Byrne.001

Dementia with Lewy Bodies: 

Dementia with Lewy Bodies Dr E Jane Byrne

Dementia with Lewy Bodies (DLB);Outline: 

Dementia with Lewy Bodies (DLB);Outline What are Lewy Bodies The History of DLB Diagnostic criteria/concepts Epidemiology Clinical Features Treatment

Lewy Body: 

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

Cortical Lewy bodies: 

Cortical Lewy bodies Alpha-synuclein stain Ubiquitin stain

DLB – LB’s LN’s: 

DLB – LB’s LN’s LB – intraneuronal filamentous inclusion body - ubiquitin, alpha synuclein - Deep cortical layers,subcortical Lewy Neurites (LN’s) - ubiquitin reactive neuritic processes in CA 2 hippocampus - alpha synuclein reactive - also found in PD, ?HD

History: 

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 4 th in(1996) Modern era Nottingham; 1987-1992,first large case series,first use of ubiquitn,first diagnostic criteria,link to PD ( Byrne et al) Newcastle;1990-present,”SDLT”,fluctuations emphasis/measures,EEG, imaging studies,host CDLB-diagnostic criteria.( McKeith ) O San Diego; 1990-present;”lewy body variant of AD”,psychology( Hansen ) Review:Gibb et al 1987,Brain; 110 ;1131-1153

History continued: 

History continued Manchester 1992-present First comparison’s with Parkinson’s disease,review of synucleinopathies,studies of carers,sleep and gender,”CLOX” Recent concepts α -synuclein immunocytochemistry (Spillantini et al 1998) Association with sleep disorders (Boeve et al 1998,2001) Re-discovery of the spectrum of LB disorders.

Concepts: 

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 Alzheimer’s Disease (Hansen et al (1990) A Synucleinopathy (Boeve et al (2000),Byrne (2001)

What is Parkinsonian ?: 

What is Parkinsonian ? Classical Tremor Rigidity Postural instability/change Bradykinesia Gait Abnormality Debateable Falls Fluctuating cognition Neuroleptic sensitivity Secondary symptoms-Depression,Hallucinations

Lewy Bodies and Dementia: 

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

Diagnostic Criteria: 

Diagnostic Criteria Nottingham (Byrne et al 1991) Probable & Possible Probable; A-Dementia; with attentional deficits or PD with late dementia or Dementia & P’ism B- No Stroke,No Focal C- 3 P’ism ( 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 P’ism. Supportive No Stroke, No Other

Validity of Diagnostic Criteria: 

Validity of Diagnostic Criteria Study Nott’m Newc’le ICC Byrne et al (1995) Sens=0.17 Spec=0.95 Sens=0.15 Spec=0.93 N/A Lopez et al (2002) N/A N/A Sens=0.31 Spec=1.0 McKeith et al (2002) N/A N/A Sens=0.83 (0.22-1-in lit) Spec=0.95

History-Nottingham: 

History-Nottingham Clinical Byrne et al (1989)-n=15 Literature-n=51 Park’ism 6(40) 3(6) P’ism & Psych 3(20) 1(2) Psych 6(40) 34(67) Other 0 2(4) Unspecified 0 11(22)

History-Nottingham & today: 

History-Nottingham & today Feature Byrne et al (1989) Literature-post 1989 Fluctuation 80%(overall) 75%(overall) Visual Hall. 26.7%(pres) 33%(pres) P’ism 40%(pres) 40-90% Depression 20% 33% Delusions 13.3% 65% Auditory H 6.6% 13%

SYMPTOMS OF DLB and/or PDD: 

SYMPTOMS OF DLB and/or PDD

Epidemiology (eg Zaccai et al 2005): 

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 2002;Ballard et al 1993) Incidence; 0.1%(commun),2-3.2 (clinical)- (Lopez-Pousa 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

DLB – A Synucleinopathy?: 

DLB – A Synucleinopathy? Synucleinopathies Tauopathies Parkinson’s Disease Alzheimer’s Disease DLB FTD (sporadic, Familial Familial AD-APP PSP) PS1, PS2 Corticobasal Degen’n Down’s Syndrome MSA Hallervarden-Spatz Adapted from:- Goedert 1999, Spillantini et al 1998, Galvin et al 2001

DLB - Synuclein: 

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

Slide 20: 

FEATURES PARKINSON’S 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 Byrne (2001)-Clinical features of the Synucleinopathies

Synucleinopathies-Age&gender: 

Synucleinopathies-Age&gender Disease Age Onset Gender Ratio MSA 90% before 65years 1:1 (Quinn 1997) PD Increased prevalence with age 1:1(de Rijk et al 1997)1.2-1.5(Lai&Tsui 2001) DLB Commoner 65y+,?F older,?pure>M 1.6:1(Ala et al 1997,Byrne et al 2003)

RBD – Rapid Eye Movement Sleep Behaviour Disorder: 

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)

RBD-History: 

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

RBD-recent prevalence studies: 

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

RBD-Treatment: 

RBD-Treatment Advice for sleep partners! Clonazepam 0.5 mg-1.5 mg nocte TCA’s(Imipramine-equivocal) Melatonin

MEASUREMENT OF FLUCTUATION IN DLB: 

MEASUREMENT OF FLUCTUATION IN DLB Clock Drawing Test Electroencephalography Clinical Assessment of Fluctuation One Day Fluctuation Assessment Scale

CLINICAL ASSESSMENT OF FLUCTUATION (Walker et al 2000): 

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

Clock Drawing Test (Gnanalingham et al 1996): 

Clock Drawing Test (Gnanalingham et al 1996)

ONE-DAY FLUCTUATION ASSESSMENT SCALE (Walker et al 2000): 

ONE-DAY FLUCTUATION ASSESSMENT SCALE (Walker et al 2000) Seven Item Scale FALLS FLUCTUATION DROWSINESS ATTENTION DISORGANISED THINKING ALTERED LEVEL OF CONSCIOUSNESS COMMUNICATION

VALIDITY OF FLUCTUATION MEASURES (v AD): 

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% Draw > copy > 5 > 6

Treatment-Pharmacological: 

Treatment-Pharmacological CHEIs Other

Cholinergic Hypothesis of DLB and PDD : 

Cholinergic Hypothesis of DLB and PDD

Slide 33: 

Summary of open label studies of cholinesterase inhibitors in Dementia with Lewy Bodies.(Byrne 2005) Study n Duration (weeks) Drug Results A/E Catt&Kaufer 1998 2 NR Donepezil Improved;somnolence& psychosis None Shea et al 1998 9 12 Donepezil Improved;cognition*& visual hallucinations Worse EPS Lancetot et al 2000 7 8 Donepezil Improved;cognition*&BPSD NR MacLean et al 2001 8 NR Rivastigmin Improved;cognition**& sleep GI Edwards et al 2004 25 24 Galantamin Improved;BPSD GI

Efficacy of Rivastigmine DLB – Cognition : 

Efficacy of Rivastigmine DLB – Cognition

Efficacy of Rivastigmine DLB – Independence: 

Efficacy of Rivastigmine DLB – Independence

Efficacy of Rivastigmine DLB – Behavioural/Psychotic Symptoms: 

Efficacy of Rivastigmine DLB – Behavioural/Psychotic Symptoms

Other Treatments-Pharmacological (Byrne 2002,2005): 

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 ?

Conclusion: 

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