L24- Brain Ageing

what are the main external brain divisions

• frontal lobe

• temporal lobe

• occipital lobe

• parietal lobe

• brainstem

• cerebellum

what are the supratentorial structures of the brain

forebrain:

• telencephalon

• diencephalon cerebrum

what are the infratentorial structures of the brain

• Mesencephalon

• Metencephalon

• Myelencephalon

what are the different types of neurones in the brain

1. multipolar neurones

• interneurones

• motorneurones

2. sensory/bipolar neurones

what do multipolar neurones do

1. Interneurones- form all the neural wiring within the CNS.

2. Motor Neurons- carry signals from the CNS to muscles and glands (efferent neurones).

Multipolar neurones have many processes originating from the cell body (e.g. spinal motor neurones, pyramidal neurones, Purkinje cells.)

what do sensory/bipolar neurons do

• Carry messages from the body's sense receptors (eyes, ears, etc.) to the CNS (afferent neurones)

• Account for 0.9% of all neurones

• They have two axons (instead of an axon and a dendrite). One axon communicates with the sense organ; the other axon communicates with the CNS (e.g. dorsal root ganglion cells in the spinal cord).

what are the 2 forms of diagnostic brain imaging techniques

structure- CT and MRI/MRS

function- PECT/SPECT and EEG/MEG

how does the functional capacity of the brain change throughout life

what is meant by multifactorial susceptibility

a mix of genetic and acquired causes

how does ageing and brain function relate

what happens to the brain as we age

• ventricles enlarge

• cortex gets thinner- lose about 0.5% per year

what happens to brain atrophy during ageing

• Reduced brain volume (atrophy)

• Widened sulci (more space between gyri)

• Enlarged ventricles

• In dementia:

  • Changes are more pronounced

  • Greater loss of cortical and subcortical tissue

what happens to the frontal lobe during ageing

frontal lobe volume declines during ageing

what happens to brain structure in dementia

• atrophy is greater in alzheimer’s diseases (AD) than in dementia with lewy bodies (DLB)

• atrophy of medial temporal lobes structures most likely in AD

Which brain regions show early volume loss in Alzheimer’s disease?

• Early atrophy occurs in:

  • Hippocampus

  • Entorhinal cortex

• Compared to healthy ageing:

  • AD shows greater and earlier volume loss in these regions

• Key idea:

  • These areas are critical for memory → explains early memory symptoms in AD

How does hippocampal atrophy differ between normal ageing and Alzheimer’s disease?

• Normal ageing:

  • ~1.6% volume loss per year

• Alzheimer’s disease (AD):

  • ~4.0% volume loss per year

  • ≈ 2× faster atrophy than controls

• Key idea:

  • Ageing → gradual hippocampal loss

  • AD → accelerated medial temporal lobe atrophy

what are the patterns of hippocampal neuronal loss in ageing and AD

• most distinctive AD related neuron loss was seen in the CA1 region (hippocampus subfield)- in normal ageing pr MCI almost no neuron loss

• - neurodegenerative processes associated with AD qualitatively different- AD is not accelerated by ageing but a distinct pathological process

how does the appearance of hippocampal neurones change during ageing

With ageing:

• Reduced dendritic length and branching

• Simpler neuronal structure (less connectivity)

What histological changes indicate neuronal injury and death?

• Early injury (e.g. ischaemia):

  • “Red neurons” (shrunken, intensely stained)

  • Vacuolation & oedema (cell swelling/damage)

• Progression:

  • Loss of neurons (e.g. Purkinje cells)

  • Gliosis (increase in supporting glial cells after injury)

• Cellular breakdown:

  • Chromatolysis (loss/disruption of Nissl substance → impaired protein synthesis)

what are the changes in mechanisms of neurodegeneration during ageing

↑ Oxidative stress mechanisms

↑ Neuroinflammatory responses

↑ Abnormal Protein-Protein Interactions

↓The Ubiquitin-Proteasome system

↑ The autophagy-lysosome system (autophagy)

↑ Apoptosis and delayed cell death

What are the key cellular mechanisms driving brain ageing?

• Oxidative stress (ROS):

  • Damages DNA, proteins, membranes

  • Creates a vicious cycle of further damage

• Mitochondrial DNA defects:

  • Accumulate with age

  • Impair mitochondrial function

• Bioenergetic decline:

  • ↓ cellular respiration → ↓ energy (ATP)

• Protein accumulation:

  • Misfolded/aggregated proteins build up

  • Impaired clearance → neurodegeneration

• Key idea:

  • These processes are interconnected and amplify each other → neuronal dysfunction and disease

How are neurodegenerative dementias classified?

• Classified by misfolded/accumulated proteins → “proteinopathies”

• Examples:

  • Alzheimer’s disease (AD): Aβ plaques, tau tangles

  • Parkinson’s disease (PD) / Lewy body dementia: α-synuclein (Lewy bodies)

  • Frontotemporal dementia (FTD): tau or TDP-43

  • Prion diseases: misfolded prion protein

  • Huntington’s disease (HD): mutant huntingtin

  • ALS: protein inclusions (e.g. TDP-43)

• Neuropathology = gold standard for diagnosis

  • Disease type depends on which protein accumulates and where in the brain

how do we define dementia

impairment in any of

• memory

• language

• visual processing and orientation

• mood, personality and social skills

• frontal executive function, including planning and problem solving

causes inability to function independently

how does normal cognitive state change over time

Which cognitive domains are affected during ageing?

• Executive function: planning, decision-making, working memory, flexibility

• Memory & learning: recall (free/cued), recognition, long-term memory

• Language: word finding, fluency, grammar, comprehension

• Attention: sustained, divided, selective attention, processing speed

• Perceptual-motor: visual perception, coordination, visuospatial skills

• Social cognition: emotion recognition, theory of mind, insight

  • Different domains decline at different rates and times during ageing

describe the prevelence if dementia worldwide

Dementia is a clinical syndrome caused by neurodegeneration . Alzheimer’s disease (AD) is the most common type followed by vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD).

what are the most common causes of degenerative dementias

• Alzheimer’s disease: ~55–70% (most common)

• Vascular dementia: ~15–25%

• Other dementias (10–30%):

  • Lewy body dementia

  • Parkinson’s disease dementia

  • Frontotemporal dementia

whatt are the 4 types of dementia

• alzheimer’s (50-75%)

• vascular (20-30%)

• lewy body (10-25%)

• frontotemporal (10-15%)

give 6 common ageing related brain disorders and dementias

• Alzheimer’s Disease

• Parkinson’s Disease

• Dementia with Lewy Bodies

• Frontotemporal Dementia

• Prion Diseases

• Vascular Dementia

what is alzheimer’s disease

a progressive degenerative brain disorder and the most common cause of dementia

how do cognitive ageing related thresholds lead to alzheimer’s disease

once decline affects ADL (activities of daily living) and social ability- considered dementia

how does cognition and brain pathology cange during ageing

progressive accumulation of brain pathology increases damage and decreases cognitive functions

How is Alzheimer’s disease diagnosed (NINCDS-ADRDA criteria)?

• Dementia required:

  • Impaired memory

  • ≥1 other cognitive domain impaired

  • Assessed by clinical exam + neuropsychological testing

• Probable/Possible AD:

  • Progressive worsening over time

  • No other disorder explaining symptoms

• Definitive diagnosis:

  • Confirmed by autopsy

what are the key pathological hallmarks od AD

accumulation of brain pathology with age

• amyloid or neuritic plaques (NP)

• neurofibrillary tangles (NFT)

what are he pathological features of AD

• neuritic plaques (NP)

• neurofibrillary tangles (NFT)

• cerebral amyloid angiopathy

• transmitter-specific neural liss

• white matter lesions (WML)

• cerebral atrophy

describe the change in brain amyloid plaques with ageing

what are amyloid plaques

Aβ protein deposits

• Aβ in neocortex and hippocampal formation- EM shows fibrillae amyloid

What initiates the amyloid β cascade in Alzheimer’s disease?

• Triggers:

  • Genetic mutations (APP, PS1)

  • Head injury

  • Ischaemia

  • Oxidative stress

• Key process:

  • Abnormal APP processing → amyloid-β (Aβ) production

  • Aβ aggregates → amyloid (neuritic) plaques

What are the downstream effects of the amyloid β cascade?

• Pathological changes:

  • Tau pathology (neurofibrillary tangles)

  • Neuronal loss

  • Neurotransmitter deficits

• Clinical outcome:

  • Cognitive impairment

  • Memory loss

  • Behavioural changes → Dementia

What does the updated Amyloid β cascade hypothesis explain?

• Aβ accumulation (genetic risk) initiates disease

• Microglia become activated → inflammation + loss of normal function

• Neuronal damage develops around plaques

• Tau pathology spreads through the brain (prion-like)

• Leads to progressive neuronal and synaptic loss

• Key idea:
  Alzheimer’s is a multistep process involving Aβ, inflammation, and tau → ultimately causing dementia

what are neurofibrillary tanges

Hyperphosphorylated tau protein

• NFT in neocortex and hippocampal formation.

• EM shows neurofibrillary twisted filaments (tangles)

describe the progression of tau positive neurofbrillary pathology

• Tau changes from normal → oligomers → filaments → neurofibrillary tangles (NFTs)

• NFTs accumulate inside neurons → disrupt function

• Neurons degenerate → release tau → extracellular “ghost” tangles

• Associated with neuritic plaques and neuropil threads

• Key idea:
  Tau pathology progressively damages neurons and spreads, driving neurodegeneration

What are the main molecular classes of neurodegenerative dementias?

• Alzheimer’s disease (Aβ + tau)

• Synucleinopathies:

  • Dementia with Lewy bodies (DLB)

  • Parkinson’s disease dementia (PDD)

• Tauopathies:

  • Frontotemporal dementia (FTD), PSP, CBD, Pick’s disease

What other disorders can cause neurodegenerative dementia?

• Frontotemporal dementias (non-tau):

  • TDP-43, ubiquitin, progranulin

• Prion diseases:

  • Creutzfeldt-Jakob disease, etc.

• Trinucleotide repeat disorders:

  • Huntington’s disease, spinocerebellar ataxias

• Motor neuron diseases:

  • ALS, PLS, SMA (with dementia)

• Key idea:
  Dementias are classified by underlying protein pathology

What protein accumulations are associated with major neurodegenerative diseases?

• Alzheimer’s disease: Aβ plaques, tau

• Parkinson’s / DLB: α-synuclein (Lewy bodies)

• Tauopathies (FTD, PSP, CBD, Pick’s): tau (3R/4R)

• FTD (non-tau): TDP-43, ubiquitin, progranulin

• Prion diseases: PrP plaques

What is the key pathological mechanism in neurodegenerative proteinopathies?

• Diseases involve misfolded proteins that:

  • Form intracellular inclusions or extracellular deposits

  • Are insoluble and aggregate

• Spread via “seeding” mechanism (prion-like propagation)

• Examples:

  • Synuclein (Parkinson’s, MSA)

  • Tau (FTD, AD)

  • Polyglutamine (Huntington’s)

• Key idea:
  Neurodegeneration is driven by toxic protein accumulation and spread

How do Aβ, tau, and α-synuclein spread in dementias?

• Spread progressively in stages across the brain

• Aβ: cortex early

• Tau: limbic → cortex

• α-synuclein: brainstem → cortex

• Higher stage = more severe disease / diagnostic pattern

what is programmed cell death (PCD) and apoptosis- mechanisms of degeneration

• PCD, a process where cell plays an active role in its own demise

• Critical role in the development of NS and in its response to insult

• Both anti-PCD and pro-PCD modulators play prominent roles, e.g. ischaemic (stroke) injury

• Non-apoptotic forms of PCD e.g. autophagy

• PCDs that do not fit the criteria for either apoptosis or autophagy – suggest other pathways?

what is necrosis vs apoptosis- mechanisms of neurodegeneration

Apoptosis is distinguished from necrosis; mechanism that allows cells to self- destruct when stimulated by the appropriate trigger

• Initiated if cell is no longer needed or becomes a threat to health

• Aberrant inhibition or initiation of apoptosis contributes to many disease processes

• Process of programmed cell death (PCD) has had broader recognition since 1972

what is autophagy in neurodegeneration

• Autophagy clears misfolded/aggregate-prone proteins

• Process: phagophore → autophagosome → lysosome → degradation

• Protective role:

  • Reduces toxic protein aggregates

  • Limits neuronal damage

• Key idea:
  Impaired autophagy → protein accumulation → neurodegeneration

what are the processes influencing neuron health

• genetically determined disease process

• ageing related decline

• environmental risk factors/comorbidity

• neuron stress and repair mechanisms

additional opportunities for interventions