L3 Pathology of Dementias Flashcards
how to do brain donation
frozen hemisphere –> brass plates for rapid freezing and stored at -80degreesc.
fixed hemisphere –> fixed for 3 weeks in formalin
what is the process during immunohistochemistry
process brain into wax
then remove wax from sections by xylene
stain areas of interest
tag with antibodies that recognise
what do we look for down the microscope
abnormalities
cell types involved
regions of brain affected
what are some glial cells
microglia, astrocytes, oligodendrocytes
what are neurons and how are messages transmitted
electrically excitable cell that receives, processes and transmits info through electrical and chemical signals
messages transmitted through synapses
what are some specialised neurons
sensory
motor
interneurons
what is the structure of neurons
cell body (nucleus and cytoplasm), dendrites, axon
what is the function of astrocytes
provide nutrients to nervous tissue
envelop synapses made by neurons
in blood brain barrier
what is the function of microglia
maintenance of CNS
inflammation
survey brain and react to any abnormalities
resident macrophages
what is the function of oligodendrocytes
support and insulation to axons
myelinate axons
what are 3 genes involved in alzheimers
AbetaPP chromosome 21
Presenilin-1 (14)
Presenilin-2(1)
what is the % of inherited forms in AD
<5%
what are macroscopic features of AD
enlarged ventricle
hippocampal atrophy, hippocampus stained with a beta antibody
-extracellular amyloid plaues formed between cells
-blood vessels in brain covering leptomeninges, build up of Abeta within cells CAA
what is the link with abeta in AD and what is it produced from
=produced from cleavage of the amyloid precursor protein
- mutations in the AbetaPP gene cause AD, implicating APP metabolism
- depending on where the mutations are located influence pathological and biochemical hallmarks (e.g. if we have mutations in the middle of the A beta peptide, see more Abeta deposition in the blood vessels compared to other mutations where we see more plaques)
summarise what tau does in AD
- positive in nerve cells
- a microtubule associated binding protein
- 6 tau isoforms expressed adult human brain
- equal amounts of 3R and4R tau in healthy
- tau twice as high in GM to WM
- hyperphosphorylated pathologically
- use electron microscopy to see
what diagnostic criteria can be used for AD to assess neuropathology
Distribution of amyloid plaques - Thal phases; 0 to 5
Distribution of Tau pathology - Braak and Braak staging; 0 to 6
Neuritic plaque frequency - CERAD score; none to frequent (in 3 different cortical regions)
how many stages are there in the thal phases and how are they divided
what do you look at in the different phases
pre-clinical - phase 1,2,3
1- look for amyloid plaques in the 4 regions and cortex
2- look for beta deposition in the hippocampus
3- look for a-beta deposition in the basal ganglia/striatum
clinical - phase 4,5
4- look for a-beta in substantia nigra
5 - look for deposition in cerebellum
who describes the pattern of progression of neurofibrillary tangles (NFT) and what are the stages?
Braak & Braak
stage I-II: NFTs in mediotemporal lobe/Transentorhinal structures
stage III-IV: NFTs in Limbic structures
Stage V-VI: NFTs numerous in isocortex
how is the CERAD diagnosis of AD graded
done by eye when neuropathologist looking at frequency of cord plaques
graded from spare-moderate-frequent
which three major clinical syndromes is frontotemporal dementia present with?
behavioural FTD
semantia dementia
progressive non-fluent aphasia
what is the 2nd most common dementia and what is the gender distribution
frontotemporal dementia (under age 65)
equal gender distribution
what are additional clinical symptoms of ftd
motor neuron disease/amyotrophic lateral sclerosis
corticobasal syndrome
progressive supranuclear palsy
what % of frontotemporal dementia is inheritable
30-50%
what mutations are in 3 genes in ftd
progranulin
microtubule-associated protein
chromosome 9 open reading frame 72 (C9orf72)
what is the pathological classification of FTLDs in tauopathies with
3R-Tau
4R-Tau
3R & 4R-tau
3R-tau - Pick’s disease, FTDP-17
4R-tau - CBD, PSP, AGD, MSTD, FTDP-17
3R & 4R tau - tangle only dementia, FTDP-17
what is the pathological classification of FTLDs in tau negative with
TDP-43 positive (Ubiquitin positive)
TDP-43 negative (ubiquitin positive / negative)
tdp-43 positive –> ubiquitin positive –> FTLD-TDP
tdp-43 negative –> ubiquitin positive –> FTLD-FUS/FTLD-UPS with CHMP28 mutation
tdp-43 negative –> ubiquitin negative –> DLDH
where is there atrophy in picks disease 3R tauopathy
frontal and temporal lobes
what is seen in CBD corticobasal dengeneration 4R tauopathy
pathology
frontal atrophy
enlarged lateral ventricle
smaller hippocampus
tau built up in neurons and seen in astrocyte
what is seen in PSP progressive supranuclear palsy - 4R tauopathy
(pathology)
tufted astrocytes
atrophied superior cerebellar peduncle
blurred/discoloured dentate nucleus
how many mutations are there in the MAPT gene that causes FTDP-17T and what does it cause
over 40 different mutations
cause 3R/4R tau pathology
what is TDP-43
member of heterogenous nuclear ribonucleoproteins
contains nuclear import and export signal
multifunctional RNA binding protein
RNA transport between intracellular compartments
human TARDBP gene located on chromosome 1p36 and encoded a 414-residue protein of 43kDa
what is the associated cortical pathology in FTLD-TDP type A
many neuronal cytoplasmic inclusions (lost from nucleus and built up in cytoplasm)
many short dystrophic neurites
predominantly 2nd cortical layer
occasional neuronal intranuclear inclusions
(short neurites dotted throughout temporal cortex
abnormal tdp-43 build up in cytoplasm)
what is the associated cortical pathology in FTLD-TDP type B
moderate neuronal cytoplasmic inclusions
few dystrophic neurites
present in all cortical layers
what is the associated cortical pathology in FTLD-TDP type C
few neuronal cytoplasmic inclusions
many long dystrophic neurites
in cortical layer 2
what is the associated cortical pathology in FTLD-TDP type D
many neuronal intranuclear inclusions
few neuronal cytoplasmic inclusions
many short dystrophic neurites
present in all cortical layers
how many pathological subgroups are FTLD-TDP divided into, what is the lesion for each type and the clinical manifestation, and genetics
4 groups:
TYPE A: -(lesions) short neurites, NCI neuronal cytoplasmic inclusion, NII neuronal intranuclear inclusion.
-(clinical) bvFTD, CBS, non-fluent aphasia.
-(genetics) GRN, C9orf72
TYPE B: (l) NCI, (c) FTD-MND (g) C9orf72
TYPE C: (l) long neurites, (c) semantic dementia
TYPE D: (l) NIIs, neurites
(c) IBMPFD (g) VCP
what are FBD familial British and FDD Danish dementias
two non a-beta cerebral amyloidoses
parenchymal amyloid and preamyloid deposits
neurofibrillary tangles composed of tau
widespread inflammatory response
cerebral amyloid angiopathy
early on-set with mutations in the BRI2 gene
FBD-stop to Arginine mutation = producing ABri amyloid
FDD- duplication insertion = producing ADan amyloid
what are the clinical symptoms of FBD and macroscopic observations
3 pedigrees described.
onset of symptoms 48 years (40-60 years)
age at death 56 years (48-70 years)
dementia, spastic paralysis, mutism, quadraplegia
macroscopic observations:
- slightly reduced brain weight
- thickening of the leptomeningeal blood vessels
- mild to moderate diffuse atrophy of cerebral and cerebellar hemispheres
- brain stem and spinal cord appeared normal
where is ABri depositon found and neurofibrillary tangles in FBD
hippocampus, cerebellum, amygdala
nft - limbic regions
what is the macroscopic description of FDD and pathology
- brain weights were within normal limits
- lateral ventricles were dilated
- thinning of the cortical ribbon and reduction in bulk of the white matter bulk
- the hippocampi were reduced in bulk. the brainstem and cerebellum were atrophic
- spinal cord can be narrowed in the antero-posterior dimension and on slicing shows yellow discolouration
- ADan amyloid found in vessels and parenchymal deposits
- widespread vascular pathology
- co-deposition of abeta in vessels and perivascular plaques
- electron micrograph of paired helical filaments. tau immunoblots of insoluble tau shows 6 tau isoforms present
what protein aggregates are associated with dementia
abeta tau TDP-43 FUD ABri ADan
