Aging in the CNS

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

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

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

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., 2008. Neurobiol. Aging.

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., 2008. Neurobiol. Aging.

Loss of myelin correlates with cognitive impairment Peters, A. 2002. J. Neurocytol., 31:581-593

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.

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

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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

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. http://library.med.utah.edu

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

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

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

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., 2004. Ann. Neurol., 55(3): 306.

either involve the APP protein or the cleavage enzymes. Mathis, et al., 2007. 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.

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.

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.

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

Nucleus basalis (of Meynert) http://library.med.utah.edu 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.