doi:10.1093/brain/awp295
Brain 2010: 133; 557–567
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BRAIN
A JOURNAL OF NEUROLOGY
Neural correlates of psychotic symptoms
in dementia with Lewy bodies
Yasuhiro Nagahama, Tomoko Okina, Norio Suzuki and Minoru Matsuda
Department of Geriatric Neurology, Shiga Medical Centre, Japan
Correspondence to: Yasuhiro Nagahama,
Department of Geriatric Neurology,
Shiga Medical Centre, 5-4-30 Moriyama,
Moriyama-city, Shiga 524-8524,
Japan
E-mail: [email protected]
The aim of this study was to investigate the association between psychotic symptoms in dementia with Lewy bodies and brain
perfusion on single photon emission tomography. Based on factor analysis in 145 patients, psychotic symptoms were classified
into five symptom domains (factor 1 to 4-related symptoms and delusions). The relationship between each symptom domain
and brain perfusion was assessed in 100 patients with dementia with Lewy bodies, while accounting for the effects of age, sex,
dementia severity, parkinsonism and dysphoria. Factor 1 symptoms (Capgras syndrome, phantom boarder, reduplication of
person and place and misidentification of person) represented misidentifications, and were significantly related to hypoperfusion
in the left hippocampus, insula, ventral striatum and bilateral inferior frontal gyri. Factor 3 symptoms (visual hallucination of
person and feeling of presence) represented hallucinations of person and were related to hypoperfusion in the left ventral
occipital gyrus and bilateral parietal areas. Delusions of theft and persecution were associated with relative hyperperfusion in
the right rostral medial frontal cortex, left medial superior frontal gyrus and bilateral dorsolateral frontal cortices. This study
revealed that different psychotic symptoms in dementia with Lewy bodies were associated with distinguishable cerebral
networks. Visual hallucinations were related to dysfunction of the parietal and occipital association cortices, misidentifications
were related to dysfunction of the limbic-paralimbic structures and delusions were related to dysfunction of the frontal cortices.
Our findings provide important insights into the pathophysiological mechanisms underlying psychotic symptoms in dementia
with Lewy bodies.
Keywords: dementia with Lewy bodies; hallucination; delusion; delusional misidentification syndrome; cerebral blood flow
Abbreviations: MNI = Montreal Neurological Institute; SPECT = single photon emission computed tomography; SPM = Statistical
Parametric Mapping
Introduction
Dementia with Lewy bodies is the second most common
neurodegenerative dementia following Alzheimer’s disease
(McKeith et al., 2003; Buracchio et al., 2005). Patients with
dementia with Lewy bodies typically exhibit psychotic symptoms.
Visual hallucinations are the most frequent symptoms and have
been identified as one of the core features in the clinical diagnostic
criteria of dementia with Lewy bodies (McKeith et al., 1996,
1999). Hallucinations in other modalities and systematized
delusions also occur in dementia with Lewy bodies, but are less
frequent and are regarded as supportive features. A wide variety
of misidentifications, from ‘delusional misidentification syndromes’
e.g. Capgras syndrome, to simple misidentification of a person are
also found in dementia with Lewy bodies (Ballard et al., 1999;
Hirono and Cummings, 1999). Psychotic symptoms have particular
Received July 24, 2009. Revised September 18, 2009. Accepted September 28, 2009. Advance Access publication November 17, 2009
ß The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
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| Brain 2010: 133; 557–567
clinical importance since neuropsychiatric symptoms are more
frequent in dementia with Lewy bodies than Alzheimer’s disease,
even in the early stages of the disease and they cause a higher
degree of caregiver distress (Ricci et al., 2009).
Several studies have attempted to determine the neural basis of
visual hallucinations in dementia with Lewy bodies (Imamura et al.,
1999; O’Brien et al., 2005; Perneczky et al., 2008), but few studies have explored that of delusions or misidentifications.
Furthermore, psychotic symptoms in dementia do not occur in
isolation. In dementia with Lewy bodies, several types of hallucinations, delusions and misidentifications can be present in a patient
(Ballard et al., 1999; Nagahama et al., 2007). In particular, one
form of misidentification usually accompanies another; Capgras
syndrome sometimes coexists with reduplicative paramnesia
(Signer, 1987; Christodoulou, 1991; Weinstein, 1994), and phantom boarder with other misidentifications (Hwang et al., 2003).
These observations suggest that such symptoms may be produced
by a common underlying pathophysiological alteration. Controlling
for a community of interrelated symptoms or confounding effects
of other coexisting symptoms is necessary in neuroimaging studies
to explore the neural basis of psychotic symptoms.
We recently reported the possible classification of psychotic
symptoms in dementia with Lewy bodies using factor analysis,
suggesting hallucinations, misidentifications and delusions as
independent symptom domains (Nagahama et al., 2007). Based
on our previous study, we tried to explore the neural correlates of
each psychotic symptom domain in dementia with Lewy bodies
patients. In the present study, we combined many psychotic
symptoms in dementia with Lewy bodies into a few symptom
domains using factor analysis and examined the relationships
between regional cerebral blood flow and the presence of each
domain symptom, while controlling for the effects of other
cognitive, behavioural and psychiatric symptoms.
Subjects and methods
Subjects
First, we examined 145 patients with dementia with Lewy bodies
who attended the Memory Clinic, Shiga Medical Centre, between
November 2000 and March 2009, to categorize psychotic symptoms.
Subjects underwent general physical, neurological and neuropsychological examinations including the Mini-Mental State Examination. All
underwent structural neuroimaging and routine laboratory investigations including vitamin B1, B12, and thyroid functions. Parkinsonism
was assessed using the motor sign scores derived from the Unified
Parkinson’s Disease Rating Scale (Scarmeas et al., 2004). Patients
with a history of stroke, significant head trauma, alcohol abuse,
major psychiatric illnesses or evidence of other neurological disorders
were excluded. Clinical diagnoses were made by agreement between
experienced geriatric neurologists (Y.N. and M.M.) according to the
consensus criteria for dementia with Lewy bodies (McKeith et al.,
1996, 1999). One hundred and thirty six patients with dementia
with Lewy bodies fulfilled probable and nine fulfilled possible dementia
with Lewy bodies criteria. Patients whose dementia developed
12 months or later after the onset of Parkinson’s disease were
excluded from the study.
Y. Nagahama et al.
Patients with an Mini-Mental State Examination score of less than
11, or who showed moderate to severe ischaemic changes on head
CT or MRI, were excluded, and finally 100 subjects (92 probable,
eight possible dementia with Lewy bodies) were selected for single
photon emission computed tomography (SPECT) analysis. Six patients
were treated with antiparkinsonian drugs (L-dopa or/and dopamine
agonist), six with antipsychotics (two with tiapride, two with sulpiride,
one with quetiapine and one with haloperidol), and two were treated
with antidepressants at their first visit to our hospital. We carefully
excluded a possible relationship between these medications and
psychotic phenomena by evaluating their detailed clinical history and
reducing/stopping the drugs.
Twenty-one age-matched control subjects without dementia
(77.2 4.8 years) were also scanned. They were patients’ spouses
and relatives who agreed to the SPECT scan.
Assessment and categorization of
psychotic symptoms
Psychotic symptoms were classified based on factor analysis of 145
dementia with Lewy bodies patients. Detailed methods were reported
previously (Nagahama et al., 2007). Briefly, a semi-structured interview according to psychoses and dysphoria was conducted by Y.N.
and M.M. with patients and their primary caregivers, in order to reveal
whether each symptom was present or absent. Then, we subjected
17 psychotic symptoms that occurred in at least five different patients
to factor analysis.
The statistical technique of factor analysis is an attempt to reduce
the dimensionality of a data set, by grouping of the original variables
into so called ‘factors’ in order to simplify interpretation (Krzanowski,
2000). The complete representation of data would (here) require
17 dimensional space, but by calculating linear functions of the original
variables that progressively account for maximum amounts of the total
variability, the patterns are hopefully compressed into fewer dimensions. This first stage is therefore simply an orthogonal transformation
of the original variables. The axes are then rotated so that as many of
the coefficients as possible, in the linear functions, are reduced to very
small values, leaving the remaining coefficients (loadings) being representative of that factor. In an ideal situation, if virtually all the variability can be compressed into a very few dimensions, interpretation
becomes much easier. In the present study, the principal factor procedure was used to extract the initial factors and this was followed by
Orthotran/Varimax oblique rotations. The number of factors to be
retained was determined by examining the eigenvalues 41.0 and
scree plot. Items with factor loadings 50.50 were entered into the
factor.
This analysis almost replicated and confirmed our previous results
(Nagahama et al., 2007) except that the order of factor 3 and 4 was
reversed. We obtained a 4-factor solution (Table 1) and correlations
between factors were very low. Eigenvalues of factors 1 to 4 were
2.38, 1.70, 1.57 and 1.47, respectively, accounting for 14.0, 10.0, 9.2
and 8.6% of the variance. Factor 1 consisted of misidentification of
person, Capgras syndrome, phantom boarder, reduplication of person
and reduplication of place. Factor 2 consisted of reduplication of
person, the belief that deceased relatives are still alive and the belief
that absent relatives are in the house. Factor 3 included hallucination
of person and feeling of presence. Factor 4 included hallucination of
animals and insects and hallucination of objects. Delusion of theft and
delusion of persecution were not loaded into these factors and were
considered as an independent category. According to the factor structure, we enrolled 100 dementia with Lewy bodies patients in SPECT
Neural basis of psychotic symptoms in dementia with Lewy bodies
Table 1 Factor loadings for psychotic symptoms in
dementia with Lewy bodies patients (n = 145)
Factor 1 Factor 2 Factor 3 Factor 4
Eigenvalues
Hallucination of person
Hallucination of animals/insects
Hallucination of objects
Elementary hallucination
Auditory hallucination
Feeling of presence
Misidentification of person
Misidentification of place
Misidentification of objects
Capgras syndrome
Phantom boarder
Reduplication of person
Reduplication of place
Belief that deceased relatives
are still alive
Belief that absent relatives
are in the house
Delusion of theft
Delusion of persecution
2.38
0.05
0.08
0.05
0.04
0.06
0.09
0.65
0.49
0.07
0.58
0.62
0.52
0.73
0.15
1.70
0.04
0.03
0.01
0.10
0.06
0.05
0.01
0.15
0.03
0.18
0.21
0.54
0.09
0.88
1.57
0.64
0.17
0.04
0.48
0.04
0.53
0.18
0.21
0.37
0.24
0.20
0.19
0.13
0.001
1.47
0.42
0.69
0.68
0.42
0.09
0.02
0.04
0.14
0.004
0.10
0.22
0.13
0.01
0.04
0.01
0.77
0.01
0.11
0.03
0.18
0.21
0.07
0.21
0.46
0.27
0.06
Significant loadings (50.50) are shown in bold.
analysis with at least one symptom in the psychotic symptom domain
(factor 1–4 and delusions).
SPECT imaging
Demographic data of the patients are shown in Table 2.
Subjects lay on the scanner bed with their eyes closed, and
740 MBq [99mTc]hexamethyl-propyleneamine oxime (HMPAO) was
administered intravenously. Ten minutes after injection, SPECT
images were acquired over 20 min using a triple-head SPECT scanner
(GCA-9300A/UI; Toshiba Medical, Tokyo, Japan) with high-resolution
fan-beam collimators. The system resolution was 7.5 mm full width at
half maximum in the centre of view. Projection data, collected in a
128 128 matrix, were prefiltered with a Butterworth filter with order
8 and a cut-off frequency of 0.11 cycles/pixel. Transaxial images were
reconstructed with a Ramp back-projection filter. Post-reconstruction
attenuation correction was not applied. The reconstruction yielded
1.7 mm 1.7 mm 1.7 mm voxels with a 128 128 matrix and 80
slices. All subjects and/or caregivers gave informed consent according
to the nature of the study and purpose of the SPECT scan.
Image analysis
SPECT data were analysed with Statistical Parametric Mapping
(SPM5, Wellcome Department of Imaging Neuroscience, London,
UK). All images were transformed into a standard stereotactic anatomical space (Mazziotta et al., 1995). The resulting voxel size was
2 mm 2 mm 2 mm. The average of spatially normalized scans was
calculated and a 20 mm-diameter volume of interest was defined on
the bilateral cerebellum. Scan intensity was then normalized by dividing each image by the mean intensity in the cerebellar volumes of
interest. The cerebellum was selected as reference region because
perfusion/metabolism of the cerebellum was preserved or, at least,
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Table 2 Subject demographics (100 dementia with Lewy
bodies patients for SPECT analysis)
Age (years)
Sex (female/male)
Education (years)
Mini-Mental State Examination
UPDRS
Factor 1 symptoms
Factor 2 symptoms
Factor 3 symptoms
Factor 4 symptoms
Delusions
Dysphoria
76.7 6.7
70/30
9.7 2.5
21.0 3.9
6.4 5.2
32
15
74
35
24
40
Number in each symptom domain shows the number of patients with at least
one of the symptoms in the category. Factor 1 symptoms: misidentification of
person, Capgras syndrome, phantom boarder, reduplication of person and
reduplication of place. Factor 2 symptoms: reduplication of person, the belief
that deceased relatives are still alive and the belief that absent relatives are in the
house. Factor 3 symptoms: visual hallucination of person and feeling of presence.
Factor 4 symptoms: visual hallucination of animals and insects and hallucination
of objects. Delusions: delusion of theft and delusion of persecution. UPDRS =
Unified Parkinson’s Disease Rating Scale subscore. Values are shown as the
mean standard deviations.
less affected than the cerebral cortex in dementia with Lewy bodies
(Ishii et al., 1998; Yong et al., 2007). Thereafter, the images were
smoothed with a 12 mm Gaussian filter.
Statistical analysis was carried out in two steps. First, group comparison between patients and controls was performed to determine
significant hypoperfusion brain areas in dementia with Lewy bodies,
treating age as a nuisance covariate. A significant threshold of
P50.01, corrected for multiple comparisons using the false discovery
rate procedure, was applied to minimize the chance of false-positive
findings. Extent threshold was set at more than 10 voxels.
Second, the relationship between the psychotic symptom domains
(factor 1–4 symptoms and delusions) and regional cerebral blood
flow in dementia with Lewy bodies patients was examined with
covariate-only design matrices, using the multiple regression model
in SPM5. Age, sex, Mini-Mental State Examination, Unified
Parkinson’s Disease Rating Scale motor sign score and the presence/
absence of dysphoria were entered into the model as nuisance covariates. The specific effects of each psychotic symptom domain were
tested using [–1] or [1] t-contrast with additional zeros for the rest
of the symptoms and nuisance covariates, assuming that the presence
of the symptoms would be uniquely associated with decreased or
increased regional cerebral blood flow. Search volumes were restricted
a priori to the hypoperfusion areas identified in the first step.
Therefore, a statistical threshold of uncorrected P 50.001 was
accepted in this second step analysis and the extent threshold was
set at more than 10 voxels. Montreal Neurological Institute (MNI)
coordinates (Mazziotta et al., 1995) were used to report brain areas,
but descriptions of the anatomical location were also based on visual
inspection of the normalized structural MRI and the atlas of Mai (Mai
et al., 2008).
Results
The significant hypoperfusion areas in dementia with Lewy bodies
relative to control subjects involved a wide range of bilateral
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Y. Nagahama et al.
Figure 1 Significant hypoperfusion areas in dementia with Lewy bodies compared with the controls. Statistical threshold was set at
P50.01 with correction for multiple comparisons.
frontal, temporal, parietal and occipital cortices (Fig. 1). Bilateral
lenticular nuclei and thalamus were also affected.
Factor 1 symptoms, representing misidentifications, were present in 32 dementia with Lewy bodies patients; misidentification of
person in 22, Capgras syndrome in 5, reduplication of person in
10, reduplication of place in 5, phantom boarder in 14. Twentyone patients had ‘delusional misidentification syndromes’ or
phantom boarder, and 11 had only misidentification of person.
Patients with factor 1 symptoms showed significant hypoperfusion
compared with those without factor 1 symptoms in the left
hippocampus, insula, the opercular part of the inferior frontal
gyrus and ventral striatum/accumbens nucleus (Fig. 2; Table 3).
A small hypoperfusion area was also found in the right opercular
part of the inferior frontal gyrus. When the threshold was lowered
to an uncorrected P 50.01 for exploratory purposes, the right
ventral striatum (MNI coordinates of x = 8, y = 10, z = 8), bilateral
inferior temporal gyri (x = 50, y = 14, z = 38 and x = 54,
y = 6, z = 38), right medial frontopolar cortex (x = 4, y = 64,
z = 8) and cingulate gyri (x = 0, y = 34, z = 2 and x = 12,
y = 8, z = 42) were also uncovered, but the right insula or
hippocampal area was not detected. There was no significant
hyperperfusion area related to factor 1.
Factor 3 symptoms, representing visual hallucinations of person,
were present in 74 dementia with Lewy bodies patients;
68 patients had hallucination of person and 29 had feeling of
presence. Patients with factor 3 symptoms showed significant
Neural basis of psychotic symptoms in dementia with Lewy bodies
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Figure 2 Significant hypoperfusion related to misidentifications in dementia with Lewy bodies. The SPM{Z} result image, thresholded at
P 50.001, was overlaid on the normalized T1 image from a patient. The ‘y’ indicates the coronal slice position in millimetres in the
stereotactic space. R = right.
Table 3 Brain regions that show significant relative
hypoperfusion in relation to misidentifications
Cluster Regions
1
2
3
4
Voxels x
Hippocampus, Lt
1969
Hippocampus, Lt
Insula, Lt
Inferior frontal gyrus,
389
opercular, Lt
Accumbens nucleus, Lt 151
Inferior frontal gyrus,
26
opercular, Rt
y
z
36
30
40
38
20
20
8
22
14
38
6
16
Z score
12
20
8
0
3.90
3.86
3.78
3.86
8 3.53
4 3.20
Voxels = number of voxels in each detected region; (x, y, z) = stereotactic
coordinates in the MNI space; Z score = SPM{Z} score; Lt = left; Rt = right.
hypoperfusion compared with those without factor 3 symptoms in
bilateral parietal areas (bilateral angular gyri and right supramarginal gyrus) and the left ventral occipital gyrus (Fig. 3; Table 4).
When the threshold was lowered to an uncorrected P 50.01, the
right ventral occipital gyrus (x = 36, y = 72, z = 12), bilateral
middle frontal gyri (x = 24, y = 30, z = 36 and x = 32, y = 24,
z = 38), and bilateral posterior cingulate gyri (x = 10, y = 56,
z = 46 and x = 10, y = 58, z = 50) were also detected. No significant hyperperfusion area was found related to factor 3.
There was no significant hypoperfusion area related to delusions. Instead, patients with delusions showed significant hyperperfusion compared with those without delusions in the right
rostral medial frontal cortex, which centred around the right
cingulate sulcus and bilateral middle frontal gyrus, right inferior
frontal gyrus, left medial superior frontal gyrus and left middle
frontopolar gyrus (Fig. 4 and Table 5).
We found no significant regional cerebral blood flow difference
related to factor 2 or factor 4 symptoms.
Discussion
We successfully uncovered significant relationships of the regional
cerebral blood flow with factor 1 and 3 symptoms and delusions,
but not with factor 2 and 4 symptoms. Our failure to obtain
significant findings may have been due to the small number of
subjects having factor 2 symptoms; however, for factor 4, the
reason is uncertain. Visual hallucinations of non-humans might
be heterogeneous and different in nature from hallucinations
of person. Alternatively, the failure to find correlation between
regional cerebral blood flow and factor 2 and 4 symptoms might
simply be that there were none; these symptoms may correlate with global deterioration of brain function and not be correlated with focal deficits. Future study is needed to clarify these
points.
Because most patients (92%) with factor 3 symptoms had visual
hallucinations of person, the effect of factor 3 on regional cerebral
blood flow was assumed to be mainly related to visual hallucinations. Hallucinations of person in dementia with Lewy bodies were
associated with significant hypoperfusion in the ventral visual
stream for face and object recognition (i.e. left ventral occipital
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Y. Nagahama et al.
Figure 3 Significant hypoperfusion related to the visual hallucinations in dementia with Lewy bodies. The statistical threshold was set
at P 50.001 for SPM{Z}. The ‘x’ (in millimetres) and ‘y’ indicate the sagittal and coronal slice positions in the stereotactic space,
respectively. L = left.
Table 4 Regions that show significant hypoperfusion in
relation to hallucinations
Cluster Regions
1
2
3
4
Voxels x
Angular gyrus, Lt
152
4th occipital gyrus, Lt
138
Supramarginal gyrus, Rt 70
Angular gyrus, Rt
71
y
38
32
46
34
z
68
76
46
72
Z score
26
10
38
22
3.63
3.44
3.39
3.37
Voxels = number of voxels in each detected region; (x, y, z) = stereotactic
coordinates in the MNI space; Z score = SPM{Z} score; Lt = left; Rt = right.
gyrus), and the dorsal stream for spatial location and motion vision
(i.e. bilateral parietal cortices). The location of the ventral occipital
gyrus closely matched the ‘occipital face area’, which is sensitive
to physical aspects of face stimulus and is a critical stage in the
face-recognition pathway (Kanwisher and Yovel, 2006). Despite
the relative heterogeneity of the previous reports (Imamura
et al., 1999; O’Brien et al., 2005), our results support the findings
of several previous studies showing that dysfunction of extrastriate
visual association areas rather than the primary visual cortex is
related to visual hallucination in dementia with Lewy bodies
Neural basis of psychotic symptoms in dementia with Lewy bodies
Figure 4 Relative hyperperfusion areas related to delusions in
dementia with Lewy bodies. The statistical threshold was set at
P 50.001 for SPM{Z}. The ‘z’ indicates axial slice position in
millimetres in the stereotactic space. L = left.
Table 5 Regions that show significant hyperperfusion in
relation to delusions
Cluster Regions
1
2
3
Voxels x
Rostral medial frontal
2119
cortex, Rt
Middle frontal gyrus, Lt
Superior frontal gyrus,
medial, Lt
Middle frontal gyrus, Rt
441
Inferior frontal gyrus, Rt
Middle frontopolar
12
gyrus, Lt
y
z
Z score
10 46 10 4.04
32 26 38 3.59
10 38 32 3.46
32 28 38 3.61
50 26 24 3.50
22 52 2 3.15
Voxels = number of voxels in each detected region; (x, y, z) = stereotactic
coordinates in the MNI space; Z score = SPM{Z} score; Lt = left; Rt = right.
(Perneczky et al., 2008) and Parkinson’s disease with dementia
(Matsui et al., 2006; Boecker et al., 2007). Dysfunction in both
ventral and dorsal streams well matched the clinical characteristics
of visual hallucinations in dementia with Lewy bodies because they
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perceived complex, non-stationary scenarios (Mosimann et al.,
2006), similar to hallucinations in patients with temporo-occipital
and parieto-occipital lesions (Lance, 1976). Furthermore, Mori
et al. (2006) demonstrated that regional cerebral blood flow in
ventral occipital regions was increased and visual hallucination
was improved in dementia with Lewy bodies after donepezil
administration (Mori et al., 2006), and suggested that hypofunction in the visual association areas, which is caused by a lack of
cholinergic inputs from the forebrain or brainstem, may be a key
to the genesis of visual hallucinations in dementia with Lewy
bodies.
Because the ‘misidentification’ factor comprised several different
symptoms (including ‘delusional misidentification syndromes’),
common regional cerebral blood flow abnormalities among misidentification syndromes may provide the basic underlying pathophysiology. Our findings of significant hypoperfusion associated
with misidentifications in limbic (left hippocampus) and paralimbic
structures (left insula and bilateral inferior frontal gyri) support and
extend earlier suggestions that the ‘delusional misidentification
syndromes’ may derive from discordance between emotional
accompaniments of sensory and mnemonic images (Signer,
1987; Christodoulou, 1991; Weinstein, 1994; Ellis and Lewis,
2001). Theoretical models of Capgras syndrome proposed that
the patient can recognize a face but fails to receive a confirmatory
feeling of familiarity, so that the joint information representing
face recognition and affective response does not match a stored
(and therefore expected) representation of the person (Breen et
al., 2000; Ellis and Lewis, 2001). Some researchers argued that the
deficit could be explained in terms of intact ventral temporal visual
recognition systems, but disrupted connections to the limbicparalimbic structures, or as impairment of the limbic-paralimbic
structures themselves (Hirstein and Ramachandran, 1997; Breen
et al., 2000).
Reduplicative paramnesia and Capgras syndrome possess many
common features beyond the idea of doubles. In reduplication
phenomena, the misidentified person or place is selective and
almost always ‘belongs’ to the patient—i.e. the person or place
normally has a strong emotional relationship to the patient
(Weinstein and Burnham, 1991; Weinstein, 1994). Some researchers (Staton et al., 1982; Fleminger and Burns, 1993) also argued
that reduplicative paramnesia is based on a false recollection, in
which a patient is unable to integrate a recent observation with
past memory stores. To our knowledge, no study has investigated
the possible neuropsychiatric mechanism of phantom boarder
symptom; however, the bizarre belief that ‘there is someone
unfamiliar in the house’ seems to be related to false memories
accompanied by strangeness (i.e. feeling of unfamiliarity). Even
the misidentification of person goes beyond a simple illusion or
naming difficulty and may be a faulty identification based on
inaccurately retrieved information and emotional experiences,
because it usually involves intimates, such as a spouse, sibling,
child or neighbour.
The hippocampus, insula, frontal operculum and accumbens
nucleus are elements of the limbic-paralimbic system. The hippocampus is relevant not only to encoding process of memory but
also to recollection of the episode (Cansino et al., 2002; Eldridge
et al., 2005; Eichenbaum et al., 2007). Functional imaging studies
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revealed that the inferior frontal opercular region was activated
when observing the emotional facial expressions of others (right
dominant) (Wicker et al., 2003; Jabbi et al., 2007), and in controlling the impact of emotions on cognitive performance (left
dominant) (Nelson et al., 2003; Dolcos et al., 2006). Similar
inferior frontal regions have been shown to be recruited during
affective autobiographical recall (Damasio et al., 2000). The insula
forms a key central network in the paralimbic system, which has
extensive reciprocal connections to inferior and orbital frontal
regions, medial temporal structures such as the hippocampus
and amygdala, as well as parietal cortex and medially to the
thalamus and basal nuclei (Augustine, 1996). The insular cortex
is engaged in tasks that depend on interactions between the extrapersonal world and the internal milieu (Mesulam and Mufson,
1982), and disturbance of the insular and temporolimbic system,
especially on the left side, is associated with the expression of
positive symptoms in schizophrenia (Bogerts, 1997; CrespoFacorro et al., 2000). The accumbens nucleus is the principal component of the ventral striatum and is most often associated with
reward-related behaviour such as emotional learning (Pavlovian
conditioning and instrumental conditioning) (Cardinal et al.,
2002; Robbins et al., 2008). Human imaging studies demonstrated
that the ventral striatum/accumbens was activated with rewarding
properties of beautiful faces (Aharon et al., 2001), faces previously
presented with a nonthreatening affect (Satterthwaite et al., 2009)
and social positive emotion (humour/joy) (Mobbs et al., 2003;
Britton et al., 2006). Thus, we speculated that an impaired
memory and emotional function, and their interactions, which
were associated with the dysfunction of the limbic-paralimbic
systems, might underlie the misidentifications in dementia with
Lewy bodies. Our results are also consistent with a previous
study showing that Alzheimer’s disease with ‘delusional misidentification syndromes’ had significant hypometabolism in paralimbic
(orbitofrontal and cingulate areas bilaterally) and left medial temporal areas compared with Alzheimer’s disease without ‘delusional
misidentification syndromes’ (Mentis et al., 1995).
Delusion of theft and persecution were related to relative hyperperfusion in the frontal cortex in dementia with Lewy bodies,
which seems in conflict with several reports showing that frontal
perfusion is decreased in Alzheimer’s disease patients with
delusions (Mega et al., 2000; Staff et al., 2000; Sultzer et al.,
2003). The conflicts may be due to differences in patient
groups, definition of delusions, clinical state at the time of studies
and image analysis techniques. Alzheimer’s disease patients in previous studies were impaired more severely in cognitive function
than our subjects (Mega et al., 2000; Staff et al., 2000; Sultzer
et al., 2003), and had both persecutory delusions and (delusional)
misidentifications (Staff et al., 2000; Sultzer et al., 2003), or hallucinations (Mega et al., 2000). However, the ‘hyperperfusion’
regions in the dementia with Lewy bodies subgroup were not
actually hyperactive but rather less hypoperfused, and can be
interpreted as dysfunctional areas because these were within significant hypoperfusion regions compared with control subjects.
Indeed, direct comparison between the dementia with Lewy
bodies subgroup with delusions and control subjects confirmed
significant frontal hypoperfusion (online Supplementary Figure).
To generate delusions, preserved functions in those frontal areas
Y. Nagahama et al.
may be required. When the functions in those regions were
severely depressed, like in frontal leucotomy, delusions may no
longer emerge. Thus, the frontal cortex in dementia with Lewy
bodies with delusions may still operate, but possibly with errors.
Several reports have demonstrated that the frontal cortex is relatively hyperactive in relation to positive symptoms of schizophrenia
(Liddle et al., 1992; Soyka et al., 2005).
Neuropsychiatric models proposed that people with persecutory delusions preferentially attend to threatening stimuli
and recall threatening episodes (i.e. attentional bias), jump to
conclusions on the basis of insufficient information, attribute
negative events to external causes such as other people or
circumstances (i.e. attributional bias), and have difficulty in
envisaging other’s intentions, motivations, or state of mind
(Blackwood et al., 2001; Bell et al., 2006). Neuroimaging studies
pointed to the rostral medial frontal cortex as a key region that
plays a crucial role in social cognition (Amodio and Frith, 2006;
Gilbert et al., 2007). Social cognitive processes, such as selfreflection, person perception and attribution have been associated
with activity extending from the anterior cingulate to the anterior
frontal pole, most typically located along the paracingulate sulcus
(Harris et al., 2005; Amodio and Frith, 2006), which matches well
with the location detected in the present study. Such social inferential processing is based on access to information stored in
episodic/autobiographical memory, including information about
the self, relationships with others and social situations. Bilateral
dorsolateral prefrontal areas and the superior medial frontal area,
which were also identified here, are known to contribute to
episodic memory retrieval (Fletcher and Henson, 2001), and monitor and manipulate information within working memory. Several
have shown impaired source monitoring (the ability to distinguish
internally from externally generated experiences) in patients with
delusions (Brebion et al., 2002; Moritz et al., 2005). Therefore, we
speculated that dementia with Lewy bodies patients with delusions
preferentially make wrong causal attributions to external people
(i.e. other-blaming attributions) based on impaired source
monitoring and insufficient information retrieved from episodic
memory.
We observed that regional cerebral blood flow differences
related to hallucinations and misidentifications were more pronounced in the left hemisphere. Boecker et al. (2007) also
reported a left dominant metabolic reduction in occipitotemporo-parietal regions in Parkinson’s disease with visual hallucinations (Boecker et al., 2007); however, our observations may be
due to random noise, since hypoperfusion related to hallucinations
was found in the bilateral occipital and parietal cortices at the
lower statistical threshold of P 50.01. In contrast, greater hypoperfusion in the left compared with right insula and hippocampus
related to misidentification was still observed even at a lower
threshold. Patients with ‘delusional misidentification syndromes’
usually have lesions in the right and/or bilateral hemispheres,
suggesting the right-side dominance of the delusional misidentification syndrome (Devinsky, 2009); however, the very great majority of patients with right hemisphere lesions do not have delusional
misidentification syndromes, and many patients that do have
bilateral pathology (Weinstein, 1994; Devinsky, 2009). Indeed,
our dementia with Lewy bodies group had significant
Neural basis of psychotic symptoms in dementia with Lewy bodies
hypoperfusion in the bilateral fronto-temporal and parieto-occipital
cortices compared with the controls, suggesting that the bilateral
hemispheres might be dysfunctional in dementia with Lewy bodies
patients with misidentifications. Alternatively, the failure to detect
the right-side hypoperfusion may be due to a lack of statistical
significance of our data. Another possibility is that some processes
related to misidentification may be really left dominant. Mentis et
al. (1995) also reported left dominant hypometabolism in the
medial temporal area in Alzheimer’s disease with delusional misidentification syndromes (Mentis et al., 1995). There is substantial
evidence that the left hemisphere plays a distinct role in the
processing of reward and positive emotional stimuli (Silberman
and Weingartner, 1986; Breiter and Rosen, 1999; Coulson and
Kutas, 2001; Mobbs et al., 2003; Satterthwaite et al., 2009), so
disruption of left-hemisphere processes might result in increased
negative views of others’ facial expressions and contribute to
generate discordance between sensory and emotional responses
to the face. These issues should be examined more closely in
future studies.
There are some limitations of our study. The diagnosis of
dementia with Lewy bodies was only based on clinical criteria
and was not pathologically proven; however, the criteria have
been validated against pathologically proven cases and are
reported to have high specificity (mean 92%) and, importantly,
a positive predictive value (McKeith et al., 2003). Another limitation is that although the patients had had psychotic symptoms
before the SPECT scan, we did not confirm whether they had
actually experienced these symptoms during the scan; therefore,
our findings may represent trait-related rather than state-related
neurophysiological changes. Thirdly, the sensitivity and spatial resolution of SPECT is inferior to positron emission tomography, so
our failure to detect right-side deficits related to misidentifications,
and also the failure to find cerebral correlates of factor 2 and 4
symptoms might be partly due to the technical limitation of SPECT
imaging. Finally, it must be recognized that the statistical technique of factor analysis has proved controversial over the years.
The problem is partly because there will always be a subjective
element in the process of axis rotation in search for so called
‘factors’. Given the complexity as well as uncertainties inherent
in the technique, we must interpret the results carefully and
should accept that the tentative combination of several variables
into ‘factors’ is simply a device to help in understanding the data
structure. Nevertheless, we successfully replicated the factor structure here in the larger dementia with Lewy bodies group than our
previous study (Nagahama et al., 2007) and so it is reasonable
to consider that these factors may be associated with certain
pathophysiological properties of the disease.
We found that, in dementia with Lewy bodies patients, the
different psychotic symptom domains were associated with distinguishable pathophysiological processes; visual hallucinations
with dysfunction of the parietal and ventral occipital cortices,
misidentifications with dysfunction of the limbic-paralimbic
structures, and delusions with dysfunction of the frontal cortices.
However, cognitive-perceptual-emotional deficit could not
account totally for the maladaptive, symbolic aspects of psychotic
symptoms, especially of delusions and misidentifications (Mentis
et al., 1995). A number of mediating factors, such as culture,
Brain 2010: 133; 557–567
| 565
life experiences, coping styles and temperament, influence the
occurrence or content of psychotic phenomena. Nevertheless,
our findings provide important insights into the pathophysiological
mechanisms underlying psychotic symptoms in dementia with
Lewy bodies and may be ultimately informative to develop new
therapies for psychotic symptoms in dementia with Lewy bodies.
Supplementary material
Supplementary material is available at Brain online.
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