The impact of cognitive reserve on the... and brain pathology in Alzheimer’s disease

The impact of cognitive reserve on the relationship between clinical expression
and brain pathology in Alzheimer’s disease
Malin Sandell
Handledare: Ove Almkvist
KANDIDATUPPSATS, PSYKOLOGI III –VETENSKAPLIG UNDERSÖKNING, VT 2014
STOCKHOLMS UNIVERSITET
PSYKOLOGISKA INSTITUTIONEN
THE IMPACT OF COGNITIVE RESERVE ON THE RELATIONSHIP BETWEEN
CLINICAL EXPRESSION AND BRAIN PATHOLOGY IN ALZHEIMER’S DISEASE
Malin Sandell
There is two different ways to react to a disease like Mild cognitive
impairment and Alzheimer’s disease, pathological and clinical. What if there
was a way to delay the clinical expression of a disease through pathology?
The cognitive reserve has been proven to show a more rapid decline in the
individuals that had higher reserve. The purpose of this study was to see if the
cognitive reserve actually had an impact on the outcome of Dementia and
Alzheimer’s disease. A total of 53 patients with varying degrees of disease
pathology and clinical symptoms participated in the study. The results
demonstrated that the cognitive reserve makes an impact on the clinica l
expression, the individuals with high cognitive reserve have a delayed clinica l
expression comparatively with those with low reserve. Studies of the
cognitive reserve may point the way to successful interventions that can help
maintain successful aging and slow the onset of dementia.
The brain is a complex thing, very fragile but incredibly strong at the same time. There is an
enormous amount of diseases that can affect the brain. An interesting question is whether there
is something that can be done, without medicine, in order to delay the disease pathology. A
study by Stern et al (1995) showed that education provided a reserve against the clinica l
expression of Alzheimer pathology. The present study will examine if the cognitive reserve has
an impact on the disease pathology of Alzheimer’s disease. To see if there is any intermed iate
position between healthy people and people with Alzheimer's disease have a few patients with
Mild Cognitive Impairment been included in the study.
Cognition is a collective term for the individuals’ mental processes in the brain, normally
volitional, that includes knowledge, thinking and information. These processes concern sensory
input that is transformed, reduced, elaborated, stored, recovered and used. (Marcusson,
Blennow, Skoog & Wallin, 2011) The features that are commonly referred to in cognition are;
attention, memory, learning, calculating, reasoning, problem solving, decision making,
language ability and executive ability. Cognition is an information processing view of an
individual's psychological functions. Cognitive disorders are a category of mental health
disorders that are characterized with brain damage and that affect many functions, primarily;
memory, learning, orientation, language, perception and problem solving. The loss of cognitive
functions has to be the primary (casual) symptom in a cognitive disorder, as it is in amnesia,
dementia and delirium.
In recent years, dementia has been emphasized as a global disturbance of intellectual functio ns.
Before that, the definition of dementia has varied extensively over the years (Marcusson et al,
2011). In DSM IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition)
dementia is defined as “a decline in the ability of memory and other intellectual abilities” and
the symptoms are often associated with changes in behaviour and personality (American
Psychiatric Association, 1995). There is a newer edition, the DSM-V, which was published in
2013. In this issue, the word "dementia" has been replaced with
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"major neurocognitive disorder" and "mild neurocognitive disorder". As the newest edition was
not available, this study continues with the word "dementia", because the very definition of the
disease has not been changed.
When a person has dementia there should be a clear decline in the individuals’ intellec tua l
capacity compared to earlier in their lives. Advanced age is associated with greater knowledge
and life experiences but also with changes in the cognitive processes that lead to a decline in
cognitive performance. The decline can even go to the extent that a diagnosis can be decided
(e.g. dementia). The reason that increasing age is of importance for the development of
dementia is likely that the number of negative influences on the brain increases with older age
and the effect of certain risk factors are dependent on the time of exposure to them. The risk
factors for dementia occur throughout life, from inborn genetic factors and neonatal, early
childhood (head injury), youth (education, loss of parents), middle age (obesity, diabetes, lung
function, exercise, activity etc) to later in life (social networking, recreation, disease etc)
(Marcusson et al, 2011). Symptoms of dementia can be seen at around seventy differe nt
disorders, the predominant diagnoses are Alzheimer's disease (AD), vascular dementia (VaD)
and frontotemporal dementia (FTD) (Marcusson et al, 2011).
It is often said that the frequency of dementia doubles for every five-year-increase in age, this
increase is especially pronounced for Alzheimer's disease (Marcusson et al, 2011). AD mainly
affects people over the age of 65 and is the third leading cause of death in the Western world
after cancer and cardiovascular diseases. A PET (Positron Emission Tomography) has
successfully been used to differentiate Alzheimer's disease from other dementias, and also to
make early diagnosis of Alzheimer's disease (Marcusson et al, 2011). The tomographic image
reconstruction by the PET is made by a gamma detector that simultaneously detects two
different gamma flares that occur when a radionuclide hits an electron of opposite charge. The
PET scan is a standard functional brain imaging method.
The aggregation of β-amyloid and plaque formation may be assumed to be the initiating factor
for Alzheimer. Plaque was discovered in the late 1900's, mostly consisting of a small peptide
called Beta-Amyloid (β-amyloid) (Marcusson et al, 2011). Around the same time,
neurofibrillary that consisted of a phosphorylated form of the protein tau was also discovered
(Marcusson et al, 2011). Tau is a protein in the nerve axons in the brain, phosphoryla tio n
enables tau from no longer form equally well to microtubules, and thus to a disturbed axonal
stability and transport capacity. This leads to a degeneration of the nerve synapses and axons,
as well as formation of neurofibrillary. According to the amyloid cascade hypothesis it is the
formation of various forms of β-Amyloid aggregates and precipitation thereof in the brain
parenchyma that leads to various reactive processes such as a low-grade inflammatio n,
oxidative stress and an imbalance between the kinases and phosphates that regulate the
phosphorylation of tau (Marcusson et al, 2011).
There is only one identified susceptibility gene for Alzheimer’s disease and it is the
Apolipoprotein E (ApoE). ApoE is a protein found on the surface of lipoproteins and thus has
significance for the metabolism of lipids (e.g., cholesterol) in the body. At various forms of
brain damage ApoE is produced to take up cholesterol and other lipids from neurons that have
been damaged, causing the formation of lipoprotein particles that later are reused in the
reconstruction of the nerve cells. There are four different ApoE allele genes, those who have
the fourth type (ApoE-ε4 allele) has up to 20 times the risk of developing Alzheimer's disease.
Alzheimer's disease is a genetic heterogeneous disease that can be divided in two types, a
familiar type and a sporadic type. Familial Alzheimer's disease has an autosomal dominant
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inheritance pattern and almost all cases have an early onset, while sporadic Alzheimer mainly
occurs in old age. The familial type can either indicate that heredity factors are of importance
or that factors in the early environment matters the most. There are twin studies that provide
support to the fact that heredity factors are most important because monozygotic twins are at
greater risk of both getting Alzheimer's disease than dizygotic twins are (Marcusson et al, 2011).
As a contrary, studies that compared Americans who are descendants of immigrants from
Nigeria with those who still live in Nigeria shows that the frequency of dementia was much
lower among those who remain in Nigeria (Marcusson et al, 2011). But this may reflect the
higher survival factor in America than in Nigeria instead of support for the environme nta l
factors. In a large randomized controlled study of healthy elderly, training of memory and
mental speed led to a less marked decline of cognitive capabilities and the ability to perform
complex everyday activities. The effect persisted even after 2 and 5-year follow- ups
(Marcusson et al, 2011). This shows that there is support for the fact that cognitive training has
beneficial effects on cognitive function in healthy elderly. These observations are in line with
the increasing realization of the plasticity of the aging brain and the fact that cognitive
intervention might be useful in aging and dementia. This evidence also suggests that
experiences at all stages of life, even in late life can slow age-related cognitive decline and
prolong healthy aging.
The partition between a healthy person, one with Mild Cognitive Syndrome (MCI) and an early
developing of Alzheimer's disease can be very difficult to do. Partly due to that Dementia and
particularly Alzheimer’s disease often begins years before it becomes clinically manife st.
Subclinical symptoms affecting; memory, language and personality begins to appear early, but
not to the point that a diagnosis can be determined. Therefore are particularly MCI difficult to
separate from normal aging (Marcusson et al, 2011). Multiple studies have found that blood
pressure is elevated 10-25 years before Alzheimer's disease will develop, and the years before
the disease becomes clinically manifest, the blood pressure will drop. The decreasing blood
pressure in patients with dementia is likely due to that the central blood pressure regulation in
the brain is eliminated (Marcusson et al, 2011).
Mild Cognitive Impairment refers to more descriptive symptoms of a condition that can have
several underlying factors. Thus, it is important to note that MCI is not a distinct disease entity
with a clear underlying disease mechanism. It is defined as an impairment for a longer period
of time of an individual's cognitive functions, it represents a transitional phase between normal
aging and dementia disorders. An individual that is suffering from MCI often complains about
increasing difficulty to remember things. This can be observed when asked targeted questions
about memory, e.g. remembering which grocery to purchase. Sometimes the patient can return
home with the groceries that were already purchased the day before. Patients with MCI have an
increased risk of developing Alzheimer’s disease (Petersen et al, 1999). Some proteins in
Cerebrospinal Fluid (CSF) have shown prognostic value in discriminating MCI patients tha t
will develop AD (Mattsson, Zetterberg, Hansson, Andreasen, & Parnetti, 2009). The proteins
in the Cerebrospinal Fluid have also been studied as a potential biomarker in MCI. CSF allows
the brain to maintain its density without being impaired by its own weight, without it the brain's
weight would cut off blood supply and kill neurons. CSF acts as a cushion for the brain’s cortex,
protecting the brain tissue from injury when bumped or hit.
There is an individual difference in how people deal with brain pathology, the active and passive
reserve capacity is the most noted once. Passive reserve capacity is linked to the premorbid
brain size, while higher education and other forms of mental training and/or stimula ting
experiences can build up the active reserve. According to the hypothesis of the passive reserve
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people with bigger brains and more neurons and synapses need more extensive damage in the
brain before receiving clinical signs of dementia. Several studies show that people with
dementia or Alzheimer's disease has a smaller brain volume than others and that dementia onset
earlier in those with smaller brain volume, which could support that the brains’ reserve capacity
is relevant. The brain reserve model says that reserve drives from brain size or neuronal count.
Larger brains can sustain more insult before clinical deficit emerges, because sufficient neural
substrate remains to support normal function. (Stern, 2013) It is also found in a
neuropathological study that it takes more extensive neuronal loss and more plaques and
neurofibrillary for people with larger brains and more neurons to develop dementia. In the
passive model, there is something called "The threshold model" and it revolves around the
construction of "brain reserve capacity". The model says that the specific clinical or functio na l
deficit occurs when the "brain reserve capacity” is depleted beyond this threshold. If two
patients have different amounts of "brain reserve capacity," an injury of a certain size exceed
the threshold of brain damage sufficient to produce a clinical loss in one of the patients but not
the other (Stern, 2003).
The other reserve capacity, the active one, speaks about the concept of Cognitive Reserve that
first emerged from epidemiologic observations (Stern, 2009). The desire to understand the
neural basis of CR has been a motivating element for functional imaging studies that can
contribute to the understanding of the changes in brain behaviour that occurs with aging. The
cognitive reserve assumes that a difference in the cognitive processes, or neural networks,
underlying task performance allows some individuals to cope better than others with brain
damage (Stern, 2009).
“The reserve model” predicts that because there are individual differences in reserve capacity,
there will be individual differences in the amount of pathology required for the initial expression
of clinical symptoms and the subsequent diagnosis of the disease (Stern, 2009). Two patients
might have the same amount of “brain reserve capacity”, but the patient with more CR would
tolerate a larger lesion than the other patient before clinical impairment is apparent. This is
because one of them can make better use of the remaining brain substrate than the other one
can (Stern, 2013). Those with higher CR tend to have better clinical outcomes for any level of
pathology and brain reserve. The hypothesis of the active reserve is supported by a study
conducted on nuns in the U.S., where the analysis of the content of an essay that the nuns wrote
when they were in their 20s could predict who would get Alzheimer's disease in older age
(Marcusson et al, 2011). A theory behind the active reserve says that mental stimula tio n
throughout life leads to increased synapse density, neurogenesis and improved efficiency and
flexibility of the neural networks, which could act as a buffer when the cells are degenerating
due to old age or illness (Stern, 2009). In recent years it has become apparent that the boundaries
between brain reserve and cognitive reserve is not clear. One way to look at this is that CR
implies anatomic variability at the level of brain networks, while the brain reserve asides
differences in the quantity of available neural substrate (Stern, 2009).
Stern et al (1995) conducted a study of 246 subjects with probable Alzheimer's disease where
they looked at if the clinical symptoms of the disease began earlier in individuals with less
education. Their study showed that education provided a reserve against the clinica l
manifestation of Alzheimer pathology. Stern performed another study together with Albert,
Tang and Tsi (1999) that included 177 AD patients. In this study they looked at the memory
decline in people with higher respective lower educational- and occupational attainment. They
found that the decline was more rapid in the individuals that had higher educational- and
occupational attainment and for those with lower.
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The purpose of this study was to get a better understanding of the cognitive reserve and if it
actually has an impact on the outcome of dementia and Alzheimer's disease. The research
question was; Can cognitive reserve delay the clinical expression (based on the test
performance) at different degrees of pathology (according to PET PIB) in people with known
or suspected Alzheimer's disease?
M e tho d
Participants
This study is a part of an ongoing research at Karolinska Institutet led by Professor Agneta
Norberg. The patients consisted of 5 healthy controls (C), 16 MCI patients and 32 AD patients
(see Table 1). The patients were referred to the Department of Geriatric Medicine, Karolinska
University Hospital in Stockholm for memory problems. The patients with Alzheimer's disease
fulfilled the diagnosis according to the criteria of the National Institute of Neurologic and
Communication Disorders, Alzheimer Disease and Related Disorders Association (NINCDSADRDA) (McKhann et al, 1984). The MCI patients also fulfilled the criteria for the diagnosis
established by Petersen (2004).
Table 1. Number of participants (N) divided into Men and Women (M/W). The mean and
standard deviation of age and number of years of education for each diagnosis
C
MCI
AD
N (M/W)
5 (3/2)
16 (5/11)
32 (15/18)
Age
62.86 (9.03)
65.03 (7.09)
67.85 (9.11)
Years of education
13.60 (2.30)
12.13 (3.96)
12.22 (3.97)
Equipment and Materials
All data was received from a research group at Karolinska Institutet; Department of
Neurobiology, Care Science and Society; Division of Translational Alzheimer Neurobiology
and led by Professor Agneta Nordberg. This group focuses on the cell structure, behaviour and
imaging of Alzheimer's disease.
Assessment of cognitive functions.
One way to test the clinical expression is to perform various neuropsychological tests. The
research team choose to use Full Scale Intelligence Quotient (FSIQ), Similarities, Block
Design, Rey Auditory Verbal learning - Retention and Digit symbols. The various tests are
explained below.
The “Full Scale Intelligence Quotient (FSIQ)” is used to measure a hypothesized general ability,
otherwise called intelligence. One of the tests might be a pattern test that is based on that the
patient is shown a complex figure and then has to draw it. The patient is given other exercises
to do in approximately 30 minutes and when those minutes are up, the patient has to draw the
figure again from memory (Lezak, Howieson & Loring, 2004). The scoring is measured in such
a way that if an individual get a score between 90-109 it is considered "Average", 69 or below
is "Well below average" and 130 or higher is "Very Superior".
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In the test called “Similarities”, the patient gets to hear two words, for example "Banana" and
"Orange" and should then mention the common denominator for these words. In this case it
would be "fruit" (Wechsler, 1981).
With “Block design” the patient uses 9 blocks coloured red on two sides and white on two, the
other two sides are half red and half white. Nine cards that have different designs printed on
them are also used. The patient will then see one of the designs of one of the cards and then try
to do the same design with the coloured blocks (Wechsler, 1981).
In the “Rey Auditory Verbal Learning – Retention” test, the patient hear a list of words and
then repeat as many of them as possible. This is done a number of times with the exact same
words. In order to get the patient on second thoughts they would do something else for a while
and when some time had passed, the patient had to name as many words as the person remember
without hearing the words again. The one used in this study is the second time the patient had
to name the words, the retention, because it is a measure of the episodic memory.
In the “Digit Symbol” test, the patient receives a worksheet, which states a bunch of numbers
in disarray, and under them it is an empty box. At the top of the paper the numbers are in order,
but beneath them are symbols. The patient's task will be to write the correct symbol under the
correct number on the worksheet, as many as possible in 90 seconds (Wechsler, 1981).
Measurement of β-Amyloid in the brain.
With the PET technology used in this study it is possible to measure the amount of Amylo id
accumulation in different brain regions, along with the glucose levels (Marcusson et al, 2011).
The method has a relatively high diagnostic accuracy (85-90%) to distinguish Alzheimer's from
normal aging and other dementias (Marcusson et al, 2011). Several PET ligands that bind to βAmyloid has been developed, the one who is most studied is a Thioflavin T analogue called
Pittsburgh Compound-B (PIB). A PIB PET is a promising diagnostic method, but is not widely
available and a very costly investigation. PET with the PIB reliably measures fibrillar βAmyloid in the brain of patients with Alzheimer’s disease in vivo (Carter et al, 2012). The PET
PIB technology was chosen to measure brain pathology because it seems as if PIB imaging
might be more effective than CSF biomarkers in the discrimination of prodromal AD patients
(Forsberg et al, 2008).
Index of the cognitive reserve.
The years of education was used to determine the cognitive reserve. Because it is a quick and
easy way to see how long time the brain has been stimulated. Then, to get a measure of where
the boundary between high and low cognitive reserves would go, the choice was made to
distinguish between those who had up to high school education and those with higher education
than that. When doing this separation half of the participants ended up in the lower group (n=29)
and the other half in the higher (n=24).
Procedure
The patients
went through
comprehensive
clinical
examinations
includ ing;
electroencephalogram, neurological and psychiatric examinations, CR or MRI, blood and
cerebrospinal fluid (CSF) analysis and neuropsychological testing. All tests were administered
following standard procedure, (see Lezak et al, 2004). A diagnosis was established through a
consensus committee that included doctors, clinical neurophysiologists and specialist nurses.
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All patients and their caregivers gave written informal consent to participate in this study. Ethics
approval was obtained from the Regional Human Ethics Committee in Stockholm and the
Faculty of Medicine and Radiation, Hazard ethics committee of Uppsala University Hospital,
Sweden.
Re s ults
The analytical methods used in this study are; one-way independent ANOVA, means and
standard deviations and a factor analysis. The results showed that the diagnosis had a significa nt
effect on all the ANOVAs.
A one-way independent ANOVA with diagnosis as the independent variable and sex, age and
years of education as the control variable was conducted. This was performed to rule out that
either age [F (2,50) = 1,088, p=0.345], sex [F (2,51) = 0,765, p=0.471] or number of years of
education [F (2,50) = 0,307, p=0.737] would be an underlying variable and interfere with the
final result.
The ApoE gene was divided into two different groups, individuals with at lease one ApoE4
allele and individuals without it. The mean and standard deviation were counted for each
diagnosis; C (m=0. 200, s=0. 447), MCI (m=0. 563, s=0. 512) and AD (m=0. 697, s=0. 467).
The results of that calculation shows that the more severe disease pathology, the higher amount
of individuals with the ApoE4 allele. A one-way independent ANOVA with the diagnosis as
the independent variable and ApoE as the dependent variable were performed. The ANOVA
showed no significant result [F (2,51) = 2,453, p=0.096].
Then, the mean and standard deviation for all the neuropsychological tests that measured the
clinical expression was counted (see Table 2). A one-way independent ANOVA with diagnosis
as the independent variable and the neuropsychological tests for the clinical expression as the
dependent variable was conducted as well. This was also done to ensure that it was the FSIQ
[F (2,41) = 9,558, p= <0.000], Similarities [F (2,47) = 7,058, p=0.002], Block design [F (2,48)
= 15,181, p= <0.000], Rey Auditory Verbal Learning - Retention [F (2,47) = 17,070, p= <0.000]
and the Digit Symbol [F (2,38) = 7,639, p=0.002] tests that influenced the diagnosis. The results
of the ANOVA showed that all the tests that measured the clinical expression had a significa nt
result of the diagnosis.
Table 2. The mean and standard deviation for all the neuropsychological tests on each diagnosis
Full Scale Intelligence Quotient (FSIQ)
C
MCI
AD
115.67
(22.72)
97.20
(18.33)
75.58
(20.01)
8
Similarities
23.00 (2.12)
21.06 (3.92) 15.52 (5.40)
Block Design
35.00 (9.27)
24.81
(10.03)
12.32 (9.69)
Rey Auditory Verbal Learning – Retentio n 11.40 (2.97)
(RAVLr)
8.00 (3.88)
3.24 (3.38)
Digit Symbol (Speed and Executive Function)
44.91
(12.65)
25.44
(18.61)
53.33 (9.71)
Brain pathology can be observed through both β-Amyloid and PET scan, the choice has been
made by the researcher to only continue with the PET PIB variable because Forsberg et al
(2008) pointed out that PIB imaging might be more effective than CSF (β-Amyloid) biomarkers
to discriminate prodromal AD patients. The PET scan was initially divided into all the differe nt
brain regions and also in the left and right sides of the brain. The variables included, among
others; Cerebellum, Cingulate Gyrus and Thalamus. All of the 49 variables were included in a
factor analysis with a varimax rotation. And all variables charged on one variable, explaining
78, 6% of the original variables. Therefore all PET data were summarized by one common
variable conducted by adding all the results means together. This summarized variable can be
observed in the x-axis of figure 1 and figure 2.
To get a good image of how the cognitive reserve influences the pathology, a figure with brain
pathology in x axis and the clinical expression in y axis was made, with high cognitive reserve
as unfilled circles and hashed black lines and low cognitive reserve as filled circles and solid
black lines. To make the figure more readable, regression lines were added, by the statistica l
program SPSS. The reason that not all the variables were combined for the neuropsychologica l
tests as the PET PIB variables were, was because the different tests that measures the clinica l
expression was scored very different from each other.
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Figure 1. The relationship between the clinical expression (The Digit Symbol test) and Brain
Pathology (PET PIB) for high respective low cognitive reserve.
Figure 2. The relationship between the clinical expression (episodic memory) and Brain
Pathology (PET PIB) for high respective low cognitive reserve.
The results of the scatter plots show two linear regression lines for the cognitive reserve on each
figure. Where the amount of variation in the outcome of figure 2 can be explained by the
independent variable for high cognitive reserve by 42% and for low cognitive reserve by 26%.
And for figure 2 the amount o variation for the high cognitive reserve is 20% and for the low
cognitive reserve, 36%.
All of the neuropsychological tests are not shown as figures because the Digit symbol test and
the Rey Auditory Verbal Learning – retention test (High CR = 34%, Low CR= 23%) had the
same result and similar regression lines. And the Full Scale Intelligence Quotient had the same
result and similar regression lines as Similarities (High CR = 4%, Low CR = 13%) and Block
Design (High CR = 26%, Low CR = 34%) tests.
Dis c us s io n
The aim of this study was to get a better picture of the cognitive reserve and if it could have an
impact on the clinical expression of dementia and Alzheimer’s disease. The initial question
was: “can cognitive reserve delay the clinical expression (based on the test performance) at
different degrees of pathology (According To PET PIB) in people with known or Suspected
Alzheimer's disease?”. With this study, a result could be obtained that can begin to answer it;
yes, it is possible that the cognitive reserve can delay the clinical expression. But once a person
gets the diagnosis it appears that those with higher education (i.e. higher cognitive reserve) may
have a faster progression. Perhaps this is because the individuals with high cognitive reserve
show symptoms of the disease when the neuropathological changes are severer than in those
with low cognitive reserve. Stern (2013) agrees with this, he believes that this difference is due
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to that once an individual with high CR reaches the point where pathology begins to affect
performance, the level of pathology is already quite advanced (as seen in Figure 1). The result
of this study states that the individuals with high cognitive reserve have a more rapid descent
into the diseases pathology than those with low cognitive reserve who have the same clinica l
expression according to some of the neuropathological tests.
Previous research from 1995 showed that the cognitive reserve had an impact on the outcome
of Alzheimer's disease which is also this study could confirm. But the research from 1999
indicated that the high cognitive reserve would decline at a higher speed than the low but this
could only 2 of our tests confirm. The major question with the outcome of this study is just why
3 of the tests show one thing while 2 of the tests show another? The Digit Symbol test and Rey
Auditory Verbal Learning - retention test demonstrates that the cognitive reserve has impact on
the outcome of disease pathology but that those with high cognitive reserve has a more rapid
decline than those with low cognitive reserve. While the Full Scale Intelligence Quotient,
Similarities and Block Design tests also shows an influence by the cognitive reserve, but that
the decline is in the same rate for both the high and low cognitive reserve.
The ApoE-ε4 allele is not an effective model for looking at these reactions for foretelling
increased vulnerability for AD in individuals with that gene variation (Stern et al, 1999).
Therefore, the ApoE-ε4 allele was not used in this study more than to see if the amount of the
ApoE-ε4 allele gene increased with severer diagnosis.
Determining whether or not there truly is a generalized CR network is important for considering
whether it will be possible to intervene and provide increased CR and thus slow the effects of
advanced age or AD pathology. Being able to delay the clinical expression of dementia and
Alzheimer’s disease would be an enormous scientific discovery to everyone. If stimulating the
CR in various ways can achieve that, then it can be used as a treatment for the early signs in
dementia. Since the PET scan can detect changes in the brain pathology even before there is
any impairment on the neuropsychological tests then, maybe, the stimulation can be distributed
already in the early stage of the disease. Still, both brain reserve and cognitive reserve can make
independent contributions to understanding the individual differences in clinical resilience to
brain pathology. In some cases the increased use of an alternative network could be associated
with a better performance in the face of brain pathology. Stern (2013) believe that individ ua ls
who have a higher reserve are able to tolerate more age-related brain changes (or disease
pathology) than individuals who have a lower reserve.
Imaging CR would be very useful for understanding an individual’s true clinical status as well,
which would be a combination of underlying age-related (Or disease-related) brain changes and
that individuals' cognitive reserve in the face of those changes. Stern (2013) agrees that the
optimal characterization of any clinical syndrome should be a combination of the measured
pathology and measured reserve. Two people who express themselves the same clinically can
significantly differ on these underlying measures. This approach to characterize the clinica l
severity of the disease has strong implications for prognosis and treatment. Further, because
PET scanning is sensitive to plaque and amyloid aggregates, amyloid neuroimaging can also be
a promising diagnostic tool. The PET scan can also be used to develop a new anti-amylo id
therapy (Forsberg et al, 2008).
An inadequacy with the Threshold model for the passive reserve is that it assumes that there is
some kind of fixed threshold and that below that, the clinical impairment will occur for
everyone. In Alzheimer's disease the threshold might be depletion of the synapses to the point
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where only a specific number remained. But the active reserve model does not assume that there
is some kind of threshold where impairment will occur. Instead, it focuses on the processes that
allow individuals to sustain brain damage and still maintain function (Stern, 2009).
If it was possible to choose, had the choice been to have a low cognitive reserve so the disease
had been discovered earlier? Or would the choice be to have high cognitive reserve so one could
delay the outcome of the disease and keep stimulating the brain so that it would never appear?
Those with high cognitive reserve might not be able to affect the outcome more than they
already have done? Since the individuals with low cognitive reserve can activate the brain to
keep the disease pathology away but the individuals with a high cognitive reserve already is
activating the brain and has kept the disease pathology away as long as possible. It is, as for
now, impossible to say what would have been the best choice. There is need for much more
research on the subject of delaying disease pathology, maybe through the cognitive reserve.
One limitation of this study is that there were only 5 individuals in the control group, it would
be more preferable with a larger number of people in that category to get a better image of it.
The low number of control subjects is most likely due to that the people who are involved in
this study were contacted when they sought help at the memory clinic at the Karolinska
University Hospital in Huddinge. It is probable that there are more people with actual memory
disorders that seek professional help than there are healthy people who visit a memory clinic.
One more caveat is the choice to use only ‘years of education’ as dividers for the high and low
cognitive reserve, it is a quick way to find out how long the brain has been stimulated. However,
a low educated person with a highly stimulating occupation should have a higher cognitive
reserve than a highly educated person with an extremely low stimulating occupation. These
exceptional individuals can actually be observed in Figure 1 as a black dot that is high on the y
axis and a white dot located low on the y axis. This could, unfortunately, not be taken into
consideration, as all the variables that were necessary for each individual to count for the
stimulus of the occupational attainment were not available.
It had also been interesting to look at where the various diagnoses were placed in Figure 1 and
Figure 2. If it actually resulted in that the subjects with AD ended up right in the figure, those
with MCI in the middle and the Control group on the far left, or if they were mixed together.
This was not done in this study due to limited time. The lack of time also made it so that the
ApoE-ε4 allele was not used in this study. It would be an interesting idea in future studies to
use it as a covariate.
The book by Marcusson et al (2011) addresses head traumas relation to dementia and that
epidemiological studies have shown inconsistent results in investigations. The authors then
discuss that this might be due to the difficulty in defining a head trauma. Could it be possible
that these inconsistent results might have a connection to the cognitive reserve? E.g. the higher
the cognitive reserve, the less effect the head trauma does? It would be an interesting thing to
study. This demonstrates the need for a lot more research on the topic of the cognitive reserve.
The decision to focus only on the active reserve in the study was made because the active
reserve (i.e. the cognitive reserve) is more testable in this case. In a more comprehensive study,
one could make use of both the active and the passive reserve, in addition to the tests conducted
in this study, by including the synapse density and weight of the brain and thus compare the
results with each other. One can also, in future research, make a variable of both years of
education and the degree of work stimulus in order to explain the cognitive reserve. Another
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idea for future studies would be to do a longitudinal experiment on two large groups of
individuals with Mild Cognitive Impairment. Where one group gets cognitive stimulation and
the other group does not receive it and then to see if the stimulus had any effect on the longterm outcome of the disease.
The concept of cognitive reserve strongly relies on the idea that there are individual differe nces
in how the information is being processed in the brain. The difference can allow some people
to cope better than others with brain changes in general and aging in particular. These
differences can be observed in healthy individuals as well according to Bergman, Blomberg
and Almkvist (2007). Individual differences are always going to exist in some ways. The age
relationship that was mentioned in the beginning of this study; that the incidence of dementia
doubles for every five-year- increase in age, that calls for consideration on whether or not
dementia is just a sign of normal aging. But what the cognitive reserve does is that it allows an
individual to find different networks, or pathways, which can compensate for the losses from
the disease pathology. A simple analogy is the use of a walking stick, which allows an elder to
walk but not as well as if he did not need it.
At present there is an increasing interest in finding diagnostic tools for detection of an increased
risk of developing Alzheimer's disease. With the realisation that dementia and Alzheimer's
disease onset begins years before it becomes clinically manifest I consider this study to be of
importance and finding a way to detect those early onsets in brain pathology and delay them
(maybe through the cognitive reserve) very relevant.
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