Dementia II Flashcards
AD definition
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
AD afflicts about _% in population over 65 yrs of age. It’s prevalence ____ every 5 yrs thereafter
5%, doubles
Etiologically only ___% AD are due to genetic abnormality and ___% sporadic
<10% AD are genetic and >90% sporadic
Gene defects (3) in AD
Beta-amyloid precursor protein gene; presenilin 1 gene ; presenilin 2 gene
Beta-amyloid precursor protein gene–chr #, age of onset, % of AD and implication
chr: 21
age of onset: 45-65 yrs
1% of all AD
causative
Presenilin 1 gene-chr #, age of onset, % of AD and implication
chr: 14
age of onset: 30-60 yrs
5-7% of all AD
causative
Presenilin 2 gene-chr #, age of onset, and implication
chr: 1
age of onset: 45-65 yrs
causative
Risk factors for AD
APOE4 allele, age, female gender, high mid-life cholesterol, head injury and stress
Average course of AD is __ years. Memory impairment is present ____
10 yrs; present at earliest stage of the the disease
Symptoms of AD
Access to distant memory is gradually lost.
Other losses include language, motor skills, orientation and judgment
Some patients show psychotic symptoms.
Late Stage AD
At late stages patients are often mute, incontinent and die of intercurrent illnesses
AD diagnosis based on
lacks a validated test or biological marker Diagnosis is based on - clinical histories - physical examination - neuropsychological tests
According to NINCDS-ADRDA criteria determine is AD is
Possible, Probable, Definite
likelihood that it is AD–confirmed with brain biopsy
DSM-IV-TR/NINCDS-ADRDA criteria divided AD into:
Preclinical, Prodromal, AD
Dementia markers in CSF used for diagnosis
Decrease A-beta, increased Tau and increased phospharylated Tau
Pet ligands used in AD diagnosis
11C-PIB, 18F-Florbetaben or 18F-AV-45 - A-beta deposition
AD is characterized neuropathologically by the presence of
- Intracellular neurofibrillary tangles
- Extracellular neuritic plaques
- Loss of neurons and synaptic density
- Cerebrovascular amyloid deposits
- brain atrophy
True/False: AD features can exist in healthy brains
TRUE
Features associated with AD are also observed in normal aged human brains but to a much lesser extent
NEUROFIBRILLARY TANGLES–what are they
NFTs are constitute paired helical and single straight filaments - made of phosphorylated tau protein - a microtubule associated protein
Tangle density correlates with dementia severity
NEUROFIBRILLARY TANGLES–where
Neurofibrillary tangles are present in cortex, amygdala, hippocampus and subcortical nuclei
Tau–types
six different isoforms
derived from a single gene which encodes proteins containing 352-441 a.a (different slicing –> different isoforms)
Tau’s role normally
Under normal conditions tau stabilizes microtubules by reversible phosphorylation and dephosphorylation mediated via protein kinases and phosphatases, respectively
Is tau phosphorylation bad?
Phosphorylated tau if not dephosphorylated
straight filaments –> PHF (paired helical filament)-Tau –> dysfunction
of neurons –> death of neurons
Tau pathologies
Apart from phosphorylation, cleavage of tau protein can also lead to neurodegeneration
Mutant tau transgenic mice leads to
tangles, loss of neurons and behavioral deficits
Tau may play a role in ____ of AD pathology
SPREADING
Neuritic plaques–defintion
Spherical, multicellular lesions containing A-beta peptides surrounded by dystrophic neurites, activated microglia and reactive astrocytes
Neuritic plaques life
Extracellular A-beta peptides deposited as diffuse plaques –> primitive plaques –> senile plaques –> burned out plaques
Diffuse plaques –unaffected areas
thalamus, striatum, cerebellum (unaffected areas)
Neuritic plaques–affected areas
cortex, hippocampus, subcortical nuclei – affected areas
T/F: Plaque density correlates to dementia severity
FALSE
Plaque density usually does not correlate
with dementia severity
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)
A-beta accumulation timeline
Intracellular A-beta accumulation precedes neurofibrillary tangles and extracellular A-beta deposition
APP is processed by 2 pathways
amyloidogenic pathway and non-amyloidogenic pathway
amyloidogenic pathway
amyloidogenic pathway mediated by beta- and gamma-secretases lead to the formation of A-beta peptides
non-amyloidogenic pathway
mediated by alpha-secretase
Does not form A-beta peptides (cleaved APP so A-beta protein is not intact)
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
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
AD neuronal loss occurred in
Neurons and synapses are lost in selected brain regions: cortex, hippocampus, amygdala and certain subcortical nuclei
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)
T/F: Loss of synaptic density correlates with dementia severity
True
Loss of basal forebrain cholinergic neurons leads to…
decrease of acetylcholine levels in the hippocampus and cortex – which correlate with dementia severity
Neuronal cell loss
Cause of cell loss is not known
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
amyloid cascade
Enhancing A-beta levels
Through oxidation, excitability, A-beta aggregation, inflammation, Tau hyperphosphorylation
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
Main FDA approved drugs for AD
i) AchE inhibitors
ii) Memantine (NMDAR antagonist)
AchE inhibitors for AD
ex. tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl)
increase acetylcholine level by blocking cholinesterase (AChE)
memantine for AD
NMDAR antag
neuroprotection and enhancement of learning and memory – can be used with AChE blockers
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
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
VaD prevalence ____ with age
increases
Risk factors for VaD
Age, hypertension, history of strokes, diabetes, smoking, APOE4 genotype
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
T/F: VaD often co-exists with other types of dementia
TRUE, includes AD, LBD
VaD clinical presentation varies with…
location of infarcts.
Executive dysfunction rather than memory loss is
prominent
VaD diagnosis based upon
family history, physical examinations,
cognitive tests and neuroimaging
Pathology of VaD
- Large vessel injury – multiple or single cortical/subcortical infarcts
- Small vessel injury – multiple subcortical and white matter lacunae/lesions
VaD treatment
- Stroke prevention - aspirin or warfarin
- Increasing acetylcholine levels - donepezil,
rivastigmine and galantamine - Neuroprotection - memantine, statins,
nimodipine, antioxidants
FTLD definition
a cluster of disorders characterized by the atrophy of the frontal and anterior temporal lobes.
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
FTLD is characterized by
apathy, loss of emotional control, loss of ability to recognize words/objects, language dysfunction and cognitive decline
FTLD diagnosis includes
physical exam,
neuropsychological tests, family
history and neuroimaging using MRI
and CT to evaluate brain atrophy
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
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)
Tau in FTLD
FTLD-Tau: hyperphosphorylated tau is deposited as paired helical and single straight filaments in neurons and glia
TDP in FTLD
FTLD-TDP: ubiquitin-conjugated, hyperphosphorylated TDP-43 (a nuclear protein) is deposited in nucleus, cytoplasm and neuritis of the neurons
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
Neurorestorative fators in AD
AD treatment includes neurotrophins, nutraceuticals, estrogens etc.
Goal: protect, rescue cell bodies
anti-inflammatory drugs in AD
ex. indomethacin
work by interfering with microglial response
antioxidants, free-radical scavengers in AD
ex. vitamin E, selegiline, red wine etc.
goal: protecting neurons against toxicity
Inhibitors of A-beta production in AD
ex. blockers of beta- or gamma-secretase
inhibit A-beta production
Vaccination using A-beta related peptide
Inject A-beta or anti-a-beta antibody
helps in animals, hasn’t worked in humans thus far
