Neuropathology Flashcards
How do we diagnose neurological disease? + misdiagnosis %s
Clinical diagnosis vs. definite diagnosis
* Clinical misdiagnosis AD: 12-23%
* Clinical misdiagnosis PD: 10-20%
* Clinical misdiagnosis FTD: ~50%
Definite diagnosis: neuropathological confirmation via post-mortem studies
process to prepare brain for post-mortem diagnosis
4 week formalin fixation of the brain
Dissection of fixed brain into tissue blocks for diagnostic evaluation
Cutting the tissue and immunohistochemistry for identifcation of pathology
Cortical cell layers
6 layers
molecular layer > external granular > external pyramidal > internal granular > internal pyramidal > multiform layer
Amyloid-beta, Tau, and a-synuclein (extracellular or intracellular)
Amyloid-beta: extracellular
Tau: intracellular
a-synuclein (lewy body): intracellular
Spread of α-synuclein: Braak stages
Braak stage 1-6: starts in brainstem spreads to neocortex
Pre-clinical stage of PD
(incidental Lewy Body Disease)
1) motor nucleus, vagal nerve, olfactory bulb
2) locus cerulus
Prodromal stage of PD
(non-motor symptoms)
3) substantia nigra, hippocampus (CA2)
Clinical phase of PD
4) amygdala
5) cingulate gyrus
6) frontal cortex
Parkinson’s disease pathology: amyloid-beta
Alpha synuclein aggregation
- Morphologies:
* Lewy Bodies (LBs)
* Lewy Neurites (LNs)
- Expected in substantia nigra
* neuromelanin = indicator of health
* loss of neuromelanin indicates loss of dopaminergic cells
* appears as brown dots
Prodromal stage of PD non-motor symptoms
Hyposmia (decreased smell)
REM sleep behaviour disorder
Autonomic dysfunction
Depression
Mild cognitive disturbances
Clinical phase of PD: what is affected / manifestation
Severe loss of monoaminergic
neurons
▪ Increased load of α-syn pathology in the brainstem, NBM and amygdala
▪ Motor symptoms
▪ Increased involvement of CA2, thalamus
▪ Limbic systems gets affected
▪ α-syn pathology in neocortex
> Cognitive and psychiatric
symptoms
Alzheimers pathology
(hyper-)phosphorylated Tau aggregation
> The role of tau is primarily to maintain the stability of microtubules in axons and are abundant in neurons
> Microtubules form part of the cytoskeleton and provide structure and shape to cells.
> Phosphorylated = detached from microtubules
> p-tau morphologies
* Neurofibrillary tangles (NFT)
* Neurophil threads (NT)
* Neuritic plaques (NP)
amyloid-beta
Amyloid-beta: 36-43 amino acid peptide derived from APP
> APP: important for many functions including synaptic functions
Amyloid-beta morphologies:
* Classic plaque
* Diffuse plaques
* Aβ around vessels
* Subpial plaque
Spread of p-Tau accumulation: Braak NFT stages
Braak stage >1 = pathogenic
Starts at hippocampus spreads to neocortex
Stage 1: transentorhinal cortex
Stage 2: entorhinal region (& CA1)
Stage 3: fusiform gyrus, also called
occipito-temporal gyrus
Stage 4: middle temporal gyrus
Stage 5: occipital cortex (peristriate area)
Stage 6: occipital cortex (striate area)
Thal phase (0-5)
Amyloid-beta
Phase 1: neocortex
Phase 2: allocortical brain regions (entorhinal region, CA1)
and insular cortex
Phase 3: diencephalic nuclei, putamen, caudate, substantia
innominate and magnocellular nuclei of the basal forebrain
Phase 4: brainstem nuclei and CA4
Phase 5: cerebellum and other brainstem nuclei
TDP-43
DNA binding protein found in the nucleus of cells > mislocalized and misfolded.
Found in:
* Amyotrophic lateral sclerosis (97% of cases) ALS
* Frontotemporal dementia (~45% of cases) FTD
* Alzheimer’s disease (~20-55% of cases) AD
* Parkinson’s disease (19% of cases) PD
When it aggregates it exits the nucleus and goes to the soma causing degeneration
Parts of the brain atrophy
> FTD atrophy: language problems, Loss of executive functioning
TDP-43 aggregation can occur as:
inclusions, neurites, or combination of both
