Dementia with Lewy Bodies

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Dementia with Lewy Bodies

• Dr E Jane Byrne

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Dementia with Lewy Bodies (DLB)Outline

• What are Lewy Bodies
• The History of DLB
• Diagnostic criteria/concepts
• Epidemiology
• Clinical Features
• Treatment

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Lewy Body

• What are they?
• Intracellular inclusion bodies
• Named (by Tretiakoff 1919) after Heinrich
  Lewy(1912)
• ContainUbiquitin,alpha-synuclein
• Ubiquitin-a heat-shock protein
• Subcortical and Cortical

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(No Transcript)
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Cortical Lewy bodies
Alpha-synuclein stain
Ubiquitin stain
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DLB LBs LNs

• LB intraneuronal filamentous inclusion
  
  body
• - ubiquitin, alpha synuclein
• - Deep cortical layers,subcortical
• Lewy Neurites (LNs)
• - ubiquitin reactive neuritic processes in
  CA2 hippocampus
• - alpha synuclein reactive
• - also found in PD, ?HD

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History

• Japan
• Described 2 cases with quadriparesis in flexion
  and cortical LBs (Okazaki et al 1961)
• Small case series (50) patients published
  1961-1989
• Yoshimura 1983 Diffuse Lewy Body Disease(Kosaka
  et al 1984)
• Kosaka 3 types (1979,1990) added 4th in(1996)

• Modern era
• Nottingham 1987-1992,first large case
  series,first use of ubiquitn,first diagnostic
  criteria,link to PD (Byrne et al)
• Newcastle1990-present,SDLT,fluctuations
  emphasis/measures,EEG,
• imaging studies,host CDLB-diagnostic
  criteria.(McKeith )
• O San Diego 1990-presentlewy body variant of
  AD,psychology( Hansen )

ReviewGibb et al 1987,Brain1101131-1153
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History continued

• Manchester 1992-present
• First comparisons with Parkinsons
  disease,review of synucleinopathies,studies of
  carers,sleep and gender,CLOX

• Recent concepts
• a-synuclein immunocytochemistry (Spillantini et
  al 1998)
• Association with sleep disorders (Boeve et al
  1998,2001)
• Re-discovery of the spectrum of LB disorders.

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Concepts

• Entity within a Spectrum of disorders with Lewy
  bodies (Kosaka (1980), Byrne et al
  (1989,1992),McKeith et al (1996)
• Separate Disease (Burkhardt et al (1988), Perry
  et al (1990 )
• Variety of Alzheimers Disease (Hansen et al
  (1990)
• A Synucleinopathy (Boeve et al (2000),Byrne (2001)

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What is Parkinsonian ?

• Classical
• Tremor
• Rigidity
• Postural instability/change
• Bradykinesia
• Gait Abnormality

• Debateable
• Falls
• Fluctuating cognition
• Neuroleptic sensitivity
• Secondary symptoms-Depression,Hallucinations

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Lewy Bodies and Dementia

• Sufficient cause?
• Yes Correlations in all cortical areas with
  Dementia (Lennox et al 1989)
• No Depends on AD pathology / Braak staging (eg
  Ince 2005,Wakisaka et al 2003,Merdes et al 2003).

The senses and intellect being uninjured James
Parkinson 1817
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Diagnostic Criteria

• Nottingham (Byrne et al 1991)
• Probable Possible
• Probable
• A-Dementia with attentional deficits or PD with
  late dementia or Dementia Pism
• B- No Stroke,No Focal
• C- 3 Pism ( mild or late )
• D- No other cause

• Consensus (McKeith et al 1996)
• Cognitive decline ( attention or visuo-spatial )
• 2 prob (1 poss ) of Fluctuation of
  cognition/visual hallucinations/spontaneaous
  Pism.
• Supportive
• No Stroke, No Other

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Validity of Diagnostic Criteria
Study Nottm Newcle ICC
Byrne et al (1995) Sens0.17 Spec0.95 Sens0.15 Spec0.93 N/A
Lopez et al (2002) N/A N/A Sens0.31 Spec1.0
McKeith et al (2002) N/A N/A Sens0.83(0.22-1-in lit) Spec0.95
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History-Nottingham
Clinical Byrne et al (1989)-n15 Literature-n51
Parkism 6(40) 3(6)
Pism Psych 3(20) 1(2)
Psych 6(40) 34(67)
Other 0 2(4)
Unspecified 0 11(22)
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History-Nottingham today
Feature Byrne et al (1989) Literature-post 1989
Fluctuation 80(overall) 75(overall)
Visual Hall. 26.7(pres) 33(pres)
Pism 40(pres) 40-90
Depression 20 33
Delusions 13.3 65
Auditory H 6.6 13
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SYMPTOMS OF DLB and/or PDD
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Epidemiology (eg Zaccai et al 2005)

• Community Studies

• Clinical Populations
• Referred for PM 20-28 of dementia cases (Byrne
  et al 1989,Perry et al 1989,Jellinger et al 1996)
• Referrals to OAP/Day Hospitals (with dementia)
  25 (Shergill et al 1994,Stevens et al
  2002Ballard et al 1993)
• Incidence 0.1(commun),2-3.2 (clinical)-(Lopez-Po
  usa et al 2003,Zaccai et al 2005)

Study Prevalence
Yamada et al (2001) 0.1
Stevens et al (2002) 2.0
Heirrera et al (2002) 0.1
De Siva et al (2003) 0.1
Rahkonen et al (2003) 5
Aarsland et al(2005)-PDD 0.2-0.5
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DLB A Synucleinopathy?

• Synucleinopathies Tauopathies
• Parkinsons Disease Alzheimers Disease
• DLB FTD (sporadic, Familial
• Familial AD-APP PSP)
• PS1, PS2 Corticobasal Degenn
  
• 
  
• Downs Syndrome
• MSA
• Hallervarden-Spatz
• Adapted from- Goedert 1999, Spillantini et al
  1998, Galvin et al 2001

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DLB - Synuclein

• Soluble proteins ? Function (127-140 Amino Acids)
• Alpha- Synuclein (NAC of amyloid precursor
  protein gene 4 q 21.3 q 22
• Beta- Synuclein similar location to alpha
  S gene 5 q 35
• ? Synaptic function
• Gamma Synuclein (breast cancer gene-specific
  product)
• Synoretin

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Byrne (2001)-Clinical features of the
Synucleinopathies
FEATURES PARKINSONS DISEASE MULTIPLE SYSTEM ATROPHY DEMENTIA WITH LEWY BODIES
Parkinsonism Autonomic Dysfunction Falls Cognitive Impairment Visual Hallucinations Sleep Disturbance Invariable Very Common Common, (especially late in course) Sub-cortical/Frontal Common Cortical c 15 Common RBD occurs Vivid dreams Very Common Almost Invariable Common Rare Rare RBD occurs Snoring in 17 Very Common Very Common Sub-cortical/Frontal Early Cortical almost invariable, late Common Common RBD Common Vivid dreams occur
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Synucleinopathies-Agegender
Disease Age Onset Gender Ratio
MSA 90 before 65years 11 (Quinn 1997)
PD Increased prevalence with age 11(de Rijk et al 1997)1.2-1.5(LaiTsui 2001)
DLB Commoner 65y,?F older,?puregtM 1.61(Ala et al 1997,Byrne et al 2003)
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RBD Rapid Eye Movement Sleep Behaviour Disorder

• Parasomnia - loss of skeletal muscle
  atonia
• - dream enactment
• - sleep related injury
• Minimal diagnostic criteria-
• Movement associated with dreaming one of-
• Potentially harmful sleep behaviour
• Acting
  out of dreams
• Behaviour that continually disrupts sleep
  
  
• ICSD (1997)

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RBD-History

• Described by Schenk et al (1987)
• Link with Synucleinopathies Olson et al
  (2000),Boeve et al (2001)
• Often proceeds Syn, by several years
• More common in males
• ? prevalence

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RBD-recent prevalence studies

• Mignot et al (2002) 0.5-(overall)
• Boeve et al (2001) 39 -(in those with Syn.PSG
  diagnosis)
• Scaglione et al (2005) 33.8 of PD

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RBD-Treatment

• Advice for sleep partners!
• Clonazepam 0.5 mg-1.5 mg nocte
• TCAs(Imipramine-equivocal)
• Melatonin

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MEASUREMENT OF FLUCTUATION IN DLB

• Clock Drawing Test
• Electroencephalography
• Clinical Assessment of Fluctuation
• One Day Fluctuation Assessment Scale

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CLINICAL ASSESSMENT OF FLUCTUATION (Walker et al
2000)

• Either a or b
• Does the patient ever have spontaneous impaired
  alertness and concentration?
• Has the level of confusion experienced by the
  patient tended to vary a lot recently from day to
  day or week to week?
• if yes to a or b
• Frequency 1 4
• Duration 0 - 4

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Clock Drawing Test(Gnanalingham et al 1996)
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ONE-DAY FLUCTUATION ASSESSMENT SCALE(Walker et
al 2000)

• Seven Item Scale
• FALLS
• FLUCTUATION
• DROWSINESS
• ATTENTION
• DISORGANISED THINKING
• ALTERED LEVEL OF CONSCIOUSNESS
• COMMUNICATION

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VALIDITY OF FLUCTUATION MEASURES (v AD)
MEASURE SENSITIVITY SPECIFICITY CUT-OFF
Clock Drawing (Gnanaligham et al 1996) C.A.F. (Walker et al 2000) O.F.A.S. (Walker et al 2000) 88 81 93 87 92 87 Drawgt copy gt5 gt6
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Treatment-Pharmacological

• CHEIs
• Other

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Cholinergic Hypothesis of DLB and PDD
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Summary of open label studies of cholinesterase
inhibitors in Dementia with Lewy Bodies.(Byrne
2005)
Study n Duration (weeks) Drug Results A/E
CattKaufer 1998 2 NR Donepezil Improvedsomnolence psychosis None
Shea et al 1998 9 12 Donepezil Improvedcognition visual hallucinations Worse EPS
Lancetot et al 2000 7 8 Donepezil ImprovedcognitionBPSD NR
MacLean et al 2001 8 NR Rivastigmin Improvedcognition sleep GI
Edwards et al 2004 25 24 Galantamin ImprovedBPSD GI
KeyMini-mental state score,Extended
Mini-mental state score, NRnot reported,
BPSDbehavioural and psychological symptoms of
dementia, GIgastro-intestinal symptoms.
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Efficacy of Rivastigmine DLB Cognition
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Efficacy of Rivastigmine DLB Independence
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Efficacy of Rivastigmine DLB
Behavioural/Psychotic Symptoms
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Other Treatments-Pharmacological (Byrne 2002,2005)

• Some Evidence
• Carbamazepine (Lebert et al 1995,1996)
• Chlormethiazole (Byrne 1995,McKeith et al 1992)
• L-Dopa (Williams et al 1993)
• Baclofen (Moutoussis Orrell 1996)

• Theoretical
• Nicotinic Agonosts
• NOS Inhibitors
• ?Co-Enzyme Q.
• Non-Pharmacological ?

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Conclusion

• DLB exists-but what is it?
• Challenge for management
• Stimulated new concepts on Neurodegeneration
• Subject to selective citation !