Neurol Clin 25 (2007) 741–760

Dementia with Lewy Bodies

Tanis J. Ferman, PhDa,*, Bradley F. Boeve, MDb
a
Department of Psychiatry & Psychology, Mayo Clinic,
Jacksonville, FL 32224, USA
b
Mayo Clinic College of Medicine, Rochester MN 55905, USA

Neocortical Lewy bodies are found in approximately 20% to 35% of

elderly persons who have dementia [1–4] and do not occur commonly in
normal brains [5]. Based on sensitive immunostaining techniques, dementia
with Lewy bodies (DLB) is now considered the second most common cause
of neurodegenerative dementia after Alzheimer’s disease (AD) [5,6]. In 1996,
consensus criteria for the clinical diagnosis of DLB were put forth that re-
quired dementia plus one or two of the following core features (two for
probable DLB or one for possible DLB): recurrent fully formed visual hal-
lucinations (VH), parkinsonism, and fluctuating cognition [7]. Using these
criteria, diagnostic accuracy varies from poor to excellent [8–11]. Problems
with reliable assessment of fluctuations, a lack of empiric data regarding
when core features should occur relative to dementia onset, and limitations
to study design (eg, circularity, absence of standardized assessment, and
inclusion of cases with advanced dementia) contribute to this discrepancy
[12–16]. The Third International Workshop meeting on DLB resulted in
publication of revised consensus diagnostic criteria for DLB in December
2005 [17]. These criteria are presented in Box 1.

Neuropsychologic function
The dementias of DLB and AD are similar in insidious onset and pro-
gressive course, and before autopsy, many patients who have Lewy body
disease are given the antemortem diagnosis of AD [3,13]. Despite some sim-
ilarities, several studies show greater deficits in attention and visual percep-
tion in DLB, whereas AD is associated with worse memory and naming

Supported by NIH grants R01-AG15866, P50-AG16574, and P50-NS40256.

* Corresponding author.
E-mail address: ferman.tanis@mayo.edu (T.J. Ferman).

0733-8619/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.ncl.2007.03.001 neurologic.theclinics.com
742 FERMAN & BOEVE

Box 1. Revised criteria for the clinical diagnosis of dementia

with Lewy bodies (DLB)
1. Central feature (essential for a diagnosis of possible or
probable DLB)
Dementia defined as progressive cognitive decline of
sufficient magnitude to interfere with normal social or
occupational function
Prominent or persistent memory impairment may not
necessarily occur in the early stages but usually is evident
with progression
Deficits on tests of attention, executive function,
and visuospatial ability may be especially
prominent
2. Core features (two core features are sufficient for a diagnosis
of probable DLB or one for possible DLB)
Fluctuating cognition with pronounced variation in attention
and alertness
Recurrent VH that typically are well formed and detailed
Spontaneous features of parkinsonism
3. Suggestive features (If one or more of these is present in the
presence of one or more core features, a diagnosis of probable
DLB can be made. In the absence of any core features, one or
more suggestive features is sufficient for possible DLB.
Probable DLB should not be diagnosed on the basis of
suggested features alone.)
REM sleep behavior disorder (RBD)
Severe neuroleptic sensitivity
Low dopamine transporter uptake in the basal ganglia
demonstrated by single photon emission CT or positron
emission tomographic imaging

From McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of
dementia with Lewy bodies: third report of the DLB consortium. Neurology
2005;65:1863–72; with permission.

[3,18–20]. Logistic regression modeling was done to determine the diagnostic

usefulness of cognitive assessment in the differentiation of a prospective
sample of persons who had DLB (n ¼ 87) from those who did not have
AD (n ¼ 138) and those who had normal aging (n ¼ 103) [21]. Patient
groups did not differ in age, education, or dementia severity. The logistic
models reveal that impairment in basic attention, visual perception, visual
 DEMENTIA WITH LEWY BODIES 743

construction, and memory distinguished DLB from normal aging (sensitiv-

ity of 88.6% and specificity of 96.1%). In contrast, impaired visual construc-
tion and attention plus preserved memory and naming skills distinguished
DLB from AD (sensitivity of 83.3% and a specificity of 91.4%). These re-
sults confirm the authors’ prior findings of a double dissociation in neuro-
cognitive function between early DLB and AD [21].
The higher-order visual processing deficits in DLB is a finding not at-
tributable to motor slowness associated with parkinsonism [3,20,22–26].
The perceptual deficits evident in DLB may be responsible for some mis-
perceptions (ie, illusions) and delusional misidentification (ie, reduplicative
paramnesia, Capgras phenomena or not recognizing family). DLB patients
with VH tend to do more poorly on visual tasks [19–25,27]. Nonetheless,
some studies have not found differences between AD and DLB on visual
tasks [28,29], although this may be because of methodologic issues, such
as the inclusion of patients in the advanced stages of dementia, which
can obfuscate group differences resulting from generalized impairment. Al-
ternately, differential impairment of other task demands may be a factor.
For example, visual problem solving may be affected negatively by execu-
tive difficulties in AD and by perceptual difficulties in DLB. Mori and col-
leagues examined this issue and revealed deficits in DLB but not AD on
basic visual tasks that do not require executive function [30]. A distinction
between spatial and perceptual processing also seems to be a distinguishing
factor, with patients who have DLB showing greater deficits in the latter
[31]. There may be group differences in how the information initially is en-
coded. Reflexive saccadic eye movements responsible for repositioning the
fovea show greater impairment for DLB compared with AD [32], and re-
gional blood flow is shown to be lower in occipital regions in DLB despite
the relative absence of Lewy pathology there [33–36]. Overall, visual pro-
cessing deficits in DLB may be the result of disruption of the cortical ex-
trastriate association areas (especially the ventral visual pathway), but
there also may be disruption to the afferent system (perhaps via mecha-
nisms subserving saccadic foveation) before reaching the primary visual
cortex.
Memory difficulties, when present in early DLB, seem to be fairly mild
and stand in direct contrast to the pronounced amnestic disturbance of
AD [18–20]. Neuropathologic and imaging studies also show significant at-
rophy in the hippocampus in AD, whereas patients who have DLB show lit-
tle difference from normal controls [37–39]. Salmon and colleagues [18]
demonstrated a pattern of poor initial learning and retrieval in four of
five patients who had DLB without the rapid forgetting that typically is ob-
served in AD. In a sample of nine cases of pure DLB, 57 of mixed DLB/AD,
and 66 of pure AD, patients who had AD pathology performed worse on
tasks of verbal memory, whereas patients who had LB pathology performed
worse on tasks of visual spatial skills, and combined pathology affected
visual spatial performance but not verbal memory [40].
744 FERMAN & BOEVE

Spontaneous motor features of parkinsonism

For diagnostic clarity, parkinsonian signs must be spontaneous and not at-
tributable to neuroleptics [7]. Cognitive impairment in Parkinson’s disease
(PD) and DLB is associated more often with rigidity and bradykinesia than
tremor [41–50]. Postural instability/gait difficulty is over-represented in DLB
and Parkinson’s disease dementia (PDD) compared with PD [51], and this
has led some to speculate that extrapyramidal signs associated with dementia
may have a dopaminergic and a nondopaminergic basis. In general, the parkin-
sonism associated with DLB tends to be less severe than that observed in PD or
PDD, at least initially. Tremor, bradykinesia, and rigidity tend to be more sym-
metric than asymmetric, and tremor tends to be maximal with posture/action
rather than at rest. One study of 14 patients who had DLB, 28 who had PD,
and 30 who had PDD showed improvement in the Unified Parkinson’s Disease
Rating Scale score for all three groups in response to levodopa but less so for the
patients who had DLB [52]. The possibility that this effect may be mediated by
greater initial motor deficits in the PDD and PD groups should be considered.

Visual hallucinations
VH in DLB consist of fully formed, detailed, 3-dimensional objects, people,
or animals that are not attributable to perceptual distortion or illusion
[3,47,53]. Patients who have DLB with auditory hallucinations typically expe-
rience VH, but auditory hallucinations rarely occur in patients who do not
have VH [54,55]. Hallucinations in DLB do not occur as a function of AD pa-
thology [56] and are not associated with levodopa dose or the presence of ‘‘on’’
(able to move) and ‘‘off’’ (unable to move) states [57]. VH have been docu-
mented to occur in 59% to 85% of autopsy-confirmed DLB samples and in
11% to 28% of autopsy-confirmed AD samples [5,15,58,59]. Autopsy studies
reveal that VH are most likely to occur early in DLB disease course, whereas
they tend to occur in the advanced stages of AD [5,60–62]. In an autopsy study
of DLB (n ¼ 41) and AD (n ¼ 70), a cutoff of 4 years for the onset of hallu-
cinations relative to dementia onset improved the positive and negative pre-
dictive values of DLB to 81% and 79%, respectively [63]. Patients who have
VH typically have greater cognitive and functional impairment [64–68], but
whether or not the presence of VH in DLB is associated with faster rate of dis-
ease progression has yet to be determined. The underlying cause of hallucina-
tions most likely is associated with the severe depletion of acetylcholine in
DLB, but other neurotransmitter systems may have a contributory role, in-
cluding dopamine and serotonin. Involvement of the basal forebrain and
the ventral temporal lobe are implicated in the causation of VH, given their re-
spective cholinergic and visual perceptual roles [5,58]. Also, the dysregulation
of rapid eye movement (REM) sleep in many patients who have DLB raises the
possibility of intrusion of dream imagery into wakefulness as a potential mech-
anism [69,70]. These etiologies are not necessarily mutually exclusive.
 DEMENTIA WITH LEWY BODIES 745

Fluctuations
The fluctuations of DLB resemble signs of delirium without identifiable
precipitants of such mental status changes. This phenomenon involves
a waxing and waning of cognition, abilities, and arousal. It has been de-
scribed as variable attention, incoherent speech, hypersomnolence, impaired
awareness of surroundings, staring into space, or appearing ‘‘glazed‘‘ or
‘‘switched off.’’ The prevalence of fluctuations in DLB samples is widely dis-
crepant and ranges from 10% to 80% with poor inter-rater reliability
[8,10,12,71,72]. Studies often do not specify how the presence of fluctuations
is determined and the usefulness of this core clinical feature has been highly
criticized. Available techniques to assess fluctuations include a brief inter-
view rating scale relying on clinical expertise, a semistructured interview
that inquires about the day before the assessment [16,73–76], and a set of
four questions derived from a lengthier questionnaire [77]. The latter ques-
tionnaire is designed to determine whether or not there are salient features
of fluctuations that reliably differentiate DLB (n ¼ 70) from AD (n ¼ 70)
and normal elderly (n ¼ 200). Results show that four items significantly dif-
ferentiated DLB from AD, including (1) daytime drowsiness and lethargy,
(2) daytime sleep of 2 or more hours, (3) staring into space for long periods,
and (4) times when a patient’s flow of ideas seems disorganized, unclear, or
not logical. The presence of three or four features of this composite occurred
in 63% of patients who had DLB compared with 12% of those who had AD
and 0.5% normal elderly (P!.01). A score of 3 or 4 yields a positive predic-
tive value of 83% for the clinical diagnosis of DLB against an alternate di-
agnosis of AD, and a score of less than 3 yields a negative predictive value of
70% for the absence of DLB in favor of AD. Because not all patients who
have DLB have fluctuations, these values suggest reasonable diagnostic use-
fulness. No particular combination of VH, parkinsonism (presence or sever-
ity), or RBD was associated with a fluctuations composite score of 3 or 4
[77]. These data indicate that an informant-based questionnaire is sensitive
to fluctuations in alertness and speech but fails to differentiate fluctuations
in ability or cognition between DLB and AD. It may be worthwhile to dis-
tinguish between fluctuations in arousal and cognition, whereby the latter
may be evaluated best with neuropsychometric tests. This is supported by
findings that attention, vigilance, and reaction time show greater impair-
ment and variability in DLB than in AD [20,73,75].

Excessive daytime drowsiness

Patients who have DLB often have daytime drowsiness or somnolence.
As such, ruling out known causes of daytime sleepiness, including medica-
tions and primary sleep disorders (ie, sleep apnea), is critical. In a clinical
referral sample of 78 patients with early DLB who underwent overnight poly-
somnography, approximately three quarters of the sample had a significant
746 FERMAN & BOEVE

number of arousals not accounted for by medication, periodic limb move-

ments of sleep, or sleep apnea [78,79]. In half of the DLB sample, sleep
efficiency fell well below the expected 80% for this age group [80–82].
This raises the possibility that dysfunction of brainstem or hypothalamic
neuronal networks subserving sleep and wakefulness may be producing
daytime drowsiness. Further studies are needed that represent a random
selection of patients who have DLB and an AD group matched for age,
gender, and dementia severity.

Rapid eye movement sleep behavior disorder

The loss of normal muscle atonia during rapid eye movement (REM)
sleep refers to the parasomnia of REM sleep behavior disorder (RBD). In
RBD, augmented muscle activity during REM sleep occurs along with
dream content and can range from elevated muscle tone to complex behav-
ioral sequences, such as pantomiming various activities that may be subdued
or vigorous [22,83]. The presumed pathophysiologic mechanism of RBD in-
volves damage to the descending pontine-medullary reticular formation (in-
cluding the magnocellular reticular formation) or sublaterodorsal nucleus
that leads to a loss of the normal REM sleep inhibition of the spinal al-
pha-motoneurons [84–87]. In humans, polysomnographic evidence of
REM sleep without atonia is considered the electrophysiologic substrate
of RBD and is found in patients with or without florid RBD [88,89].
RBD can precede the onset of neurodegenerative diseases with alpha-synu-
clein inclusions (ie, DLB, PD, or multiple system atrophy [MSA]) by years
and even decades [22,89–94]. It rarely occurs in tau-predominant neurode-
generative conditions, such as AD [92]. Neuropathologic confirmation of
Lewy body disease has been demonstrated in a patient who had a 20-year
history of idiopathic RBD [93] and in a patient who had a 15-year history
of idiopathic RBD [94], neither of whom had any other neurologic signs
or symptoms or evidence of psychosis. Of 36 patients with clear clinical his-
tories of RBD, 31 had Lewy body disease, four had MSA and one had pro-
gressive supranuclear palsy, providing further evidence that RBD usually
reflects an underlying synucleinopathy [95].
The estimated onset of RBD typically precedes the onset of dementia,
VH, and parkinsonism by many years and often decades (range, 6 months
to 55 years) [19,20,22]. Despite this relationship, patients who present ini-
tially with dementia and RBD do not meet the 1996 DLB criteria until par-
kinsonism or hallucinations become apparent. The authors examined the
neurocognitive performance of 25 patients who had RBD and dementia
(without parkinsonism or hallucinations) and compared them to 37 patients
with clinically probable DLB and 30 cases of autopsy-confirmed AD of
matched dementia severity [19]. Results indicate that the DLB and RBD
plus dementia groups were cognitively indistinguishable, but both groups
 DEMENTIA WITH LEWY BODIES 747

differed significantly from autopsy-confirmed AD group of matched demen-

tia severity. Follow-up data from a subset of patients who had RBD plus
dementia revealed the subsequent development of parkinsonism or VH 1
to 6 years later. Thus, a clinical history of RBD in the context of dementia
with disproportionate visual deficits and relatively preserved memory and
naming is likely to represent the earliest stages of DLB.

Dysautonomia
Autonomic abnormalities, in particular orthostatic hypotension and ca-
rotid sinus sensitivity, are more common in DLB than AD or elderly con-
trols [17]. A comparison of dysautonomia in DLB, PD, and MSA shows
that orthostatic hypotension is affected most severely in MSA, least severely
in PD, and of intermediate severity in DLB [96]. The DLB group tended to
respond better to medications than the MSA group. The frequency of uri-
nary symptoms and pattern of sweat loss in DLB was comparable to that
of PD but much less than MSA.

Rate of decline in dementia with Lewy bodies

Several studies of DLB indicate a more rapid progression than that of
pure AD, and earlier studies of AD suggest extrapyramidal features and
psychosis are predictors of decline [13,48,97–100]. Some recent data, how-
ever, show no difference in the rate of cognitive decline between DLB and
AD [101,102]. In an autopsy study of patients who were part of the Florida
Alzheimer’s Disease Initiative Brain Bank, there was a shorter duration of
illness for DLB compared with AD [63]. In a longitudinal study of 63 pa-
tients who had DLB and 252 who had AD, psychometric performance
and clinical staging methods did not distinguish groups in terms of rate of
cognitive decline, but DLB was associated with increased risk of mortality.
Extrapyramidal signs were a strong predictor of mortality [103].

Description and distribution of pathology in dementia with Lewy bodies

Lewy bodies are concentric, intracytoplasmic neuronal inclusions that
have long been a recognized pathology of brainstem monoaminergic and
cholinergic nuclei in idiopathic PD [104,105]. Subcortical Lewy bodies are
distributed in the dorsal motor nucleus of the vagus, medullary magnocellu-
lar reticular nuclei, locus coeruleus, raphe nucleus and midbrain tegmentum,
and are adequately detected by hematoxylin and eosin (H & E) histologic
staining [106–109]. Neocortical Lewy bodies are less eosinophilic, less cir-
cumscribed, and are best detected by alpha-synuclein immunohistochemis-
try [106]. The hypothalamus, basal forebrain, amygdale and temporal
748 FERMAN & BOEVE

cortex are particularly vulnerable to cortical Lewy bodies, with lesser in-
volvement of frontal and posterior cortical regions [108–111]. Spongiosis
also is observed in the amygdala and basal forebrain [106]. Similarly, using
MRI, the rates of whole brain atrophy and ventricular expansion during a
1- to 2-year interval do not differ between a sample of DLB later confirmed
by autopsy and normal controls [112]. When compared with AD, MRI
voxel-based morphometry reveals that DLB has little cortical involvement
but does show a discrete cluster of gray matter loss in the cholinergic-rich
regions of the nucleus basalis of Meynert in the basal forebrain and dorsal
midbrain [113].
Lewy neurites are widespread alpha-synuclein–positive inclusions that
are located in neural processes and preferentially affect limbic and temporal
lobe structures [37,38,107].
A portion of DLB cases has AD-type pathology that includes neurofibril-
lary tangles (NFTs) and neuritic plaques [3,4,13]. Plaques are composed of
extracellular beta-amyloid (Ab) protein deposits comprised of 40 and 42
amino acid peptides. The neuritic plaques that accompany AD include
a dense core of Ab40 with neuritic processes composed of the protein tau
[114]. In contrast, plaques in Lewy body disease typically are diffuse
(although some may contain a core) and are composed primarily of Ab42
with a paucity or absence of tau-positive neuritis [115–119]. Diffuse plaques
also are numerous in brains of cognitively normal elderly [37,120,121]. Most
clinicopathologic studies of DLB and AD do not take this distinction into
account, and as such, it is not known whether or not differences in plaque
type influence clinical presentation. When NFTs are present in Lewy body
disease, they are far less frequent than in AD, and regional distribution us-
ing Braak staging often is at Braak IV or less, indicating confinement to lim-
bic regions [3,47,122–125]. Clinical diagnostic accuracy of DLB is
significantly better in those who have low Braak stages and lower tangle
density [126,127].

Clinicopathologic correlates in dementia with Lewy bodies

and Alzheimer’s disease
Dementia severity is not associated with neocortical plaque density but is
related to NFT burden in AD [123,128,129]. In DLB, Lewy body density
but not plaque or NFT density is correlated with dementia severity
[123,130,131]. Lewy neurite density also is associated with the degree of cog-
nitive impairment in DLB [132], suggesting that these inclusions may inter-
fere with neuronal function, but further investigation is needed.
In AD, the CA1 region and subiculum of the hippocampus are affected
severely, whereas the CA2/3 region is considered the ‘‘resistant zone’’ and
typically is spared [133–135]. In DLB, it is the CA2/3 region that is affected,
whereas the CA1 and subiculum regions typically are spared [37,136].
Similarly, AD is associated with a near total loss of perforant pathway
 DEMENTIA WITH LEWY BODIES 749

neurons, whereas in DLB, the perforant pathway is more comparable to

that of normal controls [137]. Although damage to the CA1 region is asso-
ciated with memory impairment, is not known if CA2/3 pathology affects
memory function.
The ventral temporal lobe is burdened heavily by prominent Lewy body
pathology and spongiosis [48,106]. This neuroanatomic pattern seems to oc-
cur well before the onset of Lewy body pathology in other cortical regions,
including the parietal lobe [110]. Thus, early specific visual perceptual defi-
cits may be associated with disruption of the pattern/object recognition
pathway. Patients who have VH have higher LB densities in amygdala, par-
ahippocampus, and inferior temporal cortex [136], suggesting the involve-
ment of these regions in the development of VH. Nonetheless, VH occur
in patients with limbic-only Lewy body pathology [63] indicating that tem-
poral lobe dysfunction is not required to elicit VH, though it certainly may
have a modulating role.

The cholinergic hypothesis fits dementia with Lewy bodies

better than Alzheimer’s disease
The use of new cholinergic toxins to selectively target the nucleus basalis
of Meynert (which is 90% cholinergic and widely projects to the cortex)
[138] reveals no impairment of memory but does indicate deficits in sus-
tained and divided attention [139–143]. In addition, profound cholinergic
neuronal loss and severely depleted choline acetyltransferase levels occur
early in DLB disease course, whereas AD and normal controls show little
difference until the advanced stage of dementia [144–147]. In addition, anti-
cholinergic agents can elicit hallucinations and disturbed consciousness that
vary as a function of cholinergic deficiency [148–153]. Not surprisingly, one
hypothesized mechanism for fluctuations and VH in DLB includes choliner-
gic depletion of the basal forebrain alone [5,145,149,154]. Increasing acetyl-
choline availability with cholinesterase inhibitors improves attention,
hallucinations, and alertness in early DLB [154–159]. Thus, cholinergic de-
pletion is a critical factor in the symptom manifestation of early DLB but
may be less so in early AD. This highlights the importance of differentiating
between early versus late stages of different dementias, because patients who
have advanced AD may have similar clinical features as those who have
early DLB.

Pharmacologic treatment of dementia with Lewy bodies

When faced with a challenging behavior, it is critical first to evaluate for
potential medical contributors (eg, pain, medication side effects, injury, un-
derlying sleep disorder, depression, dehydration, metabolic disturbance, and
so on) and treat accordingly.
750 FERMAN & BOEVE

Neuroleptic medication is frequently administered to patients with de-

mentia for episodic confusion, hallucinations, delusions, and agitation
[160,161]. These clinical features are observed commonly in DLB, but there
is convincing evidence that patients who have DLB can harbor neuroleptic
sensitivity to traditional and to some atypical neuroleptics [59,162–166].
Specifically, antipsychotic agents with D2 antagonism and anticholinergic
properties precipitate or exacerbate extrapyramidal signs and cognitive im-
pairment, respectively [167,168]. Unfortunately, discontinuation of the neu-
roleptic does not necessarily lead to a reversal of the adverse reaction [59].
There is a mixed literature on the relationship between atypical antipsy-
chotics and cognition, but quetiapine has a better response profile overall
in DLB relative to AD [169–174]. Olanzepine does not seem to worsen par-
kinsonism [169], but its anticholinergic properties may exacerbate cognitive
impairment [172].
Levodopa-carbidopa is generally well tolerated in DLB, does diminish
extrapyramidal signs and does not seem to precipitate a profound worsening
of psychosis as seen in the dopamine agonists or amantadine. There is some
data to suggest that the levodopa-carbidopa response in DLB may not be at
the same magnitude as in PD [51], but further study is needed to confirm
and better characterize this [175,176].
Brain acetylcholine is severely depleted in the early stages of DLB
compared with early AD [5,145–147]. This is concerning because drugs
with anticholinergic properties are commonly prescribed to the elderly
to treat mood, psychosis, movement disorders, incontinence, and pulmo-
nary disease [150]. Several studies clearly demonstrate adverse reactions
to anticholinergic agents that mimic delirium [151–153,177]. Alternately,
improvement (sometimes dramatic) in delirium-like symptoms, fluctua-
tions and VH can occur with the use of cholinesterase inhibitors
[146,178–181]. Studies of cholinesterase inhibitors [157,182,183] reveal im-
proved cognition in DLB and AD and detrimental effects when with-
drawn suddenly [184]. A comparison of DLB (n ¼ 30) and Parkinson’s
disease with dementia (n ¼ 40) who were taking donepezil revealed im-
proved Mini–Mental State Examination scores by a mean of 3.9 points
in the DLB group and by 3.2 points in the PDD group by 20 weeks
[185]. Extrapyramidal side effects of cholinesterase inhibitors are low,
and it is recommended as a first-line treatment for DLB [186].
The goals of therapy for RBD are to minimize the injuries to patients
and their bed partners and to reduce the likelihood of disrupted nighttime
sleep. Clonazepam at a very low dose usually is effective [187]. Melatonin
also may be effective, either as monotherapy or in conjunction with clona-
zepam [188].
Excessive daytime sleepiness is challenging, and the first approach is to
try to identify if the cause may be a medication side effect, mood, or a pri-
mary sleep disorder. Although psychostimulants would be expected to exac-
erbate hallucinations and delusions in DLB, experience has shown that
 DEMENTIA WITH LEWY BODIES 751

daytime somnolence in some patients can be managed with agents, such as

modafinil and methylphenidate [69].

Nonpharmacologic treatment
Behaviors should be recognized as a form of communication and not as
random, unpredictable, or meaningless events. It may be helpful to deter-
mine in the situations where challenging behaviors occur (who is present,
when do they happen, what makes them better or worse, and what main-
tains them) and to focus on the emotions that accompany behaviors. For
example, aggressive behavior often represents frustration, fear, pain, a reac-
tion to not being taken seriously, or even mirroring a caregiver’s behavior
(ie, impatience or agitation). Addressing these feelings may help alleviate
a patient’s agitation.
In terms of nonmedical interventions, managing challenging behaviors
should be shifted from trying to change patients to modifying other factors
that may be causing or exacerbating a problem [189]. Put differently, pa-
tients cannot change, and therefore, it is up to those around them to change.
This includes modifying the environment (eg, reduce clutter, increase illumi-
nation, reduce distracting noise), modifying responses to behavior (eg, vali-
date patient concerns, apologize, reassure patients, model calm, avoid
correcting, quizzing, and ‘‘reality orienting’’), and modifying task demands
(eg, provide structure and routine, break down tasks into manageable parts,
focus on success and not failure, refrain from giving tasks that are too hard,
provide guided exercise).
Before treating hallucinations or delusions (false beliefs), it must be deter-
mined if these symptoms are harmful or distressing to patients. Educating
family members about ways to cope with these behaviors includes encourag-
ing them to validate patients’ feelings and devising strategies that go along
with behaviors (eg, checking the house for intruders or appearing to call
somebody to see what time is check-out time) that provide reassurance
and that do not involve arguing or trying to reason with patients.
Providing information for caregivers is an important part of helping to
manage challenging behaviors. Psychoeducation intervention groups for
caregivers are associated with significant improvements in agitation and
anxiety for patients who have dementia [190]. Using available support ser-
vices, including adult day programs and companion services, also are shown
to reduce caregiver-related stress and reported feelings of overload, strain,
depression, and anger [191].

Summary
Clinical features that may be helpful in distinguishing early DLB from
AD include neurocognitive presentation, VH, extrapyramidal signs, fluctu-
ations, neuroleptic sensitivity, RBD, and dysautonomia. Early and accurate
752 FERMAN & BOEVE

detection of DLB has implications for symptom management and for pro-
viding education and support to patients who have DLB and their
caregivers.

References
[1] Galasko D, Hansen LA, Katzman R, et al. Clinical-neuropathological correlations in
Alzheimer’s disease and related dementias. Arch Neurol 1994;51:888–95.
[2] Joachim CL, Morris JH, Selkoe DJ. Clinically diagnosed Alzheimer’s disease: autopsy re-
sults in 150 cases. Ann Neurol 1988;24:50–6.
[3] Hansen L, Salmon D, Galasko D, et al. The Lewy body variant of Alzheimer’s disease:
a clinical and pathologic entity. Neurology 1990;40:1–8.
[4] Hulette C, Mirra S, Wilkinson W, et al. The consortium to establish a registry for Alz-
heimer’s Disease (CERAD). Part IX. A prospective cliniconeuropathologic study of Par-
kinson’s features in Alzheimer’s disease. Neurology 1995;45:1991–5.
[5] Perry EK, Marshall E, Perry RH, et al. Cholinergic and dopaminergic activities in senile
dementia of Lewy body type. Alzheimer Dis Assoc Disord 1990;4:87–95.
[6] Lennox G, Lowe J, Landon M, et al. Diffuse Lewy body disease: correlative neuropathol-
ogy using anti-ubiquitin immunocytochemistry. J Neurol Neurosurg Psychiatry 1989;52:
1236–47.
[7] McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and path-
ologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB
international workshop. Neurology 1996;47:1113–24.
[8] McKeith IG, Ballard CG, Perry RH, et al. Prospective validation of consensus criteria for
the diagnosis of dementia with Lewy bodies. Neurology 2000;54:1050–8.
[9] Lopez OL, Becker JT, Kaufer DI, et al. Research evaluation and prospective diagnosis of
dementia with Lewy bodies. Arch Neurol 2002;59:43–6.
[10] Verghese J, Crystal HA, Dickson DW, et al. Validity of clinical criteria for the diagnosis of
dementia with Lewy bodies. Neurology 1999;53:1974–82.
[11] Litvan I, MacIntyre A, Goetz CG, et al. Accuracy of the clinical diagnoses of Lewy body
disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study.
Arch Neurol 1998;55:969–78.
[12] Mega MS, Masterman DL, Benson DF, et al. Dementia with Lewy bodies: reliability and
validity of clinical and pathologic criteria. Neurology 1996;47:1403–9.
[13] Lippa CF, Smith TW, Swearer JM. Alzheimer’s disease and Lewy body disease: a compar-
ative clinicopathological study. Ann Neurol 1994;35:81–8.
[14] Kuzuhara S, Yoshimura M. Clinical and neuropathological aspects of diffuse Lewy body
disease in the elderly. Adv Neurol 1993;60:464–9.
[15] Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse Lewy body disease: a clin-
icopathologic study using Alzheimer’s disease and Parkinson’s disease comparison groups.
Neurology 1996;47:1148–52.
[16] Walker MP, Ayre GA, Cummings JL, et al. The clinician assessment of fluctuation and the
one day fluctuation assessment scale. Two methods to assess fluctuating confusion in de-
mentia. Br J Psychiatry 2000;177:252–6.
[17] McKeith IG, Dickson DW, Lowe J, et al, for the consortium on DLB. Diagnosis and man-
agement of dementia with Lewy bodies: third report of the DLB consortium. Neurology
2005;65:1863–72.
[18] Salmon DP, Galasko D, Hansen LA, et al. Neuropsychological deficits associated with dif-
fuse Lewy body disease. Brain Cogn 1996;31:148–65.
[19] Ferman TJ, Boeve BF, Smith GE, et al. Dementia with Lewy bodies may present as demen-
tia and REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuro-
psychol Soc 2002;8:907–14.
 DEMENTIA WITH LEWY BODIES 753

[20] Ferman TJ, Boeve BF, Smith GE, et al. REM sleep behavior disorder and dementia: cog-
nitive differences when compared with AD. Neurology 1999;52:951–7.
[21] Ferman TJ, Smith GE, Boeve BF, et al. Neuropsychological differentiation of dementia
with Lewy bodies from normal aging and Alzheimer’s disease. Clin Neuropsychol 2006;
20:623–36.
[22] Boeve BF, Silber MH, Ferman TJ, et al. REM sleep behavior disorder and degener-
ative dementia: an association likely reflecting Lewy body disease. Neurology 1998;51:
363–70.
[23] Calderon J, Perry RJ, Erzinclioglu SW, et al. Perception, attention, and working memory
are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer’s
disease. J Neurol Neurosurg Psychiatry 2001;70:157–64.
[24] Ballard C, Holmes C, McKeith I, et al. Psychiatric morbidity in dementia with Lewy bodies:
a prospective clinical and neuropathological comparative study with Alzheimer’s disease.
Am J Psychiatry 1999;156:1039–45.
[25] Shimomura T, Mori E, Yamashita H, et al. Cognitive loss in dementia with Lewy bodies
and Alzheimer disease. Arch Neurol 1998;55:1547–52.
[26] Connor DJ, Salmon DP, Sandy TJ, et al. Cognitive profiles of autopsy-confirmed Lewy
body variant vs pure Alzheimer disease. Arch Neurol 1998;55:994–1000.
[27] Simard M, van Reekum R, Myran D. Visuospatial impairment in dementia with Lewy
bodies and Alzheimer’s disease: a process analysis approach. Int J Geriatr Psychiatry
2003;18:387–91.
[28] Forstl H, Burns A, Luthert P, et al. The Lewy-body variant of Alzheimer’s disease. Clinical
and pathological findings. Br J Psychiatry 1993;162:385–92.
[29] Gnanalingham KK, Byrne EJ, Thornton A, et al. Motor and cognitive function in Lewy
body dementia: comparison with Alzheimer’s and Parkinson’s diseases. J Neurol Neuro-
surg Psychiatry 1997;62:243–52.
[30] Mori E, Shimomura T, Fujimori M, et al. Visuoperceptual impairment in dementia with
L’wy bodies. Arch Neurol 2000;57:489–93.
[31] Mosimann UP, Mather G, Wesnes KA, et al. Visual perception in Parkinson disease de-
mentia and dementia with Lewy bodies. Neurology 2004;63:2091–6.
[32] Mosimann UP, Muri RM, Burn DJ, et al. Saccadic eye movement changes in Parkinson’s
disease dementia and dementia with Lewy bodies. Brain 2005;128:1267–76.
[33] Mito Y, Yoshida K, Yabe I, et al. Brain 3-D-SSP SPECT analysis in dementia with Lewy
bodies, Parkinson’s disease with and without dementia and Alzheimer’s disease. Clinical
Neurology and Neurosurgery 2005;107:396–403.
[34] Shimuzu S, Hanyu H, Kanetaka H, et al. Differentiation of dementia with Lewy bodies
from Alzheimer’s disease using brain SPECT. Dementia and Geriatric Cognitive Disorders
2005;20:25–30.
[35] Lobotesis K, Fenwick JD, Phipps A, et al. Occipital hypoperfusion on SPECT in dementia
with Lewy bodies but not AD. Neurology 2001;56:643–9.
[36] Imamura T, Ishii K, Hirono N, et al. Occipital glucose metabolism in dementia with lewy
bodies with and without Parkinsonism: a study using positron emission tomography.
Dement Geriatr Cogn Disord 2001;12:194–7.
[37] Dickson DW, Ruan D, Crystal H, et al. Hippocampal degeneration differentiates dif-
fuse Lewy body disease (DLBD) from Alzheimer’s disease: light and electron micro-
scopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology 1991;41:
1402–9.
[38] Dickson DW, Schmidt ML, Lee VM, et al. Immunoreactivity profile of hippocampal CA2/
3 neurites in diffuse Lewy body disease. Acta Neuropathol (Berl) 1994;87:269–76.
[39] Barber R, Gholkar A, Scheltens P, et al. Medial temporal lobe atrophy on MRI in dementia
with Lewy bodies. Neurology 1999;52:1153–8.
[40] Johnson DK, Morris JC, Galvin JE. Verbal and visuospatial deficits in dementia with Lewy
bodies. Neurology 2005;65:1232–8.
754 FERMAN & BOEVE

[41] Huber SJ, Paulson GW, Shuttleworth EC. Relationship of motor symptoms, intellectual
impairment, and depression in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;
51:855–8.
[42] Richards M, Stern Y, Marder K, et al. Relationships between extrapyramidal signs and
cognitive function in a community-dwelling cohort of patients with Parkinson’s disease
and normal elderly individuals. Ann Neurol 1993;33:267–74.
[43] Pearce J. The extrapyramidal disorder of Alzheimer’s disease. Eur Neurol 1974;12:94–103.
[44] Molsa PK, Marttila RJ, Rinne UK. Extrapyramidal signs in Alzheimer’s disease. Neurol-
ogy 1984;34:1114–6.
[45] Rinne UK, Laakso K, Molsa PK. Relationship between Parkinson’s and Alzheimer’s dis-
eases. Involvement of extrapyramidal, dopaminergic, cholinergic, and somatostatin mech-
anisms in relation to dementia. Acta Neurol Scand 1984;69:59–60.
[46] Mayeux R, Stern Y, Spanton S. Heterogeneity in dementia of the Alzheimer type: evidence
of subgroups. Neurology 1985;35:453–61.
[47] Crystal HA, Dickson DW, Lizardi JE, et al. Antemortem diagnosis of diffuse Lewy body
disease. Neurology 1990;40:1523–8.
[48] Byrne EJ, Lennox G, Lowe J, et al. Diffuse Lewy body disease: clinical features in 15 cases.
J Neurol Neurosurg Psychiatry 1989;52:709–17.
[49] Galasko D, Katzman R, Salmon DP, et al. Clinical and neuropathological findings in Lewy
body dementias. Brain Cogn 1996;31:166–75.
[50] Gibb WR, Esiri MM, Lees AJ. Clinical and pathological features of diffuse cortical Lewy
body disease (Lewy body dementia). Brain 1987;110(Pt 5):1131–53.
[51] McKeith I, Mintzer J, Aarsland D, et al, on behalf of the International Psychogeriatric
Association Expert Meeting on DLB. Dementia with Lewy bodies. Lancet Neurol 2004;
3:19–28.
[52] Molloy S, McKeith IG, O’Brien JT, et al. The role of levodopa in the management of de-
mentia with Lewy bodies. J of Neurol, Neurosurg and Psychiatry 2005;76:1200–3.
[53] McKeith IG, Fairbairn AF, Perry RH, et al. The clinical diagnosis and misdiagnosis of
senile dementia of Lewy body type (SDLT). Br J Psychiatry 1994;165:324–32.
[54] Ferman TJ, Boeve BF, Silber MH, et al. Hallucinations and delusions associated with the
REM sleep behavior disorder/dementia syndrome. J Neuropsychiatry Clin Neurosci 1997;
9:692.
[55] Ferman TJ, Boeve BF, Smith GE, et al. The phenomenology of psychotic features in
Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Neurology 2005;
64:A257.
[56] Cercy SP, Bylsma FW. Lewy bodies and progressive dementia: a critical review and meta-
analysis. J Int Neuropsychol Soc 1997;3:179–94.
[57] Sanchez-Ramos JR, Ortoll R, Paulson GW. Visual hallucinations associated with Parkin-
son disease. Arch Neurol 1996;53:1265–8.
[58] Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to
Lewy bodies in the temporal lobe. Brain 2002;125:391–403.
[59] McKeith I, Fairbairn A, Perry R, et al. Neuroleptic sensitivity in patients with senile demen-
tia of Lewy body type. BMJ 1992;305:673–8.
[60] Rockwell E, Choure J, Galasko D, et al. Psychopathology at initial diagnosis in dementia
with Lewy bodies versus Alzheimer disease: comparison of matched groups with autopsy-
confirmed diagnoses. Int J Geriatr Psychiatry 2000;15:819–23.
[61] Ala TA, Yang KH, Sung JH, et al. Hallucinations and signs of parkinsonism help distin-
guish patients with dementia and cortical Lewy bodies from patients with Alzheimer’s
disease at presentation: a clinicopathological study. J Neurol Neurosurg Psychiatry 1997;
62:16–21.
[62] Hope T, Keene J, Fairburn CG, et al. Natural history of behavioural changes and psychi-
atric symptoms in Alzheimer’s disease. A longitudinal study. Br J Psychiatry 1999;174:
39–44.
 DEMENTIA WITH LEWY BODIES 755

[63] Ferman TJ, Dickson DW, Graff-Radford N, et al. Early onset of visual hallucinations in
dementia distinguishes pathologically-confirmed Lewy body disease from AD. Neurology
2003;60(5):A264.
[64] Salmon DP, Kwo-on-Yuen PF, Heindel WC, et al. Differentiation of Alzheimer’s dis-
ease and Huntington’s disease with the Dementia Rating Scale. Arch Neurol 1989;46:
1204–8.
[65] Ballard C, Bannister C, Graham C, et al. Associations of psychotic symptoms in dementia
sufferers. Br J Psychiatry 1995;167:537–40.
[66] Klein C, Kompf D, Pulkowski U, et al. A study of visual hallucinations in patients with Par-
kinson’s disease. J Neurol 1997;244:371–7.
[67] Lopez OL, Becker JT, Brenner RP, et al. Alzheimer’s disease with delusions and hallucina-
tions: neuropsychological and electroencephalographic correlates. Neurology 1991;41:
906–12.
[68] Lopez OL, Brenner RP, Becker JT, et al. EEG spectral abnormalities and psychosis as pre-
dictors of cognitive and functional decline in probable Alzheimer’s disease. Neurology
1997;48:1521–5.
[69] Boeve B, Silber M, Ferman T. REM sleep behavior disorder in Parkinson’s disease and
dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2004;17:146–57.
[70] Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy pathology and REM sleep behavior
disorder plus dementia or parkinsonism. Neurology 2003;61:40–5.
[71] Lopez OL, Hamilton RL, Becker JT, et al. Severity of cognitive impairment and the clinical
diagnosis of AD with Lewy bodies. Neurology 2000;54:1780–7.
[72] Hohl U, Tiraboschi P, Hansen LA, et al. Diagnostic accuracy of dementia with Lewy
bodies. Arch Neurol 2000;57:347–51.
[73] Walker MP, Ayre GA, Perry EK, et al. Quantification and characterization of fluctuating
cognition in dementia with Lewy bodies and Alzheimer’s disease. Dement Geriatr Cogn
Disord 2000;11:327–35.
[74] Ballard CG, Aarsland D, McKeith I, et al. Fluctuations in attention: PD dementia vs DLB
with parkinsonism. Neurology 2002;59:1714–20.
[75] Ballard C, Walker M, O’Brien J, et al. The characterisation and impact of ‘fluctuating’ cog-
nition in dementia with Lewy bodies and Alzheimer’s disease. Int J Geriatr Psychiatry 2001;
16:494–8.
[76] Ballard C, O’Brien J, Gray A, et al. Attention and fluctuating attention in patients
with dementia with Lewy bodies and Alzheimer disease. Arch Neurol 2001;58:
977–82.
[77] Ferman TJ, Smith GE, Boeve BF, et al. DLB fluctuations: specific features that reliably
differentiate DLB from AD and normal aging. Neurology 2004;62:181–7.
[78] Ferman TJ, Boeve BF, Silber MH, et al. Is fluctuating cognition in dementia with sleep.
Sleep 2001;24:374.
[79] Boeve BF, Ferman TJ, Silber MH, et al. Sleep disturbances in dementia with Lewy bodies
involve more than REM sleep behavior disorder. Neurology 2003;60(5):A79.
[80] Kales A, Ansel RD, Markham CH, et al. Sleep in patients with Parkinson’s disease and nor-
mal subjects prior to and following levodopa administration. Clin Pharmacol Ther 1971;12:
397–406.
[81] Wetter TC, Collado-Seidel V, Pollmacher T, et al. Sleep and periodic leg movement pat-
terns in drug-free patients with Parkinson’s disease and multiple system atrophy. Sleep
2000;23:361–7.
[82] Bliwise DL. Sleep in normal aging and dementia. Sleep 1993;16:40–81.
[83] American Sleep Disorders Association. The international classification of sleep disorders
diagnostic and coding manual. Rochester (MN): American Sleep Disorders Association;
1997.
[84] Jouvet M, Delorme F. [Locus coeruleus et sommeil paradoxal]. C R Seances Soc Biol Fil
1965;159:895–9.
756 FERMAN & BOEVE

[85] Lai YY, Siegel JM. Physiological and anatomical link between Parkinson-like disease and
REM sleep behavior disorder. Mol Neurobiol 2003;27:137–52.
[86] Hendricks JC, Morrison AR, Mann GL. Different behaviors during paradoxical sleep with-
out atonia depend on pontine lesion site. Brain Res 1982;239:81–105.
[87] Lu J, Sherman D, Devor M, et al. A putative flip-flop switch for control of REM sleep.
Nature 2006;441:589–94.
[88] Plazzi G, Corsini R, Provini F, et al. REM sleep behavior disorders in multiple system
atrophy. Neurology 1997;48:1094–7.
[89] Gagnon JF, Bedard MA, Fantini ML, et al. REM sleep behavior disorder and REM sleep
without atonia in Parkinson’s disease. Neurology 2002;59:585–9.
[90] Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder
in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behav-
iour disorder. Neurology 1996;46:388–93.
[91] Turner RS, Chervin RD, Frey KA, et al. Probable diffuse Lewy body disease presenting as
REM sleep behavior disorder. Neurology 1997;49:523–7.
[92] Boeve BF, Silber MH, Ferman TJ, et al. Association of REM sleep behavior disorder and
neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;
16:622–30.
[93] Uchiyama M, Isse K, Tanaka K, et al. Incidental Lewy body disease in a patient with REM
sleep behavior disorder. Neurology 1995;45:709–12.
[94] Boeve BF, Dickson DW, Olson EJ, et al. Insights into REM sleep behavior disorder
pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 2007;8:
60–4.
[95] Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behavior disorder
and relevance to neurodegenerative disease. Brain, in press.
[96] Thaisetthawatkul P, Boeve BF, Benarroch EE, et al. Autonomic dysfunction in dementia
with Lewy bodies. Neurology 2004;62:1804–9.
[97] Stern Y, Albert M, Brandt J, et al. Utility of extrapyramidal signs and psychosis as pre-
dictors of cognitive and functional decline, nursing home admission, and death in Alz-
heimer’s disease: prospective analyses from the Predictors Study. Neurology 1994;44:
2300–7.
[98] Armstrong TP, Hansen LA, Salmon DP, et al. Rapidly progressive dementia in a patient
with the Lewy body variant of Alzheimer’s disease. Neurology 1991;41:1178–80.
[99] Olichney JM, Galasko D, Salmon DP, et al. Cognitive decline is faster in Lewy body variant
than in Alzheimer’s disease. Neurology 1998;51:351–7.
[100] Ballard C, Patel A, Oyebode F, et al. Cognitive decline in patients with Alzheimer’s disease,
vascular dementia and senile dementia of Lewy body type. Age Ageing 1996;25:209–13.
[101] Ballard C, O’Brien J, Morris CM, et al. The progression of cognitive impairment in demen-
tia with Lewy bodies, vascular dementia and Alzheimer’s disease. Int J Geriatr Psychiatry
2001;16:499–503.
[102] Helmes E, Bowler JV, Merskey H, et al. Rates of cognitive decline in Alzheimer’s disease
and dementia with Lewy bodies. Dement Geriatr Cogn Disord 2003;15:67–71.
[103] Williams MM, Xiong C, Morris JC, et al. Survival and mortality differences between
dementia with Lewy bodies vs. Alzheimer’s disease. Neurology 2006;67:1935–41.
[104] Dickson DW. Dementia with Lewy bodies: neuropathology. J Geriatr Psychiatry Neurol
2002;15:210–6.
[105] Pollanen MS, Dickson DW, Bergeron C. Pathology and biology of the Lewy body. J Neu-
ropathol Exp Neurol 1993;52:183–91.
[106] Dickson DW, Davies P, Mayeux R, et al. Diffuse Lewy body disease. Neuropathological
and biochemical studies of six patients. Acta Neuropathol (Berl) 1987;75:8–15.
[107] Dickson DW, Feany MB, Yen SH, et al. Cytoskeletal pathology in non-Alzheimer degen-
erative dementia: new lesions in diffuse Lewy body disease, Pick’s disease, and corticobasal
degeneration. J Neural Transm Suppl 1996;47:31–46.
 DEMENTIA WITH LEWY BODIES 757

[108] Kosaka K, Yoshimura M, Ikeda K, et al. Diffuse type of Lewy body disease: progressive
dementia with abundant cortical Lewy bodies and senile changes of varying degree–
a new disease? Clin Neuropathol 1984;3:185–92.
[109] Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol 2000;247(Suppl 2):
II3–10.
[110] Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Par-
kinson’s disease. Neurobiol Aging 2003;24:197–211.
[111] Kosaka K. Diffuse Lewy body disease in Japan. J Neurol 1990;237:197–204.
[112] Whitwell JL, Jack CR, Parisi JE, et al. Rates of cerebral atrophy differ in different degen-
erative pathologies. Brain 2007;130:1148–58.
[113] Whitwell JL, Weigand SD, Josephs KA, et al. Focal atrophy in dementia with Lewy bodies
on MRI: a distinct pattern from Alzheimer’s disease. Brain 2007;130:708–19.
[114] Dickson DW. Neuropathological diagnosis of Alzheimer’s disease: a perspective from lon-
gitudinal clinicopathological studies. Neurobiol Aging 1997;18:S21–6.
[115] Lippa CF, Smith TW, Perry E. Dementia with Lewy bodies: choline acetyltransferase par-
allels nucleus basalis pathology. J Neural Transm 1999;106:525–35.
[116] Dickson DW, Crystal H, Mattiace LA, et al. Diffuse Lewy body disease: light and electron
microscopic immunocytochemistry of senile plaques. Acta Neuropathol (Berl) 1989;78:
572–84.
[117] Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol 1997;56:
321–39.
[118] Armstrong RA, Cairns NJ, Lantos PL. Beta-amyloid deposition in the temporal lobe of pa-
tients with dementia with Lewy bodies: comparison with non-demented cases and Alz-
heimer’s disease. Dement Geriatr Cogn Disord 2000;11:187–92.
[119] Jellinger KA. Morphological substrates of mental dysfunction in Lewy body disease: an up-
date. J Neural Transm Suppl 2000;59:185–212.
[120] Katzman R, Brown T, Thal LJ, et al. Comparison of rate of annual change of mental status
score in four independent studies of patients with Alzheimer’s disease. Ann Neurol 1988;24:
384–9.
[121] Dickson DW, Crystal HA, Mattiace LA, et al. Identification of normal and pathological
aging in prospectively studied nondemented elderly humans. Neurobiol Aging 1992;13:
179–89.
[122] Hansen LA, Masliah E, Galasko D, et al. Plaque-only Alzheimer disease is usually the lewy
body variant, and vice versa. J Neuropathol Exp Neurol 1993;52:648–54.
[123] Samuel W, Galasko D, Masliah E, et al. Neocortical lewy body counts correlate with de-
mentia in the Lewy body variant of Alzheimer’s disease. J Neuropathol Exp Neurol
1996;55:44–52.
[124] Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuro-
pathol (Berl) 1991;82:239–59.
[125] Samuel W, Alford M, Hofstetter CR, et al. Dementia with Lewy bodies versus pure
Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and
synapse density. J Neuropathol Exp Neurol 1997;56:499–508.
[126] Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical
diagnostic accuracy in dementia with Lewy bodies. Neurology 2003;60:1586–90.
[127] Del Ser T, Hachinski V, Merskey H, et al. Clinical and pathologic features of two groups of
patients with Dementia with Lewy bodies: Effect of coexisting Alzheimer-type lesion load.
Alzheimer Dis and Assoc Dis 2001;15:31–44.
[128] Samuel WA, Henderson VW, Miller CA. Severity of dementia in Alzheimer disease
and neurofibrillary tangles in multiple brain regions. Alzheimer Dis Assoc Disord
1991;5:1–11.
[129] Arriagada PV, Growdon JH, Hedley-Whyte ET, et al. Neurofibrillary tangles but not
senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 1992;
42:631–9.
758 FERMAN & BOEVE

[130] Haroutunian V, Serby M, Purohit DP, et al. Contribution of Lewy body inclusions to de-
mentia in patients with and without Alzheimer disease neuropathological conditions. Arch
Neurol 2000;57:1145–50.
[131] Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate
with dementia in Parkinson’s disease. Neurology 2000;54:1916–21.
[132] Churchyard A, Lees AJ. The relationship between dementia and direct involvement of
the hippocampus and amygdala in Parkinson’s disease. Neurology 1997;49:1570–6.
[133] Ransmayr G, Cervera P, Hirsch EC, et al. Alzheimer’s disease: is the decrease of the cho-
linergic innervation of the hippocampus related to intrinsic hippocampal pathology? Neu-
roscience 1992;47:843–51.
[134] West MJ, Coleman PD, Flood DG, et al. Differences in the pattern of hippocampal neuro-
nal loss in normal aging and Alzheimer’s disease. Lancet 1994;344:769–72.
[135] Nagy Z, Jobst KA, Esiri MM, et al. Hippocampal pathology reflects memory deficit and
brain imaging measurements in Alzheimer’s disease: clinicopathologic correlations using
three sets of pathologic diagnostic criteria. Dementia 1996;7:76–81.
[136] Harding AJ, Lakay B, Halliday GM. Selective hippocampal neuron loss in dementia with
Lewy bodies. Ann Neurol 2002;51:125–8.
[137] Lippa CF, Pulaski-Salo D, Dickson DW, et al. Alzheimer’s disease, Lewy body disease and
aging: a comparative study of the perforant pathway. J Neurol Sci 1997;147:161–6.
[138] Mesulam MM, Mufson EJ, Levey AI, et al. Cholinergic innervation of cortex by the basal
forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei,
nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp
Neurol 1983;214:170–97.
[139] Himmelheber AM, Sarter M, Bruno JP. The effects of manipulations of attentional demand
on cortical acetylcholine release. Brain Res Cogn Brain Res 2001;12:353–70.
[140] McGaughy J, Kaiser T, Sarter M. Behavioral vigilance following infusions of 192 IgG-sap-
orin into the basal forebrain: selectivity of the behavioral impairment and relation to cor-
tical AChE-positive fiber density. Behav Neurosci 1996;110:247–65.
[141] McGaughy J, Everitt BJ, Robbins TW, et al. The role of cortical cholinergic afferent pro-
jections in cognition: impact of new selective immunotoxins. Behav Brain Res 2000;115:
251–63.
[142] Torres EM, Perry TA, Blockland A, et al. Behavioural, histochemical and biochemical con-
sequences of selective immunolesions in discrete regions of the basal forebrain cholinergic
system. Neuroscience 1994;63:95–122.
[143] Voytko ML, Olton DS, Richardson RT, et al. Basal forebrain lesions in monkeys disrupt
attention but not learning and memory. J Neurosci 1994;14:167–86.
[144] Davis KL, Mohs RC, Marin D, et al. Cholinergic markers in elderly patients with early
signs of Alzheimer disease. JAMA 1999;281(15):1401–6.
[145] Perry EK, Irving D, Kerwin JM, et al. Cholinergic transmitter and neurotrophic activities
in Lewy body dementia: similarity to Parkinson’s and distinction from Alzheimer disease.
Alzheimer Dis Assoc Disord 1993;7:69–79.
[146] Perry EK, Haroutunian V, Davis KL, et al. Neocortical cholinergic activities differentiate
Lewy body dementia from classical Alzheimer’s disease. Neuroreport 1994;5:747–9.
[147] Tiraboschi P, Hansen LA, Alford M, et al. Early and widespread cholinergic losses differ-
entiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry 2002;59:
946–51.
[148] Perry EK, Perry RH. Acetylcholine and hallucinations: disease-related compared to drug-
induced alterations in human consciousness. Brain Cogn 1995;28:240–58.
[149] Perry R, McKeith I, Perry E. Lewy body dementiadclinical, pathological and neurochem-
ical interconnections. J Neural Transm Suppl 1997;51:95–109.
[150] Tune LE, Egeli S. Acetylcholine and delirium. Dement Geriatr Cogn Disord 1999;10:342–4.
[151] Flacker JM, Cummings V, Mach JR Jr, et al. The association of serum anticholinergic ac-
tivity with delirium in elderly medical patients. Am J Geriatr Psychiatry 1998;6:31–41.
 DEMENTIA WITH LEWY BODIES 759

[152] Han L, McCusker J, Cole M, et al. Use of medications with anticholinergic effect predicts
clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med 2001;
161:1099–105.
[153] Tune LE, Damlouji NF, Holland A, et al. Association of postoperative delirium with raised
serum levels of anticholinergic drugs. Lancet 1981;2:651–3.
[154] Perry E, Walker M, Grace J, et al. Acetylcholine in mind: a neurotransmitter correlate of
consciousness? Trends Neurosci 1999;22:273–80.
[155] Lebert F, Pasquier F, Souliez L, et al. Tacrine efficacy in Lewy body dementia. Int J Geriatr
Psychiatry 1998;13:516–9.
[156] Wengel SP, Roccaforte WH, Burke WJ. Donepezil improves symptoms of delirium in de-
mentia: implications for future research. J Geriatr Psychiatry Neurol 1998;11:159–61.
[157] Samuel W, Caligiuri M, Galasko D, et al. Better cognitive and psychopathologic response
to donepezil in patients prospectively diagnosed as dementia with Lewy bodies: a prelimi-
nary study. Int J Geriatr Psychiatry 2000;15:794–802.
[158] Maclean LE, Collins CC, Byrne EJ. Dementia with Lewy bodies treated with rivastigmine:
effects on cognition, neuropsychiatric symptoms, and sleep. Int Psychogeriatr 2001;13:
277–88.
[159] Bergman J, Lerner V. Successful use of donepezil for the treatment of psychotic symptoms
in patients with Parkinson’s disease. Clin Neuropharmacol 2002;25:107–10.
[160] Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly.
Jama 1990;263:1097–101.
[161] Moore DP. Rapid treatment of delirium in critically ill patients. Am J Psychiatry 1977;134:
1431–2.
[162] Allen RL, Walker Z, D’Ath PJ, et al. Risperidone for psychotic and behavioural symptoms
in Lewy body dementia. Lancet 1995;346:185.
[163] Miller CH, Mohr F, Umbricht D, et al. The prevalence of acute extrapyramidal signs and
symptoms in patients treated with clozapine, risperidone, and conventional antipsychotics.
J Clin Psychiatry 1998;59:69–75.
[164] Burke WJ, Pfeiffer RF, McComb RD. Neuroleptic sensitivity to clozapine in dementia with
Lewy bodies. J Neuropsychiatry Clin Neurosci 1998;10:227–9.
[165] Sechi G, Agnetti V, Masuri R, et al. Risperidone, neuroleptic malignant syndrome and
probable dementia with Lewy bodies. Prog Neuropsychopharmacol Biol Psychiatry
2000;24:1043–51.
[166] Rosebush PI, Mazurek MF. Neurologic side effects in neuroleptic-naive patients treated
with haloperidol or risperidone. Neurology 1999;52:782–5.
[167] Piggott MA, Perry EK, Marshall EF, et al. Nigrostriatal dopaminergic activities in demen-
tia with Lewy bodies in relation to neuroleptic sensitivity: comparisons with Parkinson’s
disease. Biol Psychiatry 1998;44:765–74.
[168] Court JA, Piggott MA, Lloyd S, et al. Nicotine binding in human striatum: elevation
in schizophrenia and reductions in dementia with Lewy bodies, Parkinson’s disease
and Alzheimer’s disease and in relation to neuroleptic medication. Neuroscience
2000;98:79–87.
[169] Cummings JL, Street J, Masterman D, et al. Efficacy of olanzapine in the treatment of psy-
chosis in dementia with Lewy bodies. Dementia and Geriatric Cognitive Disorders 2002;13:
67–73.
[170] Aarsland D, Larsen JP, Lim NG, et al. Olanzapine for psychosis in patinets with Par-
kinson’s disease with and without dementia. J of Neuropsy and Clin Neurosc 1999;11:
392–4.
[171] Ellingrod VL, Schultz SK, Ekstam-Smith K, et al. Comparison of risperdone with olanze-
pine in elderly patients with dementia and psychosis. Pharmacotherapy 2002;22:1–5.
[172] Mulsant BH, Gharabawi GM, Bossie CA, et al. Correlates of anticholinergic activity in
patients with dementia and psychosis treated with risperidone or olanzepine. J of Clinical
Psychiatry 2004;65:1708–14.
760 FERMAN & BOEVE

[173] Ballard C, Margallo-Lana M, Juszczak E, Swann DS, et al. Quetiapine and rivastigmine
and cognitive decline in Alzheimer’s disease: randomised double blind placebo controlled
trial. BMJ 2005;333:857–8.
[174] Juncos JL, Roberts VJ, Evatt ML, et al. Quetiapine improves psychotic symptoms and cog-
nition in Parkinson’s disease. Movement Disorders 2004;19:29–35.
[175] Morrison CE, Borod JC, Brin MF, et al. Effects of levodopa on cognitive functioning in
moderate-to-severe Parkinson’s disease (MSPD). J Neural Transm 2004;111:1333–41.
[176] Kulisevsky J, Garcia-Sanchez C, Berthier ML, et al. Chronic effects of dopaminergic
replacement on cognitive function in Parkinson’s disease: a two-year follow-up study of
previously untreated patients. Movement Disorders 2000;15:613–26.
[177] Bedard MA, Pillon B, Dubois B, et al. Acute and long-term administration of anticholin-
ergics in Parkinson’s disease: specific effects on the subcortico-frontal syndrome. Brain
Cogn 1999;40:289–313.
[178] McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies:
a randomised, double-blind, placebo-controlled international study. Lancet 2000;356:
2031–6.
[179] Kaufer DI, Catt KE, Lopez OL, et al. Dementia with Lewy bodies: response of delirium-
like features to donepezil. Neurology 1998;51:1512.
[180] Wilcock GK, Scott MI. Tacrine for senile dementia of Alzheimer’s or Lewy body type.
Lancet 1994;344:544.
[181] Levy R, Eagger S, Griffiths M, et al. Lewy bodies and response to tacrine in Alzheimer’s
disease. Lancet 1994;343:176.
[182] Grace J, Daniel S, Stevens T, et al. Long term use of rivastigmine in patients with dementia
with Lewy bodies: an open-label trials. Int Psychogeriatr 2001;13:199–205.
[183] Bosboom JL, Stoffers D, Wolters ECh. Cognitive dysfunction and dementia in Parkinson’s
disease. J of Neural Transm 2004;111:1303–15.
[184] Minett TS, Thomas A, Wilkinson LM, et al. What happens when donepezil is suddently
withdrawn? An open label trial in dementia with Lewy bodies and Parkinson’s disease
with dementia. International J of Geriatric Psychiatry 2003;18:988–93.
[185] Thomas AJ, Burn DJ, Rowan EN, et al. A comparison of the efficacy of donepezil in Par-
kison’s’disease with dementia and dementia with Lewy bodies. Int J Geriatr Psychiatry
2005;20:938–44.
[186] Cummings J. Reconsidering diagnostic criteria for dementia with Lewy bodies. Highlights
from the Third International Workshop on Dementia with Lewy bodies and Parkinson’s
disease dementia, September 17–20, 2003, Newcastle upon Tyne, United Kingdom. Rev
Neurol Dis 2004;1(1):31–4.
[187] Boeve B, Silber M, Ferman TJ, et al. Current management of sleep disturbances in dementia.
Curr Neurol Neurosci Rep 2001;2:169–77.
[188] Boeve B, Silber M, Ferman T. Melatonin for treatment of REM sleep behavior disorder in
neurologic disorders: results in 14 patients. Sleep med 2003;4:281–4.
[189] Carlson D, Fleming K, Smith GE, et al. Management of dementia-related behavioral dis-
turbances: a non-pharmacological approach. Mayo Clin Proc 1995;70:1108–15.
[190] Haupt M, Karger A, Janner M. Improvement of agitation and anxiety in demented patients
after psychoeducative group intervention with their caregivers. International J of Geriatric
Psychiatry 2000;15:1125–9.
[191] Zarit SH, Stephens MA, Townsend A, et al. Stress reduction for family caregivers: effect of
adult day care use. J Gerontol 1998;53:S267–77.