Lectures 58, 60: Dementia and Alzheimer's Flashcards
No pathology/abnormal cognition
Cognitively frail aging
Abundant pathology/normal cognition
Resilient aging
Cognitive changes associated with normal aging (3)
Mild decline in memory, impaired prefrontal fxns, decreased fine motor coordination
T/F: Normal aging due to neuronal death?
No!
Mild Neurocognitive Disorder
Modest cog decline in 1+ domains but deficits do not interfere w/ capacity for ind.
Mild Neurocognitive Disorder: % progress to dementia per year and % improve
10% progress per year; 30% improve
Dementia (def)
Clinical syndrome marked by progressive cognitive impairment in clear consciousness
DSM-V Major Neurocognitive Disorder Dx Criteria
Significant cognitive decline from a previous level of performance in 1 or more cognitive domains based on individual concern/informant and impaired performance
Risk factors for dementia (5)
Age, female, vascular, env’t, genetics
Resilience for dementia (9)
Education, social networks, cognitive stim activities, leisure activities, exercising, conscientiousness, male, statins, control vascular factors
Why do we care about the behavioral/psychiatric symptoms of dementia?
Serious burden for caregivers and institution, associated with poor outcomes
Three broad categories of dementia, an example of each, and symptoms
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)
List some of the varied etiologies of dementia and give an example of each (5)
Primary (AD), infections (HIV), vascular/traumatic (stroke), toxic-metabolic (B12), psychiatric (schizophrenia)
MOST COMMON CAUSE OF DEMENTIA and %
Alzheimer’s Disease = 50-75%
Age of onset of AD
Typically after 65
AD consists of (dx criteria)…Death when?
Memory impairment + 1 other cognitive deficit; 8 - 10 years after sx onset
Describe dementia with Lewy Bodies: 3 hallmarks and one way to distinguish from AD
- Fluctuating cognition; 2. Visual hallucinations; 3. Spontaneous Parkinsoniasm; early frontal and visuospatial deficits before memory impairment
Vascular dementia. Dx requires?
Cognitive decline caused by ischemic or hemorrhagic injury to the brain; focal neurological symptoms/imaging
Etiology of vascular dementia (6)
Stroke, small vessel ischemic disease, hemorrhage, chronic hypoperfusion (i.e. lung disease), genetic conditions, cerebral amyloid angiopathy
Frontotemporal dementias have a proclivity for…What protein? Death?
Young people (onset 45-65 years old); tau-opathy; 3-5 years to death
Frontotemporal dementias associated with what symptoms?
Personality changes: disinhibition, executive dysfunction, frontal release sign, aphasia
Balloon or Pick cells associated with…
FTD
CJD is different from the other dementias why?
Very rapid (death 6-9 months from onset)
Reversible causes of dementia (6)
Normal pressure hydrocephalus, thyroid dysfunction, dietary deficiencies, infection (syphilis), depression, tumor
ADLs are…what’s the other group called?
Basic (toilet); Instrumental Activities of Daily Living (IADLs)
Describe delirium (what is it NOT and what is required?)
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
Everyone with delirium has…
Poor attention/vigilance
Where is delirium common?
Hospitals
T/F: Delirium often persists well after the precipitants have been successfully addressed and removed
True!
What is a good reason to diagnose delirium quickly?
Late diagnoses = worse outcomes
Description of gross and histo brain changes seen in normal aging
Widened sulci, larger ventricles that is greater in gray matter; loss of neurons, accumulation of lipofuscin pigment, more astrocytes, extra cellular plaques
T/F: Can you ever see neurofibrillary tangles in normal brains?
True
Four physiologic changes of normal aging
- Increased MHC antigens in brain; 2. Reduced synaptic plasticity; 3. Decreased hippocampal neurogenesis; 4. Increased BBB permeability
In 1907, these three characteristics of AD were described
Dementia, extracellular AB plaques and intracellular neurofibrillary tau tangles
Tangled tau proteins are…
Hyperphosphorylated
% of AD >80 years
35%
Probable Alzheimer’s disease is diagnosed if either…
- Genetic testing; 2. Clear evidence of memory decline, progressive, no evidence of mixed etiology
What do we have AD biomarkers for?
Amyloid beta deposition (low CSF AB42, PET amyloid) and Downstream neuronal injury (elevated CSF tau, PET, MRI of temporal atrophy)
Biological factors for AD
Genetic alterations, abnormal immune, medical problems (diabetes, HT, obesity, depression)
Environmental factors for AD
Traumatic injury, drugs, smoking, low education, low physical activity
Gross brain changes in AD
Cerebral cortical atrophy (frontotemporal); dilation of LVs; hippocampal atrophy
Microscopic changes in AD (3 + 3 “other”)
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
What’s interesting about tangles?
Correlated with cognitive decline and length of illness (plaques are not like that)
Describe plaques (what’s inside, what’s outside)
Central core of Aβ4 protein that has a beta-pleated sheet configuration often surrounded by abnormal neurites
Genetics of AD are associated with…
Autosomal dominant mutations in one of three genes that are involved in amyloid protein
What’s the most important genetic risk polymorphism factor for AD? Present in what % of AD patients? OR?
Abnormal ApoE gene (amyloid accumulation); 50%; 2 alleles, OR = 11
What is the Amyloid Hypothesis? Why is this hypothesis challenged?
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
What was the theory modification of the Amyloid Hypothesis
Pathological AB-oligomerization that leads to AD plaques (cannot be stained for) could be the actual problem
T/F: It seems that AB42 is better than tau to predict AD development from minor impairment
False! Tau appears to be a better predictor. It is sensitive, but maybe not very specific
Why are cortical-cortical circuits disrupted in AD? What does this disruption do?
Tangles and plaques thought to disrupt these circuits; breaks connection b/t association regions and hippocampus
Evidence for cholinergic deficiency in AD
Degeneration of cholinergic projections; loss of cell bodies in nucleus basalis; reduced CAT (makes ACh); anticholinegic drugs –> memory problems
AD Treatments and mechanism
ACHE inhib (donepezil, galantamiie, rivastigmine) and NMDA-receptor antagonist (memantine)
Why would a NMDA-receptor antagonist work?
Blocks excitotoxic effects of excess glutamate at NMDA receptor
Efficacy data for AD drugs (summary and what it does NOT do)
Small treatment effect sizes for cognitive function, activities of daily living and global assessment but does NOT modify disease course
Anti-amyloid targets for AD therapy include (2)
Immunotherapy (vaccine) and anti-aggregants via enzyme activity
Some other new targets for AD therapy are? (5)
Tau, cholinergic system, omega 3 fatty acids, inflammation, polyphenols (anti-oxidant)
What’s a simple statement behind diet/lifestyle prevention for AD?
Good for heart = good for head
How would you distinguish cortical from subcortical dementia?
Cortical = memory impairment includes recognition and language impairment includes anomia; Subcortical = motor involvement, affective involvement (depression, lability)
