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Introduction PathologyThe study of disease (study of functional and structural changes in cells, tissues and organs that cause
disease). To diagnose a disease using morphological, immunological and molecular techniques. It
contributes to therapeutic options.
Disease
Etiology: cause
Pathogenesis: mechanism of its development
Morphologic and molecular changes: structural alterations induced in cells and organs of the body
Clinical significance: relation to the clinical pictures
Approach of the pathologist
Study of changes in tissues, cells, subcellular structures, proteins and genes. Combine these with
relevant clinical information leads to the diagnosis.
- Tissue biopsy
, - Excision or resection, organs be partly or completely removed
- Intraoperative diagnosis, frozen section
- Macroscopy
- Lab flow
- Light microscopy, standard histology H (nucleus) and E (cytoplasm), stains
- Histochemical stainings
- Immunohistochemistry
- Cytology (cells), fine needle aspiration
- Molecular pathology, in situ hybridization on tissue (amplification of specific genes/gene
translocations) or sequencing on cells, tissue and liquids (mutations, amplifications fusions,
deletions, translocations etc with next generation sequencing).
The role of the pathologist
Diagnosis, TNM-classification (staging), resection margins, targets for treatment. Together with the
surgeon/oncologist/radiologist/radiotherapist they create the best treatment plan.
Types of autopsy
1. Hospital autopsy
a. Clinical pathologist
b. Almost every hospital in NL
c. Permission from relatives required
2. Medico-legal autopsy
a. Forensic pathologist
b. Nederlands Forensisch Instituut
c. Ordered by district attorney (no permission from relatives required)
Neuropathology Alzheimer Disease
know the areas and the borders!
Grey matter consists of neurons, where the actions are made.
White matter has all the connections between the area's of the grey matter. It
is white due to the myelin sheets.
The neocortex is very important in AD. The neocortex consists of 6 layers
and each layer has its own function. The red area is the motor area (5th
layer). Blue indicates the sensory part of the neocortex.
,Causes of dementia
- Alzheimer's disease (60%)
- Lewy body related dementias (10%)
- Vascular dementia (10%)
In most cases it is a mixture of causes. The common final pathway of all dementing diseases is loss of
function of neurons/synapses
Brain structures associated with dementia
- Cerebral cortex (specific functions)
- White matter (connections, myelin)
- Hippocampus ((short term)memory), first sign of AD so it might start here
- Amygdala (emotions/behaviour)
- Thalamus (relations with prefrontal cortex)
Function of cerebral cortex
Prefontral: planning, personality, emotions
Dominant insula region: language
Parietal: recognition, orientation
Diverse sites: memory and motor functions
For right handed persons, the left hemisphere is the most important. For the left handed persons you
cannot say it immediately, you have to test where the speech area is.
Macroscopy of AD
Atrophy (part of an organ gets smaller), it starts in the hippocampus, then goes to the temporal lobe,
frontal/parietal lobe and lastly occipital lobe. So the occipital lobe is mostly speared. Atrophy is not
specific for AD and not always present. No other lesions (tumors, infarcts) that can explain the
dementia.
Microscopy of AD
Neuritic plaques (NP) or DP
- Diffuse plaques - plaques without dystrophic
neurites
- Neuritic plaques (NP) - presence of dystrophic
neurites
Neurofibrillary degeneration
- Neurofibrillary tangles (NFT) in the neurons
- Near the nucleus
- Dystrophic neuritis (in plaques)
- In the dendrites
- Neutrophil threads (NT) used for grading
- Loose in the parenchyma
Cerebral amyloid angiopathy (CAA)
- Proteins in some of the vessels
White matter changes
, Amyloid B (AB)
Altered metabolism of precursor protein (APP) and leads to proteins of 40-42 amino acids. It is a
major protein in NP and CAA (occurrence of plaques and vessel abnormalities). It is mainly
extracellular (in contrast to tau) and partly present in the form of amyloid (not the same). AB-42 is
toxic and aggregates easily. Oligomers (adherence of the 40-42 amino acids) are most toxic. Seeding
goes via soluble oligomers. AB causes narrow and fragile vessels and this may cause hemorrhage
and/or infarction. AB is many years before signs of disease are present.
Tau
Normal function is the stabilization of microtubule. During abnormal phosphorylation there will form
free oligomers. Further aggregation leads to neurofibrillary degeneration (fibril formation in tissue).
Fibrils are intraneuronal deposits. Tau is mostly present inside the cytosol in the cell. It spreads via
seeding (extracellular space and synapses). It is strongly associated with severity of dementia (AB not
so much).
Topography/progression
NFT: Starts entorhinal/hippocampus and has the same progression as atrophy
NP: Starts everywhere in the neocortex. Later is progresses to the entorhinal/hippocampus and finally
it will go to the deep nuclei.
Definite diagnosis of AD
Complex scoring system. Braak stadium (see slide) is by far the most important, the latest stage is the
visual cortex impairment. Other factors are presence and distribution of AB in parenchyma and
presence and distribution of neuritic plaques. Additionally (apart from this score) a score for presence
of Lewy bodies and vascular damage must be given.
Pathogenesis of AD via AB
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