6. Normal Aging of the Brain/Alzheimer’s Disease
- Pre-Natal: Most neurons are
generated pre-natally (second trimester)
- Post-Natal: 50-70% of
neurons (and synapses) die
- Spine maturation: thin à stubby, mushroom-shaped
- third
trimester to first two years: brain growth spurt due to:
1. increase in
neuron size
2. elaboration of
dendritic processes
3. myelination
4. increase in
number and size of glial cells
I. Alzheimer’s Disease =
pre-senile dementia
- progressive
mental deterioration
- < 65 yo
- most
common neurological disease in the
- most
common cause of death due to AD:
1. Aspiration subsequent to pneumonia
2. cerebral
hemorrhage
Gross Changes: Global cortical atrophy: narrowing of gyri, widening of sulci,
compensatory ventricular dilation
·
atrophy is most
pronounced in non-primary motor and sensory areas (higher order, association
areas) of the frontal and temporal lobes
·
many of these
areas are limbic (pre-frontal)
Number of Neurons: Loss is not uniform; Greatest
in following 6 areas;
Cortex |
1. Neo-cortex |
ACh |
Limbic System |
2. Hippocampus |
|
3. Amygdala |
|
|
Reticular formation |
4. Nucleus basalis of Meynert |
ACh |
5. Nucleus Locus Coeruleus |
NE |
|
6. Raphe
Nuclei |
5HT |
1.
Neo-cortex
a.
higher order,
association areas
b.
interneurons (ACh)
c.
Area 28 (entorhinal cortex: memory/smell): first area to show
neuronal loss
2.
Hippocampus
- temporal lobe, learning, memory (autobiography), limbic
3.
Amygdala
-
learned fear, other emotional behaviour, limbic
4.
Nucleus basalis of Meynert
- inferior to basal ganglia, basal forebrain
- part of reticular formation
- projects to cortex without relay in thalamus
-
reward system (ACh)
5.
Nucleus Locus Coeruleus
-
located in pontine reticular formation
- neurons contain melanin
- NE
functions:
a.
regulation of
cerebral blood flow
b.
selective
attention
c.
sleep/wake cycles
and REM (decreased psychological integrity)
6.
Raphe Nuclei
- midline of medulla, pons, and midbrain reticular formation
-
5HT
-
relays to frontal lobe without
relay in thalamus
Changes in Neuron Cell
Bodies
-
decreased stain in
general (reduction in RNA)
-
silver stain
reveals NFTs (neurofibrillary
tangles): tau protein
Presence of Neuritic or Senile Plaques
-
found in areas of neuropil
-
diagnosis on the
basis of plaques/view/age
Other Changes
-
decreased number
of spines
-
synapse loss
-
amyloid deposits in brain blood vessels
Behavioural Changes
Early
-
slight memory loss
-
decrease in initative
-
depression
-
faulty judgment
Later
-
memory loss à long-term and short-term
-
inability to
understand jokes, cartoons
-
sundowning (diurnal variations)
-
severe anxiety,
fear, agitation, hallucinations, hypersexuality
Late
-
Severe memory loss
(forget self)
-
paranoid and
irrational
-
severe language
deficits
-
incontinence, cachectic
Diagnosis and Prognosis
-
no cure, attempts
to increase ACh, NMDA antagonist
-
MMSE, MRI
(glucose)
-
cortical biopsy: NFT’s and plaques
o
only found in a
few other disorders (Down’s, postencephalitic
Parkinson’s, boxers, toxins)
Genetics
-
familial < 10%
-
association with
Down’s, blood and lymphatic cancers
-
Chromosome 21: beta-amyloid precursor protein (normal and neurotropic
in low concentrations, neurotoxic in higher
concentrations)
-
HCHWA-Dutch (amyloidosis in
brain) do not have higher AD rates
-
Chromosome 13: presenilin 1 gene
-
Chromosome 1: presenilin 2 gene
-
Chromosome 19;
-
Chromosome 14: most familial
forms
Other possible etiologies
1.
Autoimmune
2.
Infectious agent
(1917 flu)
a.
supported by other
infections à amyloid:
i.
scrapie
ii.
Jakob-Creutzfeldt
iii.
Kuru
3.
Trauma
4.
Toxins (zinc,
aluminum)
a.
Aluminum (dialysis
dementia from renal dialysis): cause/effect?; may à mild cognitive
impairment (risk factor)
5.
E4 allele (ApoE): especially E4/E4 (binds beta amyloid)
Increased risk
1.
head injury
2.
high
fat/cholesterol
3.
depression
4.
hormone
replacement therapy
5.
Mild cognitive
impairment
Protective
1.
E2 allele:
especially E2/E2 (favours tau
stability)
2.
Continuing mental
challenge
3.
Vitamin E and
NSAIDS
4.
omega-3 fats
statins