L4 - Alzheimer’s Disease, Dementia, and Mild Cognitive
Impairment
Dementia
· There are two definitions of dementia, one of the DSM-5 and the other one in the Medical field.
Even having different names or slight differences in the definitions, it is the same disease:
→ DSM-5. Major Neurocognitive Disorder.
- Cognitive decline in comparison with their previous performance level, so the cognitive
functioning of an individual is at a lower level than before. It can be reduced to just one
cognitive domain, like language, but it can affect more than one.
- Interference or problems in daily activities (ICF: limitation in everyday activities). Patients
with dementia need some kind of support to perform the complex (or instrumental)
activities of daily living (iADL), such as using the phone, cooking, reading a book, internet
banking… (the non-instrumental activities of daily life are more like putting clothes on,
brushing your teeth and showering on your own, which are only impaired in severe cases of
dementia).
- No delirium or confusional state present.
- No other psychiatric disorder present that could explain the cognitive decline, such as
depression or schizophrenia. (but people with depression and schizophrenia could end up
developing Alzheimer’s disease and dementia).
→ Epidemiology: Dementia is
even more common when
surpassing the 65 years old,
and when also having a late
onset of dementia most common
reason is Alzheimer’s disease,
but we still have to remember
that a lot of people develop dementia even being younger than 65
(12.000 people in The Netherlands).
- There is a problem with the Double Aging, which refers to the fact that now people live almost 2
times more than we used to do before and also, in most European and western countries, there are
more older people than younger people, which means that they are estimating that a lot of older
people are going to have dementia and there is not going to be enough young people to help them
with their health care, and also financially. It’s estimated that in 2050 half a million people would
have dementia in The Netherlands, and to offer them the same resources that they offer now to
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people with dementia, everyone that was 18 or more years old would have to be working at health
care, which is not possible.
→ Subtypes: There are a lot of diseases
that could end up with dementia
(Alzheimer’s disease (most common),
Frontotemporal lobe degeneration, Lewy
body dementia, Vascular etiology,
Traumatic brain injury, Alcohol and drug
use, HIV infection (if not treated), Prion
disease, Parkinson’s disease, Huntington’s disease…).
- The prevalence varies depending on the age (early
or late onset of the disease).
● Alzheimer’s Disease
- Underlying brain disease of dementia, it determines the clinical course but also the
clinical and cognitive symptoms, maybe more related to memory or to information
processing.
- Also called “cortical dementia” but quite an old fashioned label, gray matter of the
brain, the cortex is damaged.
- 50-60% of dementia is caused by Alzheimer's disease.
- Progressive and degenerative disease, which means that the onset of the disease is
slow and that it degenerates, it deteriorates the cognitive functioning more and
more with time. Usually people end up dying because the vital parts of the brain
like the brain stem are affected (swallowing and breathing difficulties) or because
the brain parts affected don’t let the individual live and take care of themselves.
(poor prognosis, which means that this disease has a small or non likelihood of
recovery).
- Structural and functional abnormalities in the brain. (like literally you can see it in
the brain
- The difference is that Alzheimer’s disease is a disease and it’s
one of the main causes of dementia, which is a syndrome.
- Atrophy: neuronal cell death. Senile plaques (protein,
amyloid, accumulations) and neurofibrillary tangles
develop in the brain. The plaques are between the neurons
and the neurofibrillary tangles are within the neurons,
which after disrupting neuronal connections and provoking neuronal dysfunction,
end up in neuronal death. That causes synaptical loss (losing neuronal connections
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that lead to cognitive decline) and brain shrinkage (the shrinkage of the
hippocampus explains the severe memory loss that Alzheimer’s disease dementia
patients have, also the ventricles are wider). All these changes start in the Medial
Temporal Lobe, including the hippocampus, so even in early stages of the
syndrome you can see these deficits. When it’s severe it’s not limited to just
memory, it affects a lot more cognitive functions.
- The diagnosis of the disease is made with clinical criteria and specially on the
basis of exclusion of other potential diseases that could cause the severe
cognitive decline.
→ There is supporting diagnostic evidence:
- MRI/SPECT (relatively new)/PET (can show amyloid
beta accumulation in the brain, the more red and yellow
the more amyloid accumulated) scans.
* The problem is that a quarter of the population with no AD
show this accumulation of amyloids and a quarter of AD
patients with all the clinical symptoms don’t have these
accumulations. The thing is that none of these scans are capable of
giving a diagnosis of AD being a 100% sure, but it doesn’t make
sense to invest in early diagnosis machinery if we still don’t know
how to cure the disease, there is no medication, and they would still
develop the disease even with an early diagnosis.
- Look for protein abnormalities in cerebrospinal fluid (CSF or liquor)
through a spinal tap (lumbar puncture) and then check the levels of
amyloids and tau protein. If there are low levels of amyloids that could be
an indicator of Alzheimer’s disease because the lack of the amyloid proteins
in the cerebrospinal fluid could be because it’s accumulated in the brain,
creating senile plaques. Also high levels of Tau protein in the CSF it’s an
indicator of Alzheimer’s disease (tau protein is related to the creation of
neurofibrillary tangles in neurons).
- Neuropsychological assessment.:
· Montreal Cognitive Assessment (MOCA)
- Neuropsychological assessment tool for dementia and other
severe cognitive disorders. Usually administered at the beginning
of the syndrome.
- Created in Canada, but now adjusted to different languages and
culture differences, but the template is the same.
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- Paper pencil test. Number of sub-tests to challenge the visuospatial skills, switching
from numbers to letters (1A2B3C…), copying 3 dimensional figures, copying a
clock and putting the hour that they tell you, naming exotic animals, memory test
of 5 words that needs to encoded in 2 trials and then recalling them later on,
attention test, language comprehension test and question about orientation (day,
time, place, season).
Maximum score of 30, and the Memory Impairment Score (MIS) can be scored
separately and it goes up to 15.
- 3 memory trials: Free recall (they need to remember the 5 words with no
help, 3 points each word), Cued recall (you give them ques, 2 points each
word) and the Recognition (if they fail with the previous memory tasks
you offer them a multiple choice and they need to recognize the word, 1
point each word).
The cut off point depends on the type of patients that are taking the
test and the age of those patients but in general, a score around 23-24
it’s an indicator of some kind of cognitive impairment, and for people
with dementia, a score under 7 could be an indicator of a memory
impairment that could go along with Alzheimer’s disease’s dementia.
· Visual Association Test (VAT)
Brief but really powerful episodic memory test. About new
memories. Combinations and associations of visual objects. The
hippocampus and medial temporal lobe in general play an
important role in associating new memories.
The immediate test is showing them the 2 elements together,
then remove one of those and ask them which element was
removed.
· Rey figure and Raven Progressive Matrices.
With the Ray figure you have to copy the figure after watching it for
a long time. In the video we see proactive interference where she
puts elements from a previous test, the Raven Progressive Matrices.
Very typical in people with memory problems like with Alzheimer’s
disease.
- Differential diagnosis at an individual level is often difficult because it overlaps with
other diseases like vascular dementia, depression, frontotemporal dementia… that
all come with cognitive deficits.
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● The cognitive profile of Alzheimer’s dementia:
→ Memory impairment present from the start (with
temporal gradient, they remember things of when they
were younger but they don’t remember what happened
yesterday because they don’t encode the information).
→ Decline in abstract thinking (intelligence). More
difficult to engage in deep and meaningful
conversations.
→ Impaired orientation in time, place and person, we
could see this pretty early in the disease development.
→ Other cortical disorders, cognitive functions that
might be affected: language (aphasia, apraxia, agnosia),
executive dysfunction…
→ Progressive course. They become worse with time.
- Cognitive Course over time
→ In principle, all cognitive domains can be impaired.
→ Course of impairments:
- progressive episodic memory decline, especially anterograde amnesia.
- impaired orientation in time and space
→ Followed by:
- deficits in abstract reasoning (intellectual functioning)
- executive dysfunction
- reduced insight (not aware of their difficulties).
→ Later phases:
- language disorders (production, comprehension)
- increasing retrograde amnesia with temporal gradient
- apraxia
- visuospatial deficits
- social cognitive deficits
- behavioral problems (disinhibition, apathy).
→ Final phase:
- mutism, mental retardation
- Profile of Memory impairment:
→ Impairments in episodic memory tasks
- Specifically in the encoding of contextual information
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- Poor delayed recall
- Rapid forgetting
→ Semantic memory in early stages (relatively!) intact.
This is about general knowledge like saying that a
carrot is orange, stuff that you learn at school.
- However: semantic priming impaired later in the course (in subcortical
dementia, motoric priming is impaired)
- Eventually all functions are affected
* There are other types of dementia like semantic dementia that starts with
problems in semantic memory and then it starts to have problems with
episodic memory, but this has another etiology, probably a disease
underlying usually a fronto-temporal lobe degeneration.
→ Working memory
- relatively intact on span tasks, which are tasks to measure the capacity of
the working memory (phonological loop (verbal and auditory
information) and and visuospatial sketchpad)
- impaired on associative (‘binding’) and executive aspects (dual tasks) of
working memory. As the task gets more complex, the more difficulties that
the patients will have.
→ Meta- memory in early stages intact; later severely
impaired. Knowledge about your own memory functioning.
→ Implicit knowledge is often intact, because this
relies on non-cortical structure, and Alzheimer's
disease is a cortical disease. Implicit knowledge like
riding a bike, changing gears in a car…
- Skills unimpaired (already learned) but apraxia can be present
- Implicit learning intact, but ‘structured/procedural learning” required
- Medication (symptomatic): Cholinergic Hypothesis
- treatment with acetylcholinesterase inhibitors (such as rivastigmine-early stages:
Exelon and galantamine-later stages: Reminyl). The acetylcholine is an activating
neurotransmitter that we have in the brain that we use for all the functions and in
people with dementia they have low levels of them. In the past they tried to give the
patients acetylcholine but it was absorbed by the stomach so it didn't work. But
what the acetylcholinesterase does is to inhibit the breakdown of acetylcholine in
the brain when it is releases in the synaptic gap, and that makes them have higher
levels of acetylcholine
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- Even though the acetylcholinesterase makes them be more oriented and alert, it
does not cure the disease, it’s a symptomatic medication, to make the symptoms
less potent or less frequent, but at some point of the disease they don’t work
anymore.
- It might also have severe side effects.
* New medications are more focused on the amiloyd (senile) plaques of the brain.
Vaccines in the cerebrospinal fluid twice a week in the hospital but the results are
not as good. Approved in the USA, not in Europe, they say it’s really invasive, there
is not enough evidence to support their argument and it’s really expensive to take
the risk.
- Three hypotheses on Alzheimer’s disease:
- Cholinergic hypothesis (obsolete: it’s a consequence not the origin).
- Amyloid cascade hypothesis (it’s still under debate because not all the patients
with Alzheimer’s disease suffer those accumulations, and people without the
disease do have them, so)
- Vascular hypothesis (vascular problems within blood flow and vessels lead to
neuron dysfunction and to the amyloid accumulations and neurofibrillary tangles),
mixed pathology.
- Posterior Cortical Atrophy (PCA): atypical posterior variant
of Alzheimer’s disease dementia. Not as common as the medial
temporal Alzheimer’s dementia, but it is still quite common.
- Not all Alzheimer’s disease begins with memory impairments,
there are some cases with posterior cortical atrophy, affecting
the parietal and occipital lobe provoking visuospatial deficits
like Agnosia, Hemispatial neglect, spatial cognition. But this is
more common in younger patients.
● Alzheimer’s disease and brain aging.
Before it used to be thought that aging was what kind of provoked the memory
impairments due to the hippocampus getting old, that people usually develop when you
start getting older and if you get old enough you would develop dementia. Nowadays there
is a group of people that manage to be quite old, sometimes over 100 years old and they
don’t develop any dementia. They do have some problems, maybe slower in cognitive tests,
but they don’t show these severe cognitive declines that come with dementia and were
thought to be part of aging.
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→ Mild Cognitive Impairment (MCI): pre-dementia stage of cognitive
decline
- Memory (or other domain) impairment established after doing neuropsychological tests.
They don’t meet the dementia criteria but they do have memory impairments, but they
still can function independently in their daily life.
- Of course they do have problems, they need to have complaints, but as long as they don’t
have limitations on their daily life, they still can live independently and find ways to
compensate for those memory (or other) deficits.
- About 20-25% of MCI patients develop dementia in the next 2 to 5 years (often due to
Alzheimer’s disease).
- Research focuses on the predictors of conversion to dementia and early treatment to delay
onset of dementia (or even stop disease). They want to enlarged the part of the disease
where they can still function independently, because apart from being better for them,
there are no enough resources for all the people that will have dementia in the future, so
they want to decrease the amount of dementia cases, but not making them disappear, but
delaying the onset of the severeness of the disease.
→ Mild Neurocognitive Disorder (DSM-5 of MCI)
- Cognitive decline with regard to previous performance level
in one or more cognitive domains
- No interference with daily activities: no dementia (this is what distinguishes mild from
major neurocognitive disorder in the DSM 5).
- No delirium
- No other psychiatric disorder present that could explain the cognitive disorders such as
depression, schizophrenia
- Mild NCD due to: Alzheimer’s disease, Parkinson’s disease, Vascular dementia…
→ Cognitive normal Aging:
- It usually starts with the thinning of the frontal striatal, which leads to
slowly progressive declines in executive functioning and memory and
eventually sometimes in MCI and dementia (caused by more than the
frontal striatal thinning).
- However in Alzheimer's disease dementia cases, it starts in the medial
temporal and associated cortex, which affects memory and ends up in
dementia and sometimes Alzheimer’s disease.
- Are these changes in the brain related to cognitive decline? Yes. Our cognitive decline as
humans starts around the age of 25, but because of the methods used to these studies now
we know that the decline is not as severe as thought, because age is not the only thing that
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influences the speed and the severeness of our cognitive decline, factors as gender,
education, environment etc, play an important role too.
- The good thing is that as some of our brain functioning declines or gets slower, our brain
finds other ways to compensate for those declines (Harold, research of language and
fluency test and MRI scans, you could see that older adults had more activations in
more brain parts and also more bilateral).
- Cognitive Reserve (Stern, 2009). The concept that when someone has a bigger
cognitive reserve (due to “cognitive scaffolding”)higher education, reeding, sports,
culture, social interactions) it reinforces the brain structures throughout their life and that
makes the cognitive decline slower.
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