1. Aging in the CNS

2. Normal age-related changes
Overall reduction in brain weight (20%)
Narrowing of gyri
Widening of sulci
Dilation of the ventricles
Widening of the subarachnoid space
Results from:
Atrophy of large neurons
Regression of dendritic tree
Reduction in dendritic spines
Loss of myelin
Leads to:
Mild to moderate memory impairments

3. Neuronal atrophy
No generalized loss of neurons, rather atrophy of large, selectively vulnerable neurons:
Pyramidal neurons in the entorhinal and neocortices
Pyramidal neurons in the CA1 and CA2 regions of the hippocampus
Vulnerability: Large neurons
High energy requirements
Large cell surface for exposure
to toxic conditions.
Cortical pyramidal neuron
Rhesus monkey

4. Dendritic atrophy Reduced dendritic tree complexity
- Decreased spine density
- Decreased excitatory input since excitatory synapses occur on spines
- Decreased synaptic plasticity and
sprouting
Dendritic spines

5. Loss of myelin
Myelination increase most rapidly during first five years of life, but continues into the 5th decade.
Demyelination/remyelination is always ongoing, but in later life, demyelination outpaces remyelination.
Ratio of gray to white matter is 1:28 in the young brain, declines to 1:13 by 7th decade.
Primary pathology of oligodendrocytes, not secondary to neuronal dysfunction.
Total brain myelin content
Bartzokis, et al., Neurobiol. Aging.

6. Myelin loss is most evident in the anterior regions of the brain
Genu
Splenium
Head, D.,et al., 2004, Cerebral Cortex, 14:410
Genu Splenium
Total brain myelin content
Bartzokis, et al., Neurobiol. Aging.

7. Loss of myelin correlates with cognitive impairment
Peters, A J. Neurocytol., 31:

8. Accumulation of pigments and oxidation products
Lipofuscin – Lipofuscin is a pigment which accumulates primarily
within neuronal cell bodies; composed of lipid-containing residues formed by oxidative degradation in lysosomes.
Oxidation products – Oxidative modification of DNA, proteins and lipids. Reactive oxygen species (e.g., hydroxyl radicals) inactivate enzymes and alter proteins leading to abnormal accumulation and aggregation. Exacerbated by malfunction in the proteosome and lysosomal degradative pathways.

9. Results in accelerated loss of neurons
Pathological aging
Genetic or environmental factors alter or accelerate underlying mechanisms of normal brain aging
Results in accelerated loss of neurons

10. ??? ???

11. Alzheimer’s disease Normal Normal aged
Estimated 5.3 million Americans have AD
Half of all demented patients have AD
Alzheimer’s
Impairments in memory, problem solving, judgment, visual-spatial perception, sometimes hallucinations and delusions.
Generalized shrinkage of the cortex and hippocampus; neuronal loss in those areas.
CT scans
Normal AD

12. Alzheimer’s disease Neuronal loss in areas of high cognition
and memory:
Neocortex (frontal and parietal)
Entorhinal cortex
Hippocampus
Nucleus basalis (of Meynert)
Normal
Alzheimer’s
Normal Alzheimer’s
Thangavel, et al., Neuroscience, 154:667, 2008.

13. Pathologies of protein aggregation
NFTs
SPs
Silver stain
Senile (amyloid) plaques (SP)
Aggregated beta amyloid protein
Neurofibrillary tangles (NFT)
Aggregated tau protein
Occur in very low numbers in normal, aged brain; prominent in Alzheimer’s disease in areas where neuronal loss occurs

14. Senile plaques (Amyloid plaques) Senile plaque
Beta amyloid
Senile plaque
Dystrophic
processes
Extracellular, spherical structures
Senile plaques consist of a core of beta-amyloid protein surrounded by degenerated neuronal processes, reactive astrocytes and microglia
Senile plaques are most commonly found in the cerebral cortex and hippocampus

15. Plaques mature and enlarge as beta-amyloid protein aggregates
The senile plaques are an end-stage cytopathology
Diffuse plaque Mature plaque

16. Imaging Alzheimer’s disease
Previously, definitive diagnosis required
autopsy findings of senile plaques
fluorodeoxyglucose
Pittsburg Compound-B (PIB)
Crosses blood brain barrier
Binds to amyloid core in the plaque
PET imaging
The severity of AD dementia does not necessarily correlate with “plaque-load”.
Klunk, WE et al., Ann. Neurol., 55(3): 306.

17. either involve the APP protein or the cleavage enzymes.
Mathis, et al., Nucl. Med. Biol.,34:809.
The majority of human gene mutations linked to early Alzheimer’s disease onset
either involve the APP protein or the cleavage enzymes.

18. Neurofibrillary tangles (NFTs)
H&E Silver
Large, intracellular, flame shaped masses of abnormal filaments in the cell body and base of large dendrites.
Prominent in large neurons in the hippocampus, the entorhinal cortex and other neocortical sites.
Composed of abnormally hyper- phosphorylated tau in helically
wound filaments.

19. Progression of neuropathology in normal aging and Alzheimer’s disease: a continuum?
Normal young
No pathologies
Normal aging
Plaques in cortex and hippocampus
NFT’s in entorhinal cortex
Mild cognitive impairment
Plaques and tangles increased
Mild neuronal loss in entorhinal cortex
Alzheimer’s disease
Plaques and tangles highly increased
Widespread neuronal cell loss
Extent of both correlate with dementia
Yankner, et al., Annu. Rev. Pathol. Mech. Dis., 3:41, 2008.

20. of Alzheimer’s disease pathogenesis
The amyloid theory
of Alzheimer’s disease pathogenesis

21. Nucleus basalis (of Meynert)
Major cholinergic input to the cortex, neuromodulatory action.
Pharmacological basis for the main FDA approved treatment of AD, inhibitors of acetylcholinesterase (Aricept)
Cognitive function declines as the levels of acetylcholine (ACh) decline due to the loss of neurons in the basal forebrain. By inhibiting the breakdown of the remaining ACh by AChE, cognition is improved.