The transition of forgetfulness to dementia: when to intervene & how

When is memory loss more than just forgetfulness?

Escalating numbers of people are experiencing dementia in many countries.
With increasing consumer needs, there is anticipated growth in the numbers
of people providing diagnostic evaluations, treatments, and care. Ensuring a
consistent and contemporary understanding of dementia across has become
a critical issue1.Many elderly people are worried about their memory and are
afraid of falling victim to dementia and studies have revealed that even in
Japan, there appeared to be gaps in knowledge among the general publicon
biomedical aspects of dementia, [i.e. cause, treatment, and prognosis] along
with a misunderstanding of dementia, as senescence forgetfulness2.Aging is a
primary risk factor for the development of many diseases including
neurodegenerative diseases like dementia. Aging leads to numerous
physiological changes associated with loss of tissue integrity and loss of
organ function. In the brain, the age-related anatomical and physiological
changes can compromise cognitive functions including memory, attention,
executive function and perception with high variability. Although the exact
molecular mechanisms
through which aging of the
brain ultimately leads to
significant changes in some
cognitive domains and
neurodegenerative diseases
are still being elucidated, it is
widely accepted that factors
contributing to neuro-
degeneration include7:
 Increased
inflammation,
 Mitochondrial dysfunction,
 Elevated oxidative stress within the brain.

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Information on normal forgetfulness and dementia are important as studies
have revealed that 63% peopleworrying about dementia had their anxiety
either decrease or disappear on readingrelevant information3,4,5. In this
context, the adoption of preventive strategies against dementia has
repeatedly been solicited as a priceless necessity6. Is there any progress in
this regard? Is there scientifically something useful in this regard?

Forgetfulness and the need to know in Singapore

A study was conducted to study the prevalence of cognitive impairment and
dementia amongst the multiethnic Malay community in Singapore and to
examine differences in prevalence among Chinese and Malays. A total of 966
Malay subjects were examined with age > 60 years and with Cognitive
impairment no dementia (CIND) to dementia on defined criteria. The stuidy
showed that among elderly Malays in Singapore, the overall prevalence of
any cognitive impairment was 25.5%8.
In a similar study conducted in 1538 Chinese subjects, aged ≥60 years, to
examine the prevalence of and associated factors for cognitive impairment
and dementia in community dwelling Chinese from Singapore, it is seen that
the overall prevalence of cognitive impairment and dementia in Chinese was
15.2%, which is in the same range as the prevalence reported in Caucasian
and other Asian
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populations .
While mild forgetfulness can
be a normal part of aging, it
can also be a sign of more
serious memory problems,
such as amnestic mild
cognitive impairment,
dementia, or even
Alzheimer's disease. At least
half of those over age 65 say
that they are more forgetful than they were when they were younger,
experiencing “senior moments” about things like where they put things or
recalling somebody’s name. The worrisome problem is, if such forgetfulness
emerges at a younger age. Increasingly, research indicates that feeling
forgetful is a cause for concern even among the younger age
groups.Uncertainty about the condition and how to respond to it till it is
resolved, only exacerbates the status, with passage of time. As the transition
from being forgetful to having a diagnosis of dementia is characterized by
uncertainty and often by lengthy waiting, this may be misunderstood as a sign
that the problem is not of a serious or top priority nature to necessitate any
intervention. Nothing is farther from the truth.

Although consensus recommends early

recognition of memory problems,
communication about the condition with health
care professionals is not necessarily a proactive
dialogue. Doctorsoften say that they see
patients who would gladly talk if they felt they
were in pain or experiencing other health

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issues, but avoidconversations about memory worsening, and this is a
dangerous mistake.This leaves professionals unaware of an individual’s
apprehensions or situation, till it is too late.

Most researchers say that forgetfulness is the first sign of Alzheimer's disease
and although many things change as we age, the fact is that our bodies and
brains slow down, though intelligence remains stable. We are less physically
and mentally flexible, and we take more time to process information. Memory
changes occur as well, and it’s common to have greater difficulty
remembering names of people, places and other things as we age. In the
past, memory loss and confusion were considered a normal part of aging. But
now, scientists have proof that most people remain both alert and able as they
age, although a lot of people experience memory lapses and it may take them
longer to remember things. The
hormones and proteins that
repair brain cells and stimulate
growth in the brain start to
decline with age and that is the
reason why forgetfulness sets
in.

When is memory loss to be

taken seriously?
Some memory problems are
serious, and others are not. In
order to distinguish the ordinary
forgetfulness that comes with
aging from more serious
problems like Alzheimer's
disease, it helps to consider
some key symptoms of mild
cognitive impairment and the
early stages of dementia.

What is MCI?
In Mild Cognitive Impairment (MCI), a person has problems with memory or
another core brain function. These problems are severe enough to be
noticeable to other people and show up on tests of mental function, but not
serious enough to interfere with daily life. The reason to diagnose this early
and intervene stems from the fact that people with MCI have an increased risk
of developing Alzheimer’s disease in the near future, especially when their
main problem involves memory.
This is a grey area and the
balance between forgetfulness,
MCI and dementia is delicate.
While having MCI can make it
more likely you’ll go on to
develop dementia it’s really
important to remember that the

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transition ahead, from the early stages of MCI, is not straightforward. There is
potentially much uncertainty and waiting andnot everyone diagnosed withMCI
progresses to Alzheimer’s or another type of dementia.Studies have shown
that older people with subjective memory complaints [SMC] but no objective
complaints are twice as likely to develop dementia as individuals without
SMC. Approximately 2.3% and 6.6% of older people with SMC will progress to
dementia and MCI per year10.The good news is that if MCI is diagnosed, it
gives a person time to prepare for earlier access to interventions to provide
support and possibly delay the worseningthat is proven by scientific studies.

What is dementia?
The term dementia does not mean a
disease but describes a group of
symptoms that are caused by changes
in brain function. Dementia symptoms
may include asking the same questions
repeatedly; becoming lost in familiar places; being unable to follow directions;
getting disoriented about time, people, and places; and neglecting personal
safety, hygiene, and nutrition. Thus, dementia seriously affects a person's
ability to carry out daily activities. The main difference in dementia as
compared to MCI is that they’ll be more noticeable and could therefore impact
more on everyday life. Dementia can
also produce anxiety, which can in turn
increase the forgetfulness making
anxiety to be particularly pronounced in
the early stages of dementia.In addition
to being forgetful, those in the early
stages of dementia may also have
problems with judgment and planning.
Unusual changes in personality can also
occur, like showing bursts of anger for
no reason, becoming depressed or confused, or uncharacteristically clinging
to something. But, the good news is that the move from having MCI to
dementia can vary from person to person – some people plateau at quite a
mild stage for several years. Hence, people with dementia lose their abilities
at different rates and Alzheimer's disease is one of many types of dementia.
Dementia may manifest as lapses in:
1. Recent memory (the ability to
learn and recall information)
2. Language (the ability to write
or speak, or to understand
written or spoken words)
3. Visuospatial Function (the
ability to understand and use
symbols, maps, etc. and the
ability to correctly judge where objects are)
4. Executive function (the ability to plan, reason, solve problems and
focus on a task)
Dementia is caused by many conditions, some of which can be reversed, and
others cannot.Feeling sad, lonely, worried, or bored may be more common for

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older people facing retirement or coping with the death of a spouse, relative,
or friend. Adapting to these changes leaves some people feeling confused or
forgetful.Forgetfulness caused by such emotions usually is temporary and
goes away when the feelings fade and so, this cannot be called as dementia.

What is Alzheimer's disease [AD]?

AD is a progressive neurodegenerative disease with a marked late onset (late
diagnosis as well) and mainly characterized by progressive decline of
cognitive functions, memory, and changes in behavior and personality. In
Alzheimer's disease, nerve cell changes in certain parts of the brain result in
the death of a large number of cells. Symptoms of Alzheimer's disease begin
slowly and become steadily worse. As the disease progresses, symptoms
range from mild forgetfulness to serious impairments in thinking, judgment,
and the ability to perform daily activities. Eventually, patients may need total
care.
The early warning signs of
Alzheimer’s disease can begin
some 15 years before
symptoms of mild cognitive
impairment, or long before the
beginning signs of a dementia
surface. This window is the
one to latch on to and seek
interventions to delay the troublesome manifestations that are common.For
people in the early and middle stages of Alzheimer's disease, certain drugs
are prescribed to possibly delay the worsening of some of the disease's
symptoms. Although many people with dementia need no medication for
behavioral problems; some people might need medications to reduce
agitation, anxiety, depression, or sleeping problems.

What does scientific evidence based research have to say?

 Knowing where one stands and
being aware of the progress
that science is making through
assessment trials in such
forgetful states, enables
‘reflection and adaptation’.
 Due to the location of the first
lesions of AD in hippocampal
regions, memory disturbances
in AD are related to a deficit in
memorization of new
information in episodic memory.
 Conversely, memory disorders related to normal aging, depression, and
degenerative or vascular brain lesions not involving hippocampus, are
related to deficits in the processes of recall of previously memorized
informations.
 Hence, viewing dementia in such a context will enable people to modify
expectations and fears of the transition from being forgetful to being
actually diagnosed with dementia.

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 In recent years, the possibility of favorably influencing the cognitive
trajectory through promotion of lifestyle modifications has been
increasingly investigated. In particular, the relationship between nutritional
habits and cognitive health has attracted special attention.Several
substances of natural dietary origin display protective properties against
some age-related diseases including neurodegenerative ones, particularly
Alzheimer’s disease (AD). These compounds differ structurally, act
therefore at different biochemical and metabolic levels and have shown
different types of neuroprotective properties.
 Study findings indicate that the exposure to specific nutritional compounds
may result in cognitive benefits6.
Why so? Reactive oxygen
species (ROS) have important
roles in normal brain function.
Excessive production of ROS
and ensuing tissue damage are
countered by the endogenous
antioxidantmechanisms that
exist to protect the brain and its
tissue. However, weakening of
theantioxidant defense system is associatedwith aging. All of these
features ofaging contribute to a state of oxidative stress in the brain
tissue,where the organ cannot combat the deleterious effects of ROS.
Damage to proteins, lipids, and nucleotides accumulates promoting
cellular dysfunction and subsequent cognitive impairment11.
 Research has suggested that most sufferers of forgetfulness seek early
intervention because of the belief that taking control over the disorder early
is crucial and so fall prey to products with dubious claims rather than bank
on evidence based medications.In order to better understand the
mechanism of action of antioxidants that are efficacious for complex
diseases in which oxidative stress may be present, but not the only
significant pathogenic mechanism, the multiple pharmacological effects
should be considered and investigated more broadly. While there is a
plethora of empirical evidence that antioxidants can be an effective
treatmentin preliminary studies, it is important to note that thisstrategy has
been largely unsuccessful when translated inclinical trials. The failure of
this antioxidant centric approachmay be explained, in part, by the
multifaceted limitations of common antioxidants.As astaxanthin is known to
cross the blood-brain barrier, it is detectable in the brain tissue making it a
desirable anti-oxidant of immense therapeutic potential in
neurodegenerative diseases such as
dementia. There is also significant
support to the fact that AXT may
increase the levels of or promote the
activity of endogenous antioxidant
enzymes including superoxide
dismutase and catalase. It has also
been reported that astaxanthin
supplementation can stimulate the
expression of nuclear factor erythroid-

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 related factor 2 (NRF-2), known to be associated with robust cellular
protection from oxidative stress in vivo (Guerin et al. 2003). Al-Amin et al.
(2015a). This observation is relevant to neurodegeneration and protection
of cognitive function in aging11.
 Results from current research on astaxanthin suggest that
neuroprotectivebenefits are due to anti-inflammatory, anti-apoptotic and
antioxidant effects, as well as the potential to promote or maintain neural
plasticity. These emergent mechanisms of actions implicate astaxanthin as
a promising therapeutic agent for neurodegenerative disease, including
dementia7.
 The basis for the use of astaxanthin approach in the treatment of
neurodegenerative disorders is to prevent the progress of the disease by
sequestering the primary targets and to slow disease progression by
exerting activity against oxidative stress and mitochondrial dysfunction.
 The size and structure of astaxanthin allows it to become vertically
integrated through the phospholipid bilayer as the functional groups of the
astaxanthin structure are energetically favorable in this orientation (Guerin
et al. 2003; Kidd 2011). This feature precisely positions the molecule so
that it can interfere with lipid peroxidation. In this regard, astaxanthin is
especially adept at protecting the integrity of cell membranes.
 Recently, there has been emerging evidence that astaxanthin can promote
neurogenesis and plasticity. Neurogenesis is now widely accepted to
occur throughout adulthood, primarily in 2 regions of the brain: the
subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate
gyrus (DG) of the hippocampus. Because the hippocampus is essential for
learning and memory, neurogenesis likely plays a role in these cognitive
processes11.
 Animal studies have clearly demonstrated the mechanism and efficacy of
astaxanthin in Diabetes-induced cognitive deficit (DICD) through
suppression of oxidative stress, nitric oxide synthase (NOS) pathway,
inflammatory reaction, decrease in the caspase-3/9 expression and
increase in the expression of PI3K/Akt in cerebral cortex and
hippocampus11.
 Another in-vitro study has shown that in AD, astaxanthin protects neurons
from the noxious effects of A𝛽Os on mitochondrial ROS production,
NFATc4 activation and RyR2 gene expression downregulation 13.
 Ahuman study conducted in 96 subjects with complaints of age-related
forgetfulness has shown the effects of astaxanthin on cognitive
function.On administering a capsulecontainingastaxanthin-
richHaematococcuspluvialis daily for 12 weeks, improved cognitive
function was observed by performance enhancement in CogHealth battery
scores and Groton Maze Learning Test scores. This study clearly revealed
that natural astaxanthin reduces oxidisation in the brain, leading to
improved scores in tests of cognitive function12.
 Strong evidence has shown that Astaxanthin can calm microglial activation
and suppress the output of cytotoxic substances. This ability to attenuate
microglial activation and the release of pro-inflammatory cytokines is an
important mechanism of action for protecting neuronal integrity, especially
with age11.

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 In addition, astaxanthin offers neuroprotection against normal aging and
neurodegeneration by promoting neurogenesis through modulating
microglial activity and important signaling molecules such as ERK, AKT,
and BDNF in-vitro and in-vivo, therefore improving cognitive functions.
 Since the efficacy of Astaxanthin in cognitive function is
now evident in several human clinical studies, it is time
for one and all to exploit the possible neuroprotective
effects. The earlier one starts astaxanthin, the better it
is as dementia does not inform when it transitions from
cognitive inhibition.

Reference:
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survey on knowledge about dementia in the general public of Japan by Arai Y1, Arai A,
Zarit SH.
2. BMC Geriatr. 2015 Feb 6;15:5. What should we know about dementia in the 21st
century? A Delphi consensus study by Annear MJ, Toye C, McInerney F, Eccleston C,
Tranter B, Elliott KE, Robinson A.
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forgetfulness and dementia: effectiveness of a systematically developed information
pamphlet, by Commissaris CJ1, Ponds RW, Verhey FR, Damoiseaux V, Kok GJ, Jolles J.
4. TijdschrGerontolGeriatr. 1994 Aug;25(4):163-6, Education about dementia and
forgetfulness in daily and weekly press by Commissaris CJ1, Jolles J.
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and dementia: importance and effects by Commissaris CJ, Verhey FR Jr, Ponds RW,
Jolles J, Kok GJ.
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Approaches? By Canevelli M, Lucchini F, Quarata F, Bruno G, Cesari M.
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therapeutic role in preserving cognitive function in age and neurodegeneration by
Bethany Grimmig&Seol-Hee Kim & Kevin Nash & Paula C. Bickford & R. Douglas Shytle
8. Curr Alzheimer Res. 2015 Oct 2, Prevalence of cognitive impairment and dementia in
Malays - Epidemiology of Dementia in Singapore Study by Hilal S, Tan CS, Xin S, Amin
SM, Wong TY, Chen C, Venketasubramanian N, Ikram MK.
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impairment in Chinese: epidemiology of dementia in Singapore study by Hilal S, Ikram
MK, Saini M, Tan CS, Catindig JA, Dong YH, Lim LB, Ting EY, Koo EH, Cheung CY, Qiu
A, Wong TY, Chen CL, Venketasubramanian N.
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impairment in older people with subjective memory complaints: meta-analysis by Mitchell
AJ1, Beaumont H, Ferguson D, Yadegarfar M, Stubbs B.
11. J. Clin. Biochem. Nutr., September 2012, vol. 51, no. 2, page 102–107, Effects of
astaxanthin-rich Haematococcuspluvialis extract on cognitive function: a randomised,
double-blind, placebo-controlled study by MikiyukiKatagiri et al.
12. Int J ClinExpPathol 2015;8(6):6083-6094, Astaxanthin improves cognitive deficits from
oxidative stress, nitric oxide synthase and inflammation through upregulation of PI3K/Akt
in diabetes rat by LianbaoXu et al.
13. Neural Plasticity, Volume 2016, Article ID 3456783, 13 pages, Astaxanthin protects
primary hippocampal neurons against noxious effects of A𝛽-Oligomers by Pedro Lobos et
al.