Lectures 58, 60: Dementia and Alzheimer's

Question 1

No pathology/abnormal cognition

Answer 1

Cognitively frail aging

Question 2

Abundant pathology/normal cognition

Answer 2

Resilient aging

Question 3

Cognitive changes associated with normal aging (3)

Answer 3

Mild decline in memory, impaired prefrontal fxns, decreased fine motor coordination

Question 4

T/F: Normal aging due to neuronal death?

Answer 4

No!

Question 5

Mild Neurocognitive Disorder

Answer 5

Modest cog decline in 1+ domains but deficits do not interfere w/ capacity for ind.

Question 6

Mild Neurocognitive Disorder: % progress to dementia per year and % improve

Answer 6

10% progress per year; 30% improve

Question 7

Dementia (def)

Answer 7

Clinical syndrome marked by progressive cognitive impairment in clear consciousness

Question 8

DSM-V Major Neurocognitive Disorder Dx Criteria

Answer 8

Significant cognitive decline from a previous level of performance in 1 or more cognitive domains based on individual concern/informant and impaired performance

Question 9

Risk factors for dementia (5)

Answer 9

Age, female, vascular, env’t, genetics

Question 10

Resilience for dementia (9)

Answer 10

Education, social networks, cognitive stim activities, leisure activities, exercising, conscientiousness, male, statins, control vascular factors

Question 11

Why do we care about the behavioral/psychiatric symptoms of dementia?

Answer 11

Serious burden for caregivers and institution, associated with poor outcomes

Question 12

Three broad categories of dementia, an example of each, and symptoms

Answer 12

Cortical (AD: memory impairment, language deficits, apraxia, agnosia, and visuospatial deficits) vs Subcortical (PD: motor signs, recall, decreased verbal fluency without anomia, bradyphrenia, depressed mood, affective lability, apathy, and decreased attention/concentration) vs Mixed (Lewy body)

Question 13

List some of the varied etiologies of dementia and give an example of each (5)

Answer 13

Primary (AD), infections (HIV), vascular/traumatic (stroke), toxic-metabolic (B12), psychiatric (schizophrenia)

Question 14

MOST COMMON CAUSE OF DEMENTIA and %

Answer 14

Alzheimer’s Disease = 50-75%

Question 15

Age of onset of AD

Answer 15

Typically after 65

Question 16

AD consists of (dx criteria)…Death when?

Answer 16

Memory impairment + 1 other cognitive deficit; 8 - 10 years after sx onset

Question 17

Describe dementia with Lewy Bodies: 3 hallmarks and one way to distinguish from AD

Answer 17

1. Fluctuating cognition; 2. Visual hallucinations; 3. Spontaneous Parkinsoniasm; early frontal and visuospatial deficits before memory impairment

Question 18

Vascular dementia. Dx requires?

Answer 18

Cognitive decline caused by ischemic or hemorrhagic injury to the brain; focal neurological symptoms/imaging

Question 19

Etiology of vascular dementia (6)

Answer 19

Stroke, small vessel ischemic disease, hemorrhage, chronic hypoperfusion (i.e. lung disease), genetic conditions, cerebral amyloid angiopathy

Question 20

Frontotemporal dementias have a proclivity for…What protein? Death?

Answer 20

Young people (onset 45-65 years old); tau-opathy; 3-5 years to death

Question 21

Frontotemporal dementias associated with what symptoms?

Answer 21

Personality changes: disinhibition, executive dysfunction, frontal release sign, aphasia

Question 22

Balloon or Pick cells associated with…

Answer 22

FTD

Question 23

CJD is different from the other dementias why?

Answer 23

Very rapid (death 6-9 months from onset)

Question 24

Reversible causes of dementia (6)

Answer 24

Normal pressure hydrocephalus, thyroid dysfunction, dietary deficiencies, infection (syphilis), depression, tumor

Question 25

ADLs are...what's the other group called?

Answer 25

Basic (toilet); Instrumental Activities of Daily Living (IADLs)

Question 26

Describe delirium (what is it NOT and what is required?)

Answer 26

Acute, fluctuating disturbance of consciousness with reduced ability to focus, sustain or shift attention NOT better accounted for by established dementia CAUSED by a medical condition

Question 27

Everyone with delirium has...

Answer 27

Poor attention/vigilance

Question 28

Where is delirium common?

Answer 28

Hospitals

Question 29

T/F: Delirium often persists well after the precipitants have been successfully addressed and removed

Answer 29

True!

Question 30

What is a good reason to diagnose delirium quickly?

Answer 30

Late diagnoses = worse outcomes

Question 31

Description of gross and histo brain changes seen in normal aging

Answer 31

Widened sulci, larger ventricles that is greater in gray matter; loss of neurons, accumulation of lipofuscin pigment, more astrocytes, extra cellular plaques

Question 32

T/F: Can you ever see neurofibrillary tangles in normal brains?

Answer 32

True

Question 33

Four physiologic changes of normal aging

Answer 33

1. Increased MHC antigens in brain; 2. Reduced synaptic plasticity; 3. Decreased hippocampal neurogenesis; 4. Increased BBB permeability

Question 34

In 1907, these three characteristics of AD were described

Answer 34

Dementia, extracellular AB plaques and intracellular neurofibrillary tau tangles

Question 35

Tangled tau proteins are...

Answer 35

Hyperphosphorylated

Question 36

% of AD >80 years

Answer 36

35%

Question 37

Probable Alzheimer's disease is diagnosed if either...

Answer 37

1. Genetic testing; 2. Clear evidence of memory decline, progressive, no evidence of mixed etiology

Question 38

What do we have AD biomarkers for?

Answer 38

Amyloid beta deposition (low CSF AB42, PET amyloid) and Downstream neuronal injury (elevated CSF tau, PET, MRI of temporal atrophy)

Question 39

Biological factors for AD

Answer 39

Genetic alterations, abnormal immune, medical problems (diabetes, HT, obesity, depression)

Question 40

Environmental factors for AD

Answer 40

Traumatic injury, drugs, smoking, low education, low physical activity

Question 41

Gross brain changes in AD

Answer 41

Cerebral cortical atrophy (frontotemporal); dilation of LVs; hippocampal atrophy

Question 42

Microscopic changes in AD (3 + 3 "other")

Answer 42

Extracellular amyloid beta plaques; intracellular tau tangles; loss of hippocampal and cortical neurons, especially those involving diffuse cholinergic projections; other: synaptic loss, inflammation, oxidative stress

Question 43

What's interesting about tangles?

Answer 43

Correlated with cognitive decline and length of illness (plaques are not like that)

Question 44

Describe plaques (what's inside, what's outside)

Answer 44

Central core of Aβ4 protein that has a beta-pleated sheet configuration often surrounded by abnormal neurites

Question 45

Genetics of AD are associated with...

Answer 45

Autosomal dominant mutations in one of three genes that are involved in amyloid protein

Question 46

What's the most important genetic risk polymorphism factor for AD? Present in what % of AD patients? OR?

Answer 46

Abnormal ApoE gene (amyloid accumulation); 50%; 2 alleles, OR = 11

Question 47

What is the Amyloid Hypothesis? Why is this hypothesis challenged?

Answer 47

Deposition of Aβ peptides in cortex, especially Aβ42, initiates a pathogenic cascade which ultimately leads to synaptic dysfunction, neurodegeneration (tangles, cell death) and cognitive/functional decline; Plaque load (unlike tangles) does NOT predict cognitive status decline in AD

Question 48

What was the theory modification of the Amyloid Hypothesis

Answer 48

Pathological AB-oligomerization that leads to AD plaques (cannot be stained for) could be the actual problem

Question 49

T/F: It seems that AB42 is better than tau to predict AD development from minor impairment

Answer 49

False! Tau appears to be a better predictor. It is sensitive, but maybe not very specific

Question 50

Why are cortical-cortical circuits disrupted in AD? What does this disruption do?

Answer 50

Tangles and plaques thought to disrupt these circuits; breaks connection b/t association regions and hippocampus

Question 51

Evidence for cholinergic deficiency in AD

Answer 51

Degeneration of cholinergic projections; loss of cell bodies in nucleus basalis; reduced CAT (makes ACh); anticholinegic drugs --> memory problems

Question 52

AD Treatments and mechanism

Answer 52

ACHE inhib (donepezil, galantamiie, rivastigmine) and NMDA-receptor antagonist (memantine)

Question 53

Why would a NMDA-receptor antagonist work?

Answer 53

Blocks excitotoxic effects of excess glutamate at NMDA receptor

Question 54

Efficacy data for AD drugs (summary and what it does NOT do)

Answer 54

Small treatment effect sizes for cognitive function, activities of daily living and global assessment but does NOT modify disease course

Question 55

Anti-amyloid targets for AD therapy include (2)

Answer 55

Immunotherapy (vaccine) and anti-aggregants via enzyme activity

Question 56

Some other new targets for AD therapy are? (5)

Answer 56

Tau, cholinergic system, omega 3 fatty acids, inflammation, polyphenols (anti-oxidant)

Question 57

What's a simple statement behind diet/lifestyle prevention for AD?

Answer 57

Good for heart = good for head

Question 58

How would you distinguish cortical from subcortical dementia?

Answer 58

Cortical = memory impairment includes recognition and language impairment includes anomia; Subcortical = motor involvement, affective involvement (depression, lability)