BS2014: Neurological Aging

Neurological aging

progressive, biochemical, structural and functional changes in the nervous system that occur over time, leading to gradual declines in motor, sensory and cognitive functions

Hallmark features of brain atrophy

• ventricular enlargement

• cortical thinning

• white and grey matter volume loss

• sulcal widening

Clinical manifestations of white matter deteriation

• small vessel disease

• demyelination

• microbleeds

• leukoaraiosis

• lacunes

Biochemical mechanisms of neurological aging

• oxidative stress

• mitochondrial impairment

• impaired proteostasis

• neurotransmitter and neurotrphic factors decline

• neuroinflammation

Endogenous sources of ROS

• mitochondrial respiration

• enzymatic reactions

• peroxisomal activity

Exogenous sources of ROS

• environmental factors (e.g. pollutants, tobacco smoke, heavy metals)

• radiation (e.g. UV light, ionising radiation)

• chemicals and drugs (e.g. doxorubicin, paraquat)

How does ROS contribute to neurological aging

accelerates brain aging by compromising endogenous antioxidant defence systems leading to lipid and protein peroxidation as well as DNA & mitochondria impairment

Consequence of lipid peroxidation

cell membrane damage

Consequence of protein peroxidation

loss of protein function

Consequence of DNA damage

• epigenetic alterations

• mutations

Causal factors of mitochondrial impairment

• sedentary lifestyle

• genetic mutations

• infections

Sedentary lifestyle on mitochondrial impairment

• reduces oxidative enzyme activity

• lowers electron transport chain (ETC) capacity

• shifts metabolism towards glycolysis rather than oxidative phosphorylation

Genetic mutations on mitochondrial impairment

• mutations in mitochondrial DNA involved in repair and maintenance can impair oxidative phosphorylation

• structural changes in mitochondrial membrane lipids (cardiolipin)

Infections on mitochondrial impairment

• increased mitochondrial fission and mitophagy

• increased ROS

• genomic instability

Synucleinopathies

neurodegenerative disorders characterized by the abnormal accumulation of misfolded α-synuclein

Tauopathies

neurodegenerative disorders characterized by the abnormal accumulation of misfolded tau protein

Consequence of accumulation of misfolded proteins (in neurological aging)

triggers neuroinflammation which accelerates protein aggregation and deposition

Neurotransmitter and neurotrophic factor decline in neurological aging

• age-related decline in dopamine transporters

• age-related decline in dopamine receptors

• acetylcholine decline

• serotonin decline

• GABA decline

• glutamate excitotoxicity

Neurotrophins

family of secreted proteins expressed in the nervous system that support neuronal survival, synaptic plasticity and neurogenesis

Impact of hippocampal atrophy

leads to reduced synaptic plasticity (BDNF decline) leading to memory impairment

Impact of white matter deterioration

slower neural transmission leading to slower processing speed and reaction time

Impact of prefrontal cortex shrinkage

reduced working memory capacity leading to decline in attention and multitasking ability (dopamine and acetylcholine decline)

Impact of reduced frontal lobe activity

impaired planning, judgment, and flexibility leading to executive function decline (decision-making and problem-solving)

Stages of cognitive function decline

• Preclinical stage

• Prodormal stage: MCI

• Syndromal stage: dementia

Features of preclinical stage

• lasts decades

• amyloid-β accumulation in brain

• tau hyperphosphorylation gradually leads to neuronal loss

• pathology not noticeable

• biomarkers can indicate risk of disease progression

Features of prodormal stage

• lasts 7 years

• progressive MCI

• caused by Alzheimer’s disease

• amnestic syndrome of hippocampal type

• noticeable deficits in memory and/or other cognitive domains

• biomarkers can determine aetiological diagnosis

Features of syndromal stage

• lasts 7 years

• notable loss of intellectual ability affecting memory and at least 1 other cognitive domain

• impairment interferes with daily living

Examples of cognitive function assessments

• MMSE (Mini-Mental State Examination)

• MoCA (Montreal cognitive assessment)

• ADAS-Cog (Alzheimer’s Disease Assessment Scale-Cognitive Subscale

• CDR (Clinical Dementia Rating) Scale

Declines in motor function

• slower movement + reduced coordination

• weaker reflexes + impaired reaction time

• reduced balance + increased fall risk

• muscle weakness + loss of fine motor skills

Cause of slower movement + reduced coordination (motor function decline)

loss of dopaminergic neurons

Cause of weaker reflexes + impaired reaction time (motor function decline)

slower signal transmission in spinal cord and peripheral nerves due to white matter loss

Cause of reduced balance + increased fall risk (motor function decline)

• cerebellar atrophy leading to impaired postural control

• decline in proprioception and vestibular function leads to decreased spatial awareness

Cause of muscle weakness + loss of fine motor skills (motor function decline)

motor neuron degeneration leads to reduced force production and dexterity

Assessment of motor function

• gait and mobility tests (e.g. timed up and go test)

• balance and postural control tests (e.g. one-leg stand test)

• strength and coordination tests (e.g. handgrip strength test, finger tapping test, heel-to-toe walk test)

Neuroprotection

strategies that preserve neuronal function, structure, and resilience

Benefits of exercise on neuronal health

• improves learning, attention, and long-term memory

• increases hippocampus size

• increases cerebral blood flow

Exerkines

biomolecules released in response to exercise which exert their effects through endocrine, paracrine and/or autocrine pathways e.g. irisin

Irisin function

stimulates synaptic plasticity and neurogenesis by induction of expression of BDNF (brain-derived neurotrophic factor)

Actions of BDNF

• The BDNF-TrkB complex activates the PI3K/Akt signalling pathway and regulates the neuronal survival.

• The BDNF-TrkB complex activates the MAPK/Ras/ERK signalling pathway and promotes neuronal differentiation

• The BDNF-TrkB complex activates the PLC-γ/PKC signalling pathway and regulates synaptic plasticity.

Study of positive correlation between exercise, IGF-1 and cognitive function

• 12-week resistance training intervention in older sedentary women resulted in an increase in IGF-1 levels

• increased IGF-1 was positively related with cognitive function in older women in a 52-week intervention

Exercise prescription for neuroprotection

• Aerobic exercise — improving cardiorespiratory fitness and cognition, particularly in enhancing hippocampal function, memory, and executive function. e.g. walking, running, swimming, and cycling

• Resistance training — increasing muscle strength, also enhancing executive function, attention, and motor control. e.g. weightlifting, bodyweight exercises

• Balance training — maintaining postural control, reaction time, and spatial awareness. e.g. Tai Chi, yoga, and proprioceptive exercises

Exercise guidelines from CDC for adults

• Minimum — 150 mins of moderate-intensity exercise per week

• Substantial health benefits — >300 mins of moderate-intensity exercise per week

• Muscle-strengthening activities — 2 sessions per week

Mechanisms for neuroprotection

• Exercise training enhances memory performance via neuroplastic and neurogenesis alterations

• Exercise-induced memory improvement might be mediated via neurotrophic factors, neurotransmitters and exerkines

• Irisin/BDNF signalling is an important link between skeletal muscles and the brain.