Pathophysiology II - Exam 4 - Dementia 💭

what is dementia?

a syndrome of progressive memory loss with 1+ cognitive deficit that interferes with occupation or social functioning

- common, but NOT normal!

what is the most common cause of dementia in older adults?

Alzheimer's disease

- 8-10 year survival after being diagnosed with AD

one of the common etiologies of Alzheimer's (AD) is an alteration in chromosomes; which chromosomes are affected, and how do these alterations cause disease?

chromosomes 1, 14, and 21; impact the processing of amyloid precursor proteins (APP: α, β, and γ-secretase to β-amyloid proteins)

--- α-secretase: responsible for non-pathologic fragments

--- alterations in β or γ-secretase may result in pathological fragments

one of the common etiologies of Alzheimer's (AD) is apolipoprotein E (APOE); which subtype is the biggest risk?

APOE4

- 1 allele: 2-3x risk of AD

- 2 alleles: 12x risk of AD

- risk of earlier onset AD

what are some environmental risk factors of AD?

- age (65+ yo)

- reduced brain reserve capacity (developmental disability)

- head injury (CTE, boxers, football players, etc.)

- Down's syndrome

- depression

- mild cognitive impairment

- risk for vascular disease (obesity, HTN, hyperlipidemia, etc.)

what are the common microscopic features observed with AD?

- neurofibrillary tangles (NFTs)

- amyloid plaques (drug target!)

what changes to brain structure and neurons are observed with AD?

cortical atrophy and loss of neurons

- parietal and temporal lobes

- ventricular enlargement → hydrocephalus

what neurochemical changes are observed with AD?

decreased choline acetyltransferase

what are amyloid plaques? describe the amyloid cascade hypothesis of AD

patches of degenerating nerve terminals around a core of β-amyloid protein (Aβ)

- EC lesions found in the brain and cerebral vasculature

- form due to an imbalance between Aβ production and clearance, leading to accumulation of the proteins

- it is unknown if Aβ inside or outside of plaques is responsible for pathogenesis!

what are neurofibrillary tangles (NFTs)? what protein is involved in formation?

abnormal fibrous inclusions within pyramidal neurons

- found in the cytoplasm of cells in the hippocampus and cerebral cortex

- NFT density correlates with disease severity

- caused by Tau Proteins, which normally support microtubules in neurons

--- if hyper-phosphorylated, it loses its helical pattern and can no longer bind to the microtubules, leading to their collapse

what are the 3 primary locations in which plaques and tangles are found in AD?

- neocortex → part of the cerebral cortex

- hippocampus → part of the limbic system within the temporal lobe

- amygdala → located within the temporal lobe

what are the neocortex, hippocampus, and amygdala responsible for in the brain?

- neocortex → sensory perception, language, motor commands, spatial reasoning

- hippocampus → short-term memory, spatial reasoning

- amygdala → memory, emotional processing

how might inflammatory mediators play a role in the pathophysiology of AD?

amyloid deposition is associated with the release of cytokines and radical species, which may increase inflammation and promote neuronal injury

what are the 2 main components of the cholinergic hypothesis of AD?

- many neuronal paths are destroyed → prominent loss of cholinergic neurons; correlated with severity

- loss of nicotinic R's in the hippocampus and cortex → presynaptic R's control the release of ACh, glutamate, 5-HT, and NE

what changes are observed in NT's like 5-HT neurons, MAO type B, and glutamate in the brains of AD patients?

- decreased 5-HT neurons

- increased MAO type B → metabolizes DA

- abnormal glutamate → excitatory NT that can become neurotoxic through the release of IC Ca2+; altered by blockage of NMDA R

what conditions are associated with an increased risk of vascular dementia?

- HTN

- DM → associated with metabolic syndrome, toxic glucose metabolites, and disturbances in insulin signaling

- increased LDL, decreased HDL

how might vascular disease lead to dementia?

the lack of healthy brain tissue and adequate blood flow may...

- impair the delivery of nutrients

- reduce clearance of Aβ

how might oxidative stress, mitochondrial dysfunction, and loss of estrogen lead to dementia?

- oxidative stress → accumulation of free radicals

- mitochondrial dysfunction → disruption of neuronal energy metabolism

- loss of estrogen → postmenopausal women are at a higher risk; estrogen supports neuronal growth!

T/F: the onset of AD dementia is rapid, over days-weeks

FALSE

- onset is gradual; it can take years to realize the cognitive changes

- patients can compensate for minor changes for some time

- however, some patients progress faster than others

list some of the cognitive manifestations of AD dementia

- memory loss (recall, loss of items; short-term degrades before long-term)

- aphasia (loss of ability to understand or express speech)

- apraxia (unable to perform tasks or movements when asked)

- agnosia (can't recognize and identify objects, persons, or sounds)

- disorientation and inadaptability (don't do well in new environments!)

- impaired executive function

list some of the behavioral manifestations of AD dementia

- insomnia and sun-downing (worsens at night)

- wandering, falling

- inability to perform ADLs

- inappropriate social behavior

- emotion lability and depression

- restlessness, agitation

- aggressiveness and catastrophic reactions

- diminished driving skills

- delusion, hallucinations

- incontinence

- gait disturbances, immobility

- indifferences to food

- inability to communicate

what is the primary evidence of cognitive decline? what is explicitly excluded?

complex attention, executive function, learning/memory, language, perceptual-motor, or social cognition

- deficits interfere with independence in ADLs/IADLs

- delirium is EXCLUDED!

AD dementia is primarily a ____________ diagnosis

clinical Dx

- mostly reliant on memory complaints and functional disability, often provided by family/caregivers

what must be ruled out when assessing a patient for AD dementia?

- depression

- vitamin B12 and folate deficiency

- hyper-/hypo-thyroidism

- neuro-syphillis

- HIV

- anemia

- renal and hepatic dysfunction

- electrolyte imbalance

AD dementia diagnoses can be confirmed via...?

- brain biopsy (AFTER patient has passed)

- in vivo plaque detection

what are the 3 main scales used for assessment of AD dementia patients? which is the only one used more in clinical practice than in research (starred)?

- global deterioration scale (GDS; shows the stages of cognitive decline)

- Alzheimer's disease assessment scale (ADAS-cog)

- ★Folstein mini-mental status exam (MMSE; staging is mild, moderate, or severe)

what MMSE scores classify a patient as mild, moderate, or severe? what characteristics are often observed in patients under each classification?

MILD: score 26-21

- decline is IADLs

- difficulty remembering recent events

MODERATE: score 20-10

- requires help with ADLs

- disoriented, agitated, paranoid

- forgets details of their own life and names of family members

SEVERE: score 9-0

- lost ability to speak, walk, and feed themselves

- incontinent, requires 24-hour care (may also be needed in moderate patients)

what medications are associated with cognitive impairment?

- benzodiazepines (ex: alprazolam)

- sedative hypnotics (ex: zolpidem)

- anticholinergics (ex: diphenhydramine)

- opioids (ex: morphine)

- antipsychotics

- anticonvulsants

what medications are associated with delirium?

- NSAIDs

- H2RA

- digoxin

- amiodarone

- steroids

what type of dementia accounts for 20-25% of dementias and is associated with HTN, DM, MI, and PVD? describe its onset and physical findings

vascular dementia

- onset can be sudden OR gradual

- NOT associated directly with atherosclerosis, but with infarcts throughout the brain

- infarcts may appear on CT scans

what is frontotemporal dementia? how does it often manifest?

global term for dementias that attack the frontal lobe

- may manifest as behavioral or personality changes

what is mild cognitive impairment (MCI)?

syndrome of memory complaints that can NOT be diagnosed as a dementia

- no trouble with ADLs, no behavioral changes, etc.

- 10-15% chance per year of progressing to AD