1. CU-1 Summary of Neuropathological and Clinical Features of PDD Clive Ballard, MD Professor of Age Related Diseases Institute of Psychiatry King’s College London

2. CU-2 Overview  PDD is a distinct dementia syndrome  PDD can be diagnosed unambiguously in routine clinical practice  PDD is a rational target for treatment

3. CU-3 Study by Clinical informationNeuropathology NFamiliesLewy bodiesGenetic findings Golbe et al, 1990, 1996; Duda et al, 2002 601SN + NCA53T SNCA mutation Waters and Miller, 1994; Muenter et al, 1998; Farrer et al, 1999; Singleton et al, 2003 221SN + NCPARK4. SNCA gene triplication. Spira et al, 200151SN + NCA53T SNCA mutation Ohtake et al, 200411Autopsy not performed V70M beta synuclein mutation Krüger et al, 1998, 200151Autopsy not performed A30P SNCA mutation Zarranz et al, 200451 SN + NCE46K SNCA mutation Genetic Associations of PDD in Familial PD— Kurz et al, 2006 † SN = Sub-stantia nigra; NC = Neocortex. † Kurz et al. Dementia and Geriatr Cog Disorders. In press.

4. CU-4 Relationship Between Pathology and Duration of PD Before Dementia Plaques (CERAD) n (%) Braak stage n (%) Meet diagnostic criteria for AD n (%) DLB (n = 29) †§ Frequent 19 (66) 5/6 3 (10)9 (31) PD for 1 - 9.5 yr before dementia (n = 14) †‡ Frequent 2 (14) 5/6 2 (14) 2 (7) PD for > 9.5 yr before dementia (n = 14) †‡ Frequent 3 (21)5/6 0 (0) † Aarsland D, et al. Ann Neurol. 2005:58;773-776. ‡ Perry R, et al. Neurol. 2006. In press. § Ballard C, et al. Am J Psychiat. 2004:161;843-849.

5. CU-5 PDD Predicts a Characteristic Neuropathologic and Clinical Profile  Lewy body pathology (LBP) is the predominant substrate of cognitive decline in PDD  Overlapping AD plaque pathology is not the main correlate of dementia in PDD patients  93% to 94% of patients with PDD lack sufficient pathologic changes to meet diagnostic criteria for AD  Dementia in PDD has a characteristic profile of neuropsychiatric, cognitive, neurologic, and autonomic features

6. CU-6 Attention and Fluctuating Attention in PDD and AD Ballard C, et al. Neurology. 2002; 59:1714-1720. p < 0.0001

7. CU-7 Clinical Symptoms of PDD vs AD PDD (N = 34) AD (N = 92) Major depression 28% 8% Fluctuation 82% 4% Falls 71%21% Visual hallucinations 74%16% Parkinsonism100% 7% Ballard C, et al. Am J Psych. 1999;156:1039-1045. Ballard C, et al. J Clin Psych. 2001;2001:46-49.

8. CU-8 Median (IQR) Diagnosis Control (N = 42) AD (N = 39) PDD (N = 40) Median of mean change in heart rate during deep breathing 7.4 (5.3-9.7) 7.5 (3.3-9.2) 3.3 (2.3 - 5.8) Median Valsalva Ratio1.33 (1.20-1.62) 1.34 (1.19-1.56) 1.14 (1.06 - 1.22) Median heart rate response to standing 1.14 (1.09-1.19) 1.10 (1.03-1.23) 1.04 (1.01 - 1.11) Autonomic Function (Parasympathetic) in AD and PDD PDD vs. AD: p-value <0.05 for all comparisons. PDD vs. Controls: p-value <0.001 for all comparisons. Kenny RA, et al. Dementia with Lewy Bodies and Parkinson’s Disease Dementia. 2006. Taylor & Francis Pub.

9. CU-9 PDD Can be Diagnosed Simply and Unambiguously in Routine Clinical Practice  Diagnosis of PDD is straightforward in routine clinical practice using 3 simple principles – Established diagnosis of Parkinson’s disease – Developing dementia at least 1 to 2 yrs after onset of PD – Exclusion of other causes of dementia, eg, VaD, MSA, PSP

10. CU-10 Severe Neuroleptic Sensitivity Reactions in PDD and AD  Severe neuroleptic sensitivity reactions (NSR), characterized by severe parkinsonism, autonomic instability, increased confusion, rhabdomyolysis, and often death  Severe NSR occurs in – > 30% of DLB †‡§ and PDD † – 0% of AD †‡§ † Aarsland D, et al. J Clin Psych. 2005;66:633-637. ‡ McKeith I, et al. BMJ. 1992;305:673-678. § Ballard C, et al. Lancet. 1998;351:1032-1033.

11. CU-11 Cholinergic Deficits in PDD  There is established cholinergic deficit in PDD  The cholinergic deficits are associated with many of the key neuropsychiatric symptoms and cognitive deficits AuthorTechnique Disease subgroups ADPDPDD Perry, 1985Neurochem (ChAT)  Ruberg, 1986Neurochem (AChE)N/A // /  † Tiraboschi, 2000Neurochem (ChAT)  N/A  Mattila, 2001Neurochem (ChAT)N/A  ‡ Bohnen, 2003PET (AChE activity)  † AChE total/AChE 10S form. ‡ Included PD/PDD together.

12. CU-12 Conclusions  Lewy body-related alpha-synucleinopathy is the pathology predominantly associated with cognitive impairment in PDD  PDD can most effectively be diagnosed using simple clinical criteria based on the presence of PD and the time course of development of dementia  The shared cholinergic deficit in PDD and AD presents a common treatment target