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Psychiatric Aspects of Mild Cognitive Impairment

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Dec 6, 2005, 12:43:19 PM12/6/05

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Psychiatric Aspects of Mild Cognitive Impairment
Elizabeth A Crocco MD and David A Loewenstein PhD
Department of Psychiatry, 4300 Alton Road MRI Building 2nd Floor, Mount
Sinai Medical Center, Miami Beach, FL, 33140, USA

Current Psychiatry Reports 2005, 7:32-36

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Abstract

Mild cognitive impairment in the elderly may represent a transitional
phase between normal aging and early Alzheimer's disease (AD). It
recently has been recognized as a distinct clinical entity with
potentially different cognitive subtypes and etiologies. Like AD,
studies have shown that psychiatric symptoms are more common than in
the cognitively normal geriatric population. Understanding these
symptoms has been recognized as important not only because they may
impair patient function and caregiver burden, but also these symptoms
may be relevant to understanding the development of AD in general. This
article presents current information on psychiatric symptoms in mild
cognitive impairment, their suggested role in the pathophysiology of AD
and future research considerations on the subject.

Outline Introduction

Abstract
Introduction
Epidemiology of Mild Cognitive Impairment and Alzheimer's Disease
Psychiatric Symptoms and Dementia
Depression and Pseudodementia
Psychiatric Symptoms and Mild Cognitive Impairment
Treatment
Future Research Considerations
Conclusions
References

With the aging of the population, there has been an increasing emphasis
on the evaluation of memory complaints in the elderly. This is of
critical importance in that clinicians need to delineate normal aging
or benign conditions from a more serious neurodegenerative illness [1].
Mild cognitive impairment (MCI) in the elderly has recently received
considerable attention as a cognitive state between normal aging and
dementia. First operationalized by Petersen et al. [2,3], the diagnosis
of MCI requires a subjective complaint of memory impairment and
objective verification of these deficits by standardized cognitive
measures. Another requirement for the diagnosis of MCI is a lack of
general intellectual decline or dementia as defined by a preservation
of social and/or occupational function.

It has been recognized only recently that patients with MCI have
psychiatric symptoms and disorders that are more common than in the
normal elderly population and that may cause substantial impairment and
burden. Select symptoms such as depression may be precursors or
possible risk factors for the development of Alzheimer's disease (AD).

This article reviews the current literature on the psychiatric
manifestations of MCI, including its prevalence, its importance to
understanding etiologic and pathologic features of dementia, and
possible treatment strategies for these disabling symptoms. It
concludes with research considerations that currently are needed to
properly evaluate and treat the psychiatric symptoms that may occur in
patients with MCI.

Outline Epidemiology of Mild Cognitive Impairment and Alzheimer's
Disease

Mild cognitive impairment may represent a transitional phase between
normal aging and early AD. Multiple terms and definitions have been
applied, but Petersen's criteria have been formally recognized and is
the most widely used and studied. Petersen et al. [4] describe MCI as a
heterogeneous disorder with different subtypes. Amnestic MCI has been
defined as 1) subjective memory complaint, corroborated by an
informant; 2) objective memory impairment generally defined as 1.5 or
greater standard deviations below age and education-related normative
values;3) normal general cognitive function; 4) intact activities of
daily living; and 5) non-demented.

Amnestic MCI differs from age-associated memory decline, which refers
to increasing memory impairment with age in comparison to normal, young
adults 5]. The term 'cognitive impairment-no dementia' [6] is similar
to that of MCI but emphasizes cognitive impairment other than memory.
Although an early emphasis has been on amnestic MCI, recent studies
have shown that there are non-amnestic types of MCI and multiple domain
MCI in which memory and other cognitive domains are impaired. Research
from our laboratories and others [7,8] have shown that patients with
multiple-domain MCI have a higher prevalence in the community and may
be at a higher risk of conversion to dementia relative to other MCI
subtypes. Therefore, the definition and identification of different
subtypes of MCI continues to be an important area of research and under
much debate.

In patients with clinically diagnosed MCI, the rate of conversion to
dementia during a 3-year period has ranged from 20% to 53% [9]. Morris
et al. [12] reported that of 277 patients with MCI who were thought to
have prodromal AD, 60.5% had converted to dementia within 5 years and
that all had converted to dementia within 9.5 years, most with
Alzheimer's pathology on autopsy. In contrast, epidemiologic studies of
community-dwelling elderly show that MCI is an unstable entity and most
patients remained stable or reverted to a cognitively normal state on
longitudinal follow-up [13,14]. This variability in clinical versus
epidemiologic study may be explained by more stringent diagnostic
criteria and more subjective complaints by patients and informants who
are motivated to present to a memory disorder clinic. Presumably, in
memory disorder clinics, those who come in for evaluation are more
likely to present with prodromal AD, whereas those in the community
settings may have cognitive deficits that are less stable and are
attributable to other causes, some of them reversible. Therefore, in
evaluating the condition of MCI the chances of progression to dementia
in large part may be determined by the setting in which the patient was
evaluated.

In light of these discrepancies in definition and conversion rates, MCI
has been implicated as an independent clinical entity with potentially
different etiologies. There have been numerous attempts to delineate
different clinical, neuropsychologic, and neuroimaging features that
may be unique to different cognitive subtypes of MCI and its etiologic
features. There also has been increasing recognition that understanding
the psychiatric features of MCI is important. First, not only may these
symptoms increase poor patient function and caregiver burden which is
well-documented in AD, these symptoms also may be relevant to the
understanding of the pathophysiology of AD in general. Understanding
the psychiatric aspects of MCI may ultimately lead to a better
understanding of the etiology of the condition and lead us to important
treatment strategies for clinically significant memory impairment that
could prevent the development of a full-blown dementia syndrome.

Outline Psychiatric Symptoms and Dementia

It has been well-documented that neuropsychiatric symptoms are common
and persistent features of AD. The prevalence of symptoms has been
estimated to affect 50% to 80% of patients with dementia [15]. These
symptoms account for numerous adverse consequences such as greater
functional impairment [16], earlier institutionalization [17], more
rapid progression of the disease [18] and increased depression and
caregiver burden [19]. Psychiatric manifestations of dementia include
depression, apathy, psychotic symptoms, such as hallucinations and
delusions, anxiety, sleep disturbances, and behavioral disorders such
as wandering and agitation.

Depression in particular is a common psychiatric symptom in AD,
especially when compared to cognitively normal elderly. Studies
indicate a prevalence of 20% to 25% of AD patients with major
depression, whereas prevalence among patients who have minor depressive
symptoms is much greater [20]. In contrast, cognitively normal elderly
members of the community have a prevalence of depression of less than
5% [20]. This has led one author to conclude that depression in AD may
be the most common psychiatric condition in the elderly population
[21]. Depression has been well-documented to account for numerous
negative consequences and functional loss, such as impairment in
quality of life, disability and earlier placement in nursing homes
[20]. Depression in patients with AD also is associated with increased
caregiver depression and burden [20].

It has become increasingly apparent that depression could potentially
represent an early marker for the manifestation of AD. One study showed
a significant number of patients who had depression preceding a
diagnosis of progressive dementia by 26 months [22]. In addition, it
has been suggested that depression may be considered a risk factor for
the disease. Depression has been hypothesized to lead to the production
of the clinical manifestations of AD or lead to hippocampal damage
caused by elevated levels of cortisol [23]. Numerous longitudinal
cohort and case control studies have investigated whether early
depression is associated with increase risk for AD. Although numerous
case control [24] and short-term cohort studies [27] have found a
relationship between depression and AD, others [30], including a
12-year prospective cohort study [33] have found that depressive
symptomotolgy is not predictive of a dementia syndrome in the elderly.
Still other studies [34] confirm depression as early manifestations of
AD, but not a risk factor. A possible explanation for these
inconsistencies is that depression may be an early prodromal symptom of
dementia, first developing with MCI rather than an early risk factor
with causative implications.

In addition to the possible role of depression as an early marker for
dementia, a recent study by Modrego and Ferrandez [37] observed a
cohort of 114 patients with MCI during a 3-year period and found that
not only depressed patients were more likely to convert to AD, but the
depressed patients developed AD at a more rapid rate. Therefore,
depression may predict a more rapid progression of dementia along with
other known predictors such as apolipoprotein E4 allele [38], decreased
hippo-campal volume [39], difficulties with delayed recall and/or rate
of forgetting, and other potential risk factors for more rapid decline
[40].

Depression and Pseudodementia

The clinical entity of 'pseudodementia' has been well-described in the
literature [41]. The patient typically develops a full-blown dementia
syndrome in the context of a major depression, which classically remits
completely with treatment, making it a 'reversible' dementia. These
patients contrast with depressed elderly subjects who have significant
cognitive impairment and remain impaired after resolution of the
depressive symptoms. The latter group usually has an early-stage
dementia disorder in which cognitive manifestations are exacerbated
when the depressive symptoms are superimposed. Follow-up studies [42]
have indicated patients with depression and reversible dementia develop
irreversible dementia at a rate of 9% to 25% per year. This high
conversion rate suggests that late life depression with significant
cognitive impairment may be indicative of incipient AD.

Outline Psychiatric Symptoms and Mild Cognitive Impairment

As described previously, understanding psychiatric symptoms in MCI is
important not only to diagnose and treat the psychiatric comorbidity in
these patients, but also to understand the overall pathophysiology of
this distinct clinical entity. Psychiatric symptoms in MCI have been
shown to be common. In a major study done by Lyketsos et al. [43], a
cohort of community-dwelling subjects from multiple sites were
cross-sectionally evaluated for the presence of neuropsychiatric
symptoms. Subjects were classified as having MCI or dementia, and
compared with a group of cognitively normal individuals from another
study. These classifications were based on clinical criteria with
committee review by experts. The neuropsychiatric inventory, a widely
accepted measure of psychiatric symptoms associated with cognitive
disorders, was used. The results showed 75% of patients with dementia
had at least one neuropsychiatric symptom and 55% had two or more
symptoms within the past month. The MCI group had less frequent
symptoms than the demented group (43% had at least one symptom in the
last month) but was greater than the normal group (16%). The most
common symptoms in the dementia group were apathy (36%), depression
(32%), and agitation and/or aggression (30%). In the MCI group,
depression (20%), apathy (15%), and irritability (15%) were the most
common. These findings not only indicate that psychiatric symptoms in
MCI are common, but given the fact that their prevalence falls between
cognitively normal subjects and dementia subjects additionally supports
the theory that MCI is on a continuum between healthy individuals and
dementia. These results are supported by several other studies [44,45]
that show higher overall prevalence with specific psychiatric symptoms
of depression, aggression, anxiety, apathy, and irritability occurring
in more than 30% of the MCI sample. These specific symptoms follow the
pattern of common neuropsychiatric symptoms in early AD.

In contrast, another community-based cohort study by Forsell et al.
[46] reported a lower prevalence of depression in patients with MCI, at
12%. Differences may be attributed to the use of different study
instruments to measure psychiatric symptoms, and older sample, and/or
no collateral informant. Elderly patients with depression may be less
likely to report a depressed mood than their family members.

Depression and mild cognitive impairment

Recent studies have shown that, similar to patients with AD, patients
with MCI experience a significant amount of depression and depressive
symptoms. As described previously, several studies have found that
depression may precede AD, and may signify an important risk factor for
the development of the dementing illness. However, depression in MCI
may represent a more heterogeneous group with different etiologies. For
example, patients with minor depression or dysthymia may have symptoms
related to the emotional strain of having impaired cognition, whereas
patients with major depression may have a disorder with a more
biological basis.

It has been suggested [47] that cerebrovascular disease may be another
potential cause for depression in MCI. Vascular lesions may cause
problems in important neuronal pathways such as frontostriatal systems
and lead to mood symptoms in vascular dementia and AD, which have
frequent cerebrovascular lesions.

Depression in early AD also has been thought to be linked to
degenerative changes in the locus coeruleus [48]. Neuronal loss has
been noted to be more prominent here than in the nucleus basalis and
may influence the development of depression.

Making the diagnosis of depression in patients with MCI can be
challenging. Elderly patients with depression commonly have
irritability and apathy and do not report depression per se.
Additionally, depression often is associated with cognitive deficits,
but usually of insufficient severity in outpatient settings to meet
objective neuro-psychologic criteria for MCI.

Apathy and mild cognitive impairment

Apathy is a common psychiatric symptom in MCI and AD. Studies as
previously described [49] have shown it to be more common in patients
with MCI than in cognitively normal elderly patients, but not as common
as in early AD. One study [50] found apathy to be as common in both
conditions. Apathy can cause marked distress in family members and
caregivers. It also may cause significant dysfunction in patients.
Additionally, it may prevent patients from seeking necessary medical
treatment and become noncompliant with their medical regimens.
Additionally, apathy as a clinical syndrome often is mistaken for the
signs and symptoms of depression. They may share certain
characteristics, such as lack of interest and motivation, and often
patients with apathy may be misdiagnosed as having depression. Landes
et al. [50] reports that dysphoric mood, or commonly in the elderly,
irritability, is present in depression, but not in apathy. Patients
with depression also commonly have feelings of hopelessness,
worthlessness, guilt, anxiety, and preoccupation with death, whereas
patients with apathy do not.

Psychosis and mild cognitive impairment

Psychotic symptoms, such as hallucinations and delusions which are
prominent in AD are not commonly present in patients with MCI [43,44].
Even in the early stages of AD, symptoms such as persecutory delusions,
mis-identi-fication symptoms and auditory and visual hallucination may
be more prominent then in either MCI or cognitively normal subjects. Of
all the psychiatric symptoms evaluated, psychotic symptoms in AD have
been most commonly associated with a more rapid rate of deterioration
[18]. Neurochemical and neuropathologic changes in the patient with
psychosis and dementia have shown severe frontal and temporal disease
which may indicate a worsening prognosis [51]. Visual hallucinations in
concert with rigidity and MCI also should be evaluated for a potential
neuropsychiatric disorder such as diffuse Lewy body disease.

Outline Treatment

At present, there is minimal data on the treatment of psychiatric
symptoms in MCI. Treatment benefit in Alzheimer's dementia has been
documented to improve psychiatric symptoms and patients functional
abilities. Antipsychotics are efficacious in psychosis, antidepressants
improve depression and anticonvulsants can be useful for agitation and
other behavioral symptoms of dementia [43]. The same holds true for
psychiatric symptoms in groups without underlying neurodegenerative
disease. Therefore, in patients with MCI, it would seem prudent to
treat the psychiatric symptoms that are distressing to patients and to
avoid medication with anticholinergic side-effects that may exacerbate
MCI.

There has been only one small trial evaluating the benefits of
antidepressants in patients with MCI and depression. A study by
Devanand et al. [52] treated 39 patients with MCI and depression with
sertraline for 12 weeks up to a dose of 200 mg and found a moderate
response to depressive symptoms. More clinical trials are needed to
evaluate adequate treatment regimens for patients with cognitive
impairment and psychiatric symptoms, including cholinesterase
inhibitors.

Outline Future Research Considerations

Currently, there are many questions that remain about the
neuropsychiatric manifestations of individuals presenting with MCI.
Although it seems that symptoms such as depression may represent a
prodromal phase of neuro-degenerative disorders such as AD, MCI with
psychiatric sequelae may remain static or even improve in cases of mild
head trauma or a single cerebrovascular infarction. Therefore,
neuropsychiatric symptoms in patients with MCI are not all indicative
of early AD, particularly in the community where the causes of MCI may
be more variable than those associated with patients who present to
specialty memory disorder clinics.

At this time, it is not possible to conclude whether depression in and
of itself is predictive of future dementia and additional research is
required in this area. Also required is more extensive
neuropsychologicical and neuro-imaging studies to determine ways in
which MCI patients with neuropsychiatric features are different than
those without such features. Identifying specific areas of the brain or
specific biochemical abnormalities that are specific to different
cognitive and neuropsychiatric subtypes of MCI would provide important
diagnostic, heuristic, and prognostic information about this important
clinical entity.

Conclusions

It is concluded that neuropsychiatric symptoms are present in a number
of patients with MCI and a better understanding of these conditions may
have important implications for the diagnosis, prognosis and treatment
of the individual. There remains much to be learned about
neurobiological substrates of the psychiatric conditions that may
accompany MCI such as depression, apathy, agitation, and psychosis.
Identification of these entities may prompt earlier treatment and
management. This may have implications for delay of progression of
cognitive impairment in some cases and will be important in enhancing
the quality of life for the patient and family members.

It is essential to focus on delineating different subtypes of MCI with
regard to cognitive and neuropsychiatric features. This ultimately will
allow us to better understand the condition, potential etiologies, and
to provide assistance to our patients.

Outline References

Papers of particular interest have been highlighted as:
· of special interest
·· of outstanding interest

1. Celsis P: Age-related cognitive decline, mild cognitive impairment
or preclinical Alzheimer's disease?
Ann Med 2000, 32:6-14. [PubMed Abstract]