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2 Biological aging (Biomarkers of aging Jack (Biomarkers AD (Increased…
2
Biological aging
Biomarkers of aging
Jack
Multiple pathological changes underlying dementia
mostly related to Alzheimers (AD)
3 phases of AD
Pre symptomatic
cognitively normal, biological changes
Prodromal phase
Mild cogitive impairment (MCI)
earliest cognitive symptoms
episodic memory deficit
Dementia
Loss of function
Timeline
Abnormal processing of Amloid precursor protein (APP)
Leads to excess production/reduced clearance of beta-amyloid and neurofibrillary tangles (NFT)
cascade: abnormal tau aggregation, synaptic dysfunction, cell death, brain shrinkage
Biomarkers AD
Decreased CSF Aβ
Does not change in AD
Increased CSF tau
indicator of pathological changes
result of tau in axons
Decreased FDG uptake on PET
measures brain metabolim, synaptic dysfunction
PET amyloid imaging
Structural MRI measurements of cerebral atrophy
strong correlation severity of atrophy and cognitive imairment
Results
Always positive plaque load in AD
Temporal ordering
Aβ-plaque desosition
not sufficient to cause dementia
Tau mediated neuronal injury/dysfunction
MRI atrophy
Simultaneous cognitive deterioration
correlate with symptom severity
Preclinical
Plateaus before symptoms
Different brain areas affected at different stages
advantage for imaing over fluid biomarkers
PET
Posterior cingulate, lateral temporal, frontal
MRI
Medial temporal, lateral temporal, frontal
Solluble and fibrillary
Different theories on normal aging
Wear and tear
in organs other than brain
increased free radical formation
Support
Lipofuscin in used neurons
but not more lipofuscin in AD
Increased metabolic activity
Damage
Use it or lose it
In neurons
Stimulated action of protective mechanisms such as DNA repair
evidence
activity may have beneficial effects
brain volume
cells shrink io die because can be revitalized
Cells that are less active are more affected by AD
Brain differences between healthy and pathoogical aging
Maddison
Selective neuronal vulnerability
#
susceptibility of specific populations of neurons limited to region of nervous system
Unknown why
Depends on.....
Age damage
oxidative stress
perturbed energy homeostasis
accumulation of damaged proteins
Lesions in nucleic acids
ionic and metabolic changes
Neurodegenerative disorder
determined by
genetic and environmental factors that counteract/facilitate fundamental molecular/cellular mechanisms of aging
Mechanisms
Caloric restriction
decreased production of reactive oxygen species in mitochondria
highly reactive ones produced during metabolism of glucose
decrease in glucose leads to
decrease in the cumulative damage to proteins/lipids/DNA
ROS involved in dysfunction/death in neurons
Reactive oxigen species
enhanced BDNF
Hormesis
Exposure to sublethal stress increases resistance to high stress
Vulnerable neurons
large myelinated axons that extend relatively long distances
hippocampal and cortical pyramidal neurons
motor neurons, striatal medium spiny neurons
require high energy, relyance on axonal transport, large cell surface that increases exposure to toxic conditions
Dysfunction/death affects pre/post synaptic neurons
domino degeneration
AD
Entorhinal cortex first, then hippocampus, then cortex
Pathways to neuronal death
Apoptosis
programmed cell death
regulated by caspases
Proteins
triggers
oxidative stress
overactivation of glutamate receptors
trophic factor insufficiency
DNA damage
accumulation of damaged proteins
Low rate during adulthood
accelerates during later life
extra in disorders
ROS
promotes calcium uptake
apoptosis
mutations in specific genes cause specific disorder
multiple mechanisms of neuronal death
Excitotoxicity
excessive activation of glutamate receptors
sustained Ca2+ influx and ROS production
Excitotoxicity
damage to dendrites/cell death
can lead to disorders in animals, neurotoxins might play a role in neurodegeneration
Calcium dysregulation
Pertubation of calcium homeostasis in normal aging
Sustained elevation of intracellular Calcium can cause neurodegeneration and cell death by activating proteases and inducing ROS
Pyramidal neurons
Mitochondrial pertubations
associated with aging, especially of nervous system
age dependent reductions in glucose utilization in most regions, except cerebellum and occipital cortex
Dramatic reduction in disorders
increased vulnerability of mito to toxins and impaired glucose uptake
Other pathways
Accumulation of damaged molecules
increased amounts of DNA damage
can cause disorder
Neuronal proteins prone to aggregation/neural disfunction/death
Aβ,
oxidative stress
tau,
fibrillar aggregates within neurons
normal aging, more in AD
caused by oxidative stress and impaired protein clearence
alpha-synuclein,
huntingtin
Imaired mechanisms of removal
Lipofuscin
Neurotrophic factors
promote neuronal survival, growth and plasticity
Comprised in disorder
Cytoskeletal disruption
Microtubals are disrubted
causes tau
Inflammation
local and humoral inflammatory and immune responses in aging and disorders
Hedden
Models of aging change with age
neuropsychological
neurobiological
neuropharmacological
3 types of aging
Healty aging
Modest steady decline
minimal decline in hipp volume
not related to memory function
Decreased MTL activation
Deficits in executive control
PFC volume decline
Modest striatum decline
Decline of dopaminergic system
related to memory and executive control
Reduced functional asymmetry
compensation
reduced connectivity between MTL and PFC, corpus callosum
#
Less activation hippo, increase in DLPFC
compensation
Parietal lobe atrophy
contralateral recruitment
White matter decline in anterior
Dopaminergic function declines
mild cognitive impairment
transitional stage?
MTL volume/memory
severely affected
Entorhinal cortex atrophy
between hippocampus and neocortex
memory function
deseases of aging
AD
MTL volume and memory
severely affected
Only late atrophy in PFC
White matter decrease in posterior/temporal regions
gray matter volume in hippocampus affected
Increased parietal lobe atrophy
#
most Ab
Preserved memory of priming and repetition
Hippocampus not super important