DEGENERATIVE DISORDERS

• nervous system disorders

  • parkinson's disease
  • alzheimer's disease
• parkinson's disease

  • DEF: the degeneration of motor neurons of the CNS
  • where does the degeneration occur? in neurons of the substantia nigra that release dopamine to neurons in the corpus striatum
  • what does the corpus striatum control? fine movement of muscle.
• symptoms of parkinson's disease

  • Tremors: shaking
  • Rigidity
  • Flexion: bending of the body forward at the waist
  • Difficulty in movement
• types of parkinsons

  • primary parkinsons: idiopathic
  • secondary parkinsons: can result from a disturbance like drugs or trauma
• histology of parkinsons

  • Accumulation of alpha-synuclein in inclusions called Lewy bodies
  • Degeneration of neurons that make dopamine with insufficient dopamine production
• causes of primary parkinsons

  Primary PD is idiopathic: speculation for the cause of injury is the build-up of alpha-synuclein bound to ubiquitin

  • This abnormal protein accumulates as Lewy bodies and somehow injures the cells
• cause of secondary parkinsons

  secondary PD: may be caused by a number of changes caused by genetic alteration or trauma via physical or chemical agents

  • chemical agents: insecticides, paraquat, rotenone, Agent Orange
  • Heavy metals: suggested but never proven (aluminum)
  • Trauma
  • Mutation in the genes: alpha-synuclein**, parkin**, leucine-rich repeat kinases 2 (LRRK2 or dardarin), PTEN-induced putative kinase (PINK1), DJ1, and ATP13A2
• model of action of the basal ganglion in parkinsons

  • To carry out an action, inhibition by the basal ganglion is reduced for the appropriate motor system which allows the motor system to act
  • Dopamine facilitates the release of this inhibition
• how dopamine affects basal ganglion

  • High levels of dopamine function to promote motor activity
  • Low levels require greater exertion to affect a given movement
  • Loss of dopamine produces hypokinesis reducing overall motor output
• alzheimers disease

  a chronic neurodegenerative disease of the cerebral cortex with 4 stages: pre-dementia, early, moderate, advanced
• 4 stages of alzheimers

  1. Pre-dementia: beginnings of the loss of short memory, difficulty in distinguishing between simple age-related loss  
  2. Early: exhibits an increase in the degree of memory loss with a decrease in the ability to learn new things, language difficult, old memory maintains intact, may exhibit aggressiveness
  3.  Moderate: degeneration of memory continues to worsen, loss of vocabulary and independence
  4. Advanced: total dependence on others for daily activities, language reduced to simple phrases or single words, aggressiveness may continue
• 3 theories on the cause of Alzheimer's

  1. genetic hypothesis
  2. amyloid hypothesis
  3. tau hypothesis
• 1. genetic hypothesis

  • “presenile dementia: or early-onset familial Alzheimer’s”
  • Only 0.01% of patients with Alzheimer’s have this form
  • onset = before the age of 65
  • caused by an autosomal dominant gene
  • late-onset/senile dementia: lacks autosomal dominant mutations and is sporadic
• genes involved in the genetic hypothesis

  • mutations can be found in 3 genes: (1) Amyloid precursor gene (APP), (2) Presenilin 1, (3) Presenilin 2
  • These genes increase the production of a protein called amyloid beta 42 which helps to maintain senile plaques
  • Environment and genetics both play a role 
  • The best known risk factor is the inheritance of the epsilon 4 allele of the Apolipoprotein E (Apo-E) 
  • 40-80% of individuals with Alzheimer’s have the APO-Eepsilon4 
  • The risk is 3x for heterozygous and 15x for homozygous
• 2. amyloid hypothesis

  suggests that an amyloid-related mechanism removed neuronal connections during brain development

  • this mechanism is driven by N-APP and accidentally triggered in later life to cause neuronal destruction
  • stems from observations of deposition of amyloid beta
  • amyloid beta is believed to be a product of the amyloid precursor protein (APP)
  • led to the belief that Alzheimers was caused by abnormal deposition of AB
• Tau hypothesis

  tau protein abnormalities cause a disease cascade
• mechanism of tau

  1. Hyperphosphorylated TAU begins to pair with more TAU molecules 
  2. Destruction of the cytoskeleton leads to the inability of neurons to transport neurosecretory molecules
  3. This leads first to cell malfunction then death
  4. TAU polymers eventually form neurofibrillary tangles seen inside neuron cell bodies
  5. Microtubules in the cell disintegrate which leads to the destruction of the cytoskeletal structure
• neuropathology of tau hypothesis

  • leads to the loss of neurons and synapses in the cerebral cortex
  • Gross atrophy of the brain with space developing between the skull and the brain itself
  • Specific areas of atrophy: temporal lobe, parietal lobe, frontal cortex, cingulate gyrus, parts of the brain stem
  • amyloid plaques and neurofibrillary tangles appear
• osteoarthritis

  • DEF: a joint disease that causes the breakdown of joint cartilage and underlying bone
  • Referred to as “wear and tear” arthritis as it is often associated with repetitive injury to the joint
  • most common form of arthritis
  • Generally seen to be increasing with age
  • Often seen only on one side or in a single joint but may be bilateral and involve multiple joints
• symptoms of osteoarthritis

  • Pain
  • Joint stiffness
  • Loss of movement
  • Crackling noises in joints (crepitus)
  • Fingers may show Heberden’s nodules: enlargement of the most distal and second joint
  • Joint injury: mechanical stress. Usually generates a low-grade inflammatory process. No overt signs of inflammation, redness, and pain
• causes of osteoarthritis

  • Abnormal limb development
  • Inherited factors
  • Risk factors for osteoarthritis: being overweight, repetitive tasks, legs of different lengths
• secondary factors of osteoarthritis (other diseases)

  • alkaptonuria
  • ehlers-danlos syndrome
  • marfans syndrome
• 1. alkaptonuria

  • A genetic metabolic disorder caused by the body’s inability to process phenylalanine and tyrosine
  • Recessive autosomal condition
  • The condition is characterized by the accumulation of homogenistic acid in the body 
  • Caused by a mutation in the gene that codes for the enzyme homogentisate 1,2,3 deoxygenase
  • Congenital disorders of the joints
  • Diabetes (increase the risk to 2x)
• 2. ehlers danlos syndrome

  • A group of rare connective tissue disorders
  • Multiple genes are affected
  • Can be autosomal dominant or recessive
  • Caused by genetic mutation
  • Symptoms: loose joints, joint pain, stretchy skin, and abnormal scar formation
• 3. marfans syndrome

  a genetic disorder of the connective tissue that is autosomal dominant

  • Symptoms: 
  • Tall and thin individuals
  • Long arms, legs, fingers, and toes → arachnodactyly 
  • Hyperflexible joints
  • May involve heart valves (mitral valve prolapse)
  • Aortic aneurysm
  • Eyeball ligaments weakness
  • Cause: a mutation of the FBN1 gene that codes for a protein known as Fibrillin-1
  • What is Fibrillin-1? a glycoprotein of the extracellular matrix and is an essential component for the proper formation of the ECM, especially elastic fibers
• pathophysiology of osteoarthritis


  The articular cartilage is composed mainly of collagen, proteoglycans, and water. In this, the collagen matrix is a balance of forces

  • Compressive forces of the body vs the hydrostatic and osmotic pressure of the water in the cartilage itself
  • Internal to the cartilage, the preteoglycans are responsible for the maintenance of the osmotic pressure that draws in water
  • Increased compressive forces tend to cause a decrease in proteoglycan content within the cartilage
• pathophysiology pt 2

  • Decreased proteoglycan content reduces osmotic pressure, reducing the water content of the cartilage
  • The reduced osmotic pressure in cartilage causes additional stress on the collagen fiber --> breaks down
  • The breakdown of collagen fibers weakens the cartilage
  • The collagen breakdown products induce an inflammatory response in the articular cartilage and surrounding joint capsule
  • The inflammation further injures the cartilage by releasing proteolytic enzymes such as metalloproteases (common to neutrophils)
• effects of inflammation in osteoarthritis

  • Ligaments and joint capsule may become fibrotic and thickened
  • The meniscus is worn away
  • Bone outgrowth: spurs form at the margins of the head of long bone
  • Bone outgrowth may occur in the synovial space forming joint mice (bony particles inside the joint)
  • The joint may disarticulate with loss of function