APPENDIX E
Psychosis in Alzheimer’s disease
Robert A. Sweet1,2,3, Clive Ballard4, Nia A. Kin5, Cara Alfaro5,
Patrick S. Murray1,3, Susan Schultz,6
for the Neuropsychiatric Syndromes Professional Interest Area of ISTAART
1Departments
of Psychiatry and 2Neurology, University of Pittsburgh, Pittsburgh, PA
4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA
4Wolfson Centre for Age Related diseases King’s College London, Biomedical Research Unit, Institute of Psychiatry and
Alzheimer’s Society (UK)
5Division of Psychiatry Products, Office of Drug Evaluation 1/OND, Center for Drug Evaluation and Research, Food and Drug
Administration, Silver Spring, MD
6Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City IA.
3VISN
1
Abstract
This review critically examines the current literature with regard to psychosis in Alzheimer’s disease
(AD), in an effort to focus future research efforts that will advance knowledge of the biology and
treatment. Substantial evidence indicates psychosis is frequent in AD, affecting approximately half of
individuals during their illness. Psychosis serves as a marker for a subgroup of individuals with more
rapid deterioration. Current pharmacologic treatments for psychosis in AD have limited efficacy, do not
prevent more rapid decline, and confer significant toxicity. Non-pharmacologic treatments for psychosis
in AD do not have established value, but would benefit from further study. Regarding neurobiology, there
is evidence that the risk of psychosis in AD is genetically mediated. Specific contributing genetic variants
are not clearly established, although genome-wide association studies have identified some promising
leads. Neuroimaging and neuropathologic studies of psychosis in AD have pointed to the neocortex,
particularly the dorsolateral prefrontal cortex, and not the medial temporal lobe, as sites of greater loss of
gray matter, greater impairments of glucose metabolism, and greater synaptic vulnerability in AD subjects
with psychosis. Efforts should be directed towards expanding imaging and post-mortem studies,
incorporating biomarkers and intermediate phenotypes, and developing appropriate animal models.
2
Rating instruments for the assessment of
psychosis in AD were briefly discussed at the
Psychopharmacological
Drugs
Advisory
Committee (PDAC) meeting held on March 9,
2000 to discuss the psychiatric and behavioral
disturbances
associated
with
AD
[http://www.fda.gov/ohrms/dockets/ac/cder00.ht
m#Psychopharmacologic]. Based in part on
these deliberations, the current regulatory
requirement for clinical trials evaluating the
treatment of psychosis in AD are two
independent, adequate and well-controlled trials,
each of which would need to show an effect on
two primary outcomes. One primary outcome
should focus on a global or functional measure
and the other should focus on the defining
criteria for the entity (e.g. AD+P).(8) Although
the NPI total score would be considered too
broad for this symptomatic measure, the NPI
psychosis subscale would be acceptable for the
purpose of demonstrating a reduction in
psychosis.
Introduction
Psychotic symptoms are frequent in Alzheimer’s
disease (AD). AD with psychosis (AD+P)
comprises a major burden of care and is one of
the most common precipitants of nursing home
placement for persons with dementia. The severe
distress these symptoms create for both patients
and caregivers are unfortunately accompanied
by a dearth of available treatment options. In the
following review prepared by the Psychosis
Workgroup of the Neuropsychiatric Syndromes
Professional Interest Area (NPS-PIA), we
examine standardized assessment tools for
psychosis, current nosology, clinical correlates,
available treatment options, and current
understanding of the neurobiologic basis of
AD+P, with a goal towards defining a research
agenda that can drive the development of
specific therapies for this condition.
Assessment Instruments and AD+P
One further note on the assessment of delusions
in AD. Delusional misidentifications, including
the capgras syndrome and misidentifying
photographs, mirror reflections and characters
on the television as real people in the room, are
classified on most rating scales and studies as
delusions when they meet the appropriate
criteria (persistent, resistant to contrary
evidence). However, it is not firmly established
whether phenomenologically they are best
construed as delusions or as a separate group of
symptoms, as they may have different
neurobiological
correlates
than
classic
persecutory delusions (9).
A recent review comparing four of the most
frequently used assessment tools for the
measurement of psychosis in dementia was
published(1). These four assessment tools
included the Behavioral Pathology in
Alzheimer’s Disease Rating Scale (BEHAVEAD)(2), the Neuropsychiatric Inventory-Nursing
Homes (NPI-NH)(3), the Consortium to
Establish a Registry for Alzheimer’s Disease
Behavior Rating Scale for Dementia (CERADBRSD)(4), and the Columbia University Scale
for Psychopathology in Alzheimer’s Disease
(CUSPAD)(5). The BEHAVE-AD and the NPI
are the two commonly used rating instruments
for assessing behavioral disturbances, including
psychosis in Alzheimer’s patients(6). While any
of these may be appropriate for assessing
psychosis in dementia, differences between the
scales with regard to the degree of detail in the
specific behaviors queried and the nature of
administration can lead to different rates of
detection of delusions and hallucinations. With
respect to measuring change in response to
interventions, different instruments may be
preferable due to optimization of sensitivity and
specificity depending on the expected magnitude
of change (7).
Proposed Diagnostic Criteria
Diagnostic criteria for psychosis of AD were
proposed by Jeste and Finkel (Table 1) (10).
These proposed diagnostic criteria were also
discussed at the aforementioned PDAC meeting
with the FDA. It should be noted that the
original criteria stated that symptoms
(hallucinations and/or delusions) are severe
enough to cause some disruption in patients’
and/or others’ functioning. The general view of
the 2000 PDAC was that a disruption in patient
symptoms and functioning should be the
primary focus of this development program
3
[http://www.fda.gov/ohrms/dockets/ac/cder00.ht
m#Psychopharmacologic].
FDA’s Division of Psychiatry Products has
supported the premise that psychosis of AD is an
acceptable clinical target for drug development
(8). The following criteria are generally used by
FDA to evaluate the proposed clinical entity as
an appropriate target for a new claim of drug
effect: the proposed clinical entity must be
accepted in the relevant clinical/academic
community;
operationally
definable;
distinguishable from other clinical entities; and
also, must identify a reasonably homogenous
population. It should be noted that the text
revision version of DSM-IV provides for this
diagnostic entity, but does not as yet provide any
diagnostic criteria. Under DSM-IV, the ability to
document psychosis in AD is limited to a
specifier “With Delusions” in the context of
meeting criteria for Dementia of the Alzheimer’s
Type, which does not accommodate other
psychotic symptoms, such as hallucinations.
Alternatively, a patient may be documented to
have the Axis III diagnosis of AD along with the
Axis I diagnosis of “psychotic disorder,
secondary to a primary medical condition,” in
this case, AD. Using this latter diagnostic
approach, the syndromes of dementia and
psychosis would be viewed as parallel clinical
syndromes secondary to the primary AD brain
disease. DSM-5 criteria addressing this
syndrome have not been released at this time.
However, the proposed criteria for psychosis in
the context of AD have not been sufficiently
validated and are not likely to be incorporated
into the DSM-5 under the currently proposed list
of disorders for the diagnostic category,
Neurocognitive Disorders. The neuropsychiatric
and behavioral aspects of AD are an important
part of the syndrome and deserve more
prominence in the next version of DSM (11).
incidence in AD of 0.19/person-year at risk(14).
Importantly, the rate of AD+P is dependent on
AD stage, with low rates of psychosis in
prodromal and early AD, and higher rates in
middle and later stages(15;16). Perhaps as a
consequence, epidemiologic studies, which
unlike clinic populations are less biased towards
sampling of individuals with advanced disease,
find a lower point prevalence of psychosis in
AD, closer to 25% (e.g. see (17)).
The appearance of psychosis in AD is preceded
by a period of accelerated cognitive decline.
More rapid cognitive decline was the most
consistent correlate of AD+P compared to AD
without psychosis (AD-P), as reviewed by
Ropacki and Jeste(12). More recent studies have
elaborated further on the timing of cognitive
decline relative to onset of psychotic symptoms.
The more rapid cognitive deterioration precedes
the symptomatic onset of psychosis(13) (18) and
is present even in the earliest and/or prodromal
phases of disease(18).
Psychotic behaviors in AD patients have a
tremendous impact on the patient, family, and
caregiver. AD+P is significantly associated with
additional
psychiatric
and
behavioral
disturbances, the most frequent and troublesome
of which are agitation(19), and verbal and
physical
aggression(20;21).
Depressive
symptoms are also increased in AD+P(16) (22).
Overall, AD+P leads to greater distress for
family and caregivers(23), greater functional
impairment(24),
greater
rates
of
institutionalization(25-28), and worse general
health for the patient(29), with increased
mortality(30) compared to patients with AD-P.
Treatment
Non-pharmacologic. A systematic review by
Livingston and colleagues identified more than
160 studies examining the impact of specific
psychological interventions in people with AD
or dementia in general, many measuring
neuropsychiatric symptoms an outcome,
although most studies included small samples
and the number of studies for individual
psychological interventions was modest.
Reminiscence was highlighted as a therapy with
Rates, Prevalence & Associations
Ropacki & Jeste(12) comprehensively reviewed
the literature on rates of psychosis in AD from
1990 to 2003, identifying 55 predominantly
clinical studies comprised of 9,749 subjects. The
median prevalence of AD+P was 41%
(range=12.2-74.1%). One report identified a 3year cumulative incidence of AD+P of 51%(13),
more recent data is similar, with a psychosis
4
potential benefits for the treatment
neuropsychiatric symptoms (31).
of
specific effect on psychosis has not been
evaluated. There is an excellent opportunity to
better understand the potential impact of some of
these interventions on psychosis in people with
AD by re-analysis of available data.
Psychological
interventions
improve
agitation(32;33),(34) and depression in people
with AD(35;36), whilst training programmes
educating staff in person-centered care in
nursing homes can reduce the use of
psychotropic
medication
and
improve
agitation(37;38),(39). There are however no
substantive studies focusing specifically on
treating psychosis in people with dementia using
non-pharmacological approaches.
Pharmacologic. Pharmacologic treatment of
psychosis in AD patients has been suboptimal
due to the limited efficacy of the classes of drugs
available and their high risk in this age group.
To date, no pharmacologic agent is approved for
this indication. Haloperidol is the most studied
of the conventional antipsychotics, and it has
demonstrated mild to moderate efficacy relative
to placebo in AD patients with psychosis and/or
agitated behaviors. However, it also causes
serious side-effects in these patients, namely
parkinsonism, tardive dyskinesia, and akathisia
(45). More recent studies have examined the
efficacy of second generation, or atypical
antipsychotics, such as risperidone (46),
olanzapine(47), and aripiprazole (48;49). These
medications have efficacy similar to the modest
benefits of conventional antipsychotics in
reducing psychotic symptoms, with a lower
likelihood of inducing motor side effects (50).
However, they have been associated with an
increased risk of cerebral vascular adverse
events such as stroke, and increased all-cause
mortality after short-term treatment (51-54).
Furthermore, there are no current data to suggest
that any of these treatments effectively mitigate
the greater cognitive and functional burden
associated with AD+P.
There is strong evidence that visual impairments
and auditory impairments contribute to the
development of visual hallucinations(40;41) and
delusions(42) respectively in people with
dementia, and preliminary evidence that treating
impairments of visual acuity and cataracts may
improve or resolve visual hallucinations in some
patients(40). There is also limited evidence that
environmental manipulations may provide relief
for delusional misidentification (43).
Non-pharmacological approaches may offer
opportunities to prevent or delay the onset of
psychosis in people with dementia. Certainly the
physical and social environmental have an
important impact on the development of
neuropsychiatric symptoms in general and on
key symptoms such as restlessness and trying to
leave the building. But the potential benefits for
the prevention of psychosis have not been
clarified. More specifically, expressive and
receptive language impairments are associated
with psychosis in people with dementia (44),
and it is therefore likely that interventions to
improve communication and reduce social
isolation may contribute to delaying or prevent
psychosis. Based upon the relationship between
sensory impairments and psychosis in people
with dementia(40-42), treating visual and
auditory deficits may also be beneficial in
prevention.
Neurobiology
The clinical studies reviewed above place
psychosis in the course of AD, indicating that
the processes associated with the emergence of
AD+P may begin in the early stages of cognitive
decline, while the full expression of psychotic
features occurs only later, after a stage of mild to
moderate dementia is reached. Further
understanding of the neurobiology of AD+P can
be gained using this information about timing to
put AD+P in the context of the rapidly
deepening understanding of the progressive
cascade of neurobiologic changes in AD itself.
Our understanding of the neurobiology of AD
has benefited substantially from the integration
of findings from genetic, neuropathologic, and
Overall there is very limited evidence regarding
the specific value of non-pharmacological
interventions in the treatment of psychosis in
people with AD. However, many previously
reported studies have included global
evaluations of neuropsychiatric symptoms
amongst the outcome measures, although the
5
in vivo imaging/biomarker investigations,
approaches that have also been used to varying
extents to examine AD+P. Thus to provide the
context for our review of such studies in AD+P,
we first summarize current findings regarding
the neurobiology of AD (Table 1).
from a distinctive underlying neurobiology. That
is, AD+P cannot be seen as arising solely as a
non-specific consequence of neurodegeneration.
Nor can it arise solely due to a serendipitous
accumulation of neurodegenerative lesions in
vulnerable “psychosis” brain regions.
The strongest correlate of cognitive impairment
in individuals with AD is loss of synapses across
neocortical regions(55;56). Evidence now
indicates that soluble Aβ low-n oligomers are a
primary source of synaptotoxicity in AD(57).
Animals transgenic for mutant human APP show
synaptic deficits that correlate more closely with
cortical soluble Aβ levels than with plaque
numbers, and precede deposition of insoluble
Aβ into plaques(57;58). Human studies similarly
indicate that cortical synapse loss is an early
pathologic event and that cognitive impairment
and synapse loss correlate most strongly with
soluble Aβ(59), even in subjects with early
disease(60).
A number of studies have examined whether
AD+P is linked or associated with specific
genetic loci (reviewed in (67)). Evidence for
significant or suggestive linkage to loci on
chromosome 2, 7, 8, and 15 has been
reported(64;68;69) (70). Other loci on
chromosome 6 and 21 identified in the initial
report by Bacanu et al(68) did not find support
in a follow-up analysis(64). In contrast to the
above studies linking AD+P to genetic loci,
Avramopoulos et al (70) found that chromosome
14q is linked to the absence of hallucinations in
AD patients.
A number of candidate gene studies of AD+P
have been conducted, though as a group they
have been limited by small sample sizes and
incomplete assessment of genetic variation
within the genes of interest(67). More recent
studies provide an emerging picture in which
AD+P has a genetic architecture that is distinct
from that which increases risk for AD itself, and
has some limited overlap with other psychoses.
For example, there is strong evidence against an
association of AD+P with APOE(71;72), with
variation in recently identified AD risk genes
CLU, PICALM, CR1, BIN1, ABCA7, MS4A,
CD2AP, CD33 and EPHA1(72), or with other
genes that contribute to neurodegneration risk:
APP, BACE1, SORL1, and MAPT(73). In
contrast, evidence from the first genome wide
association study of AD+P suggests AD+P may
associate with several novel loci, and to a lesser
extent with a group of risk SNPs that contribute
risk to schizophrenia and bipolar illness(72).
In addition to the direct effects of Aβ on synapse
loss, Aβ is upstream of other effectors that may
enhance synapse loss, neuronal death, and
cortical atrophy. For example, Aβ contributes to
hyperphosphorylation of MAPT, enhancing its
aggregation into tangles (57). Recent evidence
indicates MAPT is both a necessary downstream
mediator of Aβ-induced synaptic impairments
(61), and aggregated MAPT can propagate in the
absence of Aβ pathology (62). Aβ in plaques
also serves as a site for inflammatory
responses(63), which may further contribute to
synapse loss and neuronal death in AD.
Genetic Studies
Strong evidence indicates that AD+P is familial,
with three independent replications(16;64;65).
The Odds Ratios (95% CI) for the presence of
psychosis in an individual affected by AD, when
another family member (usually a sibling) has
AD+P, in these three studies ranged from 1.4510.44. One study estimated the heritability of
AD+P, defined by the presence of multiple
and/or recurrent psychotic symptoms, at
61%(66). There are two important implications
of these findings. First, and most direct, is that
the risk for AD+P is likely to be influenced by
genetic variation. Second, is that AD+P results
Neuroimaging Correlates
There have been comparatively few studies
examining neuroimaging correlates of psychotic
symptoms in AD, although most suggest that the
presence of psychosis is associated with more
severe alterations. Serra et al. (74) recently
demonstrated that severity of delusions was
associated with reduced gray matter volume in
6
the right hippocampus. Howanitz et al. (75)
earlier observed that presence of hallucinations
was associated with larger lateral ventricle
volume and smaller total brain volume. Lee et
al. (76) identified white matter changes in
bilateral frontal and parieto-occipital regions
which significantly correlated with severity
ratings on the psychosis subscale of the CERAD
Behavior Rating Scale for Dementia (BRSD).
Bruen et al. (77) observed that delusions were
associated with decreased gray matter density in
the left frontal lobe and in the right
frontoparietal cortex. In general, the patterns
observed in studies of brain volume suggest
psychosis is associated primarily with loss of
gray matter.
hypometabolism in orbitofrontal and cingulate
areas bilaterally, as well as left medial temporal
areas. This group also interestingly found
significant bilateral hypermetabolism in sensory
association cortices, including the superior
temporal and inferior parietal cortex. Lastly,
Hirono et al. (85) also demonstrated that
psychosis was associated with hypermetabolism
in the left inferior temporal gyrus. These latter
observations may reflect a window of
compensatory hypermetabolism that may
immediately precede and continue early in the
course of AD+P, which would require
longitudinal studies to fully characterize.
Overall, studies of cerebral metabolic activity
tend to parallel the reduction in volume and
perfusion observed in MRI and SPECT studies,
with the exception of potential areas of higher
activity that may be attempting to accommodate
for degenerative changes in other regions.
In addition to structural studies, single photon
emission computed tomography (SPECT) has
been utilized to examine regional perfusion in
AD+P. Mega et al. (78) found lower regional
perfusion in the dorsolateral frontal cortex
bilaterally, as well as in the left anterior
cingulate gyrus in AD+P. Moran et al. (79)
observed lower perfusion in right prefrontal
cortex and inferior temporal regions in AD+P in
females. Regional hypoperfusion was also
demonstrated by Staff et al. (80), who observed
that delusions were associated with right
hemispheric hypoperfusion primarily in right
frontal regions. Conversely, Kotrla et al. (81)
demonstrated that patients with delusions had
lower left frontal perfusion relative to right
frontal. Reduced temporal perfusion was
observed bilaterally by Starkstein et al. (82).
Similar to the structural findings above, studies
of perfusion tend to reflect reduced activity in
similar regions associated with reduced volume.
Although there is variability across studies that
may reflect differences in study design and
imaging methods, overall, one may conclude
that neuroimaging abnormalities associated with
AD+P have been observed in frontal, parietal
and temporal regions. This is consistent with the
general notion that deterioration across
association cortices portends the development of
psychosis. There is support for the ability of
neuroimaging to discern differences in AD+P
patients from AD without psychosis (AD-P)
patients, with more robust findings resulting
from functional as compared to structural
studies. Importantly, longitudinal studies will be
essential to adequately map structural and
functional components that signal impending
psychosis, or more ideally, identify individuals
early on who are at risk. Since structural and
metabolic imaging may be sensitive to change
during cognitive decline (86), these may be
preferred modalities for such longitudinal
studies.
Studies using FDG-PET imaging of brain
metabolism have provided further evidence for
functional abnormalities. Sultzer et al. (83)
reported a relationship between severity of
delusions and reduced cerebral metabolism in
three frontal regions; these included right
superior dorsolateral frontal cortex, right inferior
frontal pole, and right lateral orbitofrontal
cortex. The orbitofrontal finding was also
observed in an earlier study by Mentis et al.
(84), who examined patients with delusional
misidentification. The affected patients differed
from AD patients without delusional
misidentification by showing significant
Neuropathologic Studies
A number of studies have investigated whether
AD+P correlated with more severe AD
neuropathology in cortical regions. Several early
studies reported varying results for neuritic
plaque and neurofibrillary tangle area densities
across brain regions. These early studies were
7
limited as a group, as they did not account for
the presence of Lewy Body pathology and also
because they did not correct for multiple
comparisons and/or account for the withinsubject correlation of severity of neuropathology
across brain regions (see (87) for a discussion of
these issues). Two studies redressed these latter
limitations. Sweet et al. (87) examined
categorical ratings of area densities of neuritic
plaques and neurofibrillary tangles in six brain
regions: middle frontal cortex, hippocampus,
inferior parietal cortex, superior temporal cortex,
occipital cortex, and transentorhinal cortex in 24
AD+P subjects and 25 AD-P subjects. The
groups were matched on clinical characteristics
and on the presence of Lewy Body pathology.
There were no significant associations between
neuritic plaque and neurofibrillary tangle
severity and AD+P. Farber et al. used more
sensitive parametric measures of area densities
in a larger sample of 69 AD+P and 40 AD-P
subjects(88). A significant association between
AD+P and increased neurofibrillary tangle area
density was found in heteromodal neocortical
regions (DLPFC, STG, and IPC), which
persisted even after accounting for comorbid
Lewy Body pathology. In contrast, no increase
in neurofibrillary tangle area density was found
in medial temporal lobe structures. No
association with increased area density of senile
plaques was found. Similarly, when quantitative
measures of aggregated MAPT in formic acid
extracts of cortical gray matter, were evaluated
in 18 AD subjects, AD+P was associated with a
significant increase in MAPT concentration
(89). Thus, it appears that there is little evidence
to support an association between AD+P and
measures of aggregated Aβ, but there may be
increased aggregation of neocortical MAPT in
AD+P.
in the AD+P group, without any significant
change in concentrations of Aβ1-42; however the
Aβ1-42/Aβ1-40 ratio was significantly increased,
driven by the lower Aβ1-40 (90). This finding
may highlight the importance of the ratio as an
indicator of Aβ toxicity, especially in AD+P
where there have not been consistent
associations with fibrillar Aβ neuropathology.
The findings that more rapid cognitive decline is
the strongest correlate of AD+P and that synapse
loss is the strongest neuropathologic correlate of
cognitive decline would suggest that greater
synapse loss is likely to be present in AD+P. To
date this has only been subject to limited testing.
In a post-mortem magnetic resonance
spectroscopy in AD+P subjects, Sweet et al.
identified significant reductions in neocortical
N-acetyl-L-aspartate (NAA, a marker of
neuronal integrity) concentrations and elevations
in concentrations of the phosphodiester
membrane breakdown product, glycerolphosphoethanolamine, with STG, DLPFC, and
inferior parietal cortex (IPC) most affected. In
contrast, medial temporal cortex (amygdala) and
cerebellum
were
unaffected(91).
They
interpreted these changes as evidence of excess
synaptic disruption in AD+P, in a pattern
consistent
with
generalized
neocortical
involvement.
Monoaminergic signaling is impaired differently
in AD+P than in AD-P. Recent findings have
described impaired dopaminergic activity in
AD+P compared to AD-P; nucleus accumbens
D3 receptor density is significantly higher in
AD+P, with no change in receptor affinity and
independent of neuroleptic use or Lewy body
pathology(92). A more recent PET study
identified increased striatal D2/D3 receptor
availability in AD patients with delusions(93).
While cholinergic activity is typically associated
with cognitive deficits in AD and monoamines
more so with emotional dysregulation and
psychosis, their functional interaction is
especially relevant to AD+P. Striatal dopamine
release is regulated by nicotinic receptor
activity,
and
low
concentration
acetylcholinesterase (AChE) inhibitors enhance
dopamine release(94). AD+P is associated with
an increased ratio of AChE/5-HT and reduced 5HT in the ventral temporal cortex (BA20)(95).
The presence of psychosis in AD is associated
Recent understanding of the neurobiology of AD
has shifted attention from measures of
aggregated Aβ to measures of soluble Aβ.
Recently soluble concentrations of Aβ1-40 and
Aβ1-42 were assessed in gray matter from
multiple cortical regions of 30 AD+P and 22
AD-P subjects. Cases were matched on age,
gender, duration of illness, postmortem interval,
presence of alpha-synuclein pathology, and
global severity of neurofibrilliary tangle and
neuritic
plaque
pathology.
Soluble
concentrations of Aβ1-40 were significantly lower
8
with reduced 5-HT levels in BA20 in women
and reduced adenylate cyclase activity after 5HT6 stimulation(96). An earlier postmortem
study of AD+P found reduced 5-HT in the
prosubiculum and increased norepinephrine in
the substantia nigra, compared to AD-P(97). The
consistent findings of lower 5-HT could be
linked to reduced cell counts in dorsal raphe
nucleus in AD+P(98). Importantly, M2 receptor
density is higher in orbitofrontal gyrus (BA11)
of AD with delusions and midtemporal gyrus
(BA21) of AD with hallucinations, with an
overall trend toward increase in both areas(99),
and non-M2 binding is reduced in BA11 of
AD+P(100). Thus, these studies indicate
differential
widespread
changes
in
monoaminergic and cholinergic signaling in
AD+P, with findings pointing especially to
temporal cortex.
those with limited Lewy Body pathology (e.g.
not including neocortical regions) in the
presence of both amyloid plaques and moderate
to severe neurofibrillary tangles (e.g. Braak
stage IV-VI), the clinical syndrome and
neuropathologic
diagnosis
would
be
conceptualized as primarily due to AD, not as
primarily due to Dementia with Lewy
Bodies(102).
Moreover,
while
visual
hallucinations may be more frequent in
individuals with primary AD plus comorbid
Lewy body pathology, psychosis (including
delusions, and/or auditory and visual
hallucinations) is still present in 40% to 60% of
AD subjects without any Lewy Body pathology
detectable by stringent screening(103). Thus, the
occurrence of psychosis in AD cannot be
attributed principally to Lewy Body pathology.
Future Research Recommendations
Role of comorbidities. Vascular lesions have
been implicated in occurrence of late-onset
psychosis in the absence of any other known
neurodegenerative disease(101). Consequently,
the effects of vascular disease may likely
influence clinical expression of illness at any
point in the progression of AD by creating a
lower threshold for the expression of psychosis.
However, increased rates of vascular risk factors
or vascular lesions was not found in a recent
examination of clinical and neuroimaging
correlates of AD+P(71).
The study of psychosis in AD has benefited
from relative agreement about the key
requirements in defining the clinical syndrome
and a larger extent of biologic investigation than
other behavioral syndromes in AD. As such it
may be poised for translational discovery. At a
process level this discovery will be informed by
current investigations into the mechanisms of
AD itself, and into mechanisms of idiopathic
psychosis (schizophrenia). Procedurally, then, a
research agenda may benefit from bringing
together investigators from centers with
disparate expertise (e.g. AD Research Centers
and Centers for Neuroscience in Mental
Disorders), although this may require
mechanisms to bridge what can be a wide divide
between sources of research funding.
Additionally, it is likely that investigation of
mechanisms of psychosis leading to new
treatments and/or preventions will require
engaging teams of individuals who examine this
syndrome across multiple levels of discovery
from the gene to animal models, biomarkers,
human brain tissue, and clinical manifestations.
Similarly, further comment on the relationship
of AD+P to Lewy body pathology is warranted.
The
presence
of
well-formed
visual
hallucinations is among the criteria for the
clinical diagnosis of Dementia with Lewy
bodies. Additionally, the use of dopaminergic
agents (e.g., levodopa) prescribed in an effort to
assist with the movement disorder may lead to
hallucinations. Recent neuropathologic data
using antibodies against alpha-synuclein to
detect Lewy bodies (including screening for
Lewy Body pathology in amygdala and
entorhinal cortex) have found Lewy body
pathology to be present in up to 50% of cases
with neuropathologically confirmed AD, far
more frequent than identified in vivo using
clinical diagnostic criteria for Dementia with
Lewy Bodies, or using other staining
approaches(102).
Current
understanding
indicates that in the majority of such AD cases,
Specifically we recommend:
1. Invest
in
characterization
of
intermediate phenotypes. Intermediate
phenotypes will be key in bridging from
animal models to human brain
pathology and from pathology to
9
2.
3.
4.
5.
pathophysiologic changes manifesting in
symptoms. These measures will of
course include further structural and
functional brain imaging, but must be
extended to evoked potential, cognitive,
and psychophysical measures, as well as
cerebrospinal
fluid
and
plasma
biomarkers.
Inherent in an enhanced biomarker
approach will be the implementation of
longitudinal strategies to detect those
changes that precede the late
manifestation of overt psychosis. One
way to conceptualize this phenomenon
is to consider that in earliest stages a
more rapid degeneration occurs, but
after a certain stage of degeneration has
been reached, the remaining function of
the association cortices in assimilating
perceptual information is no longer
sufficient
to integrate
incoming
information from higher order sensory
areas in a coherent manner. This leads to
increasing disintegration of global brain
function and manifests as psychosis.
Such a hypothesis could be readily
tested via multimodal longitudinal
assessment of intermediate phenotypes.
Expand the large cohorts of families and
unrelated individuals needed to pursue
further genetic discovery via GWAS,
assessment of copy number variations,
and detection of rare alleles.
Use the large existing human
postmortem collection of AD+P brains
to push beyond correlative studies of
plaques and tangles to investigate the
molecular, circuit, and synapse-based
abnormalities associated with AD+P.
Leverage current animal models of AD
to
assess
intermediate
and/or
postmortem phenotypes present in
humans with AD+P, or to manipulate
genes associated with AD+P.
10
Acknowledgements
Funding Support: Dr. Sweet receives research support for this work from the NIH (AG027224,
AG05133) and the VA-ORD (BX000452). Dr. Schultz has received research support from the NCI,
NIMH, HRSA, the Nellie Ball Foundation Trust and the NIA, including an NIA-ACDS funded project in
partnership with Baxter Healthcare. Dr. Schultz has received other support from the American Psychiatric
Association
Conflict of Interest
The authors have no conflict of interest to report. The views expressed in this paper are those of the
authors, and do not necessarily represent the official views of the the National Institutes of Health, the
Department of Veterans Affairs, the U.S. Food and Drug Administration, or the United States
Government.
11
References
1. Cohen-Mansfield J, Golander H: The measurement of psychosis in dementia: a
comparison of assessment tools. Alzheimer Dis Assoc Disord 2011; 25(2):101-108
2. Auer SR, Monteiro IM, Reisberg B: The Empirical Behavioral Pathology in Alzheimer's
Disease (E-BEHAVE-AD) Rating Scale. Int Psychogeriatr 1996; 8(2):247-266
3. Wood S, Cummings JL, Hsu MA, Barclay T, etal: The use of the neuropsychiatric
inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 2000;
8(1):75-83
4. Tariot PN, Mack JL, Patterson MB, etal:, Behavioral Pathology Committee of the
Consortium to Establish a Registry for Alzheimer's Disease: The behavior rating scale for dementia of the
Consortium to Establish a Registry for Alzheimer's Disease. Am J Psychiatry 1995; 152(9):1349-1357
5. Devanand DP, Miller L, Richards M, etal: The Columbia University Scale for
Psychopathology in Alzheimer's disease. Arch Neurol 1992; 49(4):371-376
6. Jeon YH, Sansoni J, Low LF, etal: Recommended measures for the assessment of
behavioral disturbances associated with dementia. Am J Geriatr Psychiatry 2011; 19(5):403-415
7. Ismail Z, Emeremni CA, Houck PR, etal: A Comparison of the E-BEHAVE-AD, NBRS,
and NPI in Quantifying Clinical Improvement in the Treatment of Agitation and Psychosis Associated
With Dementia. Am J Geriatr Psychiatry 2012;
8. Laughren T: A regulatory perspective on psychiatric syndromes in Alzheimer disease.
Am J Geriatr Psychiatry 2001; 9(4):340-345
12
9. Ismail Z, Nguyen MQ, Fischer CE, etal: Neurobiology of delusions in Alzheimer's
disease. Curr Psychiatry Rep 2011; 13(3):211-218
10. Jeste DV, Finkel SI: Psychosis of Alzheimer's disease and related dementias. Am J
Geriatr Psychiatry 2000; 8(1):29-34
11. Laughren T: FDA Perspective on the DSM-5 approach to classification of "cognitive"
disorders. J Neuropsychiatry Clin Neurosci 2011; 23(2):126-131
12. Ropacki SA, Jeste DV: Epidemiology of and risk factors for psychosis of Alzheimer's
disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatry 2005; 162(11):2022-2030
13. Paulsen JS, Salmon DP, Thal L, etal: Incidence of and risk factors for hallucinations and
delusions in patients with probable Alzheimer's disease. Neurology 2000; 54(10):1965-1971
14. Wilkosz PA, Miyahara S, Lopez OL, etal: Prediction of psychosis onset in Alzheimer
disease: The role of cognitive impairment, depressive symptoms, and further evidence for psychosis
subtypes. Am J Geriatr Psychiatry 2006; 14(4):352-360
15. Drevets WC, Rubin EH: Psychotic symptoms and the longitudinal course of senile
dementia of the Alzheimer type. Biol Psychiatry 1989; 25(1):39-48
16. Sweet RA, Bennett DA, Graff-Radford NR, etal: Assessment and familial aggregation of
psychosis in Alzheimer's disease from the National Institute on Aging Late Onset Alzheimer's Disease
Family Study. Brain 2010; 133(Pt 4):1155-1162
13
17. Leroi I, Voulgari A, Breitner JC, etal: The epidemiology of psychosis in dementia. Am J
Geriatr Psychiatry 2003; 11(1):83-91
18. Emanuel JE, Lopez OL, Houck PR, etal: Trajectory of cognitive decline as a predictor of
psychosis in early Alzheimer disease in the cardiovascular health study. Am J Geriatr Psychiatry 2011;
19(2):160-168
19. Gilley DW, Whalen ME, Wilson RS, etal: Hallucinations and associated factors in
Alzheimer's disease. J Neuropsychiatry 1991; 3371-376
20. Gilley DW, Wilson RS, Beckett LA, etal: Psychotic symptoms and physically aggressive
behavior in Alzheimer's disease. J Am Geriatr Soc 1997; 451074-1079
21. Sweet RA, Pollock BG, Sukonick DL, etal: The 5-HTTPR polymorphism confers
liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer's disease. Int
Psychogeriatr 2001; 13(4):401-409
22. Lyketsos CG, Sheppard JM, Steinberg M, etal: Neuropsychiatric disturbance in
Alzheimer's disease clusters into three groups: the Cache County study. Int J Geriatr Psychiatry 2001;
16(11):1043-1053
23. Kaufer DI, Cummings JL, Christine D, B etal: Assessing the impact of neuropsychiatric
symptoms in Alzheimer's disease: the Neuropsychiatric Inventory Caregiver Distress Scale. J Am Geriatr
Soc 1998; 46(2):210-15
24. Scarmeas N, Brandt J, Albert M, etal: Delusions and hallucinations are associated with
worse outcome in Alzheimer disease. Arch Neurol 2005; 62(10):1601-1608
14
25. Rabins PV, Mace NL, Lucas MJ: The impact of dementia on the family. JAMA 1982;
248333-335
26. Lopez OL, Wisniewski SR, Becker JT, etal: Psychiatric medication and abnormal
behavior as predictors of progression in probable Alzheimer disease. Arch Neurol 1999; 56(10):12661272
27. Magni E, Binetti G, Bianchetti A, etal: Risk of mortality and institutionalization in
demented patients with delusions. J Geriatr Psychiatry Neurol 1996; 9123-126
28. Cummings JL, Diaz C, Levy M, etal: Neuropsychiatric Syndromes in Neurodegenerative
Disease: Frequency and Signficance. Semin Clin Neuropsychiatry 1996; 1(4):241-247
29. Bassiony MM, Steinberg M, Rosenblatt A, etal: Delusions and hallucinations in
Alzheimer's disease: Prevalence and clinical correlates. Int J Geriatr Psychiatry 2000; 1599-107
30. Wilson RS, Tang Y, Aggarwal NT, etal: Hallucinations, cognitive decline, and death in
Alzheimer's disease. Neuroepidemiology 2006; 26(2):68-75
31. Livingston G, Johnston K, Katona C, etal: Systematic review of psychological
approaches to the management of neuropsychiatric symptoms of dementia. Am J Psychiatry 2005;
162(11):1996-2021
32. Cohen-Mansfield J, Werner P: Management of verbally disruptive behaviors in nursing
home residents. J Gerontol A Biol Sci Med Sci 1997; 52(6):M369-M377
15
33. Cohen-Mansfield J, Libin A, Marx MS: Nonpharmacological treatment of agitation: a
controlled trial of systematic individualized intervention. J Gerontol A Biol Sci Med Sci 2007; 62(8):908916
34. Bird, M. Psychosocial approaches to challenging behaviour in dementia: a controlled
trial. In: Report to the Commonwealth Department of Health and Ageing. Canberra: Office for Older
Australians. 2002.
35. Teri L, Logsdon RG, Uomoto J, etal: Behavioral treatment of depression in dementia
patients: a controlled clinical trial. J Gerontol B Psychol Sci Soc Sci 1997; 52(4):159-166
36. Teri L, Gibbons LE, McCurry SM, etal: Exercise plus behavioral management in patients
with Alzheimer disease: a randomized controlled trial. JAMA 2003; 290(15):2015-2022
37. Fossey J, Ballard C, Juszczak E, etal: Effect of enhanced psychosocial care on
antipsychotic use in nursing home residents with severe dementia: cluster randomised trial. BMJ 2006;
332(7544):756-761
38. Rovner BW, Steele CD, Shmuely Y, etal: A randomized trial of dementia care in nursing
homes. J Am Geriatr Soc 1996; 44(1):7-13
39. Chenoweth L, King MT, Jeon YH, etal: Caring for Aged Dementia Care Resident Study
(CADRES) of person-centred care, dementia-care mapping, and usual care in dementia: a clusterrandomised trial. Lancet Neurol 2009; 8(4):317-325
16
40. Chapman FM, Dickinson J, McKeith I, etal: Association among visual hallucinations,
visual acuity, and specific eye pathologies in Alzheimer's disease: treatment implications. Am J
Psychiatry 1999; 156(12):1983-1985
41. Holroyd S, Sheldon-Keller A: A study of visual hallucinations in Alzheimer's disease.
Am J Geriatr Psychiatry 1995; 3198-205
42. Ballard C, Bannister C, Graham C, etal: Associations of psychotic symptoms in dementia
sufferers. Br J Psychiatry 1995; 167(4):537-540
43. Gil-Ruiz N, Osorio RS, Cruz I, etal:, The Alzheimer Center Of The Queen Sofia
Foundation Multidisciplinary Therapy Group: An effective environmental intervention for management
of the 'mirror sign' in a case of probable Lewy body dementia. Neurocase 2012;
44. Potkins D, Myint P, Bannister C, etal: Language impairment in dementia: impact on
symptoms and care needs in residential homes. Int J Geriatr Psychiatry 2003; 18(11):1002-1006
45. Tariot PN, Profenno LA, Ismail MS: Efficacy of atypical antipsychotics in elderly
patients with dementia. J Clin Psychiatry 2004; 65 Suppl 1111-15
46. Bhana N, Spencer CM: Risperidone: a review of its use in the management of the
behavioural and psychological symptoms of dementia. Drugs Aging 2000; 16(6):451-471
47. De Deyn PP, Carrasco MM, Deberdt W, etal: Olanzapine versus placebo in the treatment
of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease. Int J
Geriatr Psychiatry 2004; 19(2):115-126
17
48. Streim JE, McQuade R, Stock E, etal: Aripiprazole for the treatment of institutionalized
patients with psychosis of Alzheimer's dementia. J Am Geriatr Soc 2004; 52(4):S15
49. Jeste DV, De Deyn P, Carson W, etal: Aripiprazole in dementia of the Alzheimer's type. J
Am Geriatr Soc 2003; 51(4):S226
50. Schneider LS, Dagerman K, Insel PS: Efficacy and adverse effects of atypical
antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr
Psychiatry 2006; 14(3):191-210
51. Herrmann N, Mamdani M, Lanctot KL: Atypical antipsychotics and risk of
cerebrovascular accidents. Am J Psychiatry 2004; 161(6):1113-1115
52. Smith DA, Beier MT: Association between risperidone treatment and cerebrovascular
adverse events: examining the evidence and postulating hypotheses for an underlying mechanism. J Am
Med Dir Assoc 2004; 5(2):129-132
53. Wooltorton E: Olanzapine (Zyprexa): increased incidence of cerebrovascular events in
dementia trials. Can Med Assoc J 2004; 170(9):1395
54. Wooltorton E: Risperidone (Risperdal): increased rate of cerebrovascular events in
dementia trials. Can Med Assoc J 2002; 167(11):1269-1270
55. Terry RD, Masliah E, Salmon DP, etal: Physical basis of cognitive alterations in
Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;
30572-580
18
56. Scheff SW, Price DA: Synaptic pathology in Alzheimer's disease: a review of
ultrastructural studies. Neurobiol Aging 2003; 24(8):1029-1046
57. Walsh DM, Selkoe DJ: A beta oligomers - a decade of discovery. J Neurochem 2007;
101(5):1172-1184
58. Selkoe DJ: Alzheimer's disease is a synaptic failure. Science 2002; 298(5594):789-791
59. Lue LF, Kuo YM, Roher AE, etal: Soluble amyloid beta peptide concentration as a
predictor of synaptic change in Alzheimer's disease. Am J Pathol 1999; 155(3):853-862
60. Naslund J, Haroutunian V, Mohs R, etal: Correlation between elevated levels of amyloid
beta-peptide in the brain and cognitive decline. JAMA 2000; 283(12):1571-1577
61. Shipton OA, Leitz JR, Dworzak J, etal: Tau protein is required for amyloid {beta}induced impairment of hippocampal long-term potentiation
1. J Neurosci 2011; 31(5):1688-1692
62. de Calignon A, Polydoro M, Suarez-Calvet M, etal: Propagation of tau pathology in a
model of early Alzheimer's disease. Neuron 2012; 73(4):685-697
63. Spires-Jones TL, Meyer-Luehmann M, Osetek JD, etal: Impaired spine stability underlies
plaque-related spine loss in an Alzheimer's disease mouse model. Am J Pathol 2007; 171(4):1304-1311
64. Hollingworth P, Hamshere ML, Holmans PA, etal: Increased familial risk and
genomewide significant linkage for Alzheimer's disease with psychosis. Am J Med Genet B
Neuropsychiatr Genet 2007; 144B(7):841-848
19
65. Sweet RA, Nimgaonkar VL, Devlin B, etal: Increased familial risk of the psychotic
phenotype of Alzheimer disease. Neurology 2002; 58907-911
66. Bacanu SA, Devlin B, Chowdari KV, etal: Heritability of psychosis in Alzheimer disease.
Am J Geriatr Psychiatry 2005; 13(7):624-627
67. DeMichele-Sweet MA, Sweet RA: Genetics of psychosis in Alzheimer's disease: a
review. J Alzheimers Dis 2010; 19(3):761-780
68. Bacanu SA, Devlin B, Chowdari KV, etal: Linkage analysis of Alzheimer disease with
psychosis. Neurology 2002; 59118-120
69. Go RC, Perry RT, Wiener H, etal: Neuregulin-1 polymorphism in late onset Alzheimer's
disease families with psychoses. Am J Med Genet B Neuropsychiatr Genet 2005; 139B(1):28-32
70. Avramopoulos D, Fallin MD, Bassett SS: Linkage to chromosome 14q in Alzheimer's
disease (AD) patients without psychotic symptoms. Am J Med Genet B Neuropsychiatr Genet 2005;
132B(1):9-13
71. DeMichele-Sweet MA, Lopez OL, Sweet RA: Psychosis in Alzheimer's disease in the
national Alzheimer's disease coordinating center uniform data set: clinical correlates and association with
apolipoprotein e. Int J Alzheimers Dis 2011; 2011926597
72. Hollingworth P, Sweet R, Sims R, etal: Genome-wide association study of Alzheimer's
disease with psychotic symptoms. Mol Psychiatry 2011;
20
73. DeMichele-Sweet MA, Klei L, Devlin B, etal: No association of psychosis in Alzheimer
disease with neurodegenerative pathway genes. Neurobiol Aging 2011; 32(3):555-11
74. Serra L, Perri R, Cercignani M, etal: Are the behavioral symptoms of Alzheimer's disease
directly associated with neurodegeneration? J Alzheimers Dis 2010; 21(2):627-639
75. Howanitz E, Bajulaiye R, Losonczy M: Magnetic resonance imaging correlates of
psychosis in Alzheimer's disease. J Nerv Ment Dis 1995; 183(8):548-549
76. Lee DY, Choo IH, Kim KW, etal: White matter changes associated with psychotic
symptoms in Alzheimer's disease patients. J Neuropsychiatry Clin Neurosci 2006; 18(2):191-198
77. Bruen PD, McGeown WJ, Shanks MF, etal: Neuroanatomical correlates of
neuropsychiatric symptoms in Alzheimer's disease. Brain 2008; 131(Pt 9):2455-2463
78. Mega MS, Lee L, Dinov ID, etal: Cerebral correlates of psychotic symptoms in
Alzheimer's disease. J Neurol Neurosurg Psychiatry 2000; 69(2):167-171
79. Moran EK, Becker JA, Satlin A, etal: Psychosis of Alzheimer's disease: Gender
differences in regional perfusion. Neurobiol Aging 2008; 29(8):1218-1225
80. Staff RT, Shanks MF, Macintosh L, etal: Delusions in Alzheimer's disease: spet evidence
of right hemispheric dysfunction. Cortex 1999; 35(4):549-560
81. Kotrla KJ, Chacko RC, Harper RG, etal: SPECT findings on psychosis in Alzheimer's
disease. Am J Psychiatry 1995; 152(10):1470-1475
21
82. Starkstein SE, Vazquez S, Petracca G, etal: A SPECT study of delusions in Alzheimer's
disease. Neurology 1994; 44(11):2055-2059
83. Sultzer DL, Brown CV, Mandelkern MA, etal: Delusional thoughts and regional
frontal/temporal cortex metabolism in Alzheimer's disease. Am J Psychiatry 2003; 160(2):341-349
84. Mentis MJ, Weinstein EA, Horwitz B, etal: Abnormal brain glucose metabolism in the
delusional misidentification syndromes: a positron emission tomography study in Alzheimer disease. Biol
Psychiatry 1995; 38(7):438-449
85. Hirono N, Mori E, Ishii K, etal: Alteration of regional cerebral glucose utilization with
delusions in Alzheimer's disease. J Neuropsychiatry Clin Neurosci 1998; 10(4):433-439
86. Jack CR, Jr., Knopman DS, Jagust WJ, etal Hypothetical model of dynamic biomarkers
of the Alzheimer's pathological cascade. Lancet Neurol 2010; 9(1):119-128
87. Sweet RA, Hamilton RL, Lopez OL, etal: Psychotic symptoms in Alzheimer's disease are
not associated with more severe neuropathologic features. Int Psychogeriatr 2000; 12(4):547-558
88. Farber NB, Rubin EH, Newhouse PA, etal: Increased neocortical neurofibrillary tangle
density in subjects with Alzheimer's disease. Arch Gen Psychiatry 2000; 571165-1173
89. Mukaetova-Ladinska EB, Harrington CR, Xuereb J, etal: Biochemical,
neuropathological, and clinical correlations of neurofibrillary degeneration in Alzheimer's disease, in
Treating Alzheimer's and other dementias. Edited by M.Bergener, S.I.Finkel. New York, Springer, 1995,
pp 57-80.
22
90. Murray, P. S., Kirkwood, CM, Gray, M. C., etal: Beta-amyloid 42/40 ratio and kalirin
expression in Alzheimer disease with psychosis. Neurobiol Aging . 2012.
91. Sweet RA, Panchalingam K, Pettegrew JW, etal: Psychosis in Alzheimer disease:
postmortem magnetic resonance spectroscopy evidence of excess neuronal and membrane phospholipid
pathology. Neurobiol Aging 2002; 23(4):547-553
92. Sweet RA, Hamilton RL, Healy MT, etal: Alterations of striatal dopamine receptor
binding in Alzheimer disease are associated with Lewy body pathology and antemortem psychosis. Arch
Neurol 2001; 58(3):466-472
93. Reeves S, Brown R, Howard R, etal: Increased striatal dopamine (D2/D3) receptor
availability and delusions in Alzheimer disease. Neurology 2009; 72(6):528-534
94. Zhang L, Zhou FM, Dani JA: Cholinergic drugs for Alzheimer's disease enhance in vitro
dopamine release. Mol Pharmacol 2004; 66(3):538-544
95. Garcia-Alloza M, Gil-Bea FJ, ez-Ariza M, etal: Cholinergic-serotonergic imbalance
contributes to cognitive and behavioral symptoms in Alzheimer's disease. Neuropsychologia 2005;
43(3):442-449
96. Marcos B, Garcia-Alloza M, Gil-Bea FJ, etal: Involvement of an altered 5-HT -{6}
receptor function in behavioral symptoms of Alzheimer's disease. J Alzheimers Dis 2008; 14(1):43-50
97. Zubenko GS, Moossy J, Martinez AJ, etal: Neuropathologic and neurochemical
correlates of psychosis in primary dementia. Arch Neurol 1991; 48(6):619-624
23
98. Forstl H, Burns A, Levy R, etal: Neuropathological correlates of psychotic phenomena in
confirmed Alzheimer's disease. Br J Psychiatry 1994; 165(2):53-59
99. Lai MK, Lai OF, Keene J, etal: Psychosis of Alzheimer's disease is associated with
elevated muscarinic M2 binding in the cortex. Neurology 2001; 57(5):805-811
100. Tsang SW, Francis PT, Esiri MM, etal: Loss of [3H]4-DAMP binding to muscarinic
receptors in the orbitofrontal cortex of Alzheimer's disease patients with psychosis. Psychopharmacology
(Berl) 2008; 198(2):251-259
101. Breitner JC, Husain MM, Figiel GS, etal: Cerebral white matter disease in late-onset
paranoid psychosis. Biol Psychiatry 1990; 28(3):266-274
102. McKeith IG, Dickson DW, Lowe J, etal: Diagnosis and management of dementia with
Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65(12):1863-1872
103. Tsuang D, Simpson K, Larson EB, etal: Predicting lewy body pathology in a communitybased sample with clinical diagnosis of Alzheimer's disease. J Geriatr Psychiatry Neurol 2006; 19(4):195201
104. Weiner MW, Veitch DP, Aisen PS, etal: The Alzheimer's Disease Neuroimaging
Initiative: A review of papers published since its inception. Alzheimers Dement 2011;
24
Table 1
Proposed diagnostic criteria for Psychosis of Alzheimer Disease.(10)
Criteria
(1) Presence of one (or more) of the following symptoms: visual or auditory hallucinations, delusions
(2) All the criteria for dementia of the Alzheimer type are met
(3) There is evidence from the history that the symptoms (hallucinations and/or delusions) have not been
present continuously since prior to the onset of the symptoms of dementia
(4) The symptoms (hallucinations and/or delusions) have been present, at least intermittently, for 1 month
or longer and symptoms are severe enough to cause some disruption in patients’ functioning
(5) Criteria for Schizophrenia, Schizoaffective Disorder, Delusional Disorder, or Mood Disorder with
Psychotic Features have never been met
(6) The disturbance does not occur exclusively during the course of a delirium
(7) The disturbance is not better accounted for by another general-medical condition or direct
physiological effects of a substance
25
Figure Legends
Fig 1. Hypothetical model summarizing the timeline of AD development. Through identification of
causative mutations in early onset familial AD, subsequent delineation of relevant mechanisms with tools
such as transgenic animal models, and the advent of multimodal imaging and biomarker studies in
humans, the timeline of causal events in AD has been substantially elaborated (58;104). As a whole these
studies are consistent with an Aβ first model, in which the accumulation of cerebral Aβ precedes by as
many as 10-15 years the development of synapse loss, tau pathology, and neuronal death, cortical
atrophy, inflammation, and cognitive impairment (86). As a result, biomarkers which reflect tau
accumulation (elevations in phosphor-tau in cerebrospinal fluid) or synapse loss (hypometabolism
measured by fluorodeoxyglucose-PET and gray matter atrophy quantified by magnetic resonance
imaging) correlate with cognitive symptom progression during clinically overt disease, while amyloid
plaque imaging does not.
26
27