The neuropathology of dementia Flashcards
The anterior part of the brain (frontal lobe) tends to be involved in which 3 functions?
Executive functions
1) Motor
2) Planning
3) Strategic thinking
The more posterior part of the brain (parieto-occipital lobe) is involved in which 2 main functions?
1) Perception and integration of sensory stimuli
2) Encoding knowledge
Which part of the brain is involved in ‘executive functions’?
Frontal lobe
What 5 functions is the limbic system involved in?
1) Arousal
2) Emotion
3) Motivation
4) Attention
5) Memory
The thalamus is an important structure in what system?
The sensory system
The basal ganglia is an important structure in what system?
The motor system
What is cognition?
The sum of brain functions which allows us to integrate in the environment
Give the 5 main intellectual skills?
1) Learning and memory
2) Language
3) Visuospatial skills
4) Emotion
5) Personality
Which 2 parts of the brain are affected in corticobasal degeneration?
Cortex and Basal ganglia
Temporal, frontal and parietal degeneration occurs in which disease?
Alzheimer’s disease
Multifocal degeneration occurs in which condition?
Corticobasal degeneration
Mutations in which 4 genes are known to be associated with Alzheimer’s disease?
1) Amyloid precursor protein amplification on Chr 21 - can be due to trisomy at birth or an aquired mutation
2) Presenilin 1 on Chr 14 (involved in amyloid processing)
3) Presenilin 2 on Chr 1 (involved in amyloid processing)
4) Apo E on Chr 19 - to dowith stability of beta amyloid deposits
Which 2 proteins are the main ones involved in Alzheimer’s disease?
1) B-amyloid
2) Tau
Which is the main protein involved in dementia with Lewy bodies and Parkinsons?
alpha-synclein
Which 4 proteins are commonly involved in dementia?
1) B-amyloid
2) Tau
3) alpha-synclein
4) Ubiquitin
What are amyloid proteins?
Insoluble fibrous protein aggregates
Where do amyloid proteins arise from and how do they form aggregates?
Arise from inappropriately folded versions of proteins and polypeptides present naturally in the body - these misfolded proteins alter their proper configurations so that they interact with one another forming insoluble fibrils
What is the role of amyloid proteins in disease?
Have been associated with 20 serious human diseases in that abnormal accumulation of amyloid fibrils in organs may lead to amyloidosis and may play a role in various neurodegenerative disorders (B-amyloid)
What are tau proteins?
A group of proteins that stabilize microtubules in neurons
How may isoforms of tau proteins exist?
6
What happens when tau proteins are defective - how are tau proteins affected in Alzheimer’s disease?
When tau proteins are defective the microtubules become instable and dysfunctioning - In AD Tau gets hyperphosphorylated and microtubules become tangles
How do amyloid plaques and tangles differ in where they form?
Amyloid plaques = extracellular
Tangles = intracellular
What is the link between amyloid plaques and tau?
Amyloid plaques can induce the cell to produce tangles ie. interrupting the function of tau
In which 2 ways can the production of amyloid plaques lead to cell death?
1) Amyloid beta plaques can induce the production of tangles, the formation of which leads to neuron death
2) Amyloid plaques can themselves be toxic, inducing inflammation which increases deposition of amyloid and leads to neuron loss
Where does alpha-synuclein exist normally?
Within the cell membrane
How does alpha-synuclein lead to neuron damage?
Different modifiers can act on the protein which globulise it leading to the production of lewy bodies - which like tangles are an intracellular structure. These lewy bodies interfere with the function of different parts of a cell such as mitochondria and lysosymes
What is ubiquitin - what is its function within the cell?
A small regulatory protein that has been found in almost all cells of eukaryotic organisms - directs proteins to compartments in the cell, including the proteasome which destroy and recycle proteins, it can be attached to proteins and label them for destruction
Why do mutations in ubiquitin lead to neuron damage?
Ubiquitin found within neurones. if mutations in ubiquitin it cant carry out its function and unwanted metabolic products accumulate in the cell, damage it and cause cell death
What are the 6 main theories of pathogenesis of neurodegeneration?
1) Oxidative stress: free radicals (damage proteins)
2) Excitotoxicity: glutamine stimulation
3) Induction of programmed cell death (apoptosis)
4) Cytokines: an inflammatory response?
5) Genetic factors: single gene mutations, multiple genes
6) Aging: age-related decline in the efficiency of some metabolic pathways (eg. RNA synthesis)
Despite the cause, accumulation of abnormal proteins is known to have a major role in the pathogenesis of dementia, name the 4 intra cellular and the 1 extra-cellular protein which accumulates?
Intracellular: 1) Tau 2) a-synuclein 3) polyglutamine 4) ubiqutin Extracellular: Amyloid
What 2 proteins accumulate in Alzheimer’s disease?
1) Tau
2) Amyloid
Which abnormal protein accumulates in dementia with Lewy bodies?
a-synuclein
Which abnormal protein accumulates in Huntington’s disease?
Polyglutamine
What are the 3 important anatomical landmarks in dementia?
1) Superiro and middle temporal gyri
2) Middle frontal gyrus
3) Inferior parietal lobule
What are the 7 MACROSCOPIC neuropathological findings in dementia in general?
1) Brain weight reduced (normal = 1200-1400g, in dementia = 900-1100g)
2) Atrophy in cerebral gyri
3) Atrophy in white matter: thin corpus callosum
4) Atrophy in deep white matter
5) Ventricular dilatation
6) Atrophy in brain stem and cerebellum
7) Pale substantia nigra and locus ceruleus
What does ubiquitin accumulate to form?
Pick’s bodies
What are the 5 MICROSCOPIC neuropathological findings in dementia in general?
1) Neuron loss from hippocampus, cerebral cortex, substantia nigra and locus ceruleus (in brainstem)
2) Microvacuolation in cerebral neocortex
3) Attenuation in white matter
4) Wide perivascular spaces in white matter
5) Accumulation of abnormal proteins
What colour histochemical (Ab) stain can be added to highlight amyloid plaques?
Brown
What 3 kinds of amyloid plaques can be seen in dementia?
1) Neuritic plaques with prominent amyloid cores
2) Perivascular plaque
3) Diffuse plaque
Where do plaques and tangles first form within the brain in dementia?
Within the hippocampus and move out - the motor - sensory cortex and the occipital cortex are relatively spared
How many stages does braak and braak staging system have and what are they based on?
6 - based on extent of distribution of NPs (plaques) and NFTs (neurofibrillary tangles) within the brain
The stages of Braak and Braak can be grouped into 3 stages, what are they?
1) Transentorhinal (clinically asymptomatic) - stages 1&2
2) Limbic (Incipient AD) - stages 3&4
3) Isocortical (symptomatic AD) - stages 5&6
Which system stages AD by plaques density?
CERAD
What are the 4 stages in the CERAD system based on plaque density?
1) Normal
2) Definite AD
3) Probable AD
4) Possible AD
What are the 3 macroscopical findings in alzheimer’s disease?
1) Reduced brain weight
2) Atrophy of gyri and widening of sulci
3) Ventricular dilatation
What is a normal brain weight in grams?
1200-1400 grams
What are the 3 microscopical findings in Alzheimer’s disease?
1) Neuronal loss
2) NP - plaques
3) NFT (neurofibrilary tangles) and neuropil threads
What are the 2 macroscopic findings in Dementia with Lewy Bodies?
1) Pale substantia nigra and locus ceruleus
2) Atrophy in amygdala, cingulate gyrus, temporal, parietal and frontal lobes
What are the 2 microscopic findings in Dementia with Lewy Bodies?
1) Neuronal loss from the substantia nigra and locus ceruleus
2) Accumulation of a-synuclein positive bodies in the neurons of the substantia nigra and later in the cerebral cortex
Give 3 types of vascular dementia?
1) Multi-infarct dementia
2) Binswanger’s disease
3) Arteriolosclerosis
What is the main pathological process in multi-infarct dementia?
Blood vessels supplying the brain start to cause ischaemic damage to some areas of the brain
Proteins are fine, there is no diffuse neuron loss or plaques etc.
What is the pathology in Binswanger’s disease?
Pathology is mainly in the white matter - blood vessels cause micro infarctions in white matter, all info transmitted in those axons is lost
What is the pathological process leading to dementia in arteriolosclerosis?
Blood vessles of the brain under pressure due to hypertension and become sclerotic
Get collagen fibres instead of smooth muscle cells in the wall - lose the ability to control blood flow to the brain by constriction/dilation
End up with infarctions
Pick’s disease is also known as what?
Fronto temporal dementia
Where is the pathology in Pick’s disease?
Frontal and Temporal lobes
Which abnormal protein accumulates in Pick’s disease?
Ubiquitin
‘Balloon cells’ (ballooned neurons) are found in which type of dementia?
Pick’s disease (frontotemporal dementia) - Neurons become swelled with pick’s bodies
What are the 2 types of dementia with Parkinsonism?
1) Idiopathic Parkinson Disease (IPD)
2) Dementia with Lewy Body (DLB)
What are the 8 major neuropathological diagnoses of dementia?
1) Alzheimer’s disease
2) Frontotemporal lobar degeneration (FTLD)
3) Dementia with Parkinsonism (IPD, DLB)
4) Corticobasal degneration (CBD)
5) Progressive supranuclear palsy (PSP)
6) Vascular dementia (VaD)
7) Normal pressure hydrocephalus (NPH)
8) Creutz-feldt-Jakob disease (CJD)
