L61 Aging and Alzheimer's Disease Flashcards
define a homogenous population
populations where people are equally susceptible to injuries, diseases and death
*homogenous population LE = 50 yo
turns out, that the real population curve has a LE of about = 70 yo
why is there an increase in LE?
due to ↑medical care and public health
define healthy life expectancy
age where seriously debilitating disorders develop
usually 10yrs less than expected life expectancy; thus ppl suffer in their last 10 years
where are regions of highest and lowest LE?
western world - highest LE
africa - lowest LE
how does SES affect LE?
↑SES = longer lifespan ↓SES = shorter lifespan
what can we expect with an increase in LE?
incidence of dementia
expected to triples in the next 25 years!
what are included in the “list” of age specific impairments that older people are more susceptible to?
SENSORY
- Visual→ acuity, accommodation and macular degeneration
- Olfactory→ olfactory neuron loss and damage to olfactory epithelium
- Hearing→ loss of inner and outer hair cells and spiral ganglion cells
- Vestibular Apparatus→ degenerative changes at several sites
- Proprioceptors→ impairment seen particularly in lower limbs
MOTOR
- Muscle→ loss of mass and replacement with fat deposition
- Gait→ impairment of gait and postural stability
- Basal Ganglia→ Parkinsons, Huntingtons
- Cerebellum→ ataxia’s
COGNITIVE
- Dementias→ Alzheimer’s, Pick’s Disease
- Personality Disturbances
what does aging of the nervous system cause? What are the symptoms of brain aging?
infirmity
- Brain weight begins to decline past age-30
- Fall in neuronal size, dendritic arborization and number of synapses
- Gyri are smaller and sulci are larger and deeper as cells shrink
what does Aging of the nervous system cause?
-losses of function, postural control, gait, reflexes, vision, sleep, memory and general intelligence
what are the possible causes of dementia?
- cerebrovascular disease
- CNS infection
- Pernicious anemia – B12 deficiency
- Folic acid deficiency
- Wernicke-Korsakoff syndrome
- tumor
- trauma
- neurologic diseases like Huntington’s and Parkinson’s as well as MS
*The most common form of Dementia is Alzheimer’s Disease (dx in 1907) whose cause/origin is uncertain - >50% of dementias
what are the 3 cardinal signs of AD?
- neuritic senile plaques
- neurofibrillary tangles
- granulovacuolar degeneration
describe neuritic senile plaques
Extracellular spherical deposits containing many neuritic and glial processes with AMYLOID protein core
describe neurofibrillary tangles
Intracellular paired helical filaments
describe granulovacuolar degeneration
Degeneration caused by formation of intracellular circular clear zones of cytoplasm (vacuolation)
what brain structures are sentile neuritic plaques and neurofibrillary tangles often seen
Hippocampus (CA1) neocortex amygdala basal forebrain locus ceruleus raphe nuceus olfactory cortex
what brain structures are neuron loss most notable in?
hippocamps
entorhinal cortex
association cortexes
basal nucleus of Meynert
what neurons does the CNS exhibit selective losses in?
noradrenergic, dopaminergic and cholinergic
*limbic system also exhibits pathology
The central core of the neuritic plaques is made of ____ with surrounding parts of damaged neurons
amyloid β-protein
The APP (amyloid precursor protein) is located in the neuronal _____
cell membrane
what chromosome codes for APP?
chromosome 21
What happens to APP in Alzheimer’s brain compared to normal brains?
The APP should normally be cleaved by an α-secretase but in this case it is the β or γ-secretase (bad!)
what happens as a result of abnormal cleavage of APP like those seen in Alzheimer’s brains?
- Abnormal cleavage of APP results in releae of small peptides in to the ECF
- Cleavage done by β-secretase and γ-secretase causing the release of Aβ1-40
- These Aβ molecules aggregate to form these plaques containing axon terminals, migroglia and astrocytes
what proteins make up the neurofibrillary tangles?
Tau proteins
*Hyperphosphorylated tau proteins in degenerating neurons are the major constituent of these tangles
what is the normal function of Tau proteins?
form the MAP’s that assist in stabilization and axonal transport for microtubules thus found in high concentration in axons
Describe Parkinson’s disease
- Loss of neurons in the Substantia Nigra happens in the 6 to 8 decade
- Characterized by tremors at rest, akinesia, rigidity, emotional changes and lack of facial expression
- In addition to depigmentation substantia nigra, LEWY BODIES develop in associated areas including the Substantia nigra, pars compacta, locus ceruleus, basal nucleus of Meynert, raphe nuclei and cerebral cortex
describe Lewy Bodies - what they are made of, where they are found.
granules (10μm) made mostly of α-synuclein found in presynaptic terminals
describe Huntington’s disease
- Typically appears in 5th decade with cognitive and emotional disturbances proceeded by chorea
- Atrophy of frontal cortices, caudate nucleus and putamen and astrogliosis is evident
- Marked decreases in GABA and glutamic decarboxylase
Intranuclear and cytoplasmic inclusions/HUNTINGTIN; striatum; frontal cerebral cortex)*
Describe ALS
-Peaks incidence in 5th decade with intellectual capacity is being retained
-loss of anterior horn cells, motor nuclei of brainstem & UMN loss causing initial weakness in
hands/limbs
-Atrophy of motor neurons, gliosis and extensive loss of myelinated fibers in lateral Corticospinal tract
Bunina bodies/SOD1*
Describe Friedrich’s ataxia
- First or second decade, progressive limb an gait ataxia with retained intellectual capacity
- Loss of deep tendon reflexes and sensory axonal neuropathy
- Atrophy of dorsal column, Corticospinal tracts and spinocerebellar tracts
Describe Pick’s disease
- Onset of 4th/5th decade; early on presents like AD and may be clinically difficult to distinguish
- Fatal course within 10yrs;; ♀>♂ usually with behavioral disturbances and aphasia
- Cortical atrophy usually frontal/temporal and unilateral with marked astrogliosis
- Cytoplasmic inclusions known as Pick Bodies→ densly packed neurofilaments;; distinguishable from AD
***Tau + pick bodies
- Progressive supranuclear palsy: Neurofibrillary tangles / tau
- Corticobasal degeneration: Neurofibrillary tangles / tau
- Frontotemporal dementia: Neurofibrillary tangles / tau
*just because a person has neurofibrillary tangles, doesn’t mean that they will have AD
Describe Creuzfeld-Jakob Disease – Prion Disease
-Onset of 4th/5th decade but incubation of infectious protein (prion, PrP) may be 10-30yrs
-Fatal w/in 2yrs; three origins→ infection, sporadic or familial (mutation of PrP)
-Pts show dementia, motor weakness, ataxia, tremors, rigidity and myoclonus
-Neuronal loss, astrogliosis and cytoplasmic vacuoles in the cortex and basal ganglia (giving a
spongiform appearance)
what is clinically significant about chromosome 21?
- Amyloid gene that encodes the Aβ precursor→ Alzheimer’s Disease
- Trisomy 21 gives rise to Down’s Syndrome→ if they live past 40 will develop Alzheimer’s Disease
- link between AD and down syndrome!
what is the believe cause of new variant of Creutzfeldt-Jakob disease?
-Prion diseases caused by an infectious protein known as a Prion
-caused by eating contaminated beef
from a cow infected with a related animal prion disease known as bovine spongiform encephalopathy
Describe Progeria
- Rapid aging in children, evident by age 2 and death b/w 8-21 years of age from heart disease
- Gene mutation causes defective protein that normally holds nucleus and cell together
what is age also a risk factor in?
CVD and stroke
what are changes seen in AD brain structure?
- Early hippocampal atrophy
- Brain weight declines
- Somas, dendrites and number of synapses decline
- Gyri narrow; sulci, fissures, ventricles & cisterns enlarge
what chromosome and gene is associated with late onset AD (sporadic)?
chromosome 19 (ApoE/ApoE4)
what chromosomes and genes are associated with familial AD?
chromosome 1 - PSEN 2
chromosome 14 -PSEN 1
chromosome 21 - APP
what chromosome and gene is VERY early onset AD associated with?
chromosome 14 - PSEN 1
ABeta is ____ to cholinergic neurons
neurotoxic
What occurs with a gradual accumulation of soluble and insoluble Abeta peptides since Aβ is neurotoxic to cholinergic neurons
Cholinergic dysfunction
-diminished acetylcholine release
-impaired coupling of the muscarinic
acetylcholine receptors (mAChRs) to heterotrimeric GTP-binding proteins (G proteins).
Prions are also known to be involved with what other diseases?
- Kuru
- Fatal Familial Insomnia
- Scrapie in sheep
- BSE in cattle (“Mad cow disease”)
what happens with the conformation of the protein with PrPC –> PrPSc?
alpha helix to beta sheet!
