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FAKULTAS KEDOKTERAN
UNIVERSITAS SAM RATULANGI
MANADO
2016
Alzheimers Disease associated with Psychiatric Comorbidities
Michelle L. Garcez1 , Ana Carolina B. Falchetti1 , Francielle Mina1 , Josiane Budni1
Programa de Ps-Graduao em Cincias da Sade, Laboratrio de Neurocincias, Unidade
Acadmica de Cincias da Sade, Universidade do Extremo Sul Catarinense, Av. Universitria, 1105,
88806-000 Cricima, SC, Brasil

Manuscript received on January 9, 2015; accepted for publication on June 19, 2015

An. Acad. Bras. Cinc. vol.87 no.2 supl.0 Rio de Janeiro Aug. 2015 Epub Aug 25, 2015

ABSTRACT

Alzheimers disease (AD) is the most common cause of dementia and has become a severe public
health issue. It is estimated that globally, 35.6% of people have some form of dementia. This number
is expected to double by 2030, and possibly even triple by 2050. The disease is associated with
deficits in cognition/memory and a reduced ability in coping with everyday life. Moreover, patients
can experience behavioral alterations such as mood swings, depression and hallucinations. Therefore,
it is common to find the presence of neuropsychiatric comorbidities such as depression, schizophrenia
and bipolar disorder during the course or development of AD. These disorders can become severe
enough to interfere with the patients daily functioning, and can worsen the course of the disease.
However, little is known about the causal3434 relationship between psychiatric comorbidities and
AD, or the reasons for the predisposition of some individuals to such disorders. Therefore, the
purpose of this review is to clarify the causal relationship between depression, schizophrenia and
bipolar disorder with AD.

Key words: Alzheimers disease, bipolar disorder, depression, schizophrenia.

INTRODUCTION

Alzheimers Disease (AD) is recognized as the major cause of dementia in modern society, and may
result in significant limitations for sufferers through cognitive impairment. The most evident symptom
in early AD is progressive memory loss (Grundman et al. 2013). Studies seek to elucidate the
pathophysiology of AD which is related to cognitive damage. Possible biochemical causes include the
accumulation of amyloid beta protein oligomers, which are responsible for synaptic damage and
sequent memory deficit in AD (Krstic and Knuesel 2013). Furthermore, hyperphosphorylation of the
Tau protein is another pathophysiological process involved in AD. Hyperphosphorylation induces the
formation of intracellular neurofibrillary tangles, leading to neuronal death and the progressive loss of
neuronal function (Krstic and Knuesel 2013), (Serrano-Pozo et al. 2011), (Chu 2012), (Nimmrich and
Ebert 2009). Despite their being studies that indicate possible biochemical causes that lead to acute
neurodegeneration over time (Shankar and Walsh 2009), the pathophysiology of AD is not still
elucidated. However, it is suggested that some etiological aspects may be involved in the development
of AD, such as environmental and genetic factors (Schipper 2011).

Considering the present limitations of our understanding of AD, the same issues could appear in the
form of cognitive symptoms, which are related to memory, learning, agnosia and apraxia. Also could
appear in the form of non-cognitive symptoms, characterized by behavioral and psychological
alterations, such as aggressiveness, irritability, hallucinations and depression, which are known as the
Behavioral and Psychological Symptoms of Dementia (BPSD) (Schiffczyk et al. 2013).

Neuropsychiatric symptoms are visible both during the development of, and throughout the course of
AD (Lyketsos et al. 2011). While the cognitive symptoms of dementia are neuropsychiatric features
present in the vast majority of the population regardless of age, the presence of depression associated
with dementia appears primarily in the elderly (Steffens et al. 2009). Thus, it is probable that
depression is the most common neuropsychiatric disorder in AD (Contador-Castillo et al. 2009).

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For this reason, AD causes a huge economic and social impact, generated by the high costs involved
in the health care of patients, such as those involved in the utilization of drug therapy and the
provision of full-time caregiver (Schaller et al. 2014). It is worth mentioning that in the United States
of America (USA), about $604 million dollars are invested annually for the assistance of patients with
dementia (WHO 2012).

Thus, this disease has become one of the most severe global public health problems, with its current
prevalence effecting 35.6% of people worldwide, with this number expected to double by 2030, and
possibly even tripling by 2050 (WHO 2012). Moreover, there is an increased risk of the incidence of
dementia in later life, which is associated with the prevalence of diseases such as AD, mainly
occurring in the seventh or eighth decade of life (Reitz et al. 2011). This demands that better
organizational and assistive solutions are required from the health professionals and public health
systems that are dealing with these patients, which would help reduce the burden being placed on the
patients families, as well as decrease the high costs involved in the treatment of this disease (Franz et
al. 2010).

The symptoms associated with AD are the major causes that lead to an early patient hospitalization
(Sansoni et al. 2013). A study performed with 1014 patients, showed that 90% of the patients studied
had BPSD, and 44% also showed depressive symptoms. In addition to this, the group also presented a
high prevalence of other symptoms such as illusions, hallucinations and delusions in those patients
with high scores in the scales of psychiatric symptoms (Fernandez et al. 2010). Furthermore,
depression and apathy appear more frequently during AD, with hallucinations, delusions and
aggressiveness also being common (Lyketsos et al. 2011).

Considering the high impact that non-cognitive symptoms have upon both the caregivers and the
patients own health, there are considerable costs involved for the public health system. Therefore, the
objective of this review is to describe the findings of previously published scientific literature,
illustrating the possible associations between patients with AD, and the presence of psychiatric
comorbidities including, bipolar disorders, depression and schizophrenia.

BIPOLAR DISORDER AND ALZHEIMERS DISEASE

Bipolar disorder (BD) is a psychiatric disorder characterized by episodes of mania or hypomania and
depression (Brenner and Shyn 2014). The DSM (Diagnostic and Statistical Manual of Mental
Disorders) is a document that reflects the consensus among leading academics, physicians and
researchers in the field of mental health and psychiatric diseases (Vahia 2013). The latest version of
the document was published by the American Psychiatric Association (APA) in May 2013, this being
its fifth edition (DSM-5 or DSM-V). This latest edition of the DSM brings some modifications to the
concepts of bipolar disorder, mainly affecting the inclusion and exclusion criteria.

BD is still classified as bipolar disorder I and II. Bipolar disorder I is characterized by manic episodes
(extremely elevated mood), mixed states (dysphoria) and major depression. Bipolar disorder II is
characterized by episodes of major depression and at least one hypomanic episode (elevated mood
and increased energy). As in DSM-IV, the presence of five of the nine diagnostic symptoms are
required with at least one manic episode lasting a week or more (bipolar I) or at least one hypomanic
episode lasting four days or more (bipolar II), leading to a total change in the life of the patient (APA
2013).

Before the diagnosis of BD can be confirmed, any medical condition, substance or drug that could
induce manic symptoms should be excluded. This is especially significant in geriatric patients, who
may have other comorbidities that can cause delirium and/or depression, such as AD. However, more
recent studies have demonstrated clinical evidence for a link between AD and BD, beyond them
sharing similar symptoms. Many epidemiological studies have linked these two diseases (Kessing and
Andersen 2004), (Zilkens et al. 2014), (da Silva et al. 2013) and have shown findings such as
neuroimaging alterations (Rej et al. 2014), dysregulation of neural calcium signaling (Berridge 2013)
and epigenetic changes (Rao et al. 2012).

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Studies undertaken on BD patients have demonstrated that they have a greater risk of getting a
dementia diagnosis than in controls matched by the gender and age of the general population. The risk
of dementia increases by 6% with every episode of bipolar disorder that leads to the hospitalization of
the patient. The authors had to indicate that the study only included patients who had been
hospitalized at least once, and that affective episodes were included only if they resulted in
hospitalization, since the study was conducted using records from hospital admissions in Denmark
(Kessing et al. 1999), (Kessing and Andersen 2004). Therefore, the increased risk of dementia in these
patients may have been underestimated. However, it should be noted that this evidence is dependent
on clinical and demographic variables

Epidemiological studies have also been conducted on other populations. A matched case-control study
using Western Australian state-wide hospital records relating to inpatient, outpatient, mental health
and emergency admissions which were linked to deaths, demonstrated that in Western Australians
aged between 65-84 years, the chances of bipolar disorder patients developing AD was twice as high,
while the chances of these patients developing non-specific dementia was six times as high (Zilkens et
al. 2014). However, a study by da Silva et al. (2013), which conducted a systematic review on the risk
of individuals with affective disorder history developing dementia, demonstrated that the risk of
developing dementia was higher when associated with depression than with bipolar disorder, and that
depression may be a an important confounding factor, since bipolar patients have alternating
depressive episodes.

Bipolar disorder and dementia may share common etiological factors, such as oxidative stress and
reduced neurotrophic factors that are both key mediators in the pathophysiology of mood disorders
(Bauer et al. 2014) and AD (Heneka et al. 2014), as well as neuroinflammation (Stich et al. 2014),
which occurs in both comorbidities, with increases shown in pro-inflammatory interleukin, tumor
necrosis factor alpha (TNF-) and arachidonic acid cascade enzymes in the postmortem brains taken
from BD and AD patients (Kim et al. 2011), (Rao et al. 2011).

Another of the etiological factors common to the comorbidities being discussed are the vascular
changes that are observed in patients affected by AD (Luchsinger et al. 2008), (Brickman et al. 2012)
which are also seen in BD patients (Sodhi et al. 2012). However, there is still some disagreement over
the data pertaining to the cerebrovascular changes found between various studies, because of the
different age of the patients and the regions where these changes are found (Almeida et al. 2009),
(Haller et al. 2011), (Rej et al. 2014). Further research is needed to establish the relationship between
bipolar disorder and AD, and to ascertain whether these changes are directly related to the cognitive
deficits found in both conditions. However, it is known that even after remission of the depressive
state, BD patients demonstrate impaired executive function and attention deficits; similarly, euthymic
individuals with bipolar disorder have deficits in declarative semantic memory and executive function
(Robinson et al. 2006), these alterations also being observed in patients suffering with AD (Bondi et
al. 2008)

raditional medicine used for treating BD, and it is known that in BD, one of the main intracellular
targets of lithium is the inhibition of GSK-3, which regulates the activity of the transcription factors
(CREB and -catenin) responsible for the expression of BDNF and Bcl-2. These control neurogenesis
and neuronal survival, as well as having mood stabilization effects. In addition, lithium increases Bcl-
2 expression and decreases the levels of cytosolic calcium by inhibiting the release of Ca+ from the
endoplasmic reticulum (Berridge 2013). The use of lithium has recently been advocated in the
treatment of AD, and the action of the drug may be a bridge between AD and BD, by operating via
the same mechanisms (Stutzmann et al. 2006), since dysregulation of Ca+ signaling occurs in both
conditions. It may also simply be acting by decreasing the phosphorylation of the Tau protein, which
occurs via the action of GSK-3, as already noted (Hernandez et al. 2013).

Studies have reported reductions in the levels of BDNF and synaptic proteins in the brains of both AD
and BD patients (Rao et al. 2011), (Kim et al. 2010), and in addition to this, there have been

4
observations of changes in the expression of inflammatory (Kim et al. 2011) and apoptotic genes
(Kim et al. 2010) common to BD and AD. In a study by Rao et al. (2012), post-mortem brains from
patients suffering with BD and AD showed statistically significant epigenetic changes in global DNA
methylation for both BD and AD, and these epigenetic changes are related to neuroinflammation,
synaptic integrity, neuroprotection and arachidonic acid metabolism in the frontal cortex. However,
while global histone H3 acetylation was found to have increased in the brains of BD patients.
However, it was not found alter in AD patients. It should be noted that the medications taken by the
patients may have also interfered with the changes found in the epigenome.

Other studies have analyzed the levels of amyloid metabolites contained in the cerebrospinal fluid
(CSF) of BD patients, and discovered that there were lower concentrations of the soluble forms of
APP ( and ) in bipolar patients, when compared to healthy controls or AD patients (Piccinni et al.
2012), (Jakobsson et al. 2013) in which the decrease in A-42 in the CSF is inversely proportional to
the number of amyloid plaques. An association between low concentrations of A and an increase in
the severity of bipolar disorder type I was also observed, but no other evidence of neurodegeneration
for the Alzheimer type was found in bipolar patients (Jakobsson et al. 2013). This finding is in
agreement with a previous study in which no increases in amyloid plaques or neurofibrillary tangles
were found in the postmortem brain tissues of psychiatric patients (Damadzic et al. 2002).

Thus, the existence of consistent points and similar findings for both BD and AD are clear. However,
although both disorders seem to have similar underlying mechanisms, there is not enough evidence to
say that the cognitive impairment found in BD has the same pathophysiology as that found in AD, nor
is it possible to assert that BD patients are predisposed to AD. The main findings and conclusions are
presented in Table I.

TABLE I Associations between AD and bipolar disorder, depression and schizophrenia.

Psychiatric
Comorbidities
Article Authors Conclusion
associated with
AD
Does the risk of
developing dementia
increase with the number Kessing The risk of dementia seems to
of episodes in patients and increase with the number of episodes
Bipolar disorder
with depressive disorder Andersen in depressive and bipolar affective
and in patients with (2004) disorders.
bipolar disorder?

Depression and Risk for

There is a high relationship between
Alzheimer Disease:
Ownby et depressive symptoms and depression
Systematic Review, Meta-
al. (2006) as a risk factor for the development
analysis, and
of AD.
Metaregression Analysis
revalence of depression
Individuals with dementia had among
Depression among older Americans: Steffens et
the highest prevalence of current
the Aging, Demographics al. (2009)
depression.
and Memory Study
Contribution of
Potter and The prevalence of depression is
Depression to Cognitive
Steffens highly in most dementias. In AD may
Impairment and Dementia
(2007) be less intense.
in Older Adults
The risk of developing Thielscher 51.4% of patients developed
depression when suffering et al. depression, one year after the

5
 from neurological (2013) diagnosis of the AD.
diseases
Late-life depression and
risk of vascular dementia
and Alzheimers disease: Association between late-life
Diniz et al.
systematic review and depression with the development of
(2013)
meta-analysis of AD.
community-based cohort
studies
Increased Hippocampal Was found that of a lifetime history
Plaques and Tangles in of depression, is associated the
Patients with Alzheimer Rapp et al. presence of a higher number of
Disease with a Lifetime (2006) neuritic plaques and neurofibrillary
History of Major tangles the hippocampus of the
Depression patients with AD.
The presence of a higher number of
neuritic plaques and neurofibrillary
Plasma amyloid ,
may be present in patients with
depression, and dementia Direk et al.
depression without AD. Depression
in community-dwelling (2013)
may also be associated with the
elderly
accumulation of these plaques in
elderly individuals
The risk of developing
Thielscher 51.4% of patients developed
depression when suffering
et al. depression, one year after the
from neurological
(2013) diagnosis of the AD.
diseases
ate-life depression and
risk of vascular dementia
and Alzheimers disease: Association between late-life
Diniz et al.
systematic review and depression with the development of
(2013)
meta-analysis of AD.
community-based cohort
studies
Increased Hippocampal Was found that of a lifetime history
Plaques and Tangles in of depression, is associated the
Patients with Alzheimer Rapp et al. presence of a higher number of
Disease with a Lifetime (2006) neuritic plaques and neurofibrillary
History of Major tangles the hippocampus of the
Depression patients with AD.
The presence of a higher number of
neuritic plaques and neurofibrillary
Plasma amyloid ,
may be present in patients with
depression, and dementia Direk et al.
depression without AD. Depression
in community-dwelling (2013)
may also be associated with the
elderly
accumulation of these plaques in
elderly individuals
Serum amyloid beta
protein in young and Kita et al. Serum Abeta40/42 ratio was higher
elderly depression: a pilot (2009) in depressive patients.
study.

6
 Impairment in executive functions,
were more severe in patients with
Neuropsychiatric
Rosenberg depression and anxiety. People with
symptoms in MCI
et al. features of depressive symptoms also
subtypes: the importance
(2011) associated with mild cognitive
of executive dysfunction.
impairment, was found an increased
risk for the development of AD.

Identified 14 schizophrenic patients

Dementia in middle-aged
Nicolas et with dementia among 96 elderly, but
patients with
al. (2014) only two were diagnosed with likely
schizophrenia
AD.
A common brain network
Suggested a common spatial pattern
links development, aging, Douaud et
of abnormalities in a brain network in
Schizophrenia and vulnerability to al. (2014)
AD and schizophrenia.
disease
Dysregulation of neural Dysregulation of the Ca(2+)
calcium signaling in signaling pathway is responsible for
Berridge
Alzheimer disease, development of neural diseases such
(2013)
bipolar disorder and as Alzheimer disease, bipolar
schizophrenia disorder and schizophrenia.
Severe psychiatric
Severe depression, bipolar disorder,
Bipolar disorders in mid-life and
schizophrenia and alcoholic
disorder, risk of dementia in late- Zilkens et
dependency disorder in mid-life are
depression and life (age 65-84 years): a al. (2014)
important risk factors for AD in the
Schizophrenia population based case-
late-life.
control study.
Affective disorders and
Increased risk for dementia in
Bipolar disorder risk of developing da Silva et
individuals with depression, and
and depression dementia: systematic al. (2013)
bipolar disorder
review

DEPRESSION AND ALZHEIMER'S DISEASE

Depression is a mental disorder characterized by the presence of a number of symptoms including: a

depressed mood, a loss of interest in pleasurable activities, changes in appetite and in sleep patterns,
and alterations in psychomotor activities such as difficulty in thinking, concentrating or making
decisions (APA 2013). This disorder is commonly associated with an increased risk of morbidity and
mortality, an increased utilization of health services, and a reduced response to therapeutic regimens.
There is also an increased risk of suicide (Paradela et al. 2005), (Rotheneichner et al. 2014).

There is an increased rate of depression within developed countries when compared to countries of
low to middle income (Bromet et al. 2011), (Kessler and Bromet 2013), adulthood is still related to
the onset of symptoms, and women have twice the risk of developing depression over a lifetime when
compared to men of the same age (Bromet et al. 2011), (Kessler and Bromet 2013). In addition, a
population-based study has assessed the prevalence of depression in the Brazilian population, finding
a greater rate of depressive symptoms in individuals over the age of 60 (da Silva 2013).

Globally, the prevalence of depressive disorders in the elderly population is between 10% and 20%,
depending on their cultural situations, indicating that it is the most common psychological disorder in
the senescence population (Barua et al. 2011). The features attributed to the onset of a major

7
depressive disorder in later life, are also associated with a higher frequency in the development of
cognitive impairment (Potter and Steffens 2007), (Steffens et al. 2009).

Studies indicate that there is a strong relationship between depressive symptoms and depression as a
risk factor for the development of AD (Ownby et al. 2006), (Thielscher et al. 2013). Two meta-
analysis (Diniz et al. 2013) and (Ownby et al. 2006) and one systematic review (da Silva et al. 2013)
found an association between late-life depression and the development of AD.

A neuropathological study was performed which assessed the post-mortem brains of 153 participants.
It was evident from the findings that depression may be related to neuronal loss in specific brain
regions, such as the hippocampus, which also occurs in AD. However, there was no evident
association between the effects of depression and AD in the neurofibrillary tangles or neuritic plaques,
which are both characteristic symptoms of AD (Tsopelas et al. 2011). Wilson et al. (2003) also found
no correlation between plaques, tangle formation and current depressive symptoms in AD patients.

A separate prospective study, which conducted a neuropathological evaluation of the post-mortem

brains of patients with a mean age of 81 years, found the presence of a higher number of neuritic
plaques and neurofibrillary tangle formations in the hippocampus of patients with AD with a history
of depression, as compared with brains of AD patients without depression history (Rapp et al. 2006).

These findings reinforce the hypothesis that neuronal changes are caused by AD. However, these
changes may also be present in patients with depression who are not suffering with AD (Direk et al.
2013), whereas the formation of neurofibrillary tangles and neuritic plaques are one of the main
processes involved in the pathophysiology of AD (Nimmrich and Ebert 2009), (Serrano-Pozo et al.
2011), (Krstic and Knuesel 2013). Depression may also be associated with the accumulation of these
plaques in elderly individuals (Kita et al. 2009).

Other studies have shown a positive relationship between a depressive state at the time of death, and
the presence of neuritic plaques in Alzheimer's disease, which is independent of the clinical severity
of dementia. A pre-clinical study has shown that beta-amyloid oligomers leads to memory impairment
and depressive-like behavior in mice (Ledo et al. 2013).

Therefore, it can be difficult to differentiate and consequently diagnose the depressive symptoms of
dementia, because a symptom from one condition can overlap the other (Bystad et al. 2014). There are
mechanisms involved in the depressive process which are characterized by increases in the production
of glucocorticoids and in cerebral vascular disease, leading to atrophy of hippocampal ischemia, and
ultimately resulting in the cognitive decline seen in AD or dementia (Butters et al. 2008). Therefore,
this relationship makes it difficult to determine whether depression is a risk factor for AD or a
prodromal symptom (Koenig et al. 2014).

For example, when assessing 211 elderly women for depression, these patients showed a cognitive
deficit in all of the tests performed in the study (Yaffe et al. 1999), yet another current study which
evaluated 1,299 women with mean age of 88 years, found that in 41% of participants there were
significant features of cognitive decline, and in those of more than 90 years of age, the association
with dementia was more prevalent (Yaffe et al. 2011).

A separate study investigating the prevalence of neuropsychiatric symptoms which assessed 1,799
patients with mild cognitive impairment, found that impairments in executive functions, i.e. cognitive
symptoms, were more severe in patients suffering with depression and anxiety (Rosenberg et al.
2011). More recently, they evaluated 527 people who had features of depressive symptoms also
associated with mild cognitive impairment. Their findings showed that in this group there was an
increased risk for the development of AD (Rosenberg et al. 2013).

These studies suggest that depression might not only be a risk factor for dementia or AD, but may also
be a feature symptom of the early stages of cognitive decline or dementia. The main findings and
conclusions are presented in Table I.

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SCHIZOPHRENIA AND ALZHEIMER'S DISEASE

Schizophrenia is a severe mental disorder with a prevalence of nearly 1% of the world's population,
and is estimated to have an incidence of 15 per 100,000 people (Rossler et al. 2005). The nature of
this disorder is heterogeneous, which makes its treatment and investigation much more difficult
(Casey et al. 2013).

The diagnosis of schizophrenia is essentially based on the description of signs and symptoms
presented by the patient. To date, there have been no pathophysiological parameters with sufficient
sensitivity or specificity to provide a positive diagnosis (Bagdy and Juhasz 2013). According to the
DSM-V (Diagnostic and Statistical Manual of Mental Disorders), the signs must have been present for
at least six months, and must also include a minimum of one month of active symptoms to confirm the
diagnosis (APA 2013). Schizophrenia is a mental disorder characterized by positive, negative and
cognitive symptoms. The positive symptoms may be expressed as delirium, hallucinations and
delusions (Penzes et al. 2011), (Howes and Murray 2014), (Murray et al. 2014). The negative
symptoms involve the blunting of affect. The cognitive symptoms are characterized by problems with
working memory (APA 2013).

The mechanisms of this disease are still poorly understood. Dysfunction of the dopaminergic system
has been postulated to be a contributing factor. This is in part, on the functional roles of dopamine
with respect to physiology, and to the decline of cognitive performance, especially in working
memory and in reward circuitry (Arnsten 2011). In addition, there are alterations in the function of
one or more neurotransmitter systems, involving the dopaminergic, glutamatergic, serotonergic and
adenosinergic systems (Carter 2006). A study comparing the prospective memory of 42 healthy
people with 42 people suffering with schizophrenia, showed a deficit in the group of patients with
schizophrenia. This reinforces the hypothesis that there is a cognitive impairment in schizophrenia
(Kumar et al. 2008).

There are several lines of study that have associated cognitive decline and schizophrenia, and this
decline can be related to changes in the frontoparietal neural networks and disorders of the
hippocampus (Joyce 2013), which are also associated with AD (Nelson et al. 1998), (Wright et al.
2000). Changes in the white matter within the ventrolateral and dorsolateral regions of the left
prefrontal cortex (Quan et al. 2013), and decreased myelination in the temporal and occipital regions
have been found in patients with schizophrenia and cognitive decline (Palaniyappan et al. 2013).
Spatial working memory abilities are impaired in those individuals with a high risk of psychosis
(Wood et al. 2003), and this memory alteration is related to AD (Serino et al. 2014).

The cognitive profile of subjects with late-onset schizophrenia differs from those of patients with AD
and depression (Ting et al. 2009), (Etkin et al. 2013). Individuals with schizophrenia show cognitive
decline at all stages of the disease (Rajji et al. 2014). This cognitive decline can be easily observed by
testing for changes in the episodic memory response of people with schizophrenia (Schaefer et al.
2013), (Barch and Sheffield 2014). It can also be observed in the speed at which they process
information (Schaefer et al. 2013), (Woodward et al. 2013), as well as in changes to their verbal
memory, which is one of the most prevalent cognitive symptoms of schizophrenia (Lepage et al.
2014).

Similarly, psychotic symptoms, delusions and hallucinations are frequent in AD, which is currently
the second most prevalent psychotic disorder (second only to schizophrenia) in the USA, and it may
become the most prevalent (Murray et al. 2014). The onset of psychotic symptoms in AD is strongly
associated with a hastening cognitive decline (Ropacki and Jeste 2005).

There are few conclusive epidemiological studies relating the development of schizophrenia with the
onset of AD. This is mainly because diagnosing elderly patients with schizophrenia is challenging,
since various stages of cognitive tests are necessary, and also because AD is only diagnosable in
patients through psychiatric assessment. Nicolas et al. (2014) identified 14 schizophrenic patients with
dementia amongst 96 elderly patients that were under study, and of these, only two were diagnosed

9
with likely AD. Other studies have shown that the cognitive decline typical in schizophrenic patients
in later life is not as consistent or as fast as that which is evident neurodegenerative diseases such as
AD (Harvey et al. 1995), (Friedman et al. 2001).

However, a recent study has led to discussions on the subject. After adjustment for several known
medical risk factors, schizophrenia in mid-life was associated with dementia at ages 65-79 (Zilkens et
al. 2014). In addition, Douaud et al. (2014) showed that some brain regions develop relatively late
during adolescence, and degenerate rapidly during aging in patients with schizophrenia and AD.
These regions are also associated with intellectual ability and episodic memory, with deficiencies in
these areas directly contributing to the main symptoms of schizophrenia and AD. Thus, the study
suggests that there is a common pattern of brain abnormalities in these two disorders.

Some other common findings are seen in the diseases in question. In a comprehensive genomic
analysis studying 108 genes from schizophrenic patients, gene associations were found. These were
specifically related to the main assumptions of the etiology and treatment of schizophrenia. Many
other genes involved in glutamatergic neurotransmission and synaptic plasticity, in addition to the
CACNA1C, CACNB2 and CACNA1Igenes, which encode subunits of voltage-dependent calcium
channels, are implicated in the schizophrenia (Schizophrenia Working Group of the Psychiatric
Genomics Consortium 2014). AD is also closely related to calcium signaling, and the upregulation of
calcium in neuronal signaling may induce an initial decline in memory. This subsequently progresses
into a later phase of apoptosis by excessively activating calcium receptors, and ultimately leads to
excitotoxic neuronal death (Berridge 2013). Although the concept of glutamatergic excitotoxicity by
calcium signaling is an underlying mechanism in various diseases, this newly discovered link between
AD and schizophrenia should be considered.

There are also other findings which are common to both conditions in question, such as a reduction in
neurotrophic factors, mainly in the levels of brain-derived neurotrophic factor (BDNF) in
schizophrenia (Ikeda et al. 2008), and in AD (Alvarez et al. 2014), which is important for
neurogenesis. There are also increases in interleukin-1, interleukin-6 and tumor necrosis factor (TNF)
in schizophrenia (Potvin et al. 2008), and in AD (Heneka et al. 2014), indicating neuroinflammation
and decreased hippocampal volume in both diseases (Mondelli et al. 2011), (Voevodskaya et al.
2014). Therefore, despite being different diseases, AD and schizophrenia are linked; however, there is
some disagreement as to how close this link actually is. The main findings and conclusions are
presented in Table I.

CONCLUSIONS

Although no causal relationship has been proven between AD and the psychiatric disorders in this
study, certainly, there is a close relationship between psychiatric comorbidities such as depression,
schizophrenia and bipolar disorder and this dementia. Considering that there is still enormous
difficulty in identifying AD at earlier stages, understanding of the mechanisms underlying the
psychiatric comorbidities and AD, can be useful. The psychiatric comorbidities could be related to an
earlier detection of a possible predisposition to development of AD. In turn, the occurrence of
depression, schizophrenia and bipolar disorder could be considered a prodromic stage of AD. In
particular, this will allow earlier treatment of patients. Moreover, the use of classical drugs for treating
these psychiatric comorbidities may possibly have beneficial therapeutic effects in AD.

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Penyakit alzheimer yang berhubungan dengan penyakit kejiwaan lain
Michelle L. Garcez 1 , Ana Carolina B. Falchetti 1 , Francielle Mina 1 , Josiane Budni 1
Naskah diterima tanggal 9 Januari 2015, diterima untuk dipublikasi 19 juni 2015
ABSTRAK

Penyakit Alzheimer (AD) adalah penyebab paling umum dari demensia dan telah menjadi masalah
kesehatan masyarakat yang parah. Diperkirakan bahwa secara global, 35,6% orang memiliki beberapa
bentuk demensia. Jumlah ini diperkirakan akan meningkat dua kali lipat pada tahun 2030, dan bahkan
mungkin tiga kali lipat pada tahun 2050. Penyakit ini berhubungan dengan kognisi/memori dan
mengurangi kemampuan dalam menghadapi kehidupan sehari-hari. Selain itupasien dapat mengalami
perubahan suasana hati, depresi dan halusinasi. secara umum mencari komorbiditas neuropsikiatri
seperti depresi, skizofrenia dan gangguan bipolar selama perkembangan alzheimer. Gangguan ini bisa
menjadi cukup berat sehingga mengganggu fungsi sehari-hari pasien, dan dapat memperburuk
perjalanan penyakit. Namun, sedikit diketahui tentang hubungan sebab akibat antara komorbiditas
psikiatrik dan alzheimer, atau alasan kecenderungan dari beberapa individu dengan gangguan
tersebut. Oleh karena itu, tujuan dari kajian ini adalah untuk memperjelas hubungan kausal antara
depresi, skizofrenia dan gangguan bipolar dengan AD.

Kata kunci: penyakit Alzheimer; gangguan bipolar; depresi; skizofrenia

PENGANTAR

Alzheimer Disease (AD) sebagai penyebab utama demensia dalam masyarakat modern, dan dapat
mengakibatkan keterbatasan yang signifikan bagi penderita akibat penurunan kognitif. Gejala yang
paling jelas pada awal AD adalah kehilangan memori yang progresif( Grundman et al. 2013 ).

Studi patofisiologi menjelaskan bahwa AD yang berhubungan dengan gangguan kognitif. Penyebab
biokimia mungkin termasuk didalamnya akibat akumulasi oligomer protein amiloid beta, yang
bertanggung jawab untuk kerusakan sinaptik defisit memori pada penyakit alzheimer( Krstic dan
Knuesel 2013 ). Lebih jauh disebutkan hyperphosphorylation dari protein Tau adalah proses
patofisiologi lain yang terlibat dalam AD. Hyperphosphorylation menginduksi pembentuka
neurofibrilasi intraseluler, yang menyebabkan kematian neuronal dan hilangnya fungsi neuronal
secara progresif. ( Krstic dan Knuesel 2013 ), ( Serrano-Pozo et al. 2011 ), ( Chu 2012 ), ( Nimmrich
dan Ebert 2009 ).

Meskipun studi ini menunjukkan penyebab biokimia mungkin menyebabkan degenerasi neuron akut
dari waktu ke waktu ( Shankar dan Walsh 2009 ), patofisiologi AD masih belum bisa dijelaskan..
Namun beberapa aspek etiologi mungkin terlibat dalam pengembangan AD, seperti faktor lingkungan
dan genetik ( Schipper 2011 ).

Mengingat keterbatasan pemahaman kita tentang AD, masalah yang sama bisa muncul gejala kognitif,
yang berhubungan dengan memori, belajar, agnosia dan apraxia. Juga bisa muncul bentuk gejala non-
kognitif, yang ditandai dengan perubahan perilaku dan psikologis, seperti agresivitas, cepat marah,
halusinasi dan depresi, yang dikenal sebagai Perilaku dan Gejala Psikologis Dementia (BPSD) (
Schiffczyk et al. 2013 ) .

Gejala neuropsikiatri yang terlihat baik selama perjalanan penyakit alzheimer.( Lyketsos et al. 2011 ).
Sedangkan gejala kognitif demensia adalah fitur neuropsikiatri hadir di sebagian besar penduduk
tanpa memandang usia, depresi terkait dengan demensia muncul terutama pada orang tua ( Steffens et
2009 al. ). Dengan demikian, ini memungkinkan bahwa depresi adalah gejala neuropsikiatri yang
paling umum di AD ( Contador-Castillo et al. 2009 ).

Penyakit alzheimer dan penyakit bipolar

11
Bipolar adalah gangguan kejiwaan yang ditandai dengan episode mania atau hypomania dan depresi (
Brenner dan SHYN 2014 ). DSM (Diagnostik dan Statistik Manual of Mental Disorders) konsensus
di antara akademisi terkemuka, dokter dan peneliti di bidang penyakit kesehatan mental dan kejiwaan
( Vahia 2013 ). Versi terbaru dari dokumen ini diterbitkan oleh American Psychiatric Association
(APA) pada bulan Mei 2013 edisi kelima (DSM-5 atau DSM-V). Edisi terbaru dari DSM ini
memodifikasi beberapa konsep gangguan bipolar, terutama yang mempengaruhi kriteria inklusi dan
eksklusi.

BD masih diklasifikasikan sebagai gangguan bipolar I dan II. Gangguan bipolar I ditandai dengan
episode manik (mood sangat tinggi), dysphoria dan depresi berat. Gangguan bipolar II ditandai
dengan episode depresi berat dan setidaknya terdapat satu episode hipomanik (penigkatan mood dan
energi). Seperti dalam DSM-IV, kehadiran lima dari sembilan gejala diagnostik yang diperlukan
dengan setidaknya satu episode manik yang berlangsung satu minggu atau lebih (bipolar I) atau
setidaknya satu episode hipomanik berlangsung empat hari atau lebih (bipolar II), yang memberi
perubahan pada kehidupan pasien ( APA 2013 ).

Sebelum diagnosis BD dapat dikonfirmasi, kondisi medis, bahan atau obat yang bisa menginduksi
gejala manik harus dikeluarkan. Hal ini sangatlah penting pada pasien geriatri, yang mungkin
memiliki penyakit penyerta lain yang dapat menyebabkan delirium dan/atau depresi, seperti AD.
Namun, penelitian terbaru menunjukkan bukti klinis yang berkaitan antara AD dan BD, karena
memiliki gejala yang sama. Banyak studi epidemiologi yang telah menghubungkan dua penyakit ini (
Kessing dan Andersen 2004 ), ( Zilkens et al. 2014 ), ( da Silva et al. 2013 ) dan mendapatkan
perubahan neuroimaging ( Rej et al. 2014 ), disregulasi dari saraf kalsium( Berridge 2013 ) dan
perubahan epigenetik ( Rao et al. 2012 ).

Studi yang dilakukan pada pasien BD telah menunjukkan bahwa mereka memiliki risiko lebih besar
untuk terkena demensia dibandingkan dengan jenis kelamin dan usia dari populasi umum. Risiko
demensia meningkat sebesar 6% dengan setiap episode gangguan bipolar yang membuat pasien
masuk rumahsakit. Para peneliti mengindikasikan penelitian ini hanya pada pasien yang pernah masuk
rumahsakit paling tidak sekali,dan termasuk episode afektif jika mereka dirawat inap, karena
penelitian ini dilakukan dengan menggunakan catatan dari rumah sakit di Denmark ( Kessing et al.
1999 ), ( Kessing dan Andersen 2004 ). Oleh karena itu, peningkatan risiko demensia pada pasien
masih dianggap remeh. Namun, perlu dicatat bukti tergantung pada variabel klinis dan demografi.

Studi epidemiologis juga telah dilakukan pada populasi lain. Sebuah studi kasus-kontrol
menggunakan catatan rumah sakit di Australia Barat yang berhubungan dengan pasien rawat inap,
rawat jalan, kedaruratan kesehatan mental yang terkait dengan kematian, menunjukkan bahwa di
Australia Barat pasien dapat terkena bipolar dua kali lipat lebih tinggi dengan usia antara 65-84 tahun,
sedangkan kemungkinan pasien terkena demensia non-spesifik enam kali lebih tinggi ( Zilkens et al.
2014 ). Namun, sebuah studi oleh da Silva et al. (2013) , yang melakukan tinjauan sistematis pada
risiko individu dengan sejarah perkembangan demensia, menunjukkan bahwa risiko demensia lebih
tinggi bila dikaitkan dengan depresi dibandingkan dengan gangguan bipolar, dan depresi dapat
menjadi faktor penting, karena pasien bipolar telah hampir sama dengan depresi.

Gangguan bipolar dan demensia mungkin mempunyai faktor etiologi umum, seperti stres oksidatif
dan penurunan faktor neurotropik yang keduanya adalah kunci dalam patofisiologi gangguan mood (
Bauer et al. 2014 ) dan AD ( Heneka et al. 2014 ), serta peradangan saraf ( Stich et al. 2014 ), yang
dapat muncul pada keduanya, dengan peningkatan yang terjadi pada interleukin pro-inflamasi, tumor
(TNF-) dan enzim asam kaskade arakidonat pada otak pada pasien BD dan AD yang telah
meninggal( Kim et al. 2011 ), ( Rao et al. 2011 ).

Faktor etiologi lain yang umum pada komorbiditas sedang dibahas adalah perubahan vaskular pada
pasien observasi yang terkena AD ( Luchsinger et al. 2008 ), ( Brickman et al. 2012 ) yang juga
terlihat pada pasien BD ( Sodhi et al. 2012 ). Namun, masih ada beberapa ketidaksepakatan atas data
yang berkaitan dengan perubahan serebrovaskular pada beberapa penelitian, karena usia yang
berbeda dari pasien dan daerah di mana perubahan ini ditemukan ( Almeida et al. 2009 ), ( Haller et

12
al. 2011 ), ( Rej et al. 2014 ). Penelitian lebih lanjut diperlukan untuk membangun hubungan antara
gangguan bipolar dan AD, dan untuk memastikan apakah perubahan ini secara langsung terkait
dengan defisit kognitif yang ditemukan di kedua penyakit. Namun, diketahui bahwa bahkan setelah
penurunan dari gejala depresi, pasien BD menunjukkan gangguan kognisi dan fungsi eksekutif mirip
dengan pasien euthymic dengan gangguan bipolar memiliki defisit dalam memori semantik deklaratif
dan fungsi eksekutif ( Robinson et al. 2006 ), perubahan ini juga sedang diamati pada penderita AD (
Bondi et al. 2008 )

penghambatan Glikogen sintase kinase-3 (GSK3). Lithium adalah obat yang biasa digunakan untuk
mengobati BD, dan salah satu target intraseluler utama lithium adalah penghambatan GSK-3, yang
mengatur aktivitas faktor transkripsi (CREB dan -catenin) bertanggung jawab untuk ekspresi BDNF
dan Bcl-2. Ini mengontrol neurogenesis dan kelangsungan hidup neuron, serta memiliki efek
stabilisasi mood. Selain itu, lithium meningkatkan Bcl-2 dan menurunkan kadar kalsium sitosol
dengan menghambat pelepasan Ca + dari retikulum endoplasma ( Berridge 2013 ). Penggunaan
lithium baru-baru ini telah dianjurkan dalam pengobatan AD, dan reaksi obat tersebut dapat menjadi
jembatan antara AD dan BD, melalui mekanisme yang sama ( Stutzmann et al. 2006 ), karena
disregulasi Ca + signaling terjadi dalam kedua kondisi. Hal ini juga hanya akan bertindak dengan
mengurangi fosforilasi protein Tau, yang terjadi melalui aksi GSK-3 ( Hernandez et al. 2013

penelitian melaporkan penurunan kadar BDNF dan protein sinaptik di otak kedua AD dan pasien BD (
Rao et al. 2011 ), ( Kim et al. 2010 ), dan di samping ini, ada pengamatan perubahan ekspresi dari
inflamasi ( Kim et al. 2011 ) dan gen apoptosis ( Kim et al. 2010 ) umum untuk BD dan AD. Dalam
sebuah studi oleh Rao et al. (2012) , otak dari pasien yang menderita dengan BD dan AD
menunjukkan perubahan statistik epigenetik yang signifikan dalam metilasi DNA global untuk kedua
BD dan AD, dan perubahan epigenetik terkait dengan peradangan saraf, integritas sinaptik, saraf
proteksi dan metabolisme asam arakidonat di frontal korteks. Namun, sementara histon H3 asetilasi
ditemukan telah meningkat dalam otak pasien BD. Namun, tidak ditemukan perubahan pada pasien
AD. Perlu dicatat bahwa obat yang dikonsumsi pasien mungkin juga menyebabkan perubahan dalam
epigenome.

Studi-studi lain telah menganalisis tingkat metabolit amyloid yang terkandung dalam cairan
serebrospinal (CSF) dari pasien BD, dan menemukan bahwa ada konsentrasi yang lebih rendah dari
bentuk larut dari APP ( dan ) pada pasien bipolar, jika dibandingkan dengan kontrol yang sehat atau
AD pasien ( Piccinni et al. 2012 ), ( Jakobsson et al. 2013 ) di mana penurunan A-42 di CSF adalah
berbanding terbalik dengan jumlah plak amiloid. Hubungan antara konsentrasi rendah A dan
peningkatan yang parah dari jenis gangguan bipolar I juga di amati, tetapi tidak ada bukti lain dari
degenerasi saraf pada Alzheimer yang ditemukan pada pasien bipolar ( Jakobsson et al. 2013 ).
Temuan ini sesuai dengan penelitian sebelumnya di mana tidak ada kenaikan plak amiloid atau
neurofibrillary yang ditemukan dalam jaringan otak postmortem dari pasien psikiatri ( Damadzic et al.
2002 ).

Dengan demikian, keberadaan poin konsisten dan temuan yang sama untuk kedua BD dan AD yang
jelas. Namun, meskipun pada kedua gangguan tampaknya memiliki mekanisme mendasari sama,
tidak ada cukup bukti untuk mengatakan bahwa penurunan kognitif yang ditemukan di BD memiliki
patofisiologi yang sama seperti yang ditemukan dalam AD, juga tidak mungkin untuk menyatakan
bahwa pasien BD cenderung untuk AD. Temuan utama dan kesimpulan disajikan dalam Tabel I .

TABEL I Hubungan antara AD dan gangguan bipolar, depresi dan skizofrenia.

Penyakit penyerta Artikel Penulis Kesimpulan

yang berhubungan
dengan alzheimer
Bipolar Bagaimana perkembangan Kessing Risiko demensia tampaknya
peningkatan demensia pada dan meningkat pada depresi dan

13
 pasien dengan depresi dan
pada pasian bipolar?
Depresi Depresi dan risiko penyakit
alzheimer: tinjauan
sistematis, metaanalisis,
dan analisis metaagresi
Penelitian prefalensi
depresi dikalangan orang
tua amerika: penuaan,
demografis,dan memori
Kontribusi Depresi untuk
Cognitive Impairment dan
Demensia pada lansia
Risiko perkembangan
depresi ketika menderita
penyakit saraf
depresi akhir-hayat dan
risiko demensia vaskuler
dan penyakit Alzheimer:
review sistematis dan meta-
analisis dari penelitian
kohor berbasis masyarakat
Peningkatan Hippocampal
plak pada pasien dengan
penyakit Alzheimer dengan
riwayat depresi seumur
hidup
amyloid Plasma, depresi, Direk et al Kehadiran jumlah yang lebih
dan demensia di 2013
masyarakat yang tinggal
lansia
Serum protein beta amiloid Kita et al Rasio serum Abeta40 / 42 lebih
pada pasien depresi muda 2009
dan lansia: penelitian pilot
gejala neuropsikiatri di Rosenberg
subtipe MCI: pentingnya et
disfungsi eksekutif. (2011)
Skizofrenia
Demensia pada masa tua
pasien dengan skizofrenia
Sebuah jaringan otak yang
umum sponsor
pengembangan, penuaan,
dan kerentanan terhadap
penyakit
Disregulasi sinyal saraf
andersen gangguan bipolar afektif
2004
Ownby et Ada hubungan yang tinggi antara
al 2006 gejala depresi dan depresi
sebagai faktor risiko
perkembangan alzheimer
Steffens et Orang dengan demensia
al 2009 memiliki prevalensi tinggi untuk
terkena depresi
Potter dan Prefalensi depresi adalah paling
Steffens tinggi pada demensia, pada
2007 alzheimer kurang intens
Thielscher 51,4% pasien menjadi depresi 1
et al 2013 tahun setelah didiagnosis
Alzheimer
Diniz et al Hubungan antara depresi dengan
2013 perkembangan alzheimer
Rapp et al Terdapat riwayat depresi seumur
200 hidup yang berhubungan dengan
tingginya
tinggi dari plak neuritik dan
neurofibrillary dapat hadir pada
pasien dengan depresi tanpa AD.
Depresi juga dapat dikaitkan
dengan akumulasi plak pada
orang tua
tinggi pada pasien depresi.
Penurunan fungsi eksekutif, yang
al. lebih parah pada pasien dengan
depresi dan kecemasan. Orang
denga gejala depresi juga terkait
dengan gangguan kognitif
ringan, ditemukan peningkatan
risiko untuk menjadi AD.
Mengidentifikasi 14 pasien
Nicolas et skizofrenia dengan demensia di
al. (2014) antara 96 lansia, tetapi hanya dua
yang didiagnosis dengan AD
Kesan umum pelainan pola
Douaud et
spasial pada jaringan otak di AD
al. (2014)
dan skizofrenia.
Berridge Disregulasi Ca (2+) sinyal jalur
14
 kalsium pada penyakit (2013) bertanggung jawab untuk
Alzheimer, gangguan pengembangan penyakit saraf
bipolar dan skizofrenia seperti penyakit Alzheimer,
gangguan bipolar dan
skizofrenia.
Bipolar, depresi dan gangguan kejiwaan berat depresi berat, gangguan bipolar,
skizofrenia pada pertengahan hidup dan schizophrenia dan
risiko demensia pada masa Zilkens et ketergantungan alkohol pada
tua (usia 65-84 tahun): al. (2014) pertengahan hidup merupakan
studi kasus-kontrol berbasis faktor risiko penting untuk AD
masyarakat. pada masa tua.
Bipolar dan depresi angguan afektif dan risiko Peningkatan risiko demensia
da Silva et
mengembangkan demensia: pada orang dengan depresi, dan
al. (2013)
review sistematis gangguan bipolar

Depresi dan penyakit Alzheimer

Depresi adalah gangguan mental yang ditandai dengan beberapa gejala termasuk: mood depresi,
kehilangan minat dalam kegiatan yang menyenangkan, perubahan nafsu makan dan pola tidur, dan
perubahan dalam kegiatan psikomotor seperti kesulitan dalam berpikir, berkonsentrasi atau membuat
keputusan ( APA 2013 ). Gangguan ini umumnya terkait dengan peningkatan risiko morbiditas dan
mortalitas, peningkatan utilisasi pelayanan kesehatan, respon regijem terapi menurun. dan
peningkatan risiko bunuh diri ( Paradela et al. 2005 ), ( Rotheneichner et al. 2014 ).

Terjadi peningkatan depresi di negara-negara maju bila dibandingkan dengan negara-negara

berpenghasilan menengah-rendah ( Bromet et al. 2011 ), ( Kessler dan Bromet 2013 ), dewasa ini
masih berkaitan dengan timbulnya gejala, dan perempuan memiliki dua kali lipat risiko menjadi
depresi seumur hidup jika dibandingkan dengan laki-laki pada usia yang sama ( Bromet et al. 2011 ), (
Kessler dan Bromet 2013 ). Selain itu, sebuah studi berbasis populasi telah menilai prevalensi depresi
pada populasi di Brasil, menemukan tingkat yang lebih besar dari gejala depresi pada orang di atas
usia 60 ( da Silva 2013 ).

Secara global, prevalensi gangguan depresi pada populasi lanjut usia adalah antara 10% dan 20%,
tergantung pada situasi budaya mereka yang mennjukkan apakah itu gangguan psikologis yang umum
para proses penuaan ( Barua et al. 2011 ). Fitur dikaitkan dengan timbulnya depresi mayor yang
kemudian berkaitan dengan penurunan fungsi kognitif yang cukup tinggi.( Potter dan Steffens 2007 ),
( Steffens et al. 2009 ).

Studi menunjukkan bahwa ada hubungan yang kuat antara gejala depresi dan depresi sebagai faktor
risiko untuk pengembangan AD ( Ownby et al. 2006 ), ( Thielscher et al. 2013 ). Dua meta-analisis (
Diniz et al. 2013 ) dan ( Ownby et al. 2006 ) dan satu review sistematis ( da Silva et al. 2013 )
menemukan hubungan antara depresi masa tua dan perkembangan AD.

Sebuah studi neuropatologis dilakukan pada otak orang mati dari 153 peserta. terbukti bahwa depresi
mungkin berhubungan dengan hilangnya neuron dibagian tertentu otak seperti hippocampus, yang
juga terjadi pada AD. Namun, tidak ada hubungan jelas antara efek depresi dan AD di neurofibrillary
atau plak neuritik, yang keduanya gejala karakteristik AD ( Tsopelas et al. 2011 ). Wilson et al. (2003)
juga tidak menemukan korelasi antara plak dan gejala depresi pada pasien AD.

Sebuah penelitian prospektif yang terpisah, yang melakukan evaluasi neuropathological dari otak
post-mortem pasien dengan usia rata-rata 81 tahun, ditemukan adanya jumlah yang lebih tinggi dari
plak neuritik dan formasi neurofibrillasi di hippokampus pasien dengan AD dengan riwayat depresi,
dibandingkan dengan otak pasien AD tanpa riwayat depresi ( Rapp et al. 2006 ).

15
Temuan ini memperkuat hipotesis bahwa perubahan saraf disebabkan oleh AD. Namun, perubahan ini
juga dapat hadir pada pasien dengan depresi yang tidak menderita dengan AD ( Direk et al. 2013 ),
sedangkan pembentukan kusut neurofibrillary dan plak neuritik adalah salah satu proses utama yang
terlibat dalam patofisiologi AD ( Nimmrich dan Ebert 2009 ), ( Serrano-Pozo et al. 2011 ), ( Krstic
dan Knuesel 2013 ). Depresi juga dapat dikaitkan dengan akumulasi plak ini pada orang tua ( Kita et
al. 2009 ).

Penelitian lain menunjukkan hubungan positif antara keadaan depresi pada saat kematian, dan adanya
plak neuritik pada penyakit Alzheimer, yang independen dari tingkat keparahan klinis demensia.
Sebuah studi pra-klinis yang dilakukan pada tikus telah menunjukkan bahwa oligomer beta-amyloid
menyebabkan gangguan memori dan perilaku depresif ( Ledo et al. 2013 ).

Oleh karena itu, bisa sulit untuk membedakan dan akibatnya mendiagnosa gejala depresi demensia,
karena gejala dari suatu keadaan dapat tumpang tindih dengan yang lain ( Bystad et al. 2014 ). Ada
mekanisme yang terlibat dalam proses depresi yang ditandai dengan peningkatan produksi
glukokortikoid dan penyakit pembuluh darah otak, menyebabkan atrofi iskemia hipokampus, dan
akhirnya mengakibatkan penurunan kognitif yang terlihat pada AD atau demensia ( Butters et al. 2008
) . Oleh karena itu, hubungan ini membuat sulit untuk menentukan apakah depresi merupakan faktor
risiko untuk AD atau gejala prodromal ( Koenig et al. 2014 ).

Sebagai contoh, ketika menilai 211 wanita lansia yang depresi, pasien ini menunjukkan defisit
kognitif dalam semua tes yang dilakukan dalam penelitian ( Yaffe et al. 1999 ), namun penelitian lain
yang mengevaluasi 1.299 wanita dengan usia rata-rata 88 tahun, ditemukan 41% dari peserta ada ada
penurunan kognitif yang signifikan dan pada mereka lebih dari 90 tahun, asosiasi dengan demensia
lebih umum terjadi ( Yaffe et al. 2011 ).

Sebuah studi terpisah menyelidiki prevalensi gejala neuropsikiatri yang menilai 1.799 pasien dengan
gangguan kognitif ringan, menemukan gangguan fungsi eksekutif, yaitu gejala kognitif, yang lebih
berat pada pasien yang menderita depresi dan kecemasan ( Rosenberg et al. 2011 ). Baru-baru ini,
mereka mengevaluasi 527 orang yang memiliki gejala depresi juga terkait dengan gangguan kognitif
ringan. Temuan mereka menunjukkan bahwa dalam kelompok ini ada peningkatan risiko untuk
pengembangan AD ( Rosenberg et al. 2013 ).

Hasil studi ini menunjukkan bahwa depresi tidak mungkin hanya menjadi faktor risiko demensia atau
AD, tetapi juga mungkin merupakan gejala fitur dari tahap awal penurunan kognitif atau demensia.
Temuan utama dan kesimpulan disajikan dalam Tabel I .

Skizofrenia dan penyakit Alzheimer

Skizofrenia adalah gangguan mental yang berat dengan prevalensi hampir 1% dari populasi dunia,
dan diperkirakan memiliki kejadian 15 per 100.000 orang ( Rossler et al. 2005 ). Sifat gangguan ini
adalah heterogen, yang membuat pengobatan dan penyelidikan lebih sulit ( Casey et al. 2013 ).

Diagnosis skizofrenia pada dasarnya berdasarkan uraian dari tanda-tanda dan gejala yang disajikan
oleh pasien. Sampai saat ini, belum ada parameter patofisiologi dengan sensitivitas atau spesifisitas
yang cukup untuk memberikan diagnosis positif ( Bagdy dan Juhasz 2013 ). Menurut DSM-V
(Manual Diagnostik dan Statistik Gangguan Mental), tanda-tanda pasti hadir untuk setidaknya enam
bulan, dan juga harus menyertakan minimal satu bulan gejala aktif untuk mengkonfirmasi diagnosis (
APA 2013 ). Skizofrenia adalah gangguan mental yang ditandai dengan gejala positif, negatif dan
kognitif. Gejala positif dapat dinyatakan sebagai delirium, halusinasi dan delusi ( Penzes et al. 2011 ),
( Howes dan Murray 2014 ), ( Murray et al. 2014 ). Gejala negatif afek tumpul. Gejala kognitif yang
ditandai dengan masalah dengan memori kerja ( APA 2013 ).

Mekanisme penyakit ini masih kurang dipahami. Disfungsi sistem dopaminergik telah diyatakan
faktor penyebabnya. Ini adalah sebagian, pada peran fungsional dopamin terhadap fisiologi, dan

16
penurunan kinerja kognitif, terutama dalam memori kerja dan di sirkuit reward ( Arnsten 2011 ).
Selain itu, ada perubahan dalam fungsi satu atau lebih sistem neurotransmitter, yang melibatkan
dopaminergik, glutamatergic, serotonergik dan sistem adenosinergic ( Carter 2006 ). Sebuah
penelitian yang membandingkan ingatan prospektif dari 42 orang sehat dengan 42 orang yang
menderita skizofrenia, menunjukkan defisit pada kelompok pasien dengan skizofrenia. Ini
memperkuat hipotesis bahwa ada penurunan kognitif pada skizofrenia ( Kumar et al. 2008 ).

Beberapa pernyataan penelitian telah dikaitkan penurunan kognitif dan skizofrenia, dan penurunan ini
dapat dikaitkan dengan perubahan dalam jaringan saraf frontoparietal dan gangguan dari
hippokampus ( Joyce 2013 ), yang juga terkait dengan AD ( Nelson et al. 1998 ) , ( Wright et al. 2000
). Perubahan dalam ventrolateral dan daerah dorsolateral korteks prefrontal kiri ( Quan et al. 2013 ),
dan penurunan mielinisasi di daerah temporal dan oksipital telah ditemukan pada pasien dengan
skizofrenia dan penurunan kognitif ( Palaniyappan et al. 2013 ) . kemampuan memori kerja terganggu
sebagian pada orang-orang dengan risiko tinggi psikosis ( Wood et al. 2003 ), dan perubahan memori
ini terkait dengan AD ( Serino et al. 2014 ).

Profil kognitif subjek penelitian dengan akhir-onset skizofrenia berbeda dari pasien dengan AD dan
depresi ( Ting et al. 2009 ), ( Etkin et al. 2013 ). Individu dengan skizofrenia menunjukkan penurunan
kognitif pada semua tahap penyakit ( Rajji et al. 2014 ). Penurunan kognitif ini dapat dengan mudah
diamati oleh pengujian untuk perubahan respon memori episodik dengan skizofrenia ( Schaefer et al.
2013 ), ( Barch dan Sheffield 2014 ). Hal ini juga dapat diamati pada kecepatan di mana mereka
memproses informasi ( Schaefer et al. 2013 ), ( Woodward et al. 2013 ), serta perubahan pada memori
verbal mereka, yang merupakan salah satu gejala kognitif yang paling umum dari skizofrenia (
Lepage et al. 2014 ).

Demikian pula, gejala psikotik, delusi dan halusinasi sering di AD, yang saat ini gangguan psikotik
paling lazim kedua (kedua hanya untuk skizofrenia) di Amerika Serikat, dan mungkin menjadi yang
paling umum ( Murray et al. 2014 ). Timbulnya gejala psikotik di AD sangat terkait dengan
percepatan penurunan kognitif ( Ropacki dan Jeste 2005 ).

Beberapa studi epidemiologi konklusif berkaitan perkembangan skizofrenia dengan timbulnya AD.
Hall ini karena mendiagnosis pasian lanjut usia dengan skizofrenia adalah hal yang menantang,
karena berbagai tahap tes kognitif dibutuhkan, dan juga karena AD hanya didiagnosis melalui
penilaian status kejiwaan pasien. Nicolas et al. (2014) mengidentifikasi 14 pasien skizofrenia dengan
demensia di antara 96 pasien usia lanjut yang diteliti, dan hanya dua yang didiagnosis dengan
kemungkinan AD. Penelitian lain menunjukkan bahwa penurunan kognitif yang khas pada pasien
skizofrenia tidak konsisten atau secepat penyakit neurodegenerative yang mempunyai bukti jelas
seperti AD ( Harvey et al. 1995 ), ( Friedman et al. 2001 ).

Namun, sebuah studi baru-baru ini telah menyebabkan diskusi pada subjek. Setelah penyesuaian
untuk beberapa faktor risiko medis dikenal, skizofrenia pada pertengahan kehidupan dikaitkan dengan
demensia di usia 65-79 ( Zilkens et al. 2014 ). Selain itu, Douaud et al. (2014) menunjukkan bahwa
beberapa daerah otak berkembang relatif terlambat selama masa remaja, dan merosot dengan cepat
selama penuaan pada pasien dengan skizofrenia dan AD. Wilayah ini juga berhubungan dengan
kemampuan intelektual dan memori episodik, dengan kekurangan di daerah-daerah secara langsung
berkontribusi terhadap gejala utama skizofrenia dan AD. Dengan demikian, studi ini menunjukkan
bahwa ada pola umum dari kelainan otak dalam dua gangguan ini.

Beberapa temuan umum lainnya terlihat di penyakit tersebut. Dalam analisis genom yang
komprehensif mempelajari 108 gen dari pasien skizofrenia, asosiasi gen yang ditemukan. Ini secara
khusus berkaitan dengan asumsi utama etiologi dan pengobatan skizofrenia. Banyak gen lain yang
terlibat dalam neurotransmisi glutamatergic dan plastisitas sinaptik, selain CACNA1C, CACNB2 dan
gen CACNA1I, yang mengkodekan subunit saluran kalsium tegangan tergantung, yang terlibat dalam
skizofrenia (Kelompok Kerja Skizofrenia dari Genomics Consortium Psychiatric 2014). AD juga
terkait erat dengan kalsium signaling, dan peningkatan regulasi kalsium dalam sinyal saraf dapat
menyebabkan penurunan memori. Hal ini kemudian berkembang ke fase selanjutnya dari apoptosis

17
oleh reseptor kalsium berlebihan mengaktifkan, dan akhirnya menyebabkan kematian neuronal
eksitotoksik ( Berridge 2013 ). Meskipun konsep excitotoxicity glutamatnergik oleh kalsium signaling
merupakan mekanisme yang mendasari berbagai penyakit, ditemukan hubungan terbaru antara AD
dan skizofrenia harus dipertimbangkan.

Ada juga temuan lain yang umum untuk kedua kondisi tersebut, seperti pengurangan faktor
neurotropik, terutama dari otak faktor neurotropik (BDNF) pada skizofrenia ( Ikeda et al. 2008 ), dan
di AD ( Alvarez et al. 2014 ), yang penting untuk neurogenesis. peningkatan interleukin-1, faktor
interleukin-6 dan tumor nekrosis (TNF) pada skizofrenia ( Potvin et al. 2008 ), dan di AD ( Heneka et
al. 2014 ), menunjukkan peradangan saraf dan penurunan volume hipokampus pada kedua penyakit (
Mondelli et al. 2011 ), ( Voevodskaya et al. 2014 ). Oleh karena itu, meskipun penyakit yang berbeda,
AD dan skizofrenia terkait; Namun, ada beberapa perbedaan pendapat mengenai seberapa penyakit ini
berkaitan . Temuan utama dan kesimpulan disajikan dalam Tabel I .

KESIMPULAN

Meskipun tidak ada hubungan kausal telah terbukti antara AD dan gangguan kejiwaan dalam
penelitian ini, tentu, ada hubungan erat antara komorbiditas psikiatrik seperti depresi, skizofrenia dan
gangguan bipolar dan demensia ini. Mengingat bahwa masih ada kesulitan besar dalam
mengidentifikasi AD pada tahap awal, pemahaman tentang mekanisme yang mendasari komorbiditas
psikiatri dan AD, dapat berguna. The komorbiditas psikiatrik dapat dikaitkan dengan deteksi awal dari
kecenderungan mungkin untuk pengembangan AD. Pada gilirannya, terjadinya depresi, skizofrenia
dan gangguan bipolar dapat dianggap sebagai tahap prodromic dari AD. Secara khusus, ini akan
memungkinkan pengobatan awal pasien. Selain itu, penggunaan obat klasik untuk mengobati ini
komorbiditas psikiatrik mungkin dapat memiliki efek terapi bermanfaat dalam AD.

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Received: January 09, 2015; Accepted: June 19, 2015

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