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Dementia with Lewy Bodies

Dementia with Lewy Bodies. Dr E Jane Byrne. Dementia with Lewy Bodies (DLB);Outline. What are Lewy Bodies The History of DLB Diagnostic criteria/concepts Epidemiology Clinical Features Treatment. What are they? Intracellular inclusion bodies

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Dementia with Lewy Bodies

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  1. Dementia with Lewy Bodies Dr E Jane Byrne

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

  3. 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 Lewy Body

  4. Cortical Lewy bodies Alpha-synuclein stain Ubiquitin stain

  5. 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 CA2 hippocampus - alpha synuclein reactive - also found in PD, ?HD

  6. 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) 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 ) History Review:Gibb et al 1987,Brain;110;1131-1153

  7. 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. History continued

  8. 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)

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

  10. 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). Lewy Bodies and Dementia “The senses and intellect being uninjured” James Parkinson 1817

  11. 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 Diagnostic Criteria

  12. Validity of Diagnostic Criteria

  13. History-Nottingham

  14. History-Nottingham & today

  15. SYMPTOMS OF DLB and/or PDD

  16. 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) Epidemiology (eg Zaccai et al 2005)

  17. 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

  18. 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 GammaSynuclein (breast cancer gene-specific product) Synoretin

  19. Byrne (2001)-Clinical features of the Synucleinopathies

  20. Synucleinopathies-Age&gender

  21. 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)

  22. 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

  23. 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

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

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

  26. 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

  27. Clock Drawing Test(Gnanalingham et al 1996)

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

  29. VALIDITY OF FLUCTUATION MEASURES (v AD)

  30. Treatment-Pharmacological • CHEIs • Other

  31. Cholinergic Hypothesis of DLB and PDD

  32. Summary of open label studies of cholinesterase inhibitors in Dementia with Lewy Bodies.(Byrne 2005) Key;*=Mini-mental state score,**=Extended Mini-mental state score, NR=not reported, BPSD=behavioural and psychological symptoms of dementia, GI=gastro-intestinal symptoms.

  33. Efficacy of Rivastigmine DLB – Cognition

  34. Efficacy of Rivastigmine DLB – Independence

  35. Efficacy of Rivastigmine DLB – Behavioural/Psychotic Symptoms

  36. 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 ? Other Treatments-Pharmacological (Byrne 2002,2005)

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

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