Neuropathology Flashcards
(14 cards)
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: alpha synuclein
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
Who was alois alzheimer
Clinical psychiatrist who worked at a hospital and started to investigate patient Auguste D.
> investigated her brain post-mortem
> discovered and described plaques and neurofibrillary tangles
> lack of response from public to this discovery
> Perusini and Alzheimer observed 3 other cases comparable to Auguste D.
> report on the case was included in Kraepelin’s famous textbook Psychiatrie
He was Kraepelin’s first research assistant which allowed him to devote all his time to research
He was head of the histopathological laboratory
Josef F. brain and issues surrounding it
Alzheimer found no neurofibrillary tangles, only plaques in his brain post-mortem
> later more modern research reinvestigated the slides and concluded plaque-only cases and cases with both are simply different stages in the development of the same disease
> Alzheimer was the first person to describe an important stage of development in Alzheimer’s Disease
