1. 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

2. 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.

3. 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

4. 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

5. Lewy Body Lesions
Lewy Bodies contain abnormal neurofilaments that contain tau and ubiquitin
medweb.bham.ac.uk

6. 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)

7. Clinicopathological Spectrum of Lewy Body Dementia
Parkinson’s
Disease
Alzheimer’s
Disease
“Dementia with Lewy Bodies”
“pure” LB “variant” of AD
Differentiation of the various dementias is challenging. Dementia can result form numerous disorders, and many treatable conditions may mirror Alzheimer’s-type dementia. It should be kept in mind that the dementia syndrome may have more than one etiologic factor in the elderly patient.
Although available data show variable prevalence of the differential diagnosis of dementia, it is estimated that 65% of cases are due to Alzheimer’s disease (AD), 5% to vascular dementia, 10% to AD plus vascular dementia, 7% to dementia with Lewy bodies (DLB), 5% to AD plus DLB, and the remaining 8% to other dementias (Small et al, 1997; Morris, 1994; American Psychiatric Association, 1997).
AD and vascular dementia (VaD) are easily confused because they share many symptoms. The onset of AD is gradual, while VaD begins abruptly and progresses in a stepwise manner. Deterioration in a broad range of intellectual abilities is seen in AD patients, with motor abilities unaffected until advanced stages of the disease; focal signs and symptoms are generally absent. Brain CT of AD patients is usually normal or shows early brain atrophy, unlike the VaD patient in which the CT scan may show evidence of stroke or stroke-related change. Individuals with VaD frequently have an underlying vascular disorder (e.g., hypertension or heart disease) while AD patients do not.
Dysexecutive
“Type 2”
Dementia
Amnestic
“Type 1”
Dementia

8. What are the stages of LBD?
AD variant much like Alzheimer’s but more falls, psychosis, agitation and a more aggressive course

9. 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

10. 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 ???

11. Braak Staging Six neuropathological Stages of Alzheimer’s Disease (AD)
Hierarchical progression
Sequence “begins” in CNI (olfactory)
Early hippocampal involvement
Limbic
Neocortex

12. Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002

13. Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002

14. Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002

15. Dementia Develops Late in AD
Royall et al., Exp Aging Res, 2002

16. Braak Staging of LBD Six neuropathological Stages
Hierarchical progression
Sequence “begins” in dorsal motor nucleus of CN X (DmX)
Early brainstem involvement

17. Braak’s Progression

18. Braak Staging Late neocortical involvement
Occipital hypometabolism
Temporal lobe hypometabolism
Orbitofrontal hypometabolism

19. Braak Staging Late neocortical involvement
Occipital hypometabolism
visual hallucinations, parkinsonism
Temporal lobe hypometabolism
Orbitofrontal hypometabolism
Kobayashi et al., Int. J. Geriatric Psychiatry, 2009

20. 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

21. 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

22. Braak Staging Early brainstem involvement
substantia nigra - DA
n. basalis - ACh
locus coerleus - NE
dorsal raphe - 5HT

23. Braak Staging Early brainstem involvement
substantia nigra - DA (parkinsonism)
n. basalis - ACh
locus coerleus - NE
dorsal raphe - 5HT

24. Braak Staging Early brainstem involvement
substantia nigra - DA (parkinsonism)
n. basalis - ACh (cognitive fluctuations)
locus coerleus - NE
dorsal raphe - 5HT

25. Braak Staging Early brainstem involvement
substantia nigra - DA (parkinsonism)
n. basalis - ACh (cognitive fluctuations)
locus coerleus - NE (agitation)
dorsal raphe - 5HT

26. Braak Staging Early brainstem involvement
substantia nigra - DA (parkinsonism)
n. basalis - ACh (cognitive fluctuations)
locus coerleus - NE (agitation)
dorsal raphe - 5HT (depression /anxiety)

28. Central Autonomic Circuit
Orthostasis /falls
Arrythmia (atrial fibrillation?)
Syncope
Constipation
Detrusor instability /“urge” incontinence

29. Extra-cranial Origins?

30. Extra-cranial Origins?

31. Extra-cranial involvement
Aurbach’s plexus (colon)
Celiac ganglion (bladder)
GE junction
Pre-glanglionic cardiac sympathetic dennervation

32. Lewy bodies in extra-CNS organs SA node, b) esophagogastric junction,
c) adrenal medulla, d) celiac ganglion.
Okada et al., Pathology International 2004

33. Lewy bodies in the sinoatrial node
Okada et al., Pathology International 2004

34. Lewy bodies in the sinoatrial node
Okada et al., Pathology International 2004
Associated with atrial fibrillation!

35. 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
      

36. Cardiac Denervation by 6-[18F]fluorodopamine (FDA)

37. 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy
4 hr. H:M Ratio
Gerson et al., 2002

38. Escamilla-Sevilla, et al., 2009

39. Meta-analysis of 2680 subjects from 46 studies 123I-MIBG discriminates PD/LBD, RBD from all other conditions (c = 0.987)
King, Mintz & Royall (in press)

42. Late
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

45. Mild Periventricular WML

46. Late 2005 - 2006 “vascular dementia”
sertraline trial > no improvement
venlafaxine trial > no improvement

47. 2007 - 2008 Feb. ‘07: fall /hip contusion Nov. ’07: galantamine added
June ’08: galantamine 12 bid
EXIT25 improved

50. 2007 - 2008 Feb. ‘07: fall /hip contusion Nov. ’07: galantamine added
June ’08: galantamine 12 bid
EXIT25 improved
July ’08: cellulitis /delirium spell

51. 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”

52. 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

53. 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

55. The “Vascular Dementia” of Lewy Body Disease?

56. 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”

57. 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

58. The “Vascular Dementia” of Lewy Body Disease?
Later brainstem involvement
REM behavioral disturbances
Cholinergic responsive cognitive fluctuations
Psychiatric manifestations
Parkinsonism /visual hallucinations
Visuospatial deficits

59. LBD symptoms emerge over ICVD
spells suggest “TIA’s”
Parkinsonism suggests “basal ganglia lesions”

60. Royall et al. J Neuropsych Clin Neurosci, 2009

61. 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

62. 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

63. 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

64. 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

65. 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…

66. 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

67. 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

68. Does Stroke Predict Lewy Body Lesions Anywhere in the Brain?

69. Does Stroke Predict Lewy Body Lesions Anywhere in the Brain?
Adjudicated “stroke” does not.
Suggests “silent” lesions, microinfarcts and lacunes.

70. In Which ROI is /are Lewy Body Lesions Related to Stroke?

71. In Which ROI is /are Lewy Body Lesions Related to Stroke?
R insula, locus coerleus , substantia nigra, L frontal, L temporal, L parietal, and L occipital do not.
Suggests autonomic mechanism.

72. In Which ROI is /are Lewy Body Lesions Related to Stroke?
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!

73. Which Ischemic Pathologies are Related to L Insula Lesions?

74. Which Ischemic Pathologies are Related to L Insula Lesions?
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.

81. Possible CNS Manifestations
Syndrome of incontinence, gait disturbance, executive impairment, and frontal WML?
Geriatric anxiety /depression
Vascular Depression?
Geriatric Suicides
Geriatric Psychoses
Hoarding
Sleep disorders
REM disorders
PTSD?
Sleep apnea
Bruxism
NPH?
Iatrogenic delirium

82. Extra-cranial LBD Syndromes?
Syncopal falls
Atrial fibrillation
Geriatric constipation
Drug sensitivities
Iatrogenic delirium
Non-traumatic hip fracture
“urge” incontinence
TMJ

83. 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

84. Contact
For questions about this audio conference please contact Dr. Donald Royall at
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