loss (atrophy) of pigmented neurons in the substantia nigra (in the midbrain); intracellular inclusion Lewy bodies also evident in nigral neurons.
Severe loss of pigment indicating loss of neurons in substantia nigra (disappears), also depigmentation of locus ceruleus; these nuclei are composed of neurons which utilize dopamine in neuronal transmission.
Substantia Nigra (dissappears in PD, gliosis where it used to be):
produce dopamine and major dopaminergic source for brain
Neurons here may be divided into 2 groups: one group supplies dopamine for caudate nucleus and putamen, involved in motor activity and severely degenerated in PD.
The second group provides dopamine for other centers in the brain under the mesolimbic dopamine system.
20% of PD patients have some degree of dementia.
Amyotrophic lateral sclerosis (ALS)
Motor Neuron Disease (MND)
Sporadic disease; may occur at any age but rarely see before the age of 20 or after age of 70.
Clinical symptoms: muscle weakness, distal extremities, which are symmetrical.
The weakness progresses to involved the whole body, including areas supplied by the cranial nerve nuclei.
Occasionally may begin with bulbar (brainstem) involvement, starting with atrophy of the tongue.
Fasiculations, which are small vermiform (worm like) movements under the skin or on the tongue; attributed to the irritation of dying neurons; degeneration of skeletal muscles, contract abnormally, this is in the early stages, with complete denervation, don’t see this anymore.
Swallowing difficulties
Course of ALS is relentless without remission; average duration of the disease is 3 years.
No dementia!
Pathology:
loss of motor neurons (upper/lower) with gliosis, atrophy of motor peripheral nerves due to loss of lower motor neruons, skeletal muscle atrophy, and denervation changes microscopically.
Severely attenuated spinal cord and atrophic motor nerve rootlets because of lower motor neuron loss in the spinal cord.
The lesion of ALS is the degeneration and eventual loss of motor neurons (and gliosis) in the spinal cord, medulla, and cerebral cortex, accompanied by degeneration of the corticospinal tracts.
Spinomuscular atrophy: what the disease process is called when without cortical motor neuron and corticospinal tract involvement.
Once the lower motor neurons are injured in this disease, the skeletal muscle enervated by these neurons will undergo denervation/neurogenic atrophy.
Groups of atrophic muscle fibers are seen with non-atrophic fibers. Some muscle fascicles consists entirely of atrophic fibers.
LFB-stain for myelin
Cholinergic hypothesis and AD
Cholinergic center: nucleus basalis destroyed
Ach in memory functions
Drugs which increase Ach function enhance memory.
The enzyme choline acetyl transferase (CAT) can be measured in post mortem brain tissue; CAT is a marker for Ach.
In AD, profound decrease in cortical and hippocampal CAT.
Other neurotransmitters are not as markedly affected.
In nucleus basalis cells, a source of Ach to the cerebral cortex, degeneration by as much as 75% occurs.
Treatment of AD: Drugs that enhance cholinergic functions have not been clinically useful (enhance short term memory)
Cholinergic drugs have side effects, since Ach is a major transmitter in the PNS also.
Genetics: 20-40% of AD cases appear to be familial or have a genetic basis; other cases are sporadic.
Genetic AD people tend to have earlier onset, more rapid progression and severe pathology.
Gene for encoding the precursor protein for amyloid beta protein is located on chromosome 21; trisomy 21 people develop beta-amyloid deposits at a relatively early age.
