Lecture neurodegenerative disorders 8: healthy centenarians - 100+ study Flashcards
How is aging described in this lecture?
The cumulative loss of the capacity to oppose damage to the body, leading to an increase in mortality in the log scale, the body has a built-in expiration date.
What data was collected for the 100+ study?
- Firsy day → Disease history, family/genetic assessment, lifestyle and blood draw.
- Second day → Cognitive testing and leftover questions.
- Yearly follow up → Cognitive testing and documentation of other changes.
Just know that this is the patient information in the 100+ study.
Ok
Name examples of data that was collected from healthy centenarians.
- Life history
- Familial heritability
- Neuropsychological performance
- Gut microbiome
- Genetics
- Immunology
- In vivo neuropathology
- Post mortem molecular brain profiling (neuropathology, proteomics, RNAseq)
Various testing methods were used to determine cognition. What test were exceptionally well performed by most centenarians?
The clock drawing and also the mini-mental state examination.
Was there a relation between the MMSE-score and survival?
Yes, with a higher score on the MMSE, the survival probability is higher.
Just study → brain donations (n=85)
Ok
One of the PET scans for amyloid-beta of a 103 year old female with a MMSE-score of 27 is depicted here. What can be concluded?
That even though she has amyloid-beta pathology, she is still cognitively able to score 27 on the MMSE. This tells us that there’s a mechanism that prevents neurodegeneration, even in presence of amyloid-beta (i.e. → resilience)
Besides the presence of amyloid-beta in the brain of healthy centenarians, what else is seen?
That in general, AD associated pathologies are prevalent in cognitively healthy centenarians. Besides amyloid beta, there’s also tau pathology and the presence of neuritic plaques.
!!!!! dia 38 What is seen here?
When it comes to Braak stages, that there’s a threshold in age, where it doesn’t really matter if you already have dementia or are healthy. You see that:
- Non-dementia and dementia patients who die after 100 years, have AD pathology in their brain
Where is this age threshold of around the age of 100 years also seen?
In brain weight
!!! Dia 40
Name centenarian-specific age-related protein-groups.
In brains of centenarians, it is found that there’s an increase in the following:
- microtubules
- intermediate filaments
- protein transport
- ATP metabolism
- Immune system
- Myelin
What is the chance of becoming a centenarian when your sister is already a centenarian?
About 60%
There are genetic components that are involved in the chances you have of becoming a centenarian. What are these genetic components?
A person is:
- Enriched with protective elements
and/or
- Depleted with risk elements
What gene is involded in the risk for or the protection against AD (above 75 years)?
APOE gene
The APOE gene has polymorphism, which means there are variants of this gene found. These variants are APOE e2, APOE e3 and APOE e4. Which variants are protective and which enhance the risk for AD? Or in other words: what variants have a lower polygenic risk score (PRS)?
- APOE e2 is the protective variant and is present in cognitive healthy centenarians → has a low PRS
- APOE e3 is neutral and doesn’t affect the risk for AD → PRS of 0.
- APOE e4 is a riskfactor for AD and highly increases the chances of developing AD → high PRS.
This picture is from a centenarian, aged 104 years old and carries the APOE e4 gene.
Why is it possible for this person to be this old and to draw an almost perfect clock, but at the same time to carry the risk gene for AD and also exhibit a lot of plaques in her brain?
This is probably due to a variant in the PLCG2 gene. It has a function in the immune system and protects againstt AD, dementia with lewy bodies and FTD.
What is the effect of the variant PLCG2 P522R on B cells and myeloid cells?
- B cells → PLCG2 expression and activation is increased and Ca2+ response is unchanged.
- Myeloid cells → PLCG2 expression and activation is increased, phagocytosis decreased and ROS production increased.
This variant seems to result in an immune system resistant to signs of aging.
What are aging-associated hematopoietic consequences?
- Less lymphoid cells (T and B cells)
- No T cell immunity
- Age related cloncal hematopoiesis associated wih age related disease.
