Treating Alzheimer s Disease. Alexander Kurz Department of Psychiatry Technische Universität München Munich, Germany

Transcription

1 Treating Alzheimer s Disease Alexander Kurz Department of Psychiatry Technische Universität München Munich, Germany

2 1What is Alzheimer s disease?

3 A complex cascade of pathological events

4 precursor molecule nerve cell

5 precursor molecule production nerve cell

6 precursor molecule degradation production nerve cell

7 precursor molecule degradation clearance blood stream production nerve cell elimination blood vessel wall

8 precursor molecule degradation clearance blood stream production re-entry nerve cell plaque aggregation elimination blood vessel wall

9 precursor molecule degradation clearance blood stream production re-entry nerve cell plaque aggregation damaged dendrites elimination blood vessel wall tau tau aggregation microtubules

10 precursor molecule degradation clearance blood stream production re-entry nerve cell plaque aggregation damaged dendrites elimination blood vessel wall tau tau aggregation microtubules acetylcholine deficient normal signal transmission

11 precursor molecule degradation clearance blood stream production re-entry nerve cell plaque aggregation damaged dendrites defunct nerve cell elimination blood vessel wall tau tau aggregation microtubules acetylcholine deficient normal signal transmission

12 precursor molecule degradation clearance blood stream production re-entry nerve cell plaque aggregation damaged dendrites defunct nerve cell elimination glutamate blood vessel wall tau tau aggregation microtubules acetylcholine deficient normal signal transmission

13 precursor molecule degradation clearance blood stream production re-entry nerve cell plaque aggregation damaged dendrites defunct nerve cell elimination glutamate blood vessel wall tau tau aggregation excessive abnormal signal transmission microtubules acetylcholine deficient normal signal transmission

14 These events gradually destroy large parts of the brain

15 First phase: Clinically silent Years 0-5 No symptoms years Braak et al., Acta Neuropathol 112: , 2006 Elias et al., Arch Neurol 57: , 2000

16 First phase: Clinically silent Years 6-10 No symptoms years Braak et al., Acta Neuropathol 112: , 2006 Elias et al., Arch Neurol 57: , 2000

17 Second phase: Mild cognitive impairment Years First symptoms: forgetfulness years Braak et al., Acta Neuropathol 112: , 2006 Elias et al., Arch Neurol 57: , 2000

18 Second phase: Mild cognitive impairment Years Memory continues to deteriorate years Braak et al., Acta Neuropathol 112: , 2006 Elias et al., Arch Neurol 57: , 2000

19 Third phase: Dementia Years Mild dementia years Braak et al., Acta Neuropathol 112: , 2006 Elias et al., Arch Neurol 57: , 2000

20 Third phase: Dementia years Years Mild dementia Diagnosis Braak et al., Acta Neuropathol 112: , 2006 Elias et al., Arch Neurol 57: , 2000

21 Third phase: Dementia Years Severe dementia years Braak et al., Acta Neuropathol 112: , 2006 Elias et al., Arch Neurol 57: , 2000

22 2 How do current treatments work?

23 They strike at the final leg of the pathological cascade Some restore deficient normal signal transmission mediated by acetylcholine acetylcholine deficient normal signal transmission

24 They strike at the final leg of the pathological cascade Others attenuate exessive abnormal signal transmission effected by glutamate defunct nerve cell glutamate excessive abnormal signal transmission

25 Cholinesterase inhibitors restore acetylcholine The neurotransmitter acetylcholine is rapidly inactivated by the enzyme cholinesterase. acetylcholine cholinesterase acetylcholine receptor

26 Cholinesterase inhibitors restore acetylcholine Cholinesterase inhibitors block the action of the enzyme and thus increase the amount of available acetylcholine. acetylcholine cholinesterase inhibitor acetylcholine receptor

27 Cholinesterase inhibitors restore acetylcholine Cholinesterase inhibitors block the action of the enzyme and thus increase the amount of available acetylcholine. acetylcholine cholinesterase inhibitor Cholinesterase inhibitors Janssen Novartis Pfizer / Eisai Galantamin Rivastigmin Donepezil acetylcholine receptor

28 Memantine attenuates glutamate toxicity Excess amounts of glutamate are released from degenerating nerve cells and over-stimulate neighbouring cells. glutamate glutamate receptor

29 Memantine attenuates glutamate toxicity Memantine partially blocks glutamate receptors and prevents nerve cells from toxic over-stimulation. memantine

30 Memantine attenuates glutamate toxicity Memantine partially blocks glutamate receptors and prevents nerve cells from toxic over-stimulation. memantine

31 Memantine attenuates glutamate toxicity Memantine partially blocks glutamate receptors and prevents nerve cells from toxic over-stimulation. memantine Glutamate receptor modulator Lundbeck / Forrest Memantine

32 performance Effects on symptoms, not on underlying disease Current treatments can only be used after the onset of dementia. dementia threshold no treatment years 30 Kurz & Lautenschlager, in: Ames et al. (eds) Dementia, 5 ed., , 2010

33 performance Effects on symptoms, not on underlying disease They delay the progression of symptoms. dementia threshold no treatment treatment years 30 Kurz & Lautenschlager, in: Ames et al. (eds) Dementia, 5 ed., , 2010

34 Example 1: Cholinesterase inhibitor 1 treatment 0 Mini Mental State Examination Score - 1 significant difference - 2 Donepezil Placebo no active treatment week Treatment with a cholinesterase inhibitor delays the decline of cognitive ability. Winblad et al., Neurology 57: , 2001

35 30 Example 1: Cholinesterase inhibitor Mini Mental State Examination Score 1 treatment units - 1 significant difference - 2 Donepezil no active treatment 10 Placebo week 10 % less decline from baseline The treatment effect is statistically significant. However, the size is small to moderate. 0 MMSE Winblad et al., Neurology 57: , 2001

36 % of patients Example 2: Cholinesterase inhibitor 100 No functional decline treatment Treatment with a cholinesterase inhibitor maintains functional ability % 35 % 0 no active treatment 0 week % lower likelihood of clinically evident functional decline Mohs et al., Neurology 57: , 2001

37 Example 3: Glutamate receptor modulator Severe Impairment Battery Score treatment Treatment with a glutamate receptor modulator provides similar benefits. significant difference no active treatment week Reisberg et al., N Engl J Med 348: , 2003

38 3 Which novel treatments are being developed?

39 precursor molecule They target upstream events in the pathological cascade.

40 precursor molecule production

41 precursor molecule production production inhibitors

42 precursor molecule Anti- production inhibitors production Bristol-Myers Squibb BMS CoMentis CTS2166 Eli Lilly Semagacestat Exonhit Glaxo Smith Kline EHT0202 GSK production inhibitors Hoffmann-LaRoche Wyeth Ro Begacestat

43 precursor molecule degradation production

44 precursor molecule degradation production degradation stimulants

45 precursor molecule degradation production degradation stimulants degradation stimulants Not in clinical trials Ginsenoside Rb3 Not in clinical trials GW 3965

46 precursor molecule degradation clearance blood stream production plaque elimination blood vessel wall

47 precursor molecule degradation clearance blood stream production plaque clearance enhancers elimination blood vessel wall

48 precursor molecule degradation clearance blood stream production plaque clearance enhancers elimination blood vessel wall clearance enhancers Not in clinical trials Not in clinical trials Nilvadipine Nitredipine

49 precursor molecule degradation clearance blood stream production re-entry plaque elimination blood vessel wall

50 precursor molecule degradation clearance blood stream production re-entry plaque re-entry blockers elimination blood vessel wall

51 precursor molecule degradation clearance blood stream production re-entry plaque re-entry blockers elimination re-entry blockers blood vessel wall Pfizer PF Baxter Gammagard

52 precursor molecule degradation clearance blood stream production re-entry plaque aggregation elimination blood vessel wall

53 precursor molecule degradation clearance blood stream production re-entry plaque aggregation aggregation inhibitors elimination blood vessel wall

54 precursor molecule degradation clearance blood stream production re-entry plaque aggregation aggregation inhibitors elimination blood vessel wall aggregation inhibitors Prana Elan PBT2 Scyllo-inositol

55 precursor molecule degradation clearance blood stream production re-entry plaque aggregation anti- immunisation elimination blood vessel wall

56 precursor molecule degradation clearance blood stream production re-entry plaque aggregation Anti- immunisation (active) anti- immunisation elimination Affiris AD01/AD02 Genentech MABT5102A Merck Novartis Pfizer United Biomedical V950 CAD-106 ACC001 UB311 blood vessel wall

57 precursor molecule degradation clearance blood stream production re-entry plaque aggregation Anti- immunisation (passive) anti- immunisation elimination Eli LIlly Solanezumab Glaxo Smith Kline GSK933776A Hoffmann-LaRoche Pfizer / Janssen Gantenerumab Bapineuzumab blood vessel wall

58 precursor molecule degradation clearance blood stream production re-entry plaque aggregation damaged dendrites elimination blood vessel wall tau tau aggregation microtubules acetylcholine

59 precursor molecule degradation clearance blood stream production re-entry plaque aggregation damaged dendrites aggregation inhibitors elimination blood vessel wall tau tau aggregation microtubules acetylcholine

60 precursor molecule degradation clearance blood stream production re-entry plaque aggregation damaged dendrites aggregation inhibitors elimination blood vessel wall tau tau aggregation Tau aggregation inhibitors Noscira Tideglusib microtubules acetylcholine TauRx Methylmethonium

61 Example: Anti- immunisation (active) No treatment Numerous deposits and neurofibrillary tangles. Boche et al., Acta Neuropathol 120: , 2010

62 Example: Anti- immunisation (active) Treatment The deposits have vanished, neurofibrillary tangles remain. Boche et al., Acta Neuropathol 120: , 2010

63 Example: Anti- immunisation (passive) Before treatment Positron emission tomography scan shows widespread deposition of. Rinne et al., Lancet Neurology 9: , 2010

64 Example: Anti- immunisation (passive) After treatment Significant reduction of load. Rinne et al., Lancet Neurology 9: , 2010

65 performance A number of strategies aim at slowing the disease If used early, severe cognitive decline and ensuing disability may be prevented. treatment dementia threshold no treatment years 30 Kurz & Perneczky Prog Neuropsycho-pharmacol Biol Psychiatry 35; , 2011

66 performance A number of strategies aim at slowing the disease current treatments The time patients and carers must cope with progressive cognitive impairment will be extended. no treatment years 30 Kurz & Perneczky Prog Neuropsycho-pharmacol Biol Psychiatry 35; , 2011

67 4Conclusions

68 Conclusions Current medications address the final leg of a complex cascade of pathological events. Benefits are of moderate size and short duration. Novel treatments are being developed which target upstream events. The aims are to slow down the pathological cascade and to prevent severe cognitive decline and ensuing disability. Several different strategies are being pursued, most of which focus on lowering the production or deposition of. In conjunction with early diagnosis the novel treatments will provide extended time and greater ability for coping with cognitive impairment. The novel treatments will increase the need for and the prospects of nonpharmacological interventions.

69 Thank you!

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