Alzheimer’s Summary 

 

• rare before 60

• 5 percent of Americans age 65 to 74

• nearly half of those age 85 and older

• 7th leading cause of death

• 5th for seniors

 

symptoms

• forgetfulness

• disorientation as to time or place

• difficulty with

  • concentration

  • calculation

  • language

  • judgment

• behavioral disturbances and may even become psychotic.

• incapable of self-care and becomes bedridden

• pneumonia or other immobility prob

 

diagnosed with high accuracy

med history, tests, images, psych tsting

 

Causes

• early onset is highly genetic but rare

• Damage to these neural systems

  • ACh, somatostatin, monoamines, and Gm.

  • all critical for attention, memory, learning, and higher cognitive abilities

 

1. abnormal accumulations of a small fibrillar peptide, termed beta amyloid, in the spaces around synapses.

   • referred to as neuritic plaques.

2. Another: neurofibrillary tangles

   • Identified as a modified form of the protein tau, which is found in the cell bodies of neurons.

 

• gene encoding the amyloid precursor protein (APP) = chromosome 21.

• In some families with early-onset Alzheimer’s, mutations have been identified in the presenilin 1 and 2 genes.

• Genes that cause dominant Alzheimer’s appear to do so by causing beta amyloid plaques to accumulate.

• Apolipoprotein E (apoE), which influences susceptibility for Alzheimer’s later in life, exists in three forms.

• The variant known as APOE epsilon 4 is clearly associated with enhanced risk.

 

Meds; 5 drugs

• Four prevent the breakdown of acetylcholine

  • important for memory and thinking

• The fifth regulates glutamate

  • may cause brain cell death when produced in large amounts.

• temporarily improve memory deficits and provide some symptomatic relief but do not prevent progression

 

• all forms of Alzheimer’s develop plaques and tangles in brain regions important for memory and intellectual functions.

 

Mice: can modulate genes which produce beta and gamma secretases, which cut amyloid peptide from a larger protein.

1. amyloid peptide rel'd from the neuron into the space around synapses, where it can accumulate and form plaques.

2. alpha secretases break up the amyloid peptide, preventing amyloid accumulation.

 

Anti-amyloid therapies for Alzh’s aim :

• remove existing amyloid or

• decrease production of new amyloid.

 

past three to five years->diet and lifestyle play in determining risk for Alzheimer’s disease.

Cognitive activity, physical activity, and heart-healthy diets lower the risk for Alzheimer’s, while obesity, high blood pressure, high cholesterol, metabolic syndrome, and diabetes raise the risk.

Some evidence indicates that successful management of these cardiovascular risks can delay the onset or slow the progression of dementia.

 

ALS Summary

• affects neurons that control voluntary muscle movements such as walking

• motor neurons in the brain and spinal cord begin to disintegrate

• signals from the brain are not carried by these damaged nerves to the body

• muscles begin to weaken and deteriorate from the lack of stimulation and resulting disuse

 

• progressive disorder

• Lou Gehrig’s disease

• strikes approximately 5,600 Americans annually,

• average survival time of just 2-5 years from symptom onset.

• typically 30,000 Americans have the disease at any given time.

• most common disorder within a group of diseases affecting motor neurons.

• affects neurons that control voluntary muscle movements such as walking.

• reasons not completely understood, motor neurons in the brain and SC begin to disintegrate.

• No cure, only meds to slow progression and muscle cramping and neurological stiffness

• costs of both care and treatment for ALS are expensive, and they continue to rise as the disease progresses.

• signals from the brain are not carried by these damaged nerves to the body, the muscles begin to weaken and deteriorate from the lack of stimulation and resulting disuse.

• eventually all muscles become affected, including respiratory ones

• Diagnose through

  • electrical tests of muscle activity

  • muscle biopsies

  • blood studies

  • computed tomography (CT), and

  • magnetic resonance imaging (MRI) scans

• 90% cases are sporadic

• rest, 5-10% are familial via superoxide dismutase, a defense against oxidative distress

• No cure, only meds to slow progression and muscle cramping and neurological stiffness

• An anti-glutamate drug slows the disease’s progression modestly.

• Mouse model is successful but not with humans

• Additional drugs are now under study.

• Protecting or regenerating motor neurons using nerve growth factors, other more potent drugs, and stem cells may someday provide additional benefits for patients.

 

Huntington’s Summary

• 30,000 Americans

• appears between the ages of 30 and 50.

• progresses slowly over a 10- to 20-year period

• named after the doctor who first described the condition.

• 200,000 more Americans at risk for inheriting from parent

• considered one of the most common hereditary brain disorders.

• eventually robs the affected individual of the ability to walk, talk, think, and reason.

• affects both

  • the basal ganglia, which controls coordination, and

  • the brain cortex, which serves as the center for thought, perception, and memory.

• due to a repeat mutation in one of the largest genes in the human genome called huntingtin.

 

• involuntary jerking movements of the limbs, torso, and facial muscles.

• mood swings

• depression

• irritability

• slurred speech

• clumsiness.

• reductions of eye movements

• can't stick tongue out

• difficulty with sustained movement

• quasi-purposeful movements (resembling purpose)

• swallowing is affected

 

then

• difficulty swallowing

• unsteady gait

• loss of balance

• impaired reasoning

• memory problems.

 

until

• death often due to

  • pneumonia

  • heart failure, or

  • another complication.

 

Diagnosis

• detailed clinical examination & family history.

• Brain scans

• 1993 indentify gene that causes Hunt’s; simplified genetic testing,

• used to help confirm a diagnosis.

 

Researchers and genetic counselors-> specific protocols for predictive genetic testing to ensure that the psychological and social consequences of a positive or negative result are understood.

• available only for adults

• children under 18 may be tested to confirm a diagnosis of juvenile-onset Huntington’s disease.

• Prenatal testing.

• ethical issues must be considered

• individual must be adequately informed

• (there is no effective treatment or cure)

 

medications help control some of the symptoms.

no effective treatments for slowing disease progression exist

 

Causes

• affects basal ganglia,

  • controls coordination, and 

• brain cortex,

  • serves as the center for thought, perception, and memory.

• disease mutation for huntingtin protein

  • an expanded triplet repeat — a kind of molecular stutter in the DNA.

  • codes for an abnormal version of the protein called huntingtin.

  • normal function is still unknown,

  • widely distributed in the brain

  • appears to be associated with proteins involved in transcription (turning genes on), protein turnover, and energy production.

  • suspected to be caused by the gain of a new and toxic function among these proteins.

 

Cell and animal models test for therapies;

meds being researched to slow the progression or delay onset of the disease while continue working to a cure.

 

PD Summary

• ~1.5 million individuals in the US

• start showing symptoms over the age of 50. 

• aging is the only known risk factor for the development of this disorder.

• slowness of movement

• muscular rigidity

• slowness

• stiffness

• tremor & unsteadiness

• walking and balance impairment 

• mirographia

• tend to be stiff 

• Overactive bladdder (blader spasms)

• may develop a resting tremor as well.

 

Besides impairment in motor movement, Parkinson’s may also cause changes in non-motor brain function.

 

early onset forms due to problems in genes coding for Parkin.

 

 

What Happens

• loss of dopamine-producing cells in substantia nigra pars compacta (midbrain).

• 40 percent of cells must be lost before symptoms occur, suggesting that perhaps the brain has a way of warding off symptoms.

• Eventually these mechanisms begin to fail, or the continued loss of cells leads to a threshold from which the brain can no longer recover.

 

Cause

• unknown

• both genetic and environmental factors that contribute to the injury and eventual loss of these dopamine-producing cells.

• most cases do not not appear to be inherited, there are certain situations in which genetic factors may be involved.

• early onset forms due to problems in genes coding for Parkin.

• Research on various forms help provide clues about it and new treatments.

 

Treatment

• 1950's: levels of dopamine are decreased

• 1960's: successul LEVODOPA treatment

  • converted to dopamine in the brain.

  • one of the greatest medical breakthroughs in the field of neurology.

 

other drugs either

• boost the effect of dopamine

  • inhibiting breakdown, or

• extend the length of dopamine-like effects 

  • through their ability to bind and act on similar brain regions for longer periods of time.

 

Dopamine Replacement Therapy

• carbidopa is often combined with levodopa;

  • combined effect reduces the breakdown of levodopa in the bloodstream

    • greater levels of dopamine to reach the brain.

    • reduces side effects, such as nausea.

• effective in alleviating many of the motor symptoms of Parkinson’s, still critical need to find better treatments.

• DRT neither cures the disease nor slows its progression.

• DRT doesn't treat non-motor aspects

  • anxiety and sleep issues.

• less effective over time in helping with gait and balance problems

 

Neurotoxin MPTP

• 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine

• Rodent and nonhuman primate

• late 1970s: accidentally synthesized by designers of illicit drugs looking for ways to produce a heroin-like compound.

• self-injected the MPTP

• developed a neurological condition that was indistinguishable from PD 

• converted in the brain to a substance that destroys dopamine neurons.

• This finding led to using MPTP as a tool for medical studies.

 

Alpha-Synuclein

• In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for alpha-synuclein. 

  • certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to PD

• alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such :

  • Parkinson's disease, 

  • dementia with Lewy bodies and 

  • multiple system atrophy.

  • These disorders are known as synucleinopathies.

• Alpha-synuclein is the primary structural component of Lewy body fibrils.

  • Occasionally, Lewy bodies contain tau protein;

  • Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.[49]

Protein aggregation is a biological phenomenon in which mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly. These protein aggregates are often toxic; protein aggregates have been implicated in a wide variety of disease known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.

 

Research on Treatments

• Primate models

  • pallidum and subthalamic nucleus are abnormally overactive

  • surgical deactivation or destruction of these overactive structures greatly reduces symptoms of Parkinson’s disease.

  • The past decade has witnessed a resurgence in this surgical procedure, called pallidotomy.

• recently, chronic deep-brain stimulation has been used.

  • highly successful for treating patients who have experienced significant worsening of symptoms and are troubled by the development of drug-related involuntary movements.

• for rapid progression 

  • surgical implantation of cells (Ex. fetal cells, stem cells) capable of producing dopamine.

• gene transfer of trophic factors

  • animal models and is being tested in clinical trials.

• gene therapy

  • clinical trials

  • testing wether it can provide symptomatic or neuroprotective benefit to patients 

 

genetic testing

1. diagnosis

2. advise other family members about their risks of

   • developing diseases, or

   • passing it on to their children.

 

The same gene defect can cause different diseases in different people, and different gene defects can cause very similar diseases. Understanding what it is that defines these differences, and how your genetic makeup interacts with the world in which you live and which you build around you, is one of the next great challenges for the genomic era in which we live.