ILE 2 Exam 2

what is the approximate prevalence of alzheimers in the US population?

approximately 5.4 million americans

what is the projection of alzheimers disease in the baby boomer population by 2050?

13.2 to 16 million people

what is the proportion of dementia cases that is caused by Alzheimer’s disease?

60% of late-life cognitive dysfunction, rising to 80% when AD pathology coexists with other neurodegenerative lesions

what is the ranking of AD in the leading cause of death in the US?

it is ranked 6th

__ in __ seniors dies with alzheimer’s or another form of dementia

1 in 3 seniors

explain the irreversible neurodegenerative dementia Alzheimer’s Disease (AD)

it is ranked #1 of the INDs, responsible for 60-80% of cases

explain the irreversible neurodegenerative dementia Vascular Dementia (VaD)

it is ranked #2 of the INDs, responsible for 20-30% of cases.
It stems from cerebrovascular events (strokes, TIAs) or chronic microvascular disease

explain the irreversible neurodegenerative dementia Dementia with Lewy Bodies (LBD)

it is ranked #3 of the INDs, responsible for 10-25% of cases
Pathologically characterized by abnormal α-synuclein protein aggregates (Lewy bodies)

what is mix dementia?

Co-occurrence of two or more dementia types (most commonly AD combined with Vascular Dementia)

what are some other irreversible neurodegenerative dementias?

Parkinson’s disease dementia (PDD), Frontotemporal dementia (FTD), Huntington’s disease, and Creutzfeldt-Jakob disease (CJD)

true of false: thyroid dysfunction is a potentially reversible cause of dementia?

True: severe hypothyroidism can cause mental impairment in some patients

why does vitamin B12 deficiencies cause reversible memory impairment in patients?

it can possible cause elevated homocysteine and neurological symptoms

how does normal-pressure-hydrocephalus cause reversible dementia symptoms?

excess cerebrospinal fluid build-up can cause gait impairment, urinary incontinence and cognitive decline

explain the late-onset AD classification?

Presentation occurring at >65 years of age (accounts for the vast majority of cases)

explain the early-onset AD classification?

Presentation occurring at <65 years of age (can present as early as 30 years of age)

explain the sex differences between males and females AD onset

Women demonstrate a slightly higher risk and overall prevalence than men, which is partly attributed to longer average life expectancy ("survivor effect")

what is the average survival time following an AD diagnosis?

the average survival time is 4 to 8 years

what is the median survival rate of a PT who is diagnosed with AD at 65?

the median survival rate is 8.3 years

what is the median survival rate of a PT who is diagnosed with AD at 90?

the median survival rate is 3.4 years

what is the clinical course and trajectory of AD?

it is displayed as a gradual, progressive downward slope in memory and cognitive function

what is the clinical course and trajectory of vascular dementia?

it is displayed as a sudden, “step-like” sloop following a vascular event

when using a cognitive screening exam such as the Mini-Mental State Examination (MMSE), what is the average decline rate of an AD patient per year?

an average of 2 to 4 points per year

explain the stage of mild AD

-has a MMSE of 26-18
-Characterized by short-term memory loss,
-difficulty with complex instrumental tasks (IADLs like managing finances or preparing meals),
-getting lost while driving, and subtle personality changes

explain the stage of moderate AD

-has a MMSE of 17-10
-marked by loss of basic ADL(requiring help with dressing, bathing, or toileting)
-behavioral/psychiatric disturbances (agitation, aggression, wandering, paranoia, delusions)
-inability to learn new information

explain the stage of Severe AD

-MMSE of 9-0
-Complete dependence; patients become nonverbal/mute, lose motor control (unstable gait, bedridden)
-develop dysphagia, suffer bowel/bladder incontinence
-require round-the-clock long-term care placement

What is the age cutoffs and relative prevalence for Early-Onset

Age: < 65 years of age (can present as early as 30 years of age)
Prevalence: < 1% of all AD cases

What is the age cutoffs and relative prevalence for late-Onset

Age: > 65 years of age
Prevalence: > 99% of all AD cases (majority of presentations)

explain the underlying causes and inheritance patterns in early-onset AD

-Driven by autosomal dominant (familial) inheritance
-Features rapid, aggressive disease progression

explain the underlying causes and inheritance patterns in late-onset AD

-Multifactorial / Sporadic etiology
-Results from a complex combination of genetic susceptibility alleles, vascular disease, and environmental risk factors

Which chromosomes and gene mutations cause Early-Onset Familial AD

-Chromosome 14: Presenilin 1 (PSEN1) mutation
-Chromosome 1: Presenilin 2 (PSEN2) mutation
-Chromosome 21: Amyloid Precursor Protein (APP) mutation

what is the pathophysiologic effect of chromosome 14?

-increases production of Aβ 42 peptides
-Represents the majority of familial cases and is the most aggressive form

what is the pathophysiologic effect of chromosome 1?

Increases production of Aβ
42 peptides

what is the pathophysiologic effect of chromosome 21?

Increases Aβ
/
Aβ
42 production

what is the clinical pearl involving chromosome 21?

Patients with Down Syndrome (Trisomy 21) have an extra copy of the APP gene on Chromosome 21, placing them at high risk for early AD pathology

Which chromosome and gene marker are associated with Late-Onset AD risk

Chromosome 19, and specifically the Apolipoprotein E (APOE) gene

how does the APOE ϵ
4 allele affect pathology?

-it increases the density of Aβ plaques and vascular deposits
-it lowers the age of onset for dementia and is presented in 20-25% of sporadic AD cases

compared the specific disease risk multiple of
ϵ2/ϵ 2 or ϵ2/ϵ3 to ϵ3/ϵ 3(average baseline)

40% risk reduction (40% less likely; protective effect)

compared the specific disease risk multiple of ϵ
2/
ϵ
4 to ϵ3/ϵ3(average baseline)

it is a 2.6x increased risk

compared the specific disease risk multiple of ϵ
3/
ϵ
4 to ϵ3/ϵ3(average baseline)

it is a 3.2x increased risk

compared the specific disease risk multiple of ϵ4/ϵ4 (Homozygote) to ϵ3/ϵ3(average baseline)

it is a 14.9x increased risk

what is the modifiable vascular risk factor that contribute to late-onset AD

Hypertension, hypercholesterolemia, atherosclerosis, coronary heart disease, smoking, and elevated homocysteine (associated with B12 deficiency)

what is the Metabolic Risk Factors that contribute to late-onset AD

Obesity, metabolic syndrome, and Type 2 Diabetes / Insulin Resistance (up to 80% of AD patients have insulin resistance or T2DM)

what is the Lifestyle & Cognitive Reserve Factors that contribute to late-onset AD

History of head injury, depression, low formal education, and physical/mental inactivity in later life

what are Extracellular Amyloid Beta (Aβ) Plaques

Accumulation of neurotoxic Aβ peptides in the extracellular space

what are Intracellular Neurofibrillary Tangles (NFTs)?

Aggregates composed of hyperphosphorylated tau protein inside neurons

what are the three neuropathological hallmarks that confirms that a PT has AD

Extracellular Amyloid Beta (Aβ) Plaques, Intracellular Neurofibrillary Tangles (NFTs), and Widespread Synaptic and Neuronal Loss

explain the amyloid cascade hypothesis

—>Aβ peptides are cleaved from Amyloid Precursor Protein (APP) by β-secretase and γ-secretase enzymes
—>An imbalance between the production and clearance of Aβ (specifically the hydrophobic Aβ42 form) causes monomers to aggregate into soluble oligomers, protofibrils, and insoluble plaques

what is the clinical significance behind the amyloid cascade hypothesis

Aβ aggregates exert direct neurotoxicity, trigger neuroinflammation, induce altered calcium homeostasis, and accelerate tau tangle formation—ultimately driving synaptic dysfunction and cell death

under normal conditions, what is the role of Tau proteins?

it is a soluble protein that binds to and stabilizes microtubules, maintaining the internal structural cytoskeleton and nutrient transport system of the axon.

what happens to tau proteins if they become hyperphosphorlated?

it looses its affinity to microtubules, causing the cytoskeleton of the axon

what damage does dislodged tau proteins do to the brain?

it misfolds and pair into paired helical filaments, forming intracellular tangles, disrupting synaptic signaling and triggering neuronal apoptosis(cell death)

explain the inflammatory factors associated with microglial cell activation

Aggregated Aβ plaques bind to microglial cells (the brain's resident innate immune cells), triggering sustained immune activation

explain the inflammatory factors associated with pro-inflammatory cytokines

when microglia and astrocytes are activated, they release a cascade of neurotoxic, pro-inflammatory mediators, thus generating reactive oxygen species and oxidative stress

what are some pro-inflammatory mediators?

TNF-α, IL-1β, and IL-6

what triggering receptor is expressed on the myeloid cells 2?

TREM2

explain the results of TREM2 and CD33 mutations

it causes impairment of the phagocytic clearance of Aβ accelerating plaque buildup and inflammatory injury

explain systemic-central cross-talk inflammation

systemic inflammation (e.g periodontitis, sepsis, chronic mid-life obesity) increases circulating cytokines that cross or alter blood-brain barrier function, further fueling central microglial hyperactivation

what is the role of acetylcholine(ACh)

it is a key neurotransmitter responsible for processing memory, learning, and attention in the cortical and hippocampal pathways

what is the pathology of acetylcholine in AD?

reductions in choline acetyltransferase (enzyme that synthesizes aCh) alongside with impaired choline reuptake and lose of presynaptic nicotinic/muscarinic receptors causes a profound, progressive loss of cholinergic neurons that originate in the nucleus basils of meynert

what structure is this?

the nucleus basalis of meynert

what pharmacologic targets are used on the cholinergic system

Acetylcholinesterase Inhibitors (AChEIs): Donepezil, Rivastigmine, Galantamine

explain the basic mechanisms for AChEIs

they inhibit the breakdown of ACh by acetylcholinesterase (AChE), increasing synaptic ACh levels to temporarily stabilize cognitive function

explain the role of glutamate

it is the primary excitatory neurotransmitter in the CNS
it is essential for synaptic plasticity, long-term potentiation (LTP), and memory formation

explain the pathology of glutamate in relation with AD

Impaired glutamate reuptake into supporting astroglia causes continuous, low-level excess glutamate leakage into the synaptic cleft. this causes a persistent overaction of he N-mnethyl-D-aspartate(NMDA) receptor

what is the result of sustained NMDA receptor activation?

it leads to excessive intracellular calcium influx, causing excitotoxicity, loss of synaptic signal detection and eventual cell death

what pharmacologic target is used on the glutamatergic system?

memantine, an NMDA receptor antagonist

explain the basic mechanism of NMDA receptor antagonist

It selectively blocks pathological, tonic Ca2+ influx during excessive glutamate stimulation without interfering with rapid, physiological bursts of glutamate required for normal learning

explain the anatomy of the upper respiratory tract

it consist of the nose, nasopharynx and larynx

explain the anatomy of the lower respiratory tract

Begins at the trachea and branches sequentially into the bronchi, bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts, and alveoli

how many generations of branches does the tracheobronchial tree of the lungs have?

23 generations

how munch lung volume does generation 0-8 of the tracheobronchial tree accounts for?

50 mL worth of lung volume

how munch lung volume does generation 9-23 of the tracheobronchial tree accounts for?

4,500 mL worth of lung volume

explain the pulmonary circuit

1.) Deoxygenated venous blood from the body enters the right atrium, moves into the right ventricle, and is pumped through the pulmonary artery into the pulmonary capillary bed surrounding the alveoli
2.)In the alveoli, carbon dioxide (CO2​) diffuses out into expired air, and oxygen (O2​) diffuses into capillary blood
3.)Oxygenated blood travels via the pulmonary veins into the left atrium

explain the systemic circuit

1.)The oxygenated blood flows into the left ventricle, which pumps it through the aorta to supply systemic tissues and organs
2.)Deoxygenated blood returns via the superior and inferior vena cava back to the right atrium

in a healthy adult at rest, what is their tidal volume? (TV)?

500 mL

how much anatomic dead space remains in the conducting airways?

150 mL

how much air volume reaches the alveolus for gas exchange?

350 mL

what is alveolar ventilation rate? (AVR)

Respiratory Frequency (breaths/min)×(TV−Dead Space)

if an adult is breathing 12 breathes per minute, how do you calculate total minute ventilation?

Total Minute Ventilation=500 mL×12 bpm=6,000 mL/min

what is the normal respiratory rate for a newborn?

30–40 breaths/min (up to 60)

what is the normal resting respiratory rate for an infant/young child (1 month - 2 years)

25–30 breaths/min

what is the normal resting repsiratory rate for a child (3-9 years)

20-25 breaths/min

what is the normal resting respiratory rate for an adolescent (10-18 years)

16-20 breaths/min

what is the normal resting respiratory rate for an adult? (>18 years)

12-20 breaths/min

explain the chemical drive of breathing

When alveolar ventilation declines, plasma PaCO2​ rises
Carbon dioxide acts as an acid in solution, lowering systemic blood pH

what is a major predisposing risk factor for someone to develop Asthma?

A positive family history of asthma or atopy

explain a household and birth protective and risk factor

protective: Natural vaginal birth, breastfeeding, being a younger sibling
risk: Caesarean section, formula feeding, household history of asthma

explain some living risk and protective factors for asthma

protective: Farm living (cattle/pig farming, animal sheds, unpasteurized milk, silage)
risk: Urban living, air pollution, exposure to second-hand cigarette smoke

explain some microbiological risk and protective factors for asthma

protective: Diverse microbiota, foodborne pathogen exposures, helminths
risk: Dysbiotic microbiota, early severe respiratory viral infections (RSV, rhinovirus), bacterial infections (M. catarrhalis, S. pneumoniae)

explain some socioeconomic & lifestyle risk and protective factors for asthma

protective: Balanced healthy diet, regular exercise, lower stress
risk: Lower socioeconomic status, obesity, active smoking, frequent early-life antibiotic use

explain the cellular elements related to asthma

it is driven by a specialized cellular orchestra: mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and airway epithelial cells

what is the 3 distinct mechanical changes associated with an asthma attack?

bronchospasm, mucosal edema/vascular leakage, and mucus hypersecretion

explain mucosal edema and vascular leak

Inflammatory cytokines loosen vascular endothelial junctions, permitting capillary leakage and airway wall swelling

explain mucus hypersecretion

Submucosal mucous gland hyperplasia and goblet cell metaplasia cause excessive secretion of thick, tenacious mucus, producing intraluminal plugging

list the chronic structural alterations that asthma causes

-Sub-basement membrane collagen deposition and fibrosis
-epithelial desquamation
-hypertrophy an hyperplasia
-angiogenesis

what is a spirometry?

it provides an objective, reproducible measure of airflow limitation and is the cornerstone of asthma diagnosis in patients capable of performing the maneuver (children ≥5 years old and adults)

true of false: a spirometry should be performed before initiating maintenance controller therapy

true: Spirometry should ideally be performed before initiating maintenance controller therapy

how is asthma characterized through the spirometry

it is characterized by airflow obstruction that is variable and reversible either spontaneously or following bronchodilator administration

how do you get the baseline spirometry from a patient?

The patient performs a maximal forced exhalation to obtain baseline FEV1​ and FVC

what is the bronchodilator reversibility challenge?

An inhaled short-acting bronchodilator (such as 400 mcg of a SABA, like albuterol) is administered, and spirometry is repeated 10–15 minutes later