Pathophysiology Exam 4 - Nervous System/Alzheimers

Common medications used in Alzheimer Disease Selegiline (Eldepryl)

- Prevents monoamine oxidase B enzyme from breaking down protein - Parkinson's disease is caused by decrease of production of dopamine in the brain. Dopamine is critical for movement and motor control.

Familial Alzheimer's disease (most common type of early-onset) is caused by any one of a number of different single-gene mutations on chromosomes __, __, and 1

21: formation of abnormal amyloid precursor protein (APP) 14: abnormal presenilin 1 is made 1: abnormal presenilin 2 is made

___________ _______ _____ undergoes proteolysis to form beta-amyloid peptide pieces

Amyloid precursor protein (APP)

Gray matter

Brain and spinal cord tissue that appears gray with the naked eye; consists mainly of neuronal cell bodies (nuclei) and lacks myelinated axons. With aging gray matter is decreased in terms of the number of dendritic processes and synaptic connections

Dementia

Clinical syndrome consisting of global cognitive decline, memory deficits plus one other area of cognition, and significant effect on day-to-day function. Not delirium

Alzheimer Dementia

Dementia syndrome that has gradual onset and slow progression and is best explained as caused by Alzheimer disease

________ _______ is a gene change that can sometimes cause a disease directly. More often, it acts to increase or decrease a person's risk of developing a disease or condition.

Genetic variant

During Alzheimer's disease in the brain the __________ which is critical to formation of new memories shrinks severely. The ______ _________ which is responsible for language and information processing shrivels up, damaging areas involved in thinking, planning, and remembering. The _________ fill with cerebrospinal fluid and grow larger.

Hippocampus Cerebral Cortex Ventricles

__________ and _____ _________ shrink during Alzheimer's progression.

Hippocampus and Cerebral Cortex

Level of education and depression may be a risk factor for dementia. T or F?

True

Central gyrus primarily ________(motor/sensory) Postcentral gyrus _______(motor/sensory)

motor Sensory

Late Onset Alzheimer's Disease __ million people with Alzheimer disease worldwide, _ million in the United States. Prevalence of Alzheimer disease rises with each decade of age. _ percent in people older than 65 years __ percent in people older than 80 years More than __ percent in those older than 95 years

- 25 - 5 - 6% - 20% - 95%

Alzheimer's Possible Protective Factors

- APOE2 allele - Regular fish consumption - Regular consumption of omega-3 fatty acids - High educational level - Regular exercise - NSAID therapy (combat inflammatory response) - Moderate alcohol intake - Adequate intake of vitamins C, E, B6, and B12, and folate

Summary of Pathogenesis of Alzheimer Disease

- Abnormal amounts of beta-amyloid are cleaved from amyloid precursor protein (APP) and released into the circulation. - The beta-amyloid fragments come together in clumps to form plaques that attach to the neuron. Microglial cells react to the plaques and an inflammatory response occurs. - Tau proteins provide structural support for the neuron microtubules. Chemical changes in the neuron produce structural changes in tau proteins. This results in twisting and tangling (neurofibrillary tangles).

_________________ gene on chromosome 19 is the major genetic source of the common forms of late onset Alzheimer disease. APOE_ allele may be protective. APOE_ allele is associated with increased risk of developing the disease. Individuals inherit a copy of one type of allele from each parent. APOE_ allele doesn't protect or increase risk of Alzheimer's (neutral). Alzheimer disease is not inevitable, even in people with two copies of the APOE4 allele.

- Apolipoprotein E (APOE) - 2 - 4 - 3

Nervous system and Aging - Cerebrovascular Changes

- Arterial atherosclerosis (may cause infarcts and scars) - Increased permeability of the blood-brain barrier - Decreased vascular density

Neuritic Plaques consist of:

- Beta amyloid proteins stuck together - fragmented axons - Altered glial cells - Cellular debris Plaque triggers an inflammatory response, resulting in increase free radicals that cause damage to the nervous system

Nervous system and aging - structural and chemical changes that automatically occur as we age

- Decreased brain weight and size, especially frontal regions - Narrowing of gyri (hills) and widening of sulci (valleys) - Increase in size of ventricles - Fibrosis and thickening of the meninges - Loss/death of neurons, decreased amount of myelin, decreased number of dendritic processes and synaptic connections, imbalance of neurotransmitters - Lipofuscin deposition (pigment resulting from cellular autodigestion) - Formation of intracellular neurofibrillary tangles (alters the ability of the neurotransmitter in vesicles to travel down the axon terminal, accumulation associated with Alzheimers)

Pathologic Alterations in the Brain with Alzheimer Disease

- Formation of neuritic plaques containing a core of amyloid beta protein * Failure to process and clear amyloid precursor protein (APP) results in the accumulation of toxic fragments of amyloid beta protein. * Leads to the formation of diffuse neuritic plaques, disruption of nerve impulse transmission, and death of neurons.

Alzheimer Disease: Possible Risk Factors

- Head injury - Depression - Progression of Parkinson-like signs in older adults - Lower thyroid-stimulating hormone within normal range - Hyperhomocysteinemia (increased homocysteine in blood, associated with ppl that eat a lot of red meat) -Folate deficiency - Hyperinsulinemia - Low educational attainment

Early-Onset Alzheimer's Disease

- Occurs in people age 30 to 60. Rare, represents less than 5 percent of all people who have Alzheimer disease. - Some cases of early-onset Alzheimer's have no known cause, but most cases are inherited, a type known as familial Alzheimer's disease (FAD). - Children whose mother or father carry a genetic mutation for FAD have a 50/50 chance of inheriting the mutation. If the mutation is inherited, the children will develop the disease. - Caused by single-gene mutations on chromosomes 21 (APP), 14 (abnormal presenilin 1), or 1 (abnormal presenilin 2) - Each of the mutations play a role in the breakdown of amyloid precursor protein, a protein whose function is not yet known. - Breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of Alzheimer disease. These mutations cause formation of abnormal proteins.

Lifetime risk of developing Alzheimer disease is __-__% percent.

12-17%

The APOE gene is on chromosome __ and E_ is the damaging allele.

19, APOE4

According to Alzheimer Disease International, the prevalence of the disease worldwide will double every __ years.

20 As life expectancy continues to rise, so does the potential for more individuals to be afflicted. It is thought that many individuals with the symptoms go undiagnosed and untreated.

People without APOE4 have an estimated risk of _-__ percent for developing Alzheimer disease by age 85 years. In people with one copy of the APOE4 allele, the risk is __-__ percent. In people with two copies of the APOE4 allele, the risk is __-__ percent. Only 2 percent of the population carries two copies of the APOE4 allele. - People with a first-degree relative (parent) with dementia have a __-__% increased risk of developing Alzheimer disease.

9-20% 25-60% 50-90% 10-30%

Genome-wide association study (GWAS)

A study approach that involves rapidly scanning complete sets of DNA, or genomes, of many individuals to find genetic variations associated with a particular disease.

APOE proteins normally remove ____ ______. Studies report the greatest deposits of _______ _______ in people with APOE4. APOE4 allele removes ____ _________ less efficiently than other APOE types.

Beta amyloid

_______ ________ _ (PKR) accumulates in the brains of patients with Alzheimer disease and can indirectly induce the phosphorylation of tau, and induce the death of neurons.

Protein kinase R

Late-stage Alzheimer's indicates involving _______ and __________ lobe

frontal and occipital

Age-associated memory impairment or benign senescent forgetfulness

- a decline in short-term memory that doesn't progress to other mental intellectual impairments - Primary difference is that with Alzheimers, the inability to perform ADL's is limited. Impacts all lobes of the brain

Myelin

A layer of fatty tissue segmentally encasing the fibers of many neurons; enables vastly greater transmission speed of neural impulses as the impulse hops from one node to the next.

Delirium

Characterized by restlessness, illusions, and incoherence of thought and speech - Most common cause is drug interactions

Mutations in the _________ 1 and 2 genes account for most cases of early onset inherited Alzheimer disease.

Presenilin

Defective genes appear to accelerate beta amyloid plaque formation and ________ (natural process by which cells self-destruct).

apoptosis

APOE4 is considered a ____ - _______ gene.

risk-factor

Alzheimer Disease Primary Risk Factors

- Age - Family history - Genetic markers such as APOE4 allele, trisomy 21, mutations in presenilins 1 and 2 - Female gender after age 80 - Cardiovascular risk factors such as hypertension, diabetes, obesity, and hypercholesterolemia

Late-onset Alzheimer disease

- Age > 65 - ApoE gene - Menopause - less estrogen - Less education - Increased BP and cholesterol - Environmental triggers, toxins - Inflammation - Altered breakdown and clearance of beta amyloid plaques - Hyperphosphorylation of Tau protein - Intracellular neurofibrillary tangles

Nervous System and Aging - Functional Changes

- Decreased tendon reflexes - Skeletal muscle atrophy - Decrease in neuromuscular control with change in gait and posture (shorter stride length, wider BOS, arms swinging wider away from side) - Progressive deficit in taste and smell - Decreased vibratory sense - Decreased vision (d/t loss of elasticity in lens) - sleep disturbances - memory impairments - Cognitive alterations associated with chronic disease

Alzheimer's progression

- Mild Cognitive Impairment: 7 years, begins in Medial temporal lobe, symptoms include short term memory loss - Mild Alzheimer's: 2 years, disease spreads to lateral temporal and parietal lobes, symptoms include reading problems, poor object recognition, poor direction sense - Moderate Alzheimer's: Duration 2 years, Disease spreads to frontal lobe, symptoms include poor judgement, impulsivity, short attention - Severe Alzheimer's: 3 years, disease spreads to occipital lobe, visual problems

Common Medications Used in Alzheimer Disease: Donepezil (Aricept)

- Moderate to severe patients - Cholinergic stimulant - Modest benefits, helps slow loss of function and reduce caregiver burden - Cholinesterase breaks down Aceteylcholine (Ach). - Medication stimulates the release of Ach and disables cholinesterase which breaks down Ach

4 Theories for pathogenesis of Alzheimer Disease

- Mutation for encoding amyloid precursor protein (APP) - Alteration in apolipoprotein E, which binds amyloid-beta Pathologic activation of N-methyl-d-aspartate receptors resulting in an influx of excess calcium - Loss of neurotransmitter stimulation by choline acetyltransferase

2 characteristics of Alzheimer's Disease

- Neurofibrillary Tangles (occur inside the neuron, causing the neuron to die) - Formation of amyloid plaques (normal proteins to see in between neurons (function partly structural, partly for neurointegrity of neuroglial cells), eventually they are broken down, but in Alzheimer's disease the proteins continue to accumulate without being degraded. When they become in contact with a neuron, they cause the neuron to die) - APOE4 allele is less efficient at removing amyloid plaques

Epigenetics

- Science focused on how and when particular genes are expressed - Diet and exposure to chemicals in the environment, among other factors, throughout all stages of life can alter a cell's DNA in ways that affect the activity of genes. That can make people more or less susceptible to developing a disease later in life. - Emerging evidence that epigenetic mechanisms contribute to Alzheimer's

Formation of neurofibrillary tangles

- Tau protein is a microtubule binding protein that normally stabilizes the microtubular transport system in neurons. - In Alzheimer disease, the tau protein detaches from the microtubule and forms an insoluble helical filament called a neurofibrillary tangle. Tangles are flame shaped. - Cortical nerve cell processes become twisted and dilated because of accumulation of the same filaments that form tangles.

Other common Medications Used in Alzheimer Disease Galantamine (Reminyl):

Cholinergic stimulant (Cholinesterase inhibitor) that ALSO ACTS ON NICOTINIC RECEPTORS, which are depleted - Used for mild to advanced-moderate patients

In _____ _________, the beta-amyloid precursor protein (source of beta amyloid) is overproduced, which almost always leads to early Alzheimer disease.

Down Syndrome

Microtubules are the structural components of neural cells. ___ proteins are responsible for holding the microtubules together. As the microtubule disintegrates, neurofibrillary tangles form and remain in the system. One of the functions of the microtubules is axonal transport.

Tau proteins

Loss of ____________ and other neurotransmitters contributes to the decline of memory and attention, as well as the decline of other cognitive functions associated with Alzheimer disease Alterations in intracellular ________ levels are functionally linked to presenilin mutations, APOE4 expression, neuritic plaques, neurofibrillary tangles, and synaptic dysfunction.

acetylcholine calcium

Cause of Alzheimer disease is unknown. Appears to be a relationship between genetic predisposition, abnormal processing of a normal cellular substance called _______, and advanced age.

amyloid

Genetic mutations in the genes that control _______ _______ _______(APP) are being considered as causes of early onset Alzheimer disease. Amyloid precursor protein gene is located on chromosome 21.

amyloid precursor protein

Alzheimer Disease

brain disease characterized by plaques, tangles, and neuronal loss 5 Stages - Stage 1-2: Pt is aware of what is going on - Stage 3-5: Pt is unaware that they are losing memory

Neuritic plaques and neurofibrillary tangles are more concentrated in the _________ ___________ and ____________ (important for memory). Greater the number of neuritic plaques and neurofibrillary tangles, the more dysfunction associated with Alzheimer disease.

cerebral cortex and hippocampus

Alzheimer disease is the most common cause of _________. One of the principal causes of disability and decreased quality of life among older adults.

dementia

An additional protein in the areas of the brain affected by Alzheimer disease is _______ ______ _________ _______ protein. It appears to combine with beta amyloid, which in turn attracts new beta amyloid from outside the cells.

endoplasmic reticulum-associated binding protein

When a genetic variant increases disease risk but does not directly cause a disease, it is called a _______ ________ _________

genetic risk factor.

Vascular factors that increase the risk for Alzheimer disease include ___________, __________, __________.

hypertension, diabetes, hyperlipedmia

Multiple Sclerosis (MS) destroys the ______ ________ in the central nervous system.

myelin sheath

multiple sclerosis

myelin sheath destruction. disruptions in nerve impulse conduction

Common medications used in Alzheimers Memantine (Namenda)

targets the N-methyl-d-aspartate (NMDA) receptors, used for moderate to severe disease. Prevents the pathologic activation of N-methyl-d-aspartate receptors resulting in an influx of excess calcium.