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PMCOL 412 > Dementia II > Flashcards

Dementia II Flashcards

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1
Q

AD definition

A

the prevalent cause of dementia in the elderly. It is a progressive neurodegenerative disorder characterized by gradual loss of memory followed by deterioration of higher cognitive functions

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2
Q

AD afflicts about _% in population over 65 yrs of age. It’s prevalence ____ every 5 yrs thereafter

A

5%, doubles

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3
Q

Etiologically only ___% AD are due to genetic abnormality and ___% sporadic

A

<10% AD are genetic and >90% sporadic

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4
Q

Gene defects (3) in AD

A

Beta-amyloid precursor protein gene; presenilin 1 gene ; presenilin 2 gene

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5
Q

Beta-amyloid precursor protein gene–chr #, age of onset, % of AD and implication

A

chr: 21
age of onset: 45-65 yrs
1% of all AD
causative

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6
Q

Presenilin 1 gene-chr #, age of onset, % of AD and implication

A

chr: 14
age of onset: 30-60 yrs
5-7% of all AD
causative

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7
Q

Presenilin 2 gene-chr #, age of onset, and implication

A

chr: 1
age of onset: 45-65 yrs
causative

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8
Q

Risk factors for AD

A

APOE4 allele, age, female gender, high mid-life cholesterol, head injury and stress

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9
Q

Average course of AD is __ years. Memory impairment is present ____

A

10 yrs; present at earliest stage of the the disease

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10
Q

Symptoms of AD

A

Access to distant memory is gradually lost.
Other losses include language, motor skills, orientation and judgment
Some patients show psychotic symptoms.

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11
Q

Late Stage AD

A

At late stages patients are often mute, incontinent and die of intercurrent illnesses

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12
Q

AD diagnosis based on

A 
lacks a validated test or biological marker
Diagnosis is based on
- clinical histories
- physical examination
- neuropsychological tests
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13
Q

According to NINCDS-ADRDA criteria determine is AD is

A

Possible, Probable, Definite

likelihood that it is AD–confirmed with brain biopsy

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14
Q

DSM-IV-TR/NINCDS-ADRDA criteria divided AD into:

A

Preclinical, Prodromal, AD

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15
Q

Dementia markers in CSF used for diagnosis

A

Decrease A-beta, increased Tau and increased phospharylated Tau

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16
Q

Pet ligands used in AD diagnosis

A

11C-PIB, 18F-Florbetaben or 18F-AV-45 - A-beta deposition

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17
Q

AD is characterized neuropathologically by the presence of

A
  • Intracellular neurofibrillary tangles
  • Extracellular neuritic plaques
  • Loss of neurons and synaptic density
  • Cerebrovascular amyloid deposits
  • brain atrophy
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18
Q

True/False: AD features can exist in healthy brains

A

TRUE

Features associated with AD are also observed in normal aged human brains but to a much lesser extent

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19
Q

NEUROFIBRILLARY TANGLES–what are they

A

NFTs are constitute paired helical and single straight filaments - made of phosphorylated tau protein - a microtubule associated protein

Tangle density correlates with dementia severity

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20
Q

NEUROFIBRILLARY TANGLES–where

A

Neurofibrillary tangles are present in cortex, amygdala, hippocampus and subcortical nuclei

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21
Q

Tau–types

A

six different isoforms

derived from a single gene which encodes proteins containing 352-441 a.a (different slicing –> different isoforms)

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22
Q

Tau’s role normally

A

Under normal conditions tau stabilizes microtubules by reversible phosphorylation and dephosphorylation mediated via protein kinases and phosphatases, respectively

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23
Q

Is tau phosphorylation bad?

A

Phosphorylated tau if not dephosphorylated
straight filaments –> PHF (paired helical filament)-Tau –> dysfunction
of neurons –> death of neurons

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24
Q

Tau pathologies

A

Apart from phosphorylation, cleavage of tau protein can also lead to neurodegeneration

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25
Mutant tau transgenic mice leads to
tangles, loss of neurons and behavioral deficits
26
Tau may play a role in ____ of AD pathology
SPREADING
27
Neuritic plaques--defintion
Spherical, multicellular lesions containing A-beta peptides surrounded by dystrophic neurites, activated microglia and reactive astrocytes
28
Neuritic plaques life
Extracellular A-beta peptides deposited as diffuse plaques --> primitive plaques –> senile plaques --> burned out plaques
29
Diffuse plaques --unaffected areas
thalamus, striatum, cerebellum (unaffected areas)
30
Neuritic plaques--affected areas
cortex, hippocampus, subcortical nuclei – affected areas
31
T/F: Plaque density correlates to dementia severity
FALSE Plaque density usually does not correlate with dementia severity
32
A-beta peptide makes up
The principal component of all plaques is a 39-43 a.a. A-beta peptide - generated from Amyloid Precursor Protein (APP)
33
A-beta accumulation timeline
Intracellular A-beta accumulation precedes neurofibrillary tangles and extracellular A-beta deposition
34
APP is processed by 2 pathways
amyloidogenic pathway and non-amyloidogenic pathway
35
amyloidogenic pathway
amyloidogenic pathway mediated by beta- and gamma-secretases lead to the formation of A-beta peptides
36
non-amyloidogenic pathway
mediated by alpha-secretase | Does not form A-beta peptides (cleaved APP so A-beta protein is not intact)
37
A-beta peptide contributions to AD pathology
i) APP/PS mutations lead to AD pathology by increasing Aβ production ii) intracellular A-beta accumulation precedes other lesions iii) A-beta peptides are toxic to neurons iv) APP transgenic mice recapitulate some features of AD
38
Familial vs. Sporadic AD
Familial AD cases are caused by increased production of A-beta peptide, whereas sporadic AD cases are caused by decreased clearance of A-beta
39
AD neuronal loss occurred in
Neurons and synapses are lost in selected brain regions: cortex, hippocampus, amygdala and certain subcortical nuclei
40
Subcortical neurons affected in AD brains:
- Forebrain cholinergic neurons (30-95%) - Noradrenergic neurons of locus ceruleus - (40-80%) - Serotonin neurons of dorsal raphe - (0-39%) - Glutamatergic neurons - (severe loss)
41
T/F: Loss of synaptic density correlates with dementia severity
True
42
Loss of basal forebrain cholinergic neurons leads to...
decrease of acetylcholine levels in the hippocampus and cortex – which correlate with dementia severity
43
Neuronal cell loss
Cause of cell loss is not known
44
AD pathologies in familial cases
at least for familial cases, is caused by amyloid cascade hypothesis i.e., increased production and/or lack of clearance can lead to AD pathology by enhancing A-beta levels --> neuronal death --> decreased levels of NTs --> cognitive deficits
45
amyloid cascade
Enhancing A-beta levels | Through oxidation, excitability, A-beta aggregation, inflammation, Tau hyperphosphorylation
46
T/F: AD drugs only provide symptomatic relief for AD patients
TRUE At present there is no cure for AD Available treatment provides symptomatic relief for a fraction of AD patients
47
Main FDA approved drugs for AD
i) AchE inhibitors | ii) Memantine (NMDAR antagonist)
48
AchE inhibitors for AD
ex. tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) increase acetylcholine level by blocking cholinesterase (AChE)
49
memantine for AD
NMDAR antag | neuroprotection and enhancement of learning and memory – can be used with AChE blockers
50
Other AD treatments under investigation
- neurorestorative factors - neurotrophins, nutraceuticals, estrogens etc. - anti-inflammatory drugs - indomethacin - antioxidants, free-radical scavengers - vitamin E, selegiline, red wine etc. - inhibitors of A-beta production - blockers of beta- or gamma-secretases - vaccination using A-beta-related peptide
51
VaD is caused by
caused by reduce or blockage of blood supply to the different parts of the brain, thus depriving them of oxygen and nutrients
52
VaD prevalence ____ with age
increases
53
Risk factors for VaD
Age, hypertension, history of strokes, diabetes, smoking, APOE4 genotype
54
Etiology of VaD
most cases are sporadic, whereas <1% are believed to be heritable: - CADASIL: caused by mutations in NOTCH3 gene - FCAA: caused by mutations in the APP, CST3 (Cystatin 3) and ITM2B (Integral membrane protein 2) genes
55
T/F: VaD often co-exists with other types of dementia
TRUE, includes AD, LBD
56
VaD clinical presentation varies with...
location of infarcts. Executive dysfunction rather than memory loss is prominent
57
VaD diagnosis based upon
family history, physical examinations, | cognitive tests and neuroimaging
58
Pathology of VaD
- Large vessel injury – multiple or single cortical/subcortical infarcts - Small vessel injury – multiple subcortical and white matter lacunae/lesions
59
VaD treatment
- Stroke prevention - aspirin or warfarin - Increasing acetylcholine levels - donepezil, rivastigmine and galantamine - Neuroprotection - memantine, statins, nimodipine, antioxidants
60
FTLD definition
a cluster of disorders characterized by the atrophy of the frontal and anterior temporal lobes.
61
FTLD's 2 subtypes
a) behavioral and personality changes: includes i) fronto-temporal dementia and ii) Pick’s disease b) language or communication changes: includes i) primary progressive aphasia and ii) semantic dementia
62
FTLD is characterized by
apathy, loss of emotional control, loss of ability to recognize words/objects, language dysfunction and cognitive decline
63
FTLD diagnosis includes
physical exam, neuropsychological tests, family history and neuroimaging using MRI and CT to evaluate brain atrophy
64
The majority of FTLD is caused by mutations of...
Tau and PGRN (progranulin) genes. | Others include CHMP2B (charged multivesicular body protein 2B), VCP (valosin containing protein) and c9orf72
65
Neuropathology of FTLD
the disease is characterized by atrophy of frontal and | temporal lobes, neuronal loss, gliosis, inclusions of proteins such as tau or TAR-DNA binding protein-43 (TDP-43)
66
Tau in FTLD
FTLD-Tau: hyperphosphorylated tau is deposited as paired helical and single straight filaments in neurons and glia
67
TDP in FTLD
FTLD-TDP: ubiquitin-conjugated, hyperphosphorylated TDP-43 (a nuclear protein) is deposited in nucleus, cytoplasm and neuritis of the neurons
68
Tretaments of FTLD
Not promising Drugs used: - peroxetine (SSRI) to reduce behavioral symptoms - selegeline (MAOB inhibitor) to decrease agitation, aggressiveness and improve executive function anticholinergic, NMDAR inhib do not work here
69
Neurorestorative fators in AD
AD treatment includes neurotrophins, nutraceuticals, estrogens etc. Goal: protect, rescue cell bodies
70
anti-inflammatory drugs in AD
ex. indomethacin | work by interfering with microglial response
71
antioxidants, free-radical scavengers in AD
ex. vitamin E, selegiline, red wine etc. | goal: protecting neurons against toxicity
72
Inhibitors of A-beta production in AD
ex. blockers of beta- or gamma-secretase | inhibit A-beta production
73
Vaccination using A-beta related peptide
Inject A-beta or anti-a-beta antibody | helps in animals, hasn't worked in humans thus far

PMCOL 412 (35 decks)

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