Mild cognitive impairment associated with limbic and - Brain

BRAINA JOURNAL OF NEUROLOGY

Mild cognitive impairment associated withlimbic and neocortical lewy body disease:a clinicopathological studyJennifer Molano,1 Bradley Boeve,1 Tanis Ferman,2 Glenn Smith,2 Joseph Parisi,1,3

Dennis Dickson,4 David Knopman,1 Neill Graff-Radford,1 Yonas Geda,2 John Lucas,2

Kejal Kantarci,5 Maria Shiung,5 Clifford Jack,5 Michael Silber,1 V. Shane Pankratz6 andRonald Petersen1,6

1 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, and Jacksonville, FL 32224, USA

2 Psychology and Psychiatry, Mayo Clinic College of Medicine, Rochester, MN 55905, and Jacksonville, FL 32224, USA

3 Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, and Jacksonville, FL 32224, USA

4 Neuropathology Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, and Jacksonville, FL 32224, USA

5 Diagnostic Radiology, Mayo Clinic College of Medicine, Rochester, MN 55905, and Jacksonville, FL 32224, USA

6 Health Science Research, Mayo Clinic College of Medicine, Rochester, MN 55905, and Jacksonville, FL 32224, USA

Correspondence to: Bradley F. Boeve, MD,

Mayo Clinic,

200 First Street SW,

Rochester, MN 55905,

USA

E-mail: [email protected]

There are little data on the relationship between Lewy body disease and mild cognitive impairment syndromes. The Mayo Clinic

aging and dementia databases in Rochester, Minnesota, and Jacksonville, Florida were queried for cases who were diagnosed

with mild cognitive impairment between 1 January 1996 and 30 April 2008, were prospectively followed and were subsequently

found to have autopsy-proven Lewy body disease. The presence of rapid eye movement sleep behaviour disorder was specif-

ically assessed. Mild cognitive impairment subtypes were determined by clinical impression and neuropsychological profiles,

based on prospective operational criteria. The diagnosis of clinically probable dementia with Lewy bodies was based on the

2005 McKeith criteria. Hippocampal volumes, rate of hippocampal atrophy, and proton magnetic resonance spectroscopy were

assessed on available magnetic resonance imaging and spectroscopy scans. Eight subjects were identified; six were male. Seven

developed dementia with Lewy bodies prior to death; one died characterized as mild cognitive impairment. The number of cases

and median age of onset (range) for specific features were: seven with rapid eye movement sleep behaviour disorder—60 years

(27–91 years), eight with cognitive symptoms—69 years (62–89 years), eight with mild cognitive impairment—70.5 years

(66–91 years), eight with parkinsonism symptoms—71 years (66–92 years), six with visual hallucinations—72 years (64–90

years), seven with dementia—75 years (67–92 years), six with fluctuations in cognition and/or arousal—76 years (68–92 years)

and eight dead—76 years (71–94 years). Rapid eye movement sleep behaviour disorder preceded cognitive symptom onset in six

cases by a median of 10 years (2–47 years) and mild cognitive impairment diagnosis by a median of 12 years (3–48 years). The

mild cognitive impairment subtypes represented include: two with single domain non-amnestic mild cognitive impairment, three

with multi-domain non-amnestic mild cognitive impairment, and three with multi-domain amnestic mild cognitive impairment.

The cognitive domains most frequently affected were attention and executive functioning, and visuospatial functioning.

Hippocampal volumes and the rate of hippocampal atrophy were, on average, within the normal range in the three cases

who underwent magnetic resonance imaging, and the choline/creatine ratio was elevated in the two cases who underwent

doi:10.1093/brain/awp280 Brain 2010: 133; 540–556 | 540

Received April 26, 2009. Revised August 26, 2009. Accepted September 13, 2009. Advance Access publication November 4, 2009

� 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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proton magnetic resonance spectroscopy when they were diagnosed as mild cognitive impairment. On autopsy, six had neo-

cortical-predominant Lewy body disease and two had limbic-predominant Lewy body disease; only one had coexisting high-

likelihood Alzheimer’s disease. These findings indicate that among Lewy body disease cases that pass through a mild cognitive

impairment stage, any cognitive pattern or mild cognitive subtype is possible, with the attention/executive and visuospatial

domains most frequently impaired. Hippocampal volume and proton magnetic resonance spectroscopy data were consistent with

recent data in dementia with Lewy bodies. All cases with rapid eye movement sleep behaviour disorder and mild cognitive

impairment were eventually shown to have autopsy-proven Lewy body disease, indicating that rapid eye movement sleep

behaviour disorder plus mild cognitive impairment probably reflects brainstem and cerebral Lewy body disease.

Keywords: mild cognitive impairment; dementia; dementia with Lewy bodies; Lewy body disease; neuropathology

Abbreviations: DRS = Mattis Dementia Rating Scale; REM = rapid eye movement

IntroductionMild cognitive impairment refers to the intermediate state between

normal ageing and dementia that was initially conceptualized

as a prodrome of Alzheimer’s disease. Subsequently, it has

been recognized that there are both amnestic and non-amnestic

forms of mild cognitive impairment. Patients with non-amnestic

mild cognitive impairment have deficits in the domains of language,

attention/executive functioning or visuospatial functioning. If mild

cognitive impairment is an intermediate state between normal

ageing and dementia, those with dementia due to other neuro-

degenerative aetiologies are also likely to pass through an mild

cognitive impairment state.

Dementia with Lewy bodies is a syndrome characterized by

dementia, plus at least two of the following features: (i) recurrent,

fully formed visual hallucinations; (ii) spontaneous parkinsonism;

and (iii) fluctuations in cognition and/or arousal (McKeith et al.,

2005). Neuropsychological data have shown that those with

dementia with Lewy bodies typically have impaired attention/

executive functioning and visuospatial skills (Salmon et al., 1996;

Ferman et al., 1999, 2002, 2006; Mori et al., 2000). Language

skills such as confrontation naming are often preserved (Ferman

et al., 2006), while performance on measures of learning and

memory is more variable. We hypothesized that patients with

a non-amnestic form of mild cognitive impairment, with impair-

ment in attention/executive functioning and/or visuospatial skills

would evolve to have other clinical features of dementia of Lewy

bodies and ultimately Lewy body disease on autopsy.

Rapid eye movement (REM) sleep behaviour disorder is a para-

somnia that is characterized by loss of normal skeletal muscle

atonia during REM sleep, with prominent motor activity and

dreaming (Schenck et al., 1986; Olson et al., 2000). REM sleep

behaviour disorder has been associated with synucleinopathies

such as dementia with Lewy bodies, Parkinson’s disease, multiple

system atrophy and pure autonomic failure, but is far less com-

monly associated with non-synucleinopathy disorders (Boeve

et al., 2001, 2003, 2007b; Iranzo et al., 2006; Postuma et al.,

2009). REM sleep behaviour disorder often precedes the onset of

cognitive impairment and/or parkinsonism by years or even dec-

ades (Schenck and Mahowald, 2002; Iranzo et al., 2006; Boeve

et al., 2007b; Postuma et al., 2009). We further hypothesized

that patients with mild cognitive impairment and REM sleep

behaviour disorder, regardless of the mild cognitive impairment

subtype, would represent prodromal Lewy body disease.

We characterized the clinical features, neuropsychological

profiles and structural neuroimaging patterns of those who were

diagnosed with mild cognitive impairment (any subtype), were

prospectively followed, and were subsequently found to have

autopsy-proven limbic or neocortical Lewy body disease.

Materials and methodsSubjects were identified through the combined databases of the

Alzheimer’s Disease Research Center at Mayo Clinic Rochester and

Mayo Clinic Jacksonville and the Alzheimer’s Disease Patient Registry

at Mayo Clinic Rochester. Both of these programmes are approved by

the Mayo Foundation Institutional Review Board. Written consent for

participation was provided by the subjects or their proxies. The data-

bases were queried to identify patients who were diagnosed with mild

cognitive impairment between 1 January 1996 and 30 April 2008,

were prospectively followed, and were subsequently found to have

autopsy-proven limbic- or neocortical-predominant Lewy body disease.

The clinical, neuropsychological, neuroimaging and neuropathological

features were analysed.

Clinical assessmentPatients were initially evaluated using a standardized clinical protocol

and followed prospectively. The same research protocol was com-

pleted at 12–15 month intervals, with additional evaluations in

between research assessments depending on active clinical issues. A

behavioural neurologist (B.B., D.K., R.P., N.G.R. or the late

Emre Kokmen) evaluated each patient by obtaining a medical history

from the patient and their corroborating sources and by performing a

complete neurological examination (Members of the Department of

Neurology, 1998). Features of parkinsonism (e.g. tremor, rigidity, bra-

dykinesia, postural instability, shuffling gait, masked facies, etc.) were

noted when present, and Parkinson’s disease was diagnosed if a

patient fulfilled United Kingdom Brain Bank criteria for the disorder

(Hughes et al., 1992). The Clinical Dementia Rating scale (Morris,

1993), Folstein Mini-Mental State Exam (Folstein et al., 1975),

and Kokmen Short Test of Mental Status (Kokmen et al., 1991;

Tang-Wai et al., 2003), were completed on all cases. The Mayo

Fluctuations Scale—a validated operationalized measure for determin-

ing the presence of fluctuations in cognition and/or arousal (Ferman

et al., 2004)—was completed by the informants. This scale has been

MCI-Lewy body disease Brain 2010: 133; 540–556 | 541

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used in the standard research protocol at our institution since it was

developed in 1999. Affirmative answers on at least three out of the

four questions were considered necessary for the presence of fluctua-

tions. All patients underwent a neuropsychological evaluation assessing

for memory, language, attention/executive functioning and visuospa-

tial functioning. Structural neuroimaging of the brain with magnetic

resonance imaging was performed in a subset of cases that were

having data acquired for volumetric magnetic resonance analyses

and magnetic resonance spectroscopic analyses.

Neuropsychological assessmentTesting included assessment of global cognitive functioning [Mattis

Dementia Rating Scale (DRS) (Mattis, 1988)]; learning and memory

[percent retention on immediate and delayed recall on the Logical

Memory subtest of the Weschler Memory Scale-Revised (Wechsler,

1987), learning over trials and percent retention on the Rey-

Auditory Verbal Learning Test (Rey, 1964)]; language functioning

[Boston Naming Test (Kaplan et al., 1978), Controlled Oral Word

Association Test (Benton and Hamsher, 1978), and category/semantic

fluency (animals, fruit, vegetables)]; attention/executive functioning

[Trail Making Test parts A and B (Reitan, 1958), and Digit Span of

the Wechsler Adult Intelligence Scale-Revised (Wechsler, 1981)]; and

visuospatial/perceptual functioning [Block Design and Picture

Completion subtests of the Wechsler Adult Intelligence Scale-

Revised, and copy of Rey-Osterreith Complex Figure (Rey, 1941;

Osterrieth, 1944)]. Additional tests were also administered and used

by the neuropsychologists in their assessments of individual patients.

Mayo Older American Normative Studies norms were used to deter-

mine scaled scores for these tests, in which 10 represents the mean

and the standard deviation is 3 (Ivnik et al., 1992, 1996, 1997; Lucas

et al., 1998a, b). Therefore, a Mayo Older American Normative

Studies scaled score of 7 is 1 SD below the mean and 4 is 2 SDs

below the mean.

Neuroimaging examinationsThree of the cases (Cases 3, 7 and 8) had MRI and two had1H-magnetic resonance spectroscopy (Cases 3 and 7) examinations

performed at the time they were diagnosed with mild cognitive

impairment. MRI was performed using a General Electric scanner at

1.5 Tesla, and images of the brain were obtained in the sagittal

(T1-weighted), axial (proton-density, T2-weighted and fluid attenua-

tion inversion recovery), and coronal (T1-weighted) planes.

Hippocampal volume measurements were derived from a

T1-weighted 3D volumetric spoiled gradient-recalled echo sequence

in the coronal plane by manually tracing their anatomic boundaries

for each image slice sequentially from posterior to anterior. Volumes

were adjusted for age, gender and head size; normal percentiles are

referred to as W scores, using age- and gender-specific normal per-

centiles based on a previous study (Jack et al., 2000). A value of zero

corresponds to the 50th percentile, +1.64 corresponds to the 95th

percentile, –1.64 corresponds to the 5th percentile among normal

subjects. The rate of change in hippocampal volumes was calculated

as the annualized percent change in hippocampal volume, which was

computed as the volume in cubic millimeters of scan 2 minus that of

scan 1 divided by volume on scan 1, divided by the duration (in years)

between the two scans (�100).

T1-weighted images in the sagittal plane were used for localizing the1H-magnetic resonance spectroscopy voxel. Point resolved spectros-

copy pulse sequence with repetition time/echo time = 2000/30 ms

was used for the examinations. An 8 cm3 (2 cm�2 cm�2cm) voxel,

prescribed on a mid-sagittal T1-weighted image, included right and left

posterior cingulate gyri and inferior precunei (Kantarci et al., 2000).

We quantified metabolite intensities by referencing to an internal stan-

dard, the creatine peak, to correct for coil loading, relaxation times

and inter subject differences in atrophy (i.e. partial volume averaging

of the magnetic resonance spectroscopy voxel).

Consensus diagnosisWeekly consensus meetings were held to review each patient’s

diagnosis. All information, including neurological, neuropsychological,

laboratory and imaging sources, were used. Subjects were diagnosed

as having normal cognition, mild cognitive impairment using published

criteria (Petersen, 2004), or dementia according to the Diagnostic and

Statistical Manual of Mental Disorders, revised third edition (1987).

The specific dementia diagnosis for Alzheimer’s disease, dementia

with Lewy bodies, frontotemporal dementia and other dementia

syndromes were made based on established criteria (McKhann et al.,

1984; Neary et al., 1998; McKeith et al., 2005).

For the diagnosis of mild cognitive impairment, subjects are required

to meet the following criteria: (i) a cognitive complaint, preferably

corroborated by an informant; (ii) essentially normal activities of

daily living; (iii) normal general cognitive functioning; (iv) abnormal

performance in one or more cognitive domains; and (v) not demented.

Impairment in cognitive domains was determined by neuropsycholo-

gical test scores; scores one SD below the mean (i.e. a Mayo Older

Adult Normative Scale Standard Score 47) were considered borderline

to clearly abnormal, but clinical impression based on these and other

tests scores and all other available information were also considered, as

is routine in clinical practice. Some tests can be abnormal and reflect

abnormalities in one and/or another domain (e.g. impaired perfor-

mance on the Controlled Oral Word Association Test can be due to

language and/or attention/executive dysfunction), again underscoring

the need for the clinical impression to be based on all data. Based on

the domains which were impaired, subjects were further classified as

having amnestic mild cognitive impairment, multiple-domain amnestic

mild cognitive impairment, single-domain non-amnestic mild cognitive

impairment and multiple-domain non-amnestic mild cognitive

impairment.

Neuropathologic assessmentAll cases underwent a standardized neuropathologic assessment, with

evaluation of gross and microscopic findings and analysis of Alzheimer-

type pathology, Lewy body pathology, cerebrovascular pathology and

concomitant pathology according to established and published guide-

lines (Braak and Braak, 1997; Fujishiro et al., 2008). Sections were

taken from six regions of the cortex, hippocampus, amygdala, basal

ganglia, thalamus, midbrain, pons, medulla and cerebellum. Counts of

senile plaques and neurofibrillary tangles were made in six cortical

sections, four sectors of the hippocampus, two regions of the amyg-

dala, and the basal nucleus of Meynert with thioflavin-S fluorescent

and/or Bielschowsky microscopy. The presence of amyloid angiopathy

was assessed. Senile plaques and neurofibrillary tangles were counted

at �100 and �400, respectively, in cortex, hippocampus and amyg-

dale. A Braak neurofibrillary tangle stage (Braak and Braak, 1991) was

assigned to all cases based on the distribution of neurofibrillary tangles

with thioflavin-S fluorescent microscopy, as previously described (Togo

et al., 2002; Josephs et al., 2004). The severity of senile plaque

pathology was also assessed using the Consortium to Establish a

Registry for Alzheimer Disease guidelines (Mirra et al., 1991). All

cases underwent immunostaining with a monoclonal antibody to

542 | Brain 2010: 133; 540–556 J. Molano et al.

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phospho-tau (CP13 [24]; Peter Davies, Albert Einstein College of

Medicine, Bronx, NY) and a polyclonal antibody to �-synuclein

(Gwinn-Hardy et al., 2000) using immunostaining with a Dako

Autostainer. The subtypes of Lewy body pathology (i.e. brainstem,

limbic/transitional, or neocortical/diffuse) were determined based on

Lewy body counts in five cortical sections and the amygdala.

Semiquantitative grading of Lewy body pathology and assignment of

Lewy body type were also determined according to recommendations

from the Third Consortium of Dementia with Lewy Bodies (McKeith

et al., 2005). The two methods gave similar results. The Lewy body

density was determined at �200 magnification from the following

regions: middle frontal (Brodmann area 46), superior temporal

(Brodmann area 38), inferior parietal (Brodmann area 39), anterior

cingulate (Brodmann area 24) and parahippocampal gyri (Brodmann

area 35). The recently published and validated Dementia with Lewy

Bodies Consensus criteria for the diagnosis of Lewy body disease was

used to characterize cases (Fujishiro et al., 2008).

Cerebrovascular pathology was assessed in all cases using

a semiquantitative scale similar to that previously reported (Jellinger

and Attems, 2003). Briefly, cases with no cerebrovascular lesions were

scored 0, those with minimal cerebrovascular pathology (including one

to two small lacunes, mild cerebral amyloid angiopathy or mild leu-

koencephalopathy) were scored 1, those with moderate lesions

(including more than 2 lacunes, severe cerebral amyloid angiopathy,

or diffuse leukoencephalopathy) were scored as 2, and those with

marked cerebrovascular pathology (including old cortical infarcts, mul-

tiple microinfarcts or hippocampal sclerosis) were scored 3.

Concomitant pathologies were noted when present. Argyrophilic

grains, neuronal threads, oligodendroglial coiled bodies, astrocytic pla-

ques and globose neurofibrillary tangles were assessed using monoclo-

nal antibody to phospho-tau (CP13). Glial intracytoplasmic inclusions

were assessed by �-synuclein immunohistochemistry.

The final neuropathologic diagnosis was made according to the

Dementia with Lewy Body Consensus criteria for the diagnosis

of Lewy body disease (Fujishiro et al., 2008; McKeith et al., 2005)

and the National Institute on Aging-Reagan criteria for Alzheimer’s

disease (Consensus recommendations for the post mortem diagnosis

of Alzheimer’s disease, 1997).

Results

Clinical and neuropsychological dataEight patients were identified. All had an education level of 10

years or greater, and six of the patients were male. The demo-

graphic and clinical features are indicated in Table 1, and the

neuropathologic findings are shown in Table 2. Narrative descrip-

tions of each patient’s clinical course are in Supplementary Text

E1, and the longitudinal clinical data and neuropsychological

profile of impairment at the time of mild cognitive impairment

diagnosis for each patient are shown in the Figures 1–8.

Neuroimaging dataQuantitative neuroimaging data were available in a subset of

cases. In the three cases who underwent serial magnetic reso-

nance imaging exams, baseline hippocampal volumes at the time

of mild cognitive impairment diagnosis and the rate of hippocam-

pal atrophy at follow-up were on average within the range of the

cognitively normal subjects, when compared to previously

published data (Jack et al., 2000). In two of the cases who under-

went baseline 1H-magnetic resonance spectroscopy exams, the

choline/creatine ratio and myoinositol/creatine ratio were elevated

in both cases, and the n-acetyl aspartate/creatine ratio was

decreased in one of the cases compared to previously published

data (Kantarci et al., 2000).

Summary of longitudinalante-mortem dataSeven patients’ condition declined and they experienced other

symptoms and received a diagnosis of clinically probable dementia

with Lewy bodies prior to death; one patient died while classified

as mild cognitive impairment. All patients had a Clinical Dementia

Rating score of 0.5 at the time of the mild cognitive impairment

diagnosis. The median age of cognitive symptoms onset was 69

years (range 61–89 years), mild cognitive impairment diagnosis

was 70.5 years (range 66–91 years), and dementia onset was

78 (range 67–90 years), with a median Clinical Dementia Rating

score of 2 (range 1–3). Mini-Mental State Examination data were

available for all patients when initially diagnosed with mild

cognitive impairment; the median Mini-Mental State Examination

score was 28 (range 23–29).The median number of years between

the onset of cognitive symptoms and dementia was 4 years (range

2–6 years) and between the onset of mild cognitive impairment and

dementia was 2.5 years (range 1–5 years). The median number of

years from a diagnosis of mild cognitive impairment onset to death

was 6.5 years (range 5–9 years). Among the seven patients who

developed dementia, the median number of years from dementia

onset to death was 3 years (range 0–4 years).

In this cohort, both amnestic mild cognitive impairment and

non-amnestic mild cognitive impairment subtypes were

represented, including three with multi-domain amnestic mild

cognitive impairment, three with multi-domain non-amnestic

mild cognitive impairment and two with single-domain non-

amnestic mild cognitive impairment. Attention/executive function-

ing (n = 6) and visuospatial functioning (n = 6) were the cognitive

domains most frequently affected.

Seven patients had REM sleep behaviour disorder with a median

onset age of 60 years (range 27–91 years). Polysomnogram was

performed in four cases, in whom REM sleep behaviour disorder

was confirmed in all. The onset of REM sleep behaviour disorder

features preceded onset of cognitive symptoms in six patients by

a median of 10 years (range 2–47 years) and mild cognitive

impairment diagnosis by of 12 years (range 3–48 years). One

patient developed REM sleep behaviour disorder 2 years after

the onset of cognitive symptoms and at the same time as the

diagnosis of mild cognitive impairment.

Six patients had visual hallucinations, with a median onset age

of 72 years (range 64–90 years). Among these patients, five

developed hallucinations at a median of 3 years after the onset

of cognitive symptoms (range 1–4 years); one patient developed

hallucinations 3 years prior to the onset of cognitive impairment.

Seven patients had parkinsonism, with a median onset age of 71

years (range 71–92 years). In five patients, parkinsonism occurred


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at a median of 3 years after onset of cognitive symptoms (range

2–5 years). Two patients developed parkinsonism at the same time

as cognitive symptoms onset, and one patient developed

parkinsonism 1 year prior to onset of cognitive symptoms. None

of the patients fulfilled criteria for the diagnosis of Parkinson’s

disease prior to the onset of dementia.

Fluctuations were classified as present in six patients based on

Mayo Fluctuations Scale data, with a median onset age of 76 years

(range 68–92 years). Fluctuations evolved after onset of cognitive

symptoms in all six cases, at a median of 4.5 years (range

3–6 years). Mayo Fluctuations Scale data were not available in

one patient who died prior to the development of the scale;

however, the clinical notes did not suggest the presence of

fluctuations.

All three core features of dementia with Lewy bodies eventually

developed in five patients. Both patients with two core features

had spontaneous parkinsonism. The patient who died with a clas-

sification of mild cognitive impairment had parkinsonism and REM

sleep behaviour disorder, but no hallucinations or fluctuations.

Visual hallucinations and fluctuations tended to occur after the

onset of cognitive impairment at a median of 3 and 4.5 years,

respectively. Parkinsonism tended to manifest after the onset of

cognitive symptoms, though also did occur before and at the same

time as the cognitive symptoms onset in a few patients. Seven

patients had clinical evidence of REM sleep behaviour disorder,

with six patients having dream enactment behaviour preceding

the onset of mild cognitive impairment.

Neuropathological dataThe neuropathological data is shown in Table 2. Six patients had a

pathological diagnosis of neocortical Lewy body disease, and two

patients had limbic Lewy body disease. Concomitant pathology

was present in five patients; one met high likelihood National

Institute of Aging-Reagan criteria for Alzheimer’s disease, another

had agyrophilic grain disease, another had mild cerebrovascular

disease (none had cerebrovascular pathology beyond lacunes,

mild amyloid angiopathy, or a small focal infarct in the caudate

head), and three had pathological ageing with diffuse plaques but

sparse or no neuritic plaques.

Discussion

The mild cognitive impairmentconstruct in dementia with Lewybodies/Lewy body diseaseOur principal findings were that (i) Lewy body disease can

evolve through a mild cognitive impairment intermediate state;

(ii) amnestic or non-amnestic mild cognitive impairment subtypes

can evolve into dementia with Lewy bodies; and (iii) mild cognitive

impairment subtypes with impairment in attention-executive func-

tion and/or visuospatial functioning may be particularly suggestive

of underlying Lewy body disease.Tab

le1

Cli

nic

alfe

ature

sof

eight

pat

ients

wit

hm

ild

cognit

ive

impai

rmen

t�su

bse

quen

tdem

enti

aas

soci

ated

wit

hLe

wy

body

dis

ease

pat

holo

gy

Cas

eSe

xEd

uca

tional

leve

lin

year

s

Age

of

RB

Donse

tin

year

s

Age

of

cognit

ive

sym

pto

monse

tin

year

s

Age

of

MC

Idia

gnosi

sin

year

s

Age

of

par

kinso

nis

monse

tin

year

s

Age

of

VH

onse

tin

year

s

Fluct

uat

ions

bas

edon

MFS

,an

donse

tin

year

s

MC

Isu

bty

pe

and

spec

ific

cognit

ive

dom

ains

of

impai

rmen

tA

ge

atco

nve

rsio

nfr

om

MC

Ito

dem

enti

ain

year

s

Age

of

dea

thin

year

s

1M

16

61

66

70

71

–N

om

d-M

CI-

na

Att

ention/v

isuosp

atia

l–

71

2M

10

83

85

86

84

88

Yes

90

sd-M

CI-

na

Att

ention

88

90

3M

14

57

PSG

+69

70

69

72

Yes

74

sd-M

CI-

na

Att

ention

75

76

4F

13

91

PSG

+89

91

92

90

Yes

92

md-M

CI-

na

Att

ention/v

isuosp

atia

l92

94

5M

16

27

PSG

+74

75

74

–Y

es78

md-M

CI-

na

Att

ention/v

isuosp

atia

l77

81

6M

12

51

62

66

66

66

Yes

68

md-M

CI+

aM

emory

/att

ention/v

isuosp

atia

l67

71

7M

14

60

PSG

+69

71

71

72

Yes

72

md-M

CI+

aM

emory

/lan

guag

e/vi

suosp

atia

l73

76

8F

12

–67

67

69

64

No

(no

MFS

)m

d-M

CI+

aM

emory

/lan

guag

e/vi

suosp

atia

l69

73

M=

mal

e;F

=fe

mal

e;R

BD

=R

EMsl

eep

beh

avio

ur

dis

ord

er;

PSG

+=

poly

som

nogra

m-p

rove

nR

BD

;M

CI=

mild

cognitiv

eim

pai

rmen

t(a

=am

nes

tic;

na

=nonam

nes

tic;

sd=

single

dom

ain;

md

=m

ultip

ledom

ain);

VH

=vi

sual

hal

luci

nat

ions;

MFS

=M

ayo

Fluct

uat

ions

Scal

e.


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Figure 1 Case 1. Clinical features (top): The evolution of clinical features according to age is shown in the top schematic, with the

evaluation number sequence and diagnosis (e.g. mild cognitive impairment, dementia with Lewy bodies) or event (e.g. death) also

shown. The onset ages (in years) of features for this patient were: REM sleep behaviour disorder (R)—61; cognitive changes (C)—65;

parkinsonism (P)—70; and death—71. He was diagnosed with mild cognitive impairment at evaluation 1 at age 70 years. Autopsy

showed neocortical-predominant Lewy body disease (N-LBD). Neuropsychological profile at mild cognitive impairment diagnosis

(bottom): The patient’s performance on key tests in the neuropsychological battery are shown graphically, with performance on each

test displayed using the Mayo Older American Normative Studies Standard Score (MOANS SS) reference (mean is 10, 1 SD is 3). The

impairment on tests assessing attention/executive functioning (Auditory Verbal Learning Test learning over trials was viewed borderline

impaired and interpreted as borderline learning impairment, which along with poor performance on Trail Making Test—B, indicated

impaired attention/concentration) and visuospatial functioning along with the patient’s cognitive symptoms led to the consensus

diagnosis of mild cognitive impairment, specifically multiple domain (attention/executive and visuospatial) nonamnestic mild cognitive

impairment. AVLT = Auditory Verbal Learning Test (LOT = learning over trials and PR = percent retention); BNT = Boston Naming Test;

CAT FLU = category/semantic fluency; COWAT = Controlled Oral Word Association Test; DRS = Mattis Dementia Rating Scale; Rey-

O = Rey-Osterreith Complex Figure; TMT = Trail Making Test; WAIS-R = Wechsler Adult Intelligence Scale-Revised (DS = digit span,

BD = block design and PC = picture completion); WMS-R = Wechsler Memory Scale-Revised (LM = logical memory).

Table 2 Specific neuropathologic findings in eight patients with mild cognitive impairment� subsequent dementiaassociated with Lewy body disease pathology

Case LBD pathologytype

CERAD neuriticplaque score

Braak stageof NFTpathology

NIA-reagan—likelihoodrating of AD

CDLB criteria—likelihoodRating of DLB

Cerebro-vascularscore

Other findings Final neuropathologicdiagnosis

1 Neocortical/diffuse Sparse III Low High 1 Diffuse plaques Neocortical LBD +Pathological aging

2 Neocortical/diffuse Frequent IV High Intermediate 0 Neocortical LBD +AD (high)

3 Limbic/transitional Sparse II Low High 0 Limbic LBD

4 Limbic/transitional Possible II Low High 1 Diffuse plaquesOld infarcts

Limbic LBD + Pathologicaging + Mildcerebrovascular disease

5 Neocortical/diffuse Sparse III Low High 0 Diffuse plaques Neocortical LBD +Pathological aging

6 Neocortical/diffuse Sparse V Low High 1 Neocortical LBD

7 Neocortical/diffuse – I Low High 1 Neocortical LBD

8 Neocortical/diffuse Frequent I Low High 1 Argyrophilicgrains

Neocortical LBD + AGD

AGD = argyrophilic grain disease; CDLB = Consortium on Dementia with Lewy Bodies; CERAD = Consortium to Establish a Registry in Alzheimer’s Disease;NFT = neurofibrillary tangle; NIA = National Institute on Aging; AD = Alzheimer’s disease; LBD = Lewy body disease. See text for details regarding cerebrovascular score.


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Results from previous research have shown that those who

died with an amnestic mild cognitive impairment subtype

(n = 15) may have some degree of medial temporal lobe changes

in essentially every case (e.g. neurofibrillary tangles, argyrophilic

grain disease, hippocampal sclerosis, etc), with only a few

meeting criteria for fully expressed Alzheimer’s disease (Petersen

et al., 2006). While data in those who evolved from amnestic

mild cognitive impairment to dementia did show that most met

criteria for Alzheimer’s disease (Jicha et al., 2006), a minority of

patients had other pathological diagnoses (note the single case

with Lewy body disease pathology in that series was not included

in the current series of eight cases as she developed dementia

prior to 1996). Three of the patients in our series had an amnes-

tic mild cognitive impairment subtype and Lewy body disease on

autopsy. Though it has been suggested that all cases of amnestic

mild cognitive impairment reflect evolving Alzheimer’s disease

(Morris et al., 2001; Dubois and Albert, 2004; Sarazin

et al., 2007), our findings suggest that the neuropathological

substrate for amnestic mild cognitive impairment is more

heterogeneous.

The cognitive domains most frequently affected in the mild

cognitive impairment of dementia with Lewy bodies were atten-

tion/executive functioning and visuospatial functioning. Moreover,

seven patients had a history of dream enactment behaviour during

sleep, even if it was no longer an active problem. Our experience

suggests that patients with a history of dream enactment

behaviour during sleep who present with attention/executive

and/or visuospatial difficulty despite preserved complex activities

of daily living may represent underlying Lewy body disease.

Indeed, seven of the eight patients were followed longitudinally

and eventually developed a dementia and corresponding core

clinical features of dementia with Lewy bodies.

Several of the subjects in this series were relatively easy to char-

acterize, with clear cognitive complaints that were corroborated by

their informants and neuropsychological features that permitted a

straight-forward determination of which domains were impaired.

However, the neuropsychological features of mild cognitive

impairment associated with Lewy body disease are variable.

Determining which domains are impaired and classifying them

into a specific mild cognitive impairment subtype can be

Figure 2 Case 2. Clinical features (top). The evolution of clinical features according to age is shown in the top schematic, with the


shown. The onset ages (in years) of features for this patient were: REM sleep behaviour disorder (R)—83; parkinsonism (P)—84;

cognitive changes (C)—85; visual hallucinations (VH)—88; fluctuations (F)—90; and death—71. He was diagnosed with mild cognitive

impairment (MCI) at evaluation 1 at age 86, and with dementia with Lewy bodies (DLB) at evaluation 2 at age 88. Autopsy showed

neocortical-predominant Lewy body disease (N-LBD). The encircled ‘D’ represents the timing when donepezil was initiated.

Neuropsychological profile at mild cognitive impairment diagnosis (bottom). The patient’s performance on key tests in the

neuropsychological battery are shown graphically, with performance on each test displayed using the MOANS SS reference (mean is

10, 1 SD is 3). The impairment on tests assessing attention/executive functioning along with the patient’s cognitive symptoms led to

the consensus diagnosis of mild cognitive impairment, specifically single domain (attention/executive) nonamnestic mild cognitive

impairment. Refer to Fig. 1 caption for abbreviations.


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challenging in some patients. Case 3 exemplifies this challenge, as

he repeatedly voiced concerns over his cognitive symptoms and

used notes obsessively, yet his performance on neuropsychological

testing over the initial 4 years of his symptoms was normal or only

mild impaired. Even on testing just prior to the diagnosis of

dementia with Lewy bodies, performance was in the average

range across most tests. To what degree this represents cognitive

fluctuations, or the ability of some patients to ‘rise to the occasion’

and perform better than expected on formal testing despite florid

symptoms and modest functional changes, is unclear. This case

also underscores that not all patients who voice strong cognitive

concerns yet perform normally on neuropsychological testing are

‘worried well’; indeed, this patient had autopsy-proven Lewy body

disease.

We again emphasize the need to incorporate all clinical and

neuropsychological data when making determinations on mild

cognitive impairment diagnoses; following a strict algorithmic

approach to interpreting neuropsychological data does not capture

the complexity of some cases. On the other hand, it may be

argued that the more impaired multi-domain mild cognitive

impairment cases may have been much closer to a diagnosis of

dementia than those with more restricted patterns of cognitive

difficulty. Nonetheless, adamant assurances from family members

that their activities of daily living continued to be unchanged at

the time of the evaluation warranted that a diagnosis of mild

cognitive impairment be made, rather than dementia. In either

case, the family’s observations are critically important when

making a determination of functional status. As noted in the

‘Methods’ section, many of the tests included in the study

cannot be completely compartmentalized to a single cognitive

domain, so poor performance on some tests can be interpreted

as reflecting impairment in more than one domain. Also, we

purposefully gave more weight to delayed recall than immediate

recall of paragraph material, given data that shows delayed recall

is a useful discriminator of Alzheimer’s disease from dementia with

Lewy bodies (Ferman et al., 2006), realizing that results on


evaluation number sequence and diagnosis (e.g. mild cognitive impairment, dementia with Lewy bodies) or event (e.g., death) also


parkinsonism (P)—69; visual hallucinations (VH)—72; fluctuations (F)—74; and death—76. He was diagnosed with questionable mild

cognitive impairment (qMCI) at evaluation 2 at age 70, and more definite mild cognitive impairment (MCI) at evaluation 3 at eval-

uation 72. The core clinical features and marked functional decline led to his diagnosis of dementia with Lewy bodies (DLB) at

evaluation 6 at age 75. Autopsy showed limbic-predominant Lewy body disease (L-LBD). The encircled ‘D’ represents the timing when

donepezil was initiated. Neuropsychological profile at mild cognitive impairment diagnosis (bottom): The patient’s performance on key

tests in the neuropsychological battery are shown graphically, with performance on each test displayed using the MOANS SS reference

(mean is 10, 1 SD is 3). Although there was only modest impairment on tests assessing attention/executive functioning (Trail Making

Test-A and -B), the scores of these measures were clearly lower than on previous evaluations—the patient’s progressive cognitive

symptoms along with the decline on neuropsychological testing led to the consensus diagnosis of mild cognitive impairment, specifically

single domain (attention/executive) nonamnestic mild cognitive impairment. Refer to Fig. 1 caption for abbreviations.


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immediate recall are also similarly different between mild cognitive

impairment associated with Alzheimer’s disease pathology com-

pared with that associated with Lewy body disease pathology

(Jicha et al., 2008).

The neuroimaging features of mildcognitive impairment associated withLewy body diseaseOur observations should be considered preliminary since we had

structural MRI on only three subjects and 1H-magnetic resonance

spectroscopy on only two. Hippocampal volumes and atrophy

rates were within the normal range of values in all three of the

mild cognitive impairment cases. This result is consistent with

results from studies of patients who have dementia with Lewy

bodies, in whom hippocampal volumes are notably larger than

patients with Alzheimer’s disease (Whitwell et al., 2007).1H-magnetic resonance spectroscopy analysis showed significantly

elevated choline/creatine ratios in the two mild cognitive

impairment cases we studied. Dementia with Lewy body patients

are characterized by significantly elevated choline/creatine ratios,

which tend to be higher than the choline/creatine elevation in

patients with Alzheimer’s disease (Kantarci et al., 2004).

Although the number of subjects with 1H-magnetic resonance

imaging was very small, our results in mild cognitive impairment

are consistent with those of dementia with Lewy bodies.

The early characterization andevolution of clinical featuresThis series is small, but a relatively consistent evolution of clinical

features occurred. All but one had REM sleep behaviour disorder

preceding the onset of mild cognitive impairment, and most devel-

oped parkinsonism concurrently or after the onset of their cogni-

tive symptoms. None of these patients fulfilled criteria for

Parkinson’s disease prior to the onset of cognitive symptoms,

nor during their phase of mild cognitive impairment; and hence

none could be considered as representing Parkinson’s disease with

dementia. Visual hallucinations tended to evolve after both



shown. The onset ages (in years) of features for this patient were: cognitive changes (C)—89, REM sleep without atonia noted on

polysomnography (R�)—89, visual hallucinations (VH)—90, REM sleep behaviour disorder (R)—91, parkinsonism (P)—92, fluctuations

(F)—92 and death—94. She was diagnosed with mild cognitive impairment (MCI) at evaluation 2 at age 91 and with dementia with

Lewy bodies (DLB) at evaluation 3 at age 92. Autopsy showed limbic-predominant Lewy body disease (L-LBD). The encircled ‘D’

represents the timing when donepezil was initiated. Neuropsychological profile at mild cognitive impairment diagnosis (bottom): The

patient’s performance on key tests in the neuropsychological battery are shown graphically, with performance on each test displayed

using the MOANS SS reference (mean is 10, 1 SD is 3). The impairment on tests assessing attention/executive functioning and

visuospatial functioning along with the patient’s cognitive symptoms led to the consensus diagnosis of mild cognitive impairment,

specifically multiple domain (attention/executive and visuospatial) nonamnestic mild cognitive impairment. Refer to Fig. 1 caption for

abbreviations


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cognitive impairment and parkinsonism, and fluctuations, at least

as measured by the Mayo Fluctuations Scale (Ferman et al.,

2004), tended to be the final core feature to evolve. Dementia

onset along with two or more of the other core features led to

the diagnosis of clinically probable dementia with Lewy bodies

2–6 years after a diagnosis of mild cognitive impairment was

made. These data are consistent with prior work that has

shown that dementia plus REM sleep behaviour disorder in the

absence of other core features of dementia with Lewy bodies

probably reflects underlying Lewy body disease (Ferman et al.,

2002).

There were exceptions to the evolution of features noted above.

One patient initially experienced recurrent fully formed visual

hallucinations and was thought to have Charles–Bonnet syndrome

due to the absence of any other neurological signs or symptoms.

The hallucinations spontaneously remitted but were followed

3 years later by cognitive decline, with the hallucinations returning

years later. Another patient complained vehemently about his

memory problems, urinary incontinence and erectile dysfunction,

though neuropsychological performance early in his course was

minimally abnormal. And one patient underwent a polysomno-

gram to evaluate obstructive sleep apnoea as a possible con-

tributor to her cognitive symptoms. While REM sleep without

atonia—the electrophysiologic substrate for REM sleep behaviour

disorder—was evident on her polysomnogram, she did not begin

exhibiting recurrent dream enactment behaviour until 2 years

later.

In addition, it may be challenging to elicit a history of fluctua-

tions in a clinical setting. For this study, the Mayo Fluctuations

Scale was used to operationalize a more consistent determination

of fluctuations. Asking whether the patient fluctuates does not

distinguish dementia with Lewy bodies from Alzheimer’s disease

(Ferman et al., 2004). In order to make more definitive general-

izations about the early characteristics and evolution of dementia

with Lewy bodies/Lewy body disease, more subjects need to be

assessed in a comprehensive manner and followed longitudinally

using scales that adequately capture the concept of fluctuations in

cognition and/or arousal.




parkinsonism (P)—74; fluctuations (F)—78; and death—81. He was diagnosed with mild cognitive impairment (MCI) at evaluation 1 at

age 75 years, and with dementia with Lewy bodies (DLB) at evaluation 2 at age 77 years. Autopsy showed neocortical-predominant

Lewy body disease (N-LBD). Neuropsychological profile at mild cognitive impairment diagnosis (bottom): The patient’s performance on

key tests in the neuropsychological battery are shown graphically, with performance on each test displayed using the MOANS SS

reference (mean is 10, 1 SD is 3). The impairment on tests assessing attention/executive functioning (poor performance on the

Controlled Oral Word Association Test can reflect language and/or attention/executive dysfunction, and was interpreted as poor

attention/executive functioning considering the poor performance on the Wechsler Adult Intelligence Scale-Revised (Digit Span) and

visuospatial functioning along with the patient’s cognitive symptoms led to the consensus diagnosis of mild cognitive impairment,

specifically multiple domain (attention/executive and visuospatial) nonamnestic mild cognitive impairment. Refer to Fig. 1 caption for

abbreviations.


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Implications of the presence andevolution of clinical features onthe topography of degenerationin Lewy body diseaseA clinical feature or sign in neurodegenerative disease reflects

sufficient neuronal/glial/neurotransmitter dysfunction in a critical

neuronal network. While some of these features or signs have

known or suspected networks of dysfunction, the underlying

substrate for other features or signs is less clear. Parkinsonism is

most likely to be associated with dopaminergic depletion due

to sufficient degeneration in the nigrostriatal system, and cognitive

impairment is likely to be associated, at least in part, with choli-

nergic depletion due to basal forebrain/limbic system/neocortex

degeneration. It is highly likely that REM sleep behaviour dis-

order reflects sufficient degeneration in brainstem networks,

although the precise structures have yet to be identified in

humans (for review, see Boeve et al., 2007b). The underlying

pathology of visual hallucinations and fluctuations is not well

understood.

The evolution of clinical features must reflect the topography of

degeneration over time. Many of our patients tended to experi-

ence REM sleep behaviour disorder prior to cognitive impairment,

with subsequent development of parkinsonism. This evolution sug-

gests that dysfunction in the pontomedullary circuitry precedes

dysfunction in the basal forebrain, limbic system and neocortical

circuitry. Dysfunction in the nigrostratial circuitry appears to occur

subsequently. One could argue that this evolution of features and

presumed pathophysiologic basis does not support the Braak

staging scheme (Braak et al., 2003, 2004) of Parkinson’s disease

(Burke et al., 2008), yet it may provide some clues into Lewy

body disease pathology of the dementia with Lewy bodies

phenotype.

A ‘bottom-to-top’ or ascending progression of Lewy neurites,

Lewy bodies and neuronal degeneration as proposed in Stages 1–6

of the Braak scheme explains the evolution of features in typical

Parkinson’s disease quite well (Braak et al., 2003, 2004) but is




parkinsonism (P)—66; visual hallucinations (VH)—66; fluctuations (F)—68; and death—71. He was diagnosed with mild cognitive

impairment (MCI) at evaluation 1 at age 66 years. The core clinical features, functional decline neuropsychological profile led to his

diagnosis of dementia with Lewy bodies (DLB) at evaluation 2 at age 67 years. Autopsy showed neocortical-predominant Lewy body

disease (N-LBD). The encircled ‘D’ represents the timing when donepezil was initiated. Neuropsychological profile at mild cognitive

impairment diagnosis (bottom): The patient’s performance on key tests in the neuropsychological battery are shown graphically, with

performance on each test displayed using the MOANS SS reference (mean is 10, 1 SD is 3). The patient’s cognitive symptoms along

with the impairment in the memory, attention/executive and visuospatial domains led to the consensus diagnosis of mild cognitive

impairment, specifically multiple domain amnestic mild cognitive impairment. Note that the low score on the Controlled Oral Word

Association Test was interpreted as reflecting poor set shifting/psychomotor slowing as the Trail Making Test -B was performed so

poorly. Refer to Fig. 1 caption for abbreviations.


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less satisfactory for dementia with Lewy bodies. Findings on many

ancillary tests support the contention that those with idiopathic

REM sleep behaviour disorder (i.e. REM sleep behaviour disorder

not associated with any other neurological symptoms

or disorders) reflects underlying Lewy body disease (Albin et al.,

2000; Eisensehr et al., 2000, 2003; Ferini-Strambi et al., 2004;

Stiasny-Kolster et al., 2005; Caselli et al., 2006; Mazza et al.,

2006; Terzaghi et al., 2008; Postuma et al., 2009) and brain-

stem-predominant Lewy body disease has been documented

in two cases of idiopathic REM sleep behaviour disorder

(Uchiyama et al., 1995, Boeve et al., 2007a), which also supports

this staging system.

A similar evolution of degenerative changes may occur in both

Parkinson’s disease and dementia with Lewy bodies, and the

timing of clinical features may reflect when the critical thresholds

of neuronal network degeneration are reached. Consider a hypo-

thetical example (this example is for illustrative purposes and does

not imply these percent depletions are entirely accurate), in which

an 80% depletion of dopaminergic neurons may be needed to

manifest parkinsonism, and a 50% depletion of cholinergic neu-

rons may be needed to manifest cognitive impairment; it would

be reasonable to suggest a ‘bottom-to-top’ progression of Lewy

body disease pathology could still explain the onset of cognitive

symptoms prior to parkinsonism if both systems are affected grad-

ually over years but the thresholds for the expression of clinical

deficits are different such that cognitive impairment becomes

evident prior to parkinsonism. In other words, the evolution of

features in the dementia with Lewy bodies phenotype does not

necessarily refute the Braak staging system for Lewy body disease

progression.

Another explanation is that, at least in some cases, a ‘top-to-

bottom’ or descending progression of degenerative changes from

the neocortex/limbic system to the nigrostriatal system may better

explain the onset of cognitive impairment prior to parkinsonism in

many dementia with Lewy bodies cases. Or a more patchy and

discontinuous progression could evolve (Frigerio et al., 2009),

with the cholinergic neurotransmitter system reaching a critical

threshold of degenerative changes prior to the nigrostriatal

neuronal networks. This is similar to variations of neurodegenera-

tive disease progression in Alzheimer’s disease. Most cases of

evolving Alzheimer’s disease tend to follow the Braak stages of

neurofibrillary tangle deposition and develop amnestic mild




parkinsonism (P)—71; visual hallucinations (VH)—72; fluctuations (F)—72; and death—76. He was diagnosed with mild cognitive

impairment (MCI) at evaluation 1 at age 71 years. The core clinical features, functional decline and neuropsychological profile led to his

diagnosis of dementia with Lewy bodies (DLB) at evaluation 3 at age 73 years. Autopsy showed neocortical-predominant Lewy body

disease (N-LBD). The encircled ‘G’ represents the timing when galantamine was initiated. Neuropsychological profile at mild cognitive

impairment diagnosis (bottom): The patient’s performance on key tests in the neuropsychological battery are shown graphically, with

performance on each test displayed using the MOANS SS reference (mean is 10, 1 SD is 3). The patient’s cognitive symptoms along

with the impairment most consistently in the memory, language and visuospatial domains led to the consensus diagnosis of mild

cognitive impairment, specifically multiple domain amnestic mild cognitive impairment. Refer to Fig. 1 caption for abbreviations.


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cognitive impairment prior to language, attention/executive and

visuospatial dysfunction; however, there are certainly cases of

pathologically confirmed atypical Alzheimer’s disease that have

presented as focal cortical syndromes such as primary progressive

aphasia (Josephs et al., 2008), corticobasal syndrome (Boeve

et al., 1999), and posterior cortical atrophy (Tang-Wai et al.,

2004). As a result, exceptions to any model of neurodegenerative

disease progression will always exist, and surely Lewy body disease

will evolve in more than one manner.

Further support of the REM sleepbehaviour disorder-synucleinopathyassociationThese cases add to growing evidence that REM sleep behaviour

disorder in the setting of neurodegenerative disease strongly

suggests an underlying synucleinopathy—particularly Lewy body

disease or multiple system atrophy (Boeve et al., 2001, 2003,

2007b; Gagnon et al., 2006; Iranzo et al., 2006; Postuma et al.,

2009). Furthermore, REM sleep behaviour disorder tends to pre-

cede the onset of cognitive and motor features by years or

decades in the synucleinopathies, whereas REM sleep behaviour

disorder typically evolves concurrently or after the onset of motor

and cognitive features in the non-synucleinopathy disorders.

Hence, REM sleep behaviour disorder preceding the motor and

cognitive features of a neurodegenerative disorder may be partic-

ularly specific for synucleinopathies (Boeve et al., 2003, 2007b;

Gagnon et al., 2006; Iranzo et al., 2006; Postuma et al., 2009).

The almost complete absence of REM sleep behaviour disorder

in autopsy-proven cases of amyloidopathies and tauopathies con-

vincingly suggests that selective vulnerability of key brainstem net-

works underlying REM sleep behaviour disorder occurs in the

synucleinopathies. There are virtually no features in clinical neu-

rology which are 100% specific for an aetiological category of

disease, and such degeneration therefore is not specific to a partic-

ular proteinopathy, but rather the same neuronal network(s) is

(are) involved in patients with REM sleep behaviour disorder

associated with any neurodegenerative disorder. Yet the REM

sleep behaviour disorder-synucleinopathy association is strong.

Knowledge about the associated neuronal networks of REM

sleep behaviour disorder in humans may provide insights into

why these and other key structures such as the dorsal motor

nucleus of the vagus, olfactory bulb and substantia nigra pars



shown. The onset ages (in years) of features for this patient were: visual hallucinations (VH)—64; cognitive changes (C)—67;

parkinsonism (P)—69; and death—73. She was diagnosed with mild cognitive impairment (MCI) at evaluation 1 at age 67 years. The

clinical features, functional decline and neuropsychological profile led to his diagnosis of dementia with Lewy bodies (DLB) at evaluation

2 at age 69 years. Autopsy showed neocortical-predominant Lewy body disease (N-LBD). The encircled ‘D’ represents the timing when

donepezil was initiated. Neuropsychological profile at mild cognitive impairment diagnosis (bottom): The patient’s performance on key

tests in the neuropsychological battery are shown graphically, with performance on each test displayed using the MOANS SS reference

(mean is 10, 1 SD is 3). The patient’s cognitive symptoms along with the impairment in the memory, language and visuospatial

domains led to the consensus diagnosis of mild cognitive impairment, specifically multiple domain amnestic mild cognitive impairment.

Refer to Fig. 1 caption for abbreviations.


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reticularis are consistently affected in the synucleinopathy spec-

trum disorders.

Clinical relevance of REM sleepbehaviour disorder in the evaluationof patients with cognitive impairmentREM sleep behaviour disorder was incorporated into the dementia

with Lewy bodies diagnostic criteria and functions as a feature

that increases the diagnostic confidence from one of clinically pos-

sible, to clinically probable dementia with Lewy bodies (McKeith

et al., 2005). This feature has been added as a variable of interest

by the National Alzheimer’s Coordinating Center. Currently, the

presence of recurrent dream enactment behaviour suggests a clin-

ical diagnosis of dementia with Lewy bodies in the setting of

dementia, particularly when REM sleep behaviour disorder can

be verified by polysomnogram. Given that all seven patients

with REM sleep behaviour disorder and mild cognitive impairment

developed Lewy body disease on autopsy, the presence of

Figure 9 Representative coronal magnetic resonance images (top): Representative coronal T1-weighted magnetic resonance images

of cases 3, 7 and 8 are shown. Note the appearance of the hippocampi are not significantly atrophic simply by visual inspection.

Box plots of MRI and magnetic resonance spectroscopy data (bottom): Box plots of hippocampal volume estimates for CN, mild

cognitive impairment (MCI) and Alzheimer’s disease (AD) subjects (data published in Jack et al., 2004) compared with the three

dementia with Lewy bodies (DLB) subjects with MRI in the current study, labelled ‘A’ for case 8, ‘B’ for case 3 and ‘C’ for case 7. Panel

(a) shows hippocampal W scores which may be considered hippocampal volumes adjusted for age, sex and total intracranial volume

standardized to a cognitively normal elderly reference group. One Alzheimer’s disease subject with a W score of �15.4 is not shown in

the figure. Values shown for the dementia with Lewy bodies cohort are from the earliest MRI available when the subject was diagnosed

with mild cognitive impairment. Panel (b) shows annualized percent change in hippocampal volume, where annual percent change is

defined as the percentage change between the first and second volume estimate, divided by the number of years between the scans.

The shaded boxes indicate the 25th percentile, median and 75th percentile of the group with vertical lines extending to the furthest

data point within 1.5 times the inter-quartile range. Points beyond this are indicated with an open circle. Panel (c) shows box plots of1H-Magnetic resonance spectroscopy (1H MRS) metabolite ratios for CN, mild cognitive impairment and Alzheimer’s disease subjects

(data published in Kantarci et al., 2000) compared with the two dementia with Lewy bodies subjects in the current study, labelled ‘B’

and ‘C’, who had magnetic resonance spectroscopy available. The choline/creatine (Cho/Cr) ratio is shown. For both subjects, the

magnetic resonance spectroscopy was performed in 2002 when the subjects were diagnosed with mild cognitive impairment. The

shaded boxes indicate the 25th percentile, median and 75th percentile of the group with vertical lines extending to the furthest data

point within 1.5 times the inter-quartile range. Points beyond this are indicated with an open circle.


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REM sleep behaviour disorder—regardless of the mild cognitive

impairment subtype—is likely to reflect evolving Lewy body

disease.

The strengths of the study include well-characterized and pro-

spectively followed patients who developed mild cognitive impair-

ment and had autopsy-proven Lewy body disease. Importantly,

mild cognitive impairment diagnoses were made in real-time.

Subjects were not assigned mild cognitive impairment diagnoses

retrospectively after a diagnosis of dementia with Lewy bodies had

been made. A weakness of this clinicopathologic series is that it

involves only eight cases. As a result, generalizations about the

progression of symptoms in mild cognitive impairment to dementia

with Lewy bodies will require further longitudinal studies. Another

limitation is that due to slight changes in the neuropsychological

battery over time, an identical set of neuropsychological data was

not obtained on all patients. Also, at least one patient was not

testable, and another was unable to complete testing due to

fatigue.

Our findings indicate that Lewy body disease can pass through

a mild cognitive impairment intermediate state, with any mild

cognitive impairment subtype potentially evolving into dementia

with Lewy bodies. All cases with REM sleep behaviour disorder

and mild cognitive impairment eventually were shown to have

autopsy-proven Lewy body disease, indicating that REM sleep

behaviour disorder plus mild cognitive impairment probably

reflects brainstem and cerebral Lewy body disease. These findings

also underscore the importance of expanding the characterization

beyond cognition in the dementing neurodegenerative disorders;

attempts should be made to perform longitudinal assessments of

the cognitive/neuropsychological, neuropsychiatric/behavioural,

motor, sleep, autonomic and other features to improve the under-

standing of early clinical manifestations of Lewy body disease and

other neurodegenerative disorders.

AcknowledgementsThe authors thank their staff at the Mayo Alzheimer’s Disease

Research Center and Mayo Center for Sleep Medicine for their

evaluation and education/counselling for many of the patients

and families included in this report. They particularly extend

their gratitude to the patients and their families for participating

in research on ageing, cognition and sleep.

FundingNational Institutes of Health [AG15866 to B.F.B., T.J.F. (PI),

G.E.S., V.S.P., D.W.D.; AG16574 to B.F.B., T.J.F., G.E.S., J.E.P.,

D.W.D., D.S.K., N.G.R., J.A.L., K.K., C.J., V.S.P., R.C.P. (PI);

NS40256 to B.F.B., T.J.F., D.W.D. (PI); AG06786 to B.F.B.,

G.E.S., J.E.P., D.S.K., Y.E.G., V.S.P., R.C.P. (PI); and AG23195

to K.K., M.S., C.R.J. (PI)], and the Robert H. and Clarice Smith

and Abigail Van Buren Alzheimer’s Disease Research Program of

the Mayo Foundation.

Supplementary materialSupplementary material is available at Brain online.

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