Lewy Body Disease:
The Undiscovered
Country
Donald R. Royall, MD
Departments of Psychiatry, Medicine, Pharmacology,
Family & Community Medicine
The University of Texas Health Science Center San Antonio
and the Audie L. Murphy VA GRECC
Objectives

The purpose of this presentation is to describe the
propagation of Lewy Body pathology within the CNS and
to illustrate how that has the potential to integrate a wide
variety of geriatric symptoms and syndromes into a
common neurodegenrative model. Dr. Royall will use a
case-vignette to illustrate the potential overlap between
Lewy Body disease (LBD) and so-called “vascular
dementia”. As a result of their participation, the audience
will be able to discuss the potential utility of cardiac
imaging as a bio-marker for LBD. No pharmaceutical is
is indicated for the diagnosis or treatment of LBD. All
discussed interventions are “off-label”. Dr. Royall reports
no conflicts of interest.
Lewy Body Dementia
•
•
•
•
•
•
•
•
Most common “non-AD’ dementia
21% of Clinically Diagnosed “AD” cases
Has an early cholinergic deficit
Worse problem behavior
Parkinsonism
Falls
Psychosis
Excess mortality
Friederich Heinrich Lewy
1885 - 1950
• 1913 – “eosinophilic inclusion bodies”
in Parkinson’s disease
• 1919 – Tretiakoff: “corps de Lewy”
in “locus niger” (substantia nigra)
• 1962 – “Lewy Body Disease”
• 1976 –1990s: Japan
then UK & US reports
Lewy Body Lesions
• Lewy Bodies contain
abnormal
neurofilaments that
contain tau and
ubiquitin
medweb.bham.ac.uk
What are the diagnostic
symptoms?
• Geriatric onset
• Cortical “Type 1” dementia presentation
• Two of three:



Parkinsonism (gait, rigidity, “poker” face)
Hallucinations (little people, animals,
children)
“Spells” (fluctuations, “good” day /
”bad”day, “sundowning”, nocturnal
confusion)
Clinicopathological Spectrum
of Lewy Body Dementia
Parkinson’s
Disease
Alzheimer’s
Disease
“Dementia with Lewy Bodies”
“pure”
Dysexecutive
“Type 2”
Dementia
LB “variant” of AD
Amnestic
“Type 1”
Dementia
What are the stages of LBD?
• AD variant much like Alzheimer’s but more
falls, psychosis, agitation and a more
aggressive course
What are the stages of LBD?
• AD variant much like Alzheimer’s but more
falls, psychosis, agitation and a more
aggressive course
• Cognitive features may reflect comorbid AD lesions
What are the stages of LBD?
• AD variant much like Alzheimer’s but more
falls, psychosis, agitation and a more
aggressive course
• Cognitive features may reflect comorbid AD lesions
• Pure LBD ???
Braak Staging
 Six
neuropathological Stages of
Alzheimer’s Disease (AD)
 Hierarchical progression
 Sequence “begins” in CNI (olfactory)
 Early hippocampal involvement
 Limbic
 Neocortex
Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Braak Staging of LBD
 Six
neuropathological Stages
 Hierarchical progression
 Sequence “begins” in dorsal motor
nucleus of CN X (DmX)
 Early brainstem involvement
Braak’s Progression
Braak Staging
Late neocortical involvement
 Occipital
hypometabolism
 Temporal
lobe hypometabolism
 Orbitofrontal
hypometabolism
Braak Staging
Late neocortical involvement
 Occipital

hypometabolism
visual hallucinations, parkinsonism
 Temporal
lobe hypometabolism

 Orbitofrontal
hypometabolism

Kobayashi et al., Int. J. Geriatric Psychiatry, 2009
Braak Staging
Late neocortical involvement
 Occipital

hypometabolism
visual hallucinations, parkinsonism
 Temporal

lobe hypometabolism
delusions /psychosis
 Orbitofrontal
hypometabolism

Kobayashi et al., Int. J. Geriatric Psychiatry, 2009
Braak Staging
Late neocortical involvement
 Occipital

hypometabolism
visual hallucinations, parkinsonism
 Temporal

lobe hypometabolism
delusions /psychosis
 Orbitofrontal

hypometabolism
depression /anxiety
Kobayashi et al., Int. J. Geriatric Psychiatry, 2009
Braak Staging
Early brainstem involvement
 substantia
nigra - DA
 n. basalis - ACh
 locus coerleus - NE
 dorsal raphe - 5HT
Braak Staging
Early brainstem involvement
 substantia
nigra - DA (parkinsonism)
 n. basalis - ACh
 locus coerleus - NE
 dorsal raphe - 5HT
Braak Staging
Early brainstem involvement
 substantia
nigra - DA (parkinsonism)
 n. basalis - ACh (cognitive fluctuations)
 locus coerleus - NE
 dorsal raphe - 5HT
Braak Staging
Early brainstem involvement
 substantia
nigra - DA (parkinsonism)
 n. basalis - ACh (cognitive fluctuations)
 locus coerleus - NE (agitation)
 dorsal raphe - 5HT
Braak Staging
Early brainstem involvement
 substantia
nigra - DA (parkinsonism)
 n. basalis - ACh (cognitive fluctuations)
 locus coerleus - NE (agitation)
 dorsal raphe - 5HT (depression /anxiety)
Central Autonomic Circuit
 Orthostasis
/falls
 Arrythmia (atrial fibrillation?)
 Syncope
 Constipation
 Detrusor instability /“urge” incontinence
Extra-cranial Origins?
Extra-cranial Origins?
Extra-cranial involvement
 Aurbach’s
plexus (colon)
 Celiac ganglion (bladder)
 GE junction
 Pre-glanglionic cardiac sympathetic
dennervation
Lewy bodies in extra-CNS organs
a) SA node, b) esophagogastric junction,
c) adrenal medulla, d) celiac ganglion.
Okada et al., Pathology International 2004
Lewy bodies in the sinoatrial node
Okada et al., Pathology International 2004
Lewy bodies in the sinoatrial node
Okada et al., Pathology International 2004
Associated with atrial fibrillation!
Extracranial Organs
May be Affected First
• Cardiac sympathetic denervation,
diagnosable via cardiac scintigraphy
• 123I-metaiodobenzylguanidine (MIBG) is a
highly sensitive and specific diagnostic marker
(Tateno et al., 2008)
• 6-[18F]fluorodopamine (FDA) impaired before
the onset of parkinsonism
•
Cardiac Denervation by
6-[18F]fluorodopamine (FDA)
123I-metaiodobenzylguanidine
(MIBG) cardiac scintigraphy
4 hr. H:M Ratio
Gerson et al., 2002
1.02
1.55
Escamilla-Sevilla, et al., 2009
Meta-analysis of 2680 subjects
from 46 studies
123I-MIBG discriminates PD/LBD, RBD from all
other conditions (c = 0.987)
Sensitivity
ROC Curve
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
1-Specificity
King, Mintz & Royall (in press)
Late 2005 - 2006

79 yo HM
 PMHx: remote CHI (no LOC), AODM, HTN, Ao valve
repair, CAD (CABG x 2), hyperlipidemia
 B12 = 545; folate = 434.2; TSH = 3.1
 “Type 1” dementia





MMSE = 19 /30 (recalls 3/3 w/ prompts; intact olfaction)
EXIT25 = 24/50 (skilled nursing mean)
CLOX1 = 06/15
CLOX2 = 12/15
GDS = 01/15
Mild Periventricular WML
Late 2005 - 2006
 “vascular
dementia”
 sertraline trial > no improvement
 venlafaxine trial > no improvement
2007 - 2008



Feb. ‘07: fall /hip contusion
Nov. ’07: galantamine added
June ’08: galantamine 12 bid

EXIT25 improved
2007 - 2008



Feb. ‘07: fall /hip contusion
Nov. ’07: galantamine added
June ’08: galantamine 12 bid


EXIT25 improved
July ’08: cellulitis /delirium spell
2007 - 2008



Feb. ‘07: fall /hip contusion
Nov. ’07: galantamine added
June ’08: galantamine 12 bid

EXIT25 improved

July ’08: cellulitis /delirium spell

Oct. ‘08: UTI /“confusional spells”
2007 - 2008



Feb. ‘07: fall /hip contusion
Nov. ’07: galantamine added
June ’08: galantamine 12 bid

EXIT25 improved

July ’08: cellulitis /delirium spell

Oct. ‘08: UTI /“confusional spells”

Nov. ‘08: sees “cats” in clinic
2009

Jan. ’09: hypersomnolence, REM behavioral
disturbance, parkinsonian gait; modafanil added

March ’09: visual hallucinations; constipation

June ’09: galantamine 24mg bid, modafanil 200mg qd
Eating well, sleeping less, more talkative, no recent
hallucinations; positional tremor
EXIT25 = 25; MMSE = 21;
CLOX1 = 10; CLOX2 =11, GDS = 2

Aug. ‘09; resting tremor R >L
The “Vascular Dementia”
of Lewy Body Disease?
The “Vascular Dementia”
of Lewy Body Disease?
 Early
cardiac involvement

Atrial arrythmia, atrial fibrillation
Syncope, orthostasis, falls & vasovagal
“spells”
“Ischemic” WML, executive impairment

“Vascular Dementia”


The “Vascular Dementia”
of Lewy Body Disease?
 Early



cardiac involvement
Atrial arrythmia, atrial fibrillation
Syncope, orthostasis, falls & vasovagal
“spells”
“Ischemic” WML, executive impairment
“Vascular Dementia”
 Extra-cardiac involvement


Incontinence, constipation, sensitive
pharmacology
The “Vascular Dementia”
of Lewy Body Disease?
 Later





brainstem involvement
REM behavioral disturbances
Cholinergic responsive cognitive fluctuations
Psychiatric manifestations
Parkinsonism /visual hallucinations
Visuospatial deficits
LBD symptoms emerge over ICVD
 spells
suggest “TIA’s”
 Parkinsonism suggests “basal ganglia
lesions”
Royall et al.
J Neuropsych Clin Neurosci, 2009
Incident LBD among VCI Cases!
• 6 /35 (17.2%) have gone on to convert to clinical
LBD at a mean follow-up of 857  408 days
 2 /6 (33%) had MRI confirmed focal ischemic lesions
 5 /6 (88.3%) had white matter lesions
• An additional 10 (28.6%) are suspected of LBD,
but do not yet meet formal criteria
• 123I-MIBG confirms cardiac sympathetic
dennervation
• The probable and possible LBD cases did not
differ at baseline from VCI subjects without LBD
symptoms on any clinical measure in our dataset
• At the time of their conversion, 4 /6
(66.7%) have parkinsonism, 6 /6 (100%)
have REM sleep behavioral issues, 5 /6
(83.3%) have visual hallucinations, and
4 /6 (66.7%) have confusional spells
Clinicians Sensitized?
• We have considered the possibility that our clinicians
have become sensitized to LBD symptoms over time
• Time from first clinical evaluation to diagnosis of LBD
(excluding possible cases) ranges from 469 to 1463
days and is strongly positively correlated (r = 0.84) with
the date of diagnosis
• This argues FOR a linear delay between first evaluation
and diagnosis, and AGAINST a bias towards shorter
delays to diagnosis as a function of the date of clinic
enrollment
Hachinski Ischemic Scale (HIS)
(Hachinski 1975):
“nightime confusion”
= REM disturbance?
“depression”
= raphe or L insula involvement?
“fluctuating course”
= cognitive spells?
“somatic complaints”
= extracranial involvement?
These symptoms should load on the same factor
NINDS-ARIENS “VaD”

1.C.II: “Clinical features consistent with the
diagnosis of probable vascular dementia
include:

A. Early presence of a gait disturbance (small-step gait
or marche à petis pas, … or parkinsonian gait.

B. History of unsteadiness and frequent unprovoked
falls.

C. Early urinary frequency, urgency, and other urinary
symptoms…
Honolulu-Asia
Aging Study (HAAS)
 Longitudinal
study of heart disease and
stroke established in 1965
 8006 Japanese-American men
 Cognitive screening and autopsies since
1991
 650 autopsies
 350 w/ histology
Honolulu-Asia
Aging Study (HAAS)
 Lewy






body counts in:
locus coerleus locus coerleus
substantia nigra
L insula
L temporal lobe
L frontal lobe
L occipital lobe
 240
w/ L and R insular histology
Does Stroke Predict Lewy Body
Lesions Anywhere in the Brain?
“Stroke”
Age
“Depression”
(CESD >9)
OR
1. 96
1. 07
1. 63
CI
1.14 – 3.35
1.03 – 1.12
0.85 – 3.10
DF
1
1
1
2
6 .0
9 .9
2 .2
p
0 .0 2
0.002
0 .1 4
Does Stroke Predict Lewy Body
Lesions Anywhere in the Brain?
“Stroke”
Age
“Depression”
(CESD >9)
OR
1. 96
1. 07
1. 63
CI
1.14 – 3.35
1.03 – 1.12
0.85 – 3.10
DF
1
1
1
Adjudicated “stroke” does not.
Suggests “silent” lesions, microinfarcts and lacunes.
2
6 .0
9 .9
2 .2
p
0 .0 2
0.002
0 .1 4
In Which ROI is /are Lewy Body
Lesions Related to Stroke?
L Insula
Age
“Depression”
(CESD >9)
OR
2 .0 7
1 .0 7
2 .4 3
CI
1.09 – 3.94
1.02 – 1.13
1.10 – 5.38
DF
1
1
1
2
5 .0
6 .8
4 .8
p
0 .0 3
0 .0 1
0 .0 3
In Which ROI is /are Lewy Body
Lesions Related to Stroke?
L Insula
Age
“Depression”
(CESD >9)
OR
2 .0 7
1 .0 7
2 .4 3
CI
1.09 – 3.94
1.02 – 1.13
1.10 – 5.38
DF
1
1
1
2
5 .0
6 .8
4 .8
p
0 .0 3
0 .0 1
0 .0 3
R insula, locus coerleus , substantia nigra, L frontal, L temporal, L parietal,
and L occipital do not.
Suggests autonomic mechanism.
In Which ROI is /are Lewy Body
Lesions Related to Stroke?
L Insula
Age
“Depression”
(CESD >9)
OR
2 .0 7
1 .0 7
2 .4 3
CI
1.09 – 3.94
1.02 – 1.13
1.10 – 5.38
DF
1
1
1
2
5 .0
6 .8
4 .8
p
0 .0 3
0 .0 1
0 .0 3
R insula, locus coerleus , substantia nigra, L frontal, L temporal, L parietal,
and L occipital do not.
Suggests autonomic mechanism.
“Vascular Depression” may be LBD as well!
Which Ischemic Pathologies
are Related to L Insula Lesions?
BG /thal
microinfarcts
Age
“Depression”
(CESD >9)
Estimate
0 .4 4
SE
0 .2 3
t
1 .9 2
p
0.056
0 .0 4
0 .2 9
0 .0 2
0 .2 8
2 .2 7
1 .0 5
0 .0 2
0 .3 0
Which Ischemic Pathologies
are Related to L Insula Lesions?
BG /thal
microinfarcts
Age
“Depression”
(CESD >9)
Estimate
0 .4 4
SE
0 .2 3
t
1 .9 2
p
0.056
0 .0 4
0 .2 9
0 .0 2
0 .2 8
2 .2 7
1 .0 5
0 .0 2
0 .3 0
No associations with embolic and hemorrhagic lesions, neocortical
microvascular lesions, or total white matter microvascular lesions.
Specific subcortical frontal circuit pathology suggests end-arteriolar
hypoperfusion events.
Possible CNS Manifestations


Syndrome of incontinence, gait disturbance, executive
impairment, and frontal WML?
Geriatric anxiety /depression





Geriatric Suicides
Geriatric Psychoses
Hoarding
Sleep disorders
 REM disorders




Vascular Depression?
• PTSD?
Sleep apnea
Bruxism
NPH?
Iatrogenic delirium
Extra-cranial LBD Syndromes?








Syncopal falls
Atrial fibrillation
Geriatric constipation
Drug sensitivities
Iatrogenic delirium
Non-traumatic hip
fracture
“urge” incontinence
TMJ
Conclusions
 Lewy
Body Disease is the second most
common degenerative pathology
 Lewy Body Syndrome is also common and
often misdiagnosed
 Still, Lewy Body Syndrome may follow
years of extracranial organ dysfunction
 and, Lewy Body Syndrome may be but
one CNS manifestation of Lewy Body
Disease
Contact



For questions about this audio conference please
contact Dr. Donald Royall at royall@uthscsa.edu
For any questions about the monthly GRECC Audio
Conference Series please contact Tim Foley at
tim.foley@va.gov or call (734) 222-4328
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