Neurobiology of ageing les 1 15/4/2020 Van der Zee
Introduction brain ageing; learning and memory (1)
General vision about ageing: it is not possible to determine when someone belongs to the elderly as
ageing goes so slowly, and these changes per individual differ greatly. The boundary is often drawn
based on biological age and not on the basis of physical fitness and resilience although this is what is
should be.
Healthy ageing: to understand the underlying mechanisms and to reduce the morbidity.
Mortality = death rate; morbidity = disease rate
Comorbidity = the presence of one or more additional conditions co-occurring with a primary
condition.
The age structure in the Netherlands
The grey wave: in 2040 >25% of the population will be 65 or older (now: ca. 15%). In 2050 we have a
lot of elderly people in the population. This is not only a problem for the Netherlands, but for nearly
all of Europe, China and Canada. The life expectancy of the Dutch population is still increasing.
The role of the brain and cognition in ageing: the older (vital) brain has not yet been given its own
place and it needs more investigation.
What is normal ageing, what is pathological ageing?
They can be viewed as continuum without a clear turning point. The ageing process
(doesn’t matter for what function) does not run smoothly.
Individual variation in cognitive ageing
The target area stands for that your cognitive performance is good enough (you
can handle and function well in the society). The ‘special ones’ is an area above
the target area, these are the old people that are still very sharp minded. An
example of good cognitive ageing: the use of a new ING app at the age of 98
years.
Scientists hoped to show that the brain of a 115-year-old women had no traces
of Alzheimer’s or Parkinson’s. This could demonstrate for the first time that these are real diseases,
and therefore no signs of ageing. Alzheimer’s and Parkinson disease are clear examples of pathology.
This indicates that society is still struggling with the difference between ageing and
neurodegenerative diseases.
Parkinson’s disease movement disorder, you lose >60% of your dopaminergic cells this leads to all
kinds of physical problems. There can be Lewy bodies within a dopaminergic cell. Lewy bodies are
filled with deposits of the protein alpha-synuclein. Lewy bodies are abnormal aggregations of protein
that develop inside nerve cells, contributing to Parkinson’s disease.
Hallmarks of Alzheimer’s disease (AD)
- Senile (amyloid) plaques and neurofibrillary tangles (NFT). NFT is related to tau proteins. The
plaque is based on beta amyloid that has been cut in the wrong way, you keep a piece of the
protein that is not functioning, and you get accumulations typically in the form of plaques. In
AD, patients have massive amounts of amyloid.
, - The consequence of severe AD is a massive shrinkage of the brain; pattern of the Braak
stages. 60-70% of AD patients have these stages, but there are still quite a lot of patients that
do not fit very well in this model.
The Snowdon Nun study: there are healthy nuns despite that they have plaque presence. This
indicates that AD is a complex disease, having only plaques is not the whole story of Alzheimer.
If you talk to a pathologist: There are also people diagnosed with AD without above average
numbers of plaques and tangles.
The older brain in general has less brain activity in both the conscious and the unconscious part of
brain activity.
A lot of our brain activity goes unnoticed (habits, thoughts, emotions etc.), these are all going on, but
we are not aware of it. It is estimated that about 11 million pieces of information at any
one time is coming in, the brain can only process 40 pieces of information at any one
time. This shows that the info that is entering the brain and what is processed is much
higher than what we are aware of.
The cingulate gyrus is a very important area for the personal identity. This area reduces
between age 20-80 years, in volume with about 5.5%. The cingulate gyrus exists of several
subregions and it is somewhat larger in females compared to males, it is part of the limbic
system.
Anatomical features of brain ageing in different conditions: normal, sMCI (stable), cMCI (converted,
getting worse) and AD.
MCI mild cognitive impairment. Overall it can be said that if you are in the state of cMCI, you have
10% chance that the next year you fall in the category of AD.
- Ventricle: they will increase in size in normal individuals; this is mainly due
to the fact that you lose neurons and brain tissue. This increase in size is
even worse in cMCI and in AD.
- White matter (axons): in normal ageing, you see a reduction of the white
matter. Especially in cMCI and AD, the decrease in white matter is much
larger compared to the controls.
- Grey matter: in normal ageing you see a reduction of the grey matter. Especially in cMCI and
AD the decrease in grey matter is much larger compared to the controls.
The default modus is a network of brain regions that are active when an individual is not focused on
the outside world (but still ‘awake’). Other names are default mode network (DMN), defaults state
network, task negative network. In the default mode other areas are active compared to the areas
which are active during cognitive performance (alert state). The brain is constantly switching from
being in rest (default mode) to cognitive performance state (alert) which makes the brain tired. In the
old brain, the brain stays in the default mode much longer and it is more difficult to get the brain into
the alert state. The default modus is a state where you can make association between information, it
is a functional state.
Ageing hotspots in the brain brain areas that change as first and strongest with ageing.
Dorsolateral PFC; Hippocampus; Cerebellum.
These are the 3 brain regions where the first problems occur.
It follows more or less the ‘last in, first out’ principle. This can be used as a rule of thumb, it is not
entirely accurate. The brain areas latest developed contain the vulnerable links, forming the ageing
hotspots.
,Prefrontal cortex (dorsolateral) – hippocampus (dentate gyrus) – cerebellum (Purkinje cells)
These hotspots need to be regulated to work properly. The four ascending systems are used for this,
they have input to hotspots. Acetylcholine, serotonin, dopamine and noradrenaline.
There is a certain difference in the rate of ageing of these systems. Rate of ageing: noradrenaline =
dopamine > acetylcholine > serotonin. NE and dopamine age earlier than acetylcholine and
serotonin. NE & dopamine ageing starts at young adult; ca. 10% loss per 10 years.
Brain imaging studies show three general features of ageing:
1. PFC over-activation (especially in the dorsolateral PFC)
2. Posterior anterior shift (in brain activity)
3. Loss of lateralization
PFC functions: executive functions; planning; impulse-inhibition; working memory.
1 PFC over-activation (especially in the dorsolateral PFC)
At low cognitive load there is larger PFC activation seen is the elderly.
Situation 1: elderly people show a little more PFC activity at relatively low cognitive
load. Situation 2: the elderly show much more PFC activity in case of slightly higher
cognitive load. Situation 3: the elderly show much less PFC activity in case of high
cognitive load, the older brain sort of gives up.
2 activity shifts from posterior anterior
There is an increase in activity of the anterior parts of the older brain and a reduction of activity in
the posterior parts. In a young brain, there is a lot of activity in the posterior parts and less activity in
the anterior parts of the brain.
Frontal – occipital (posterior) activity ratio: much more frontal activity in the elderly.
3 loss of lateralization
In the young brain you typically see that a task can be done by one hemisphere. In the old brain you
see that the peek activity is lower, and it is not unilateral anymore, it is now bilateral.
Successful cognitive ageing: especially those elderly people who have PFC over-activation, posterior-
anterior shift and loss of lateralization. If you are old and you are not able to show these
compensations (changes) you are typically declining quickly in cognitive performance.
, Neurobiology of ageing les 2 15/4/2020 Van der Zee
Learning and memory (2); brain training
The most common memory complaints (later in life) are: forgetting names, cannot find the right
word, forgetting where you put your belongings, cannot reproduce texts or conversations, forgetting
planned actions, forgetting appointments, forget who said something, or where it was read (source
errors).
The long-term memory can be divided in declarative (explicit) memory and
non-declarative (implicit) memory. Declarative memory basically is
everything about facts. Non-declarative functions have more to do with
procedures, skills, priming, conditioning. At the bottom of the scheme you
see the most important brain areas linked to these different types of long-
term memory systems.
Do all cognitive functions deteriorate by ageing?
Speed of information processing and memory decline with age. But on the
other hand, general knowledge is built up over the years and this is increasing with age. So, not all
cognitive functions deteriorate by ageing, you also gain something.
The difference between implicit and explicit memory
The first test has a lot of implicit knowledge, task 2 and task 3 have more to do with
explicit knowledge (you need certain facts). The cognitive performance in young people
does not differ too much between the different tasks. In the elderly, they outperform
the youngsters in task 1 (implicit), they can lean on their general knowledge and
experience. But, if it becomes more explicit, it is more difficult for the elderly. The youngster
outperforms the older people in explicit tasks.
The different memory stages
When you are in the middle of the direct memory phase, there is already a little
bit of permanent memory formation and the other memory phases also already
started. The short-term memory aspects (direct and working memory) don’t
need protein synthesis. Long-term memory and permanent memory require
protein synthesis. In the older brain, the memory strength declines.
There are different brain areas associated with the forms of memory.
Short-term memory is associated with the PFC and with the hippocampus.
Long-term memory is associated with the neocortex, striatum, cerebellum and the hippocampus. The
memory that is formed stays in the hippocampus for about 3 weeks. After this there is memory
transformation from the hippocampus to the cortex. The amygdala plays an important role as soon
as emotions come in. it can influence the PFC, the hippocampus, neocortex, striatum and cerebellum.
There are four critical memory systems
- Hippocampus = declarative memory
- Striatum = procedural memory
- Amygdala = emotional memory
- Cerebellum = motor performance, timing and many other aspects related to cognitive
performance. But also, it can be seen as a general-purpose search engine for the brain to
detect co-incidences. Based on this function it becomes clear that the cerebellum will be
involved in many (cognitive tasks).
You can test the function of these brain regions in different ways.
