Aging of the Central Nervous System

• Aging of the nervous system includes the central and peripheral nervous systems.
• Aging is present from birth, is a gradual and insidious evolving process, and is a normal process.

Aging of the Central Nervous System (CNS)

• It can be difficult to distinguish normal aging from pathological conditions like dementia, especially senile dementia.
• The rate and extent of chemical and physical changes in the brain, including their effects on intellectual capacity, varies considerably between individuals.
• Multiple mechanisms of cerebral senescence exist.

CNS Macroscopic Modifications

• A key question is whether normal aging involves cerebral atrophy and neuronal loss.
• Cortical and subcortical atrophy occurs with an increase in ventricular space.
• There is dilation of the Virchow-Robin spaces, and a loss of white and gray matter.
• Structures preferentially affected include the frontal lobes, hippocampus, and temporal lobes.
• There is physiological reduction in cerebral volume of the cortex at a rate of 3 cm³/year, leading to widening of the sulci and a decrease in cortex thickness.
• The volume of white matter decreases at a rate of 3 cm³/year, leading to enlargement of the ventricles.
• These changes are visible in people 50+ years, usually after 60 years, but are inconsistent; they represent a visually harmonious phenomenon linked to age.
• It's imprecise to diagnose normal vs. pathological atrophy based solely on imaging.
• Dementia subjects has more atrophy that someone who is healthy.
• There is individual variability with no clear dividing line between normal and pathological states.
• There is no direct relationship between brain volume and function.
• Atrophy tends to be homogenous between white and grey matter and the lobes.
• Clinical effects of changes are difficult to determine since brain weight and ventricle size do not correlate with intelligence.
• Severe dementia can occur in people that have normal ventricular size for their age, and vice versa.
• Infra-clinical atrophy exists in non-demented aging individuals.
• Cerebral atrophy is inconsistent and varies in intensity.
• Brain weight decreases starting at age 50, at about 2% per decade.
• Some studies suggest loss of brain weight reaches 200 g (>15%), and that the surface area of the ventricles can increase 3 to 4 times.
• Brain atrophy is partly due to age but also conditions like arterial hypertension and arteriopathy.

CNS Histological Modifications

• Neuronal modifications
• Glial modifications
• Interstitial modifications
• Vascular modifications include amyloid angiopathy
• Neuro-hormonal modifications

Neuronal Loss

• The brain includes billions of neurons and an equal number of glial cells.
• The human brain has ~86 to 100 billion neurons (10^11).
• The total amount of neurons lost per day is unknown and published figures are likely overestimations.
• Neurons die at a rate of 5-7% per decade starting at age 20, culminating in a potential loss of ~50% by age 90.
• Significant nerve cell loss during aging is uncertain and hard to find.
• Perfect brains from centenarians are a counterexample that shows resistance with aging.
• It is suggested that neurons become "sick" with age and don't function well but still live, with reduced energy activity.
• Atrophy of dendrites, axons and cellular bodies occurs.
• Significant frontal lobe loss occurs.
• Minimal medulla and paraventricular neuron loss in the neurons exists in the cerebral trunk.
• Frontal cerebral regions experience a drop in neuron number and size, decreased synapse density, and reduced neurotransmitter concentration.
• Lower scores are seen on tasks specific to the frontal lobe regions.
• The hypothesis regarding the frontal lobes affect on cognition is based on psychometric evaluations of deficits that are noticeable when performing frontal tasks: coordination, strategy planning, intellectual performance and concentration.
• The loss of cells isn't uniform in all brain areas.
• The substantia nigra (SuN) experiences the highest neuronal loss with one study claiming a 40%-50% loss after age 90.
• Gross neurons atrophy in the cerebral cortex, the anterior basal brain, or the hippocampus.
• Some neurons atrophy or die in the thalamus or the hippocampus.
• Neurons die in the locus coeruleus.
• Modest substantia nigra dimensions are functionally very important as it plays a role in dopamine metabolism.
• Motor problems frequently observed in the elderly include rigidity, tremors, slumped posture, and difficult walking.
• Parkinson's disease is when >70% of the substantia nigra neurons are gone and severely disrupts motor functions.
• Normal aging corresponds to a much lower degree of neuron loss, but elderly subjects with PD-like symptoms may have >40% of the substantia nigra neurons dead.

Histological Modifications - Presence of Senile Plaques

• Senile plaques will contain amyloid substance.
• Neurofibrillary tangles

Senile Plaques (SP)

• Spherical formations present in the gray matter with extracellular accumulation of amyloid.
• The peptide is formed by abnormal cleavage of glycosylated membrane protein (physiological) called “amyloid β protein precursor.”
• SP include insoluble proteins that capture neuron useful metabolites inducing inflammation and the production of free radicals, thus the appearance of dystrophic effects surround the neurons.
• Amyloid is deposited in the nervous parenchyma and diffuses into the SG across all cerebral regions.
• Depots can accumulate at variable rates where the arterioles and capillaries cause amyloid angiopathy.
• SP are often absent in the very old but can be numerous in non-demented older people.
• The location of plaques in the brain remains stable, with the hippocampus and the entorhinal cortex particularly vulnerable.
• Normally, there is no cognitive disturbance if there is limited change the cortex.
• Cognitive functions can be compromised when the temporal area is overtaken by neurodegeneration.

Neurofibrillary Tangles (NFT)

• There's presence of abnormal fibrils: paired helical filaments, abnormal Tau protein filaments.
• Cellular lesions are successive because with age the capacity is increased.
• Abnormal accumulation causes the Tau protein to be non-functional.
• Neurons are unable to function and eventually die due to the substances needed being unavailable to the structure.
• Alzheimer's disease includes extracellular aggregated amyloid beta peptide plaques, and intracellular hyperphosphorylated tau protein neurofibrillary tangles.

Neurofibrillary Degeneration (DNF)

• The number of DNFs increases with age.
• They are rare from ages 55 - 70, while after age 70 it is present in almost all individuals.
• The pathological filaments are excellent ultrastructural markers of Alzheimer’s.
• Those who had no traces of DNF were younger than the age of 75 because DNF is a degenerative process that develops systemically after age 75.
• Lesions of Alzhiemer's are the same lesions of aging.
• Alzhiemer's has a common phenomenon that it's lesions have with aging.
• DNF is predictably sequential, hierarchical and characteristic along a path from the hippocampal region to the temporal cortex, then the cortical association regions, then primary motor and sensory regions.
• The progression of degenerative neurofibrilles goes from the transentorhinal region to the hippocampus, then to entorhinal, temporal anterior, temporal mid, then the frontal or the parietal.
• The pathology of sporadic allzhiemer's is the result of the neurofibrillary tangles that will then deposit APP amyloid, but the degree of amyloid plaques and tangle is higher than with aging.
• Early-onset familial Alzhiemer's develops plaques and tangles at a much younger age which then progresses at a high speed.
• Pathological Tau can reach stage 6 without simultaneous deposits of amyloid Aβ peptides.
• Patients that aren't demented may have simultaneous deposits of pathogenic Tau proteins and deposits of peptides Aβ, but the phase will be much before >6.
• Mild Cognitive Impairment (MCI) has Tau and hippocampe pathology.
• Tau pathology affects cooperative regions because of the peptide.
• It appears there's a synergy between Tau.
• Those with Alzhiemer's have pathologies for both and there's an important neocortical presence.

Markers for Alzheimer's

• Alzheimer's results from a combination of processes involving neurofibrillary and amyloido pathic degeneration.
• Tau and Phospho-Tau levels plus the amount of Ab42 from LCR increase.
• If all three are normal, you don't have Alzheimer's. Certain diagnosis happens post-mortem.
• Plaques of amyloids are indicators for Alzheimer’s disease.

Other Microscopic Alterations

• Surcharge Lipopigmentaire
• Accumulation of Iipofuscine normally is visible in cytoplasm.
• Cortex in the neurons represent remanements in the Pallidium.
• Occurs normal and has no effect.
• Gliose Astrocytaire volume increases with age; however it is moderate.
• It contributes to astrocytes
• Affects cytokine neurotrophins.

Changes in the Neurotransmitter System

• Alteration in density varies depending on the nervous structure.
• Lower choline, Butyric acid, and serotonin occurs with Parkinson's.
• Low free radicals, which happen w/ age affect the cells in the brain.

Vascular Modifications

• These happen with age.
• Affect extracellular matrix in cells.
• Happens a lot.
• A lot happens with the arteries.
• Changes happen to outside the vessel.

Circulation Changes in the Brain

• Blood flow goes down around 20%
• The region can't get as much oxygen.

Compensatory Mechanisms

• Properties can reduce the clinic.
• There is a lot of nerves so there is plasticity.
• EX when diabetics have to have their nerves removed in the brain.

Mechanisms of nerve cells

• Reserve cells.
• These are plastic and can be repaired in normal cells.

Dendritic arbors

• Compensation happens after age 50.

Stimulating brain.

• Stimulating the mind increases synapses and help stimulation.

Peripheral nervous system

• Affect nerves.
• Instability happens.
• Hard time with balance.
• Electrophysiology does not work.
• Nerves are lost.
• Innervation is not effective with aging.

Autonomic

• Sensitivity is down.
• Tachycardia is rare with old.

Expectations

• You can live optimal!
• Brain plasticity is huge.
• Treatment is multiplied.