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” 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

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 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 1.02 1.55 Gerson et al., 2002

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) 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?

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

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

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.

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!

Which Ischemic Pathologies are Related to L Insula Lesions?

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.

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

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 To evaluate this conference for CE credit please obtain a „Satellite Registration‟ form and a „Faculty Evaluation‟ form from the Satellite Coordinator at you facility. The forms must be mailed to EES within 2 weeks of the broadcast