Lewy Body Disease: Lewy Body Disease: The Undiscovered The Undiscovered Country Country Donald R. Royall, MD Donald R. Royall, MD Departments of Psychiatry, Medicine, Departments of Psychiatry, Medicine, Pharmacology, Pharmacology, Family & Community Medicine Family & Community Medicine The University of Texas Health Science Center The University of Texas Health Science Center San Antonio San Antonio and the Audie L. Murphy VA GRECC and the Audie L. Murphy VA GRECC
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Lewy Body Disease: The Undiscovered Country Donald R. Royall, MD Departments of Psychiatry, Medicine, Pharmacology, Family & Community Medicine The University.
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Lewy Body Disease:Lewy Body Disease:The Undiscovered The Undiscovered
CountryCountryDonald R. Royall, MDDonald R. Royall, MD
Departments of Psychiatry, Medicine, Pharmacology, Departments of Psychiatry, Medicine, Pharmacology,
Family & Community MedicineFamily & Community Medicine
The University of Texas Health Science Center San AntonioThe University of Texas Health Science Center San Antonio
and the Audie L. Murphy VA GRECCand the Audie L. Murphy VA GRECC
ObjectivesObjectives
The purpose of this presentation is to describe the The purpose of this presentation is to describe the propagation of Lewy Body pathology within the CNS and to propagation of Lewy Body pathology within the CNS and to illustrate how that has the potential to integrate a wide illustrate how that has the potential to integrate a wide variety of geriatric symptoms and syndromes into a variety of geriatric symptoms and syndromes into a common neurodegenrative model. Dr. Royall will use a common neurodegenrative model. Dr. Royall will use a case-vignette to illustrate the potential overlap between case-vignette to illustrate the potential overlap between Lewy Body disease (LBD) and so-called “vascular Lewy Body disease (LBD) and so-called “vascular dementia”. As a result of their participation, the audience dementia”. As a result of their participation, the audience will be able to discuss the potential utility of cardiac will be able to discuss the potential utility of cardiac imaging as a bio-marker for LBD. No pharmaceutical is is imaging as a bio-marker for LBD. No pharmaceutical is is indicated for the diagnosis or treatment of LBD. All indicated for the diagnosis or treatment of LBD. All discussed interventions are “off-label”. Dr. Royall reports discussed interventions are “off-label”. Dr. Royall reports no conflicts of interest. no conflicts of interest.
Lewy Body DementiaLewy Body Dementia
• Most common “non-AD’ dementiaMost common “non-AD’ dementia• 21% of Clinically Diagnosed “AD” cases21% of Clinically Diagnosed “AD” cases• Has an early cholinergic deficitHas an early cholinergic deficit• Worse problem behaviorWorse problem behavior• ParkinsonismParkinsonism• FallsFalls• PsychosisPsychosis• Excess mortality Excess mortality
Friederich Heinrich LewyFriederich Heinrich Lewy1885 - 19501885 - 1950
• 1913 – “eosinophilic inclusion bodies” 1913 – “eosinophilic inclusion bodies” in Parkinson’s disease in Parkinson’s disease
• 1919 – Tretiakoff: “1919 – Tretiakoff: “corps de corps de LewyLewy” ” in “locus niger” (substantia nigra) in “locus niger” (substantia nigra)
• 1962 – “Lewy Body Disease”1962 – “Lewy Body Disease”
• 1976 –1990s: Japan 1976 –1990s: Japan then UK & US reportsthen UK & US reports
Lewy Body LesionsLewy Body Lesions
• Lewy Bodies contain Lewy Bodies contain abnormal abnormal neurofilaments that neurofilaments that contain tau and contain tau and ubiquitinubiquitin
medweb.bham.ac.uk
What are the diagnostic What are the diagnostic symptoms?symptoms?
Clinicopathological SpectrumClinicopathological Spectrum ofof Lewy Body Dementia Lewy Body Dementia
Parkinson’sDisease
Alzheimer’sDisease
“Dementia with Lewy Bodies”
“pure” LB “variant” of AD
Dysexecutive“Type 2”Dementia
Amnestic“Type 1”Dementia
What are the stages of LBD?What are the stages of LBD?
• AD variant much like Alzheimer’s but more AD variant much like Alzheimer’s but more fallsfalls, psychosis, agitation and a more , psychosis, agitation and a more aggressive courseaggressive course
What are the stages of LBD?What are the stages of LBD?
• AD variant much like Alzheimer’s but more AD variant much like Alzheimer’s but more fallsfalls, psychosis, agitation and a more , psychosis, agitation and a more aggressive courseaggressive course• Cognitive features may reflect comorbid AD lesionsCognitive features may reflect comorbid AD lesions
What are the stages of LBD?What are the stages of LBD?
• AD variant much like Alzheimer’s but more AD variant much like Alzheimer’s but more fallsfalls, psychosis, agitation and a more , psychosis, agitation and a more aggressive courseaggressive course• Cognitive features may reflect comorbid AD lesionsCognitive features may reflect comorbid AD lesions
• Pure LBD ??? Pure LBD ???
Braak StagingBraak Staging
Six neuropathological Stages of Six neuropathological Stages of Alzheimer’s Disease (AD)Alzheimer’s Disease (AD)
Hierarchical progressionHierarchical progression Sequence “begins” in CNI (olfactory)Sequence “begins” in CNI (olfactory) Early hippocampal involvementEarly hippocampal involvement LimbicLimbic NeocortexNeocortex
Dementia Develops Late in ADDementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Dementia Develops Late in ADDementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Dementia Develops Late in ADDementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Dementia Develops Late in ADDementia Develops Late in AD
Royall et al., Exp Aging Res, 2002
Braak Staging of LBDBraak Staging of LBD
Six neuropathological StagesSix neuropathological Stages Hierarchical progressionHierarchical progression Sequence “begins” in dorsal motor Sequence “begins” in dorsal motor
nucleus of CN X (DmX)nucleus of CN X (DmX) Early brainstem involvementEarly brainstem involvement
Braak’s ProgressionBraak’s Progression
Braak Staging Braak Staging Late neocortical involvementLate neocortical involvement
Kobayashi et al., Kobayashi et al., Int. J. Geriatric Psychiatry,Int. J. Geriatric Psychiatry, 2009 2009
Braak Staging Braak Staging Early brainstem involvementEarly brainstem involvement
substantia nigra - DAsubstantia nigra - DA n. basalis - AChn. basalis - ACh locus coerleus - NElocus coerleus - NE dorsal raphe - 5HTdorsal raphe - 5HT
Braak Staging Braak Staging Early brainstem involvementEarly brainstem involvement
substantia nigra - DA substantia nigra - DA (parkinsonism)(parkinsonism) n. basalis - ACh n. basalis - ACh locus coerleus - NE locus coerleus - NE dorsal raphe - 5HT dorsal raphe - 5HT
Braak Staging Braak Staging Early brainstem involvementEarly brainstem involvement
substantia nigra - DA substantia nigra - DA (parkinsonism)(parkinsonism) n. basalis - ACh n. basalis - ACh (cognitive fluctuations)(cognitive fluctuations) locus coerleus - NElocus coerleus - NE dorsal raphe - 5HTdorsal raphe - 5HT
Braak Staging Braak Staging Early brainstem involvementEarly brainstem involvement
substantia nigra - DA substantia nigra - DA (parkinsonism)(parkinsonism) n. basalis - ACh n. basalis - ACh (cognitive fluctuations)(cognitive fluctuations) locus coerleus - NE locus coerleus - NE (agitation)(agitation) dorsal raphe - 5HTdorsal raphe - 5HT
Braak Staging Braak Staging Early brainstem involvementEarly brainstem involvement
substantia nigra - DA substantia nigra - DA (parkinsonism)(parkinsonism) n. basalis - ACh n. basalis - ACh (cognitive fluctuations)(cognitive fluctuations) locus coerleus - NE locus coerleus - NE (agitation)(agitation) dorsal raphe - 5HT dorsal raphe - 5HT (depression /anxiety)(depression /anxiety)
Central Autonomic CircuitCentral Autonomic Circuit
Lewy bodies in extra-CNS organs Lewy bodies in extra-CNS organs a)a) SA node, b) esophagogastric junction, SA node, b) esophagogastric junction, c) adrenal medulla, d) celiac ganglion.c) adrenal medulla, d) celiac ganglion.Okada et al., Okada et al., Pathology International Pathology International 20042004
Lewy bodies in the sinoatrial nodeLewy bodies in the sinoatrial nodeOkada et al., Okada et al., Pathology International Pathology International 20042004
Lewy bodies in the sinoatrial nodeLewy bodies in the sinoatrial nodeOkada et al., Okada et al., Pathology International Pathology International 20042004
Associated with atrial fibrillation!Associated with atrial fibrillation!
Extracranial Organs Extracranial Organs May be Affected FirstMay be Affected First
• Cardiac sympathetic denervation, Cardiac sympathetic denervation, diagnosable via cardiac scintigraphydiagnosable via cardiac scintigraphy• 123123I-metaiodobenzylguanidine (MIBG) is a I-metaiodobenzylguanidine (MIBG) is a
highly sensitive and specific diagnostic marker highly sensitive and specific diagnostic marker (Tateno et al., 2008)(Tateno et al., 2008)
• 6-[6-[1818F]fluorodopamine (FDA) impaired before F]fluorodopamine (FDA) impaired before the onset of parkinsonismthe onset of parkinsonism
•
Cardiac Denervation by Cardiac Denervation by 6-[6-[1818F]fluorodopamine (FDA)F]fluorodopamine (FDA)
Royall et al. Royall et al. J Neuropsych Clin NeurosciJ Neuropsych Clin Neurosci, 2009, 2009
Incident LBD among VCI Cases!Incident LBD among VCI Cases!
• 6 /35 (17.2%) have gone on to convert to clinical 6 /35 (17.2%) have gone on to convert to clinical LBD at a mean follow-up of 857 LBD at a mean follow-up of 857 408 days 408 days 2 /6 (33%) had MRI confirmed focal ischemic lesions 2 /6 (33%) had MRI confirmed focal ischemic lesions 5 /6 (88.3%) had white matter lesions5 /6 (88.3%) had white matter lesions
• An additional 10 (28.6%) are suspected of LBD, An additional 10 (28.6%) are suspected of LBD, but do not yet meet formal criteria but do not yet meet formal criteria
• The probable and possible LBD cases did not The probable and possible LBD cases did not differ at baseline from VCI subjects without LBD differ at baseline from VCI subjects without LBD symptoms on any clinical measure in our datasetsymptoms on any clinical measure in our dataset
• At the time of their conversion, 4 /6 At the time of their conversion, 4 /6 (66.7%) have parkinsonism, 6 /6 (100%) (66.7%) have parkinsonism, 6 /6 (100%) have REM sleep behavioral issues, 5 /6 have REM sleep behavioral issues, 5 /6 (83.3%) have visual hallucinations, and (83.3%) have visual hallucinations, and 4 /6 (66.7%) have confusional spells4 /6 (66.7%) have confusional spells
Clinicians Sensitized?Clinicians Sensitized?
• We have considered the possibility that our clinicians We have considered the possibility that our clinicians have become sensitized to LBD symptoms over timehave become sensitized to LBD symptoms over time
• Time from first clinical evaluation to diagnosis of LBD Time from first clinical evaluation to diagnosis of LBD
(excluding possible cases) ranges from 469 to 1463 (excluding possible cases) ranges from 469 to 1463 days and is strongly days and is strongly positively positively correlated (r = 0.84) with correlated (r = 0.84) with the date of diagnosisthe date of diagnosis
• This argues FOR a linear delay between first evaluation This argues FOR a linear delay between first evaluation
and diagnosis, and AGAINST a bias towards shorter and diagnosis, and AGAINST a bias towards shorter delays to diagnosis as a function of the date of clinic delays to diagnosis as a function of the date of clinic enrollmentenrollment
These symptoms should load on the same factorThese symptoms should load on the same factor
NINDS-ARIENS “VaD”NINDS-ARIENS “VaD”
1.C.II: “Clinical features consistent with the 1.C.II: “Clinical features consistent with the diagnosis of diagnosis of probableprobable vascular dementia vascular dementia include:include:
A. Early presence of a A. Early presence of a gait disturbancegait disturbance (small-step gait (small-step gait or marche à petis pas, … or parkinsonian gait.or marche à petis pas, … or parkinsonian gait.
B. History of unsteadiness and frequent unprovoked B. History of unsteadiness and frequent unprovoked fallsfalls..
C. Early C. Early urinary frequencyurinary frequency, urgency, and other urinary , urgency, and other urinary symptoms…symptoms…
Honolulu-Asia Honolulu-Asia Aging Study (HAAS)Aging Study (HAAS)
Longitudinal study of heart disease and Longitudinal study of heart disease and stroke established in 1965 stroke established in 1965
8006 Japanese-American men8006 Japanese-American men Cognitive screening and autopsies since Cognitive screening and autopsies since
Honolulu-Asia Honolulu-Asia Aging Study (HAAS)Aging Study (HAAS)
Lewy body counts in:Lewy body counts in: locus coerleus locus coerleuslocus coerleus locus coerleus substantia nigrasubstantia nigra L insulaL insula L temporal lobeL temporal lobe L frontal lobeL frontal lobe L occipital lobeL occipital lobe
240 w/ L and R insular histology240 w/ L and R insular histology
Does Stroke Predict Lewy Body Does Stroke Predict Lewy Body Lesions Anywhere in the Brain?Lesions Anywhere in the Brain?
R insula, locus coerleus , substantia nigra, L frontal, L temporal, L parietal, R insula, locus coerleus , substantia nigra, L frontal, L temporal, L parietal, and L occipital do not. and L occipital do not.
R insula, locus coerleus , substantia nigra, L frontal, L temporal, L parietal, R insula, locus coerleus , substantia nigra, L frontal, L temporal, L parietal, and L occipital do not. and L occipital do not.
No associations with embolic and hemorrhagic lesions, neocortical No associations with embolic and hemorrhagic lesions, neocortical microvascular lesions, or total white matter microvascular lesions. microvascular lesions, or total white matter microvascular lesions.
Specific subcortical frontal circuit pathology suggests end-arteriolar Specific subcortical frontal circuit pathology suggests end-arteriolar hypoperfusion events.hypoperfusion events.
Possible CNS ManifestationsPossible CNS Manifestations Syndrome of incontinence, gait disturbance, executive Syndrome of incontinence, gait disturbance, executive
impairment, and frontal WML?impairment, and frontal WML? Geriatric anxiety /depressionGeriatric anxiety /depression
Lewy Body Disease is the second most Lewy Body Disease is the second most common degenerative pathologycommon degenerative pathology
Lewy Body Syndrome is also common and Lewy Body Syndrome is also common and often misdiagnosedoften misdiagnosed
Still, Lewy Body Syndrome may follow Still, Lewy Body Syndrome may follow years of extracranial organ dysfunctionyears of extracranial organ dysfunction
and, Lewy Body Syndrome may be but one and, Lewy Body Syndrome may be but one CNS manifestation of Lewy Body Disease CNS manifestation of Lewy Body Disease
ContactContact
For questions about this audio conference please For questions about this audio conference please contact Dr. Donald Royall at contact Dr. Donald Royall at [email protected]
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