1. Changes in the age profile until the year 2030 19882030 Number in thousands 100 80 60 40 20 0 400 Age 1910 04008004000 8004000 Men Women From Maurer K., Ihl R., Fröhlich L., Alzheimer, Springer-Verlag, Heidelberg, 1993

2. World Population Prospects, The 2002 Revision Average annual growth rates of the world population Percentage (%) 4 3 2 1 0 0 – 14 3.39 15 – 59 60+80+ Age 2.29 0.72 -0.04 Average Annual Growth (2000-2050 Medium variant) One way or another we will all have to deal with the topic „dementia“!

3. Prevalence of dementia Prevalence Rate (%) 25 20 15 10 5 0 65–6970–7475–7980–84 Age 11.1 5.6 World (estimated) 85+ 23.6 2.8 1.4 Jorm et al., Acta Psychiatrica Scandinavica 1987 In the future, there will be more people in the higher-risk age groups!

4. The definition of dementia according to ICD-10 Symptoms Degree of severity Duration of symptoms Exclusion criteria Course Impairment of higher cortical functions, e.g. MemoryCalculation Learning abilitySpeech ThinkingOrientation Discriminatory capacity Impairment of personal activities of daily living 6 months+ Disturbed consciousness Chronic, progressive MemoryCalculation Learning abilitySpeech ThinkingOrientation Discriminatory capacity

5. Types of dementia EuropeNorth America Asia Fratiglioni et al., Drugs Aging 1999 Alzheimer‘s disease Vascular dementia Other 61.4%27.6% 11.0% 74.5% 10.0% 15.5% 46.5% 38.1% 15.4%

6. The classification of dementia - an overview From Ebert D, Psychiatrie systematisch. UNI-MED Verlag: Bremen 2. Aufl, 97/98 Dementia Degenerative (50%) 1° forms of dementia (90%) Vascular (15 – 30%) Mixed (15 – 25%) 2° forms of dementia (10%)  Cardiovascular disorders (13%)  Alcohol abuse (8%)  Metabolic diseases, vitamin deficiencies (4%)  Hydrocephalus (4%)  Encephalitis (1%)  Drugs (1%)  Cardiovascular disorders (13%)  Alcohol abuse (8%)  Metabolic diseases, vitamin deficiencies (4%)  Hydrocephalus (4%)  Encephalitis (1%)  Drugs (1%)

7. Dementia Degenerative (50%) 1° forms of dementia (90%) Vascular (15 – 30%) Mixed (15 – 25%) 2° forms of dementia (10%) Vascular dementia Macroangiopathy (infarcts or haemorrhages) – Strategic single infarcts Microangiopathy – Binswanger disease – Leukoencephalopathy – Lacunae – Amyloid angiopathy – Cerebral Autosomal Dominant Arteriopathy w/Subcortical Infarcts and Leukoencephalopathy CADASIL Disease progresses in steps At early stages, patient is aware of disease. often accompanied by emotional instability, depression, personality changes = degenerative dementia

8. Dementia Degenerative (50%) 1° forms of dementia (90%) Vascular (15 – 30%) Mixed (15 – 25%) 2° forms of dementia (10%) Degenerative dementia

9. Alzheimer-type dementia 53 % Parkinson´s disease 25 % Lewy body dementia 17 % Others 5 %

10. Diagnosis and treatment statistics of Alzheimer‘s disease On average, AD patients live 8 - 10 yrs post diagnosis AD can last for up to 20 years treated with modern therapy < 6% diagnosed (most in later stages) 52% treated 9% patients with AD in Europe ~ 8 Mio. Cognos Report, 2002

11. The costs of treating dementia with and w/o drug therapy Beske F, Geriatrie Praxis 5. 24 – 27, 1993 25 20 1990 Year Costs in billion EURO 1995200020052010 With therapyWithout therapy Example: Germany

12. Caregiver costs increase with increasing severity of dementia (Germany) Annual Costs (€) 16,000 12,000 8,000 4,000 Community Setting Institutional Setting Hallauer, 2002 MMSE 26 – 21 MMSE 20 – 15 MMSE 14 – 10 MMSE <10

13. Potential Reduction in Caregiver Time Figure adapted according to references Potential to reduce caregiver time increases with severity of the disease 30 mildmoderatesevereAD MMSE Score 20100 52h/month (Memantine) 3 7h/month (Donepezil) 1 12h/month (Galantamine) 2 1 Dement Geriatr Cogn Disord 2003; Erratum 2003 2 Chemical Business News Base 2001 3 Wimo et al., Pharmacoeconomics 2003

14. Socio-economic aspects of moderate to severe Alzheimer’s disease Caregiver burden and cost of illness is high in patients with moderate to severe AD. A treatment which is efficacious in these stages is expected to reduce caregiver and societal cost. Memantine treatment has been shown to reduce caregiver and societal costs (Wimo et al., 2003).

15. Criteria for assessing the severity of dementia Mild  Work and social activities clearly affected  Ability to live independently with adequate personal hygiene  Intact discriminative ability retained Moderate  Independent life possible, but w/certain reduction of competence  Certain, increasing amount of supervision required Severe  Activities of daily living are affected  Need for constant assistance and care  Patient is incapable of maintaining minimal personal hygiene  Loss of motor functions

16. 0 Age Level of performance 306090 Long-term memory Short-term memory Learning & Memory Long- and short-term memory over time

17. Criteria to differentiate age-associated memory impairment From Maurer K, Ihl R, Frölich L, Alzheimer. Springer-Verlag: Heidelberg 1993 Age 50+ years Complaints of disturbed memory in everyday situations

18. Criteria to differentiate age-associated memory impairment From Maurer K, Ihl R, Frölich L, Alzheimer. Springer-Verlag: Heidelberg 1993 Memory tests deviate from the performance of younger healthy subjects by more than one standard deviation No indication of dementia in relevant, dementia-specific tests (e.g. not below 24 MMSE points) Intellectual capacity and social competence adequate for everyday life Nature of deficits not progressive

19. Course of mental capacity and subjective symptoms in dementia patients Mild Severity of dementia After Lehrl, Blaha, Geistig Fit. Vless Verlag 1993 ModerateSevere Objective mental capacity Subjective sensation of symptoms

20. Typical symptoms of the onset of dementia Disturbed concentration Feeling of overstrain Quick exhaustibility Diffuse anxiety Depressive mood Lack of drive Loss of interest

21. Typical symptoms of advanced dementia Significant memory impairment (e.g. agnosia) Spatial and temporal disorientation Lack of motivation for house-work Neglect of personal hygiene Disturbed social behaviour (e.g. irritability) Disturbed motor functions

22. Clinical disease progression Years From Diagnosis 0 5 10 15 20 25 30 0123456789 MMSE Score MildSevereModerateCognitiveSymptoms Diagnosis Loss of Functional Independence Behavioral Problems Nursing Home Placement Death Reprinted from Clinical Diagnosis and Management of Alzheimer’s Disease, H Feldman and S Gracon; Alzheimer’s Disease:symptomatic drugs under development, pages 239-259, copyright 1996, with permission from Elsevier.

23. Progressive Loss of Activities of Daily Living Activities of Daily Living Progressive Loss of Function MMSE Score Keep Appointments Use the Telephone Obtain Meal/Snack Travel Alone Use Home Appliances Find Belongings Select Clothes Dress Groom 2520151050 02468 Years Maintain Hobby Dispose of Litter Clear Table Walk Eat MildModerateSevere Adapted from Galasko D, et al. Eur J Neurol. 1998;5(suppl 4):S9-S17.

24. Cerebral atrophy in Alzheimer-type dementia Top panel w/ kind permission of Prof. Dr. Braak, Klinikum der Johann Wolfgang Goethe University, (Centre for Morphology), Frankfurt, Germany Diseased Healthy

25. Clean-up debris & dead neuronal matter Structural & nutritional support Quantitative morphology in Alzheimer-type dementia Deviation from norm Hemisphere volumes- 13 to - 18% Number of neurones in cortical areas  Temporal lobes - 22 to - 44%  Frontal lobes - 26 to - 60%  Hippocampus - 43 to - 57% After Jellinger 1990. In: Maurer K, Ihl R, Frölich L, Alzheimer. Springer-Verlag: Heidelberg 1993 Number of synapses  Mid-frontal - 45 to - 55%  Parietal - 45 to - 55% Number of neurones in subcortical areas  N. basalis Meynert up to - 90%  N. raphe dorsalis - 36 to - 77% Volume of the ventricles + 35 to +55% Number of astroglia + 400 %

26. Alois Alzheimer 1864 - 1915 Historic background of AD Auguste D.(eter) 1850 - 1906

27. Neurofibrillary tangles and senile plaques in brain tissue Right: After Brun A, Englund E. Ann Neurol 19, 253–262, 1986

28. Hypotheses for the development of dementia After Frölich L, Psycho 12. 734–740, 1995 Apolipoprotein E risk factor hypothesis Glutamate toxicity hypothesis Oxygen radical hypothesis Glucose metabolism-insulin hypothesis Cortisol „stress“ hypothesis Immune hypothesis Glutamatergic cytotoxicity is the rationale for the effectiveness of NMDA antagonists, e.g. memantine!

29. Neurotransmitter disturbances in dementia Cholinergic system Glutamatergic system Noradrenergic systemDopaminergic system 70% Less than 30%

30. NMDAGlutamateACh ACh receptor Acetylcholinesterase Ca 2+ Glutamate uptake Glutamatergic and cholinergic transmission AChE Glia Neuron 2 Neuron 1 Neuron 3 AChE Choline + acetate Choline + acetate e.g. NBM Parsons and Danysz, unpublished Neuron 2

31. Glutamate is involved in physiological and pathophysiological processes Pathology Epileptogenesis Acute neuropathology Hypoxia/Ischaemia Stroke Trauma Chronic neuropathology Alzheimer‘s disease Huntington‘s disease Parkinson‘s disease Physiology Neuronal synaptic transmission Learning and memory Development Plasticity COOH CH 2 CH H2NH2N Glutamate

32. Autoradiographic imaging of glutamate binding sites Anatomie I, University of Cologne, Germany Control Alzheimer´s patient Hippocampus = site of memory Hippocampus = extremely high density of glutamate binding sites Rationale for drug Tx of memory loss: Target the glutamatergic pathway!!

33. NMDA receptor AMPA receptor Glutamate Magnesium + - - + Relevant signal arrivesGlutamate is released and binds to NMDA & AMPA receptors Na + flows through AMPA rec. - NMDA rec. remain blocked by Mg 2+ Na + flows leads to partial depolarisation Depolarisation removes Mg 2+ block of NMDA receptors Ca 2+ flows through NMDA channels Intracellular Ca 2+ levels increase Ca 2+ levels reach threshold leading to stabilization of plasticity (LTP) Danysz and Parsons, Int J Geriatr Psychiatry 2003 NMDA receptor and synaptic plasticity

34. Normal glutamatergic neurotransmission 2+ Ca Signal detection Learning signal Ca Resting state Signal Magnesium Glutamate NMDA receptor Calcium

35. Danysz and Parsons, unpublished Metabolic compromise NMDA receptor Inflammation ß-amyloid NMDA Receptor: A common target downstream of converting insults

36. Danysz et al., Neurotox Res 2000 Neurodegenerative dementia Pathological activation of NMDA receptors noise rest Ca 2+ Glutamate Magnesium Chronic neurodegeneration damaged neurons Ca 2+ signal noise signal not detected Impairment of plastic processes learning Ca 2+

37. The diagnosis of dementia After Füsgen I, Demenz. Medizin Verlag: Munich1992 Rationale: Differentiate 2° dementia Case history Supplemented by history reports third party Clinical status Laboratory diagnostics Psychiatric status Psychometric tests Examinations using technical equipment Neurological status

38. Guidelines for the doctor-patient interview - I Discriminatory ability, logical thinking – Conversation about daily events and hobbies – Explanation of a well-known saying – Difference and similarity: lake – river; stairs – ladder) Memory impairment – Questions about recent events – Naming 4 terms, terms to be repeated by the patient, recall test after 3 minutes

39. Guidelines for the doctor-patient interview - II Orientation Speech – Finding words, fluency of speech, content – Naming as many animals as possible within 1 min. State of consciousness Mood, drive, psychotic symptoms

40. Guidelines for the doctor-relative interview - I Daily living relevance of observed impairment – Forgetting previously well-known names or people – Losing important objects of everyday use – Frequent repetition of questions Thinking capacity – Difficulty in solving problems and making decisions, compared to earlier ability – Increasing avoidance of demanding activities

41. Guidelines for the doctor-relative interview - II Chronological course of the symptoms – First onset – Daily fluctuations Speech – Difficulty in finding words of everyday speech – Reduction in fluency of speech Behavioral problems – Aggressiveness, anxiety, depressive mood, restlessness, especially in demanding or complicated situations

42. Clinical examination to rule out 2° dementia - I Clinical examination – Cardiovascular system (ECG, blood pressure) – Pulmonary status (pulmonary function, thoracic X-ray) – Risk factor profile: Hypertension, diabetes mellitus, smoking, alcohol, obesity From Füsgen I, Demenz. Urban u. Vogel, 2001

43. Clinical examination to rule out 2° dementia - II Laboratory diagnostics – Blood sedimentation rate– Urea/Creatinine – Blood count– Folic acid and vitamin B 12 – Blood sugar– Urinalysis – Lipid levels– Thyroid function – Hepatic function (T 3, T 4, basal TSH) – Electrolytes From Füsgen I, Demenz. Urban u. Vogel, 2001

44. Typical symptoms of the onset of dementia Disturbed concentration Feeling of overstrain Quick exhaustibility Diffuse anxiety Depressive mood Lack of drive Loss of interest

45. Differentiation depression vs. dementia - I DementiaDepression After Füsgen I, Demenz. Urban u. Vogel, 2001 Rapid onset Duration < 6 months Fluctuating performance re. tasks of similar difficulty Oriented Knows how to find help Rather slow onset, Duration 6+ months Steady performance re. tasks of similar difficulty Disoriented Does not know how to find help

46. Differentiation depression vs. dementia - II After Füsgen I, Demenz. Urban u. Vogel, 2001 Dementia Depression Objective deficits < Subjective suffering Emotional morning low Libido reduced Antidepressant therapy successful Feeling of guilt Fear of failure Blame put on others Denial Libido retained Objective deficits > Subjective suffering Swift emotional changes Antidepressant therapy unsuccessful

47. Testing depression: The Geriatric Depression Scale (GDS) 47

48. Identification of cognitive deficits: The clock drawing test Patient #1 Errors Q1 1 Q2 1 Q3 1 Q4 4 Total 7 Patient #3 Errors Q1 1 Q2 1 Q3 1 Q4 4 Total 7 Patient #2 Errors Q1 1 Q2 0 Q3 1 Q4 0 Total 2 Test sheet

49. Typical MMSE Scores 29 – 30 pts = Healthy 20 – 24 pts = Mild Dementia 10 – 19 pts = Moderate Dementia 9 pts or less = Severe Dementia NOTE! „Ceiling Effect“: Well-educated patients w/mild dementia might be able to compensate for some deficits NOTE! „Floor Effect“: MMSE scores less useful in low-score range characteristic of patients w/severe dementia Identification of cognitive deficits & their severity: The Mini-Mental State Exam MMSE

50. Activities of Daily Living Progressive Loss of Function MMSE Score Keep Appointments Use the Telephone Obtain Meal/Snack Travel Alone Use Home Appliances Find Belongings Select Clothes 2520151050 02468 Years Dress Groom Maintain Hobby Dispose of Litter Clear Table Walk Eat MildModerateSevere Adapted from Galasko D, et al. Eur J Neurol. 1998;5(suppl 4):S9-S17. Identification of cognitive deficits & their severity: The Mini-Mental State Exam MMSE

51. Monitoring test - The NOSGER observer‘s rating scale

52. Imaging diagnostics in dementia Detection of morphological changes: – Computed tomography – Magnetic resonance imaging Evaluation of functional changes: – Functional MRI – Positron emission tomography – Single photon emission computed tomography

53. FDG-PET for diagnosis of dementia M. Pick – 69y male MID – 50y male Healthy control DAT – 60y maleSevere DAT – 64y female

54. The objectives of dementia therapy - I Mild Dementia Improve or stabilize cognitive performance Maintain or recover ability to care for oneself Maintain everyday competence

55. The objectives of dementia therapy - II Advanced Dementia Activate patient physically & mentally Delay (complete) nursing care Facilitate care Delay hospitalization

56. Important approaches to dementia therapy Psychosocial Therapy Pharmacotherapy Mental & Physical Training Care of Caregivers Consider social situation of patient Carefully setup timely care plan incl. all available caregivers Symptomatic therapy (stabilization of neurotransmission) Often improving cognition/emotions/motor functions Preserve cognitive & motor functions necessary to carry out activities of daily living as long as possible. Psychosocial support to caregivers should be integral part of any therapeutic concept

57. Advice for caregivers of dementia patients Short, simple sentences Fixed habits, simple rulesPatient, understanding attitude Avoid excessive demandsMake sure patient drinks enough fluid Don’t argue, distract

58. Antidementia drugs and nootropics – Mode of action Nootropics Effect on neuronal metabolismPiracetam Anti-dementia drugs Donepezil Rivastigmine Galantamine Cholinesterase inhibitors (AChEIs) Cholinergic neurotransmitter system Gingko biloba Vascular dilatationNicergoline Cerebral blood flow, radical scavenger NMDA antagonism Glutamatergic neurotransmitter system Memantine

59. Modified from: Handbuch der Arzneimitteltherapie I, 2001 (Fox et al.) +++ much improved; ++ clearly improved; + improved; Ø little/no effect; ? no data * ADL = Activities of Daily Living Antidementia drugs and nootropics - Positive selection criteria

60. Herschaft, H., Antidementiva in der Praxis, Uni-Med 2001 Tolerability of donepezil

61. Contraindications and restrictions on use After: Handbuch der Arzneimitteltherapie I, 2001 (Fox et al.) Ø no restrictions; ? no data; RU restriction on use; CI contraindication

62. Effect of memantine on AChE inhibitors Modified form Wenk et al., (2000) Life Sci. 12, 1079-1083 110 100 50 40 30 20 10 0 Cholinesterase activity (%) Control Donepezil 1 µM Tacrine 1 µM Galantamine 2 µM Memantine 5 µM – + Memantine and AChEIs use different neurotransmitter systems!

63. Neuroprotective effect of memantine Miguel-Hidalgo et al. (1998) Neurobiol. Aging 19: 542 Extent of ß-amyloid-induced damage in the CA1 region Placebo Extent (µm) 1000 Memantine 800 600 400 200 0 Memantine Placebo

64. Danysz et al., Neurotox Res 2000 Neurodegenerative dementia Pathological activation of NMDA receptors noise rest Ca 2+ Glutamate Magnesium Chronic neurodegeneration damaged neurons Ca 2+ signal noise Impairment of plastic processes learning Ca 2+

65. Effects of memantine Ca Resting state Neuroprotection by memantine Memantine improves dementia symptoms Pathological activation of NMDA receptors 2+ Ca Resting state Increased noise Physiological noise Signal Magnesium Glutamate Memantine NMDA receptor Calcium 2+ Ca Noise Learning signal Detection of signal

66. Kinetics of NMDA-Receptor Blockade Intermediate between Mg 2+ and MK-801 Mg 2+ shows very fast blockade of NMDA receptors and also fast unblockade MK-801 (+)MK-801 shows very slow blockade of NMDA receptors and also slow unblockade Memantine shows fast blockade of NMDA receptors Memantine Mg 2+ Peaks represent responses to application of NMDA time and also relatively fast unblockade Parsons et al., Neuropharmacology 1993

67. Improvement of activities of daily living (ADL) with memantine Görtelmeyer R, Erbler H. Drug Res 42, 904–913, 1992. (n = 82) * * * * * 10–1–2–3–4–5–6Time (sec) Improvement of ADL Dialing a telephone number Attaching a sticking plaster Tying a bow Closing a safety pin Fastening buttons Placebo Memantine Improvement of motor skills Improvement of cognition

68. Memantine-induced improvement of ADL in severe dementia Winblad B, Poritis N, Int. J. Geriat. Psychiatry 14, 135-146, 1999 (M-Best) * * * * * * * * Frequency of improvement (%) 0204060 Ability to stand up Ability to move Ability to wash Ability to take a bath/shower Ability to dress Toilet use Group activities Hobbies / interest Memantine Placebo * p < 0,05 63% of severely demented patients on memantine showed improvement of ADL

69. Improvement in cognition with memantine Stöffler et al., World Alzheimer’s Congress 2000, Washington, D.C., USA Memantine Decline Improvement Week 0Week 12Week 28  ADAS-cog score 2 1 0 -2 -3 -4 Placebo

70. Memantine-induced benefit re. cognition in moderately severe to severe AD Reisberg et al., 2000 Memantine Placebo p = 0.0018 Observed cases  SIB Score -12 -10 -8 -6 -4 -2 0 2 Week 4Week 12Week 28 Means ± SEM Decline Improvement

71. Placebo Means ± SEM p = 0.025 Reisberg et al., 2000 Decline Memantine Memantine-induced benefit re. global clinical impression (moderately severe/severe AD) CIBIC-Plus Global Score 4,0 4,2 4,4 4,6 4,8 5,0 Week 12Week 28 Observed cases

72. Increase in drive by memantine Pantev M, Ritter R, Görtelmeyer R, Zeitschr. f. Gerontopsychologie u. -psychiatrie 6: 103–117, 1993. (n = 66) Score 0 2 4 6 8 10 12 14 0 Improvement 1234Weeks BGP-Item: Inactivity Placebo Memantine

73. Long- term treatment with memantine Görtelmeyer, Pantev, Parsons, Quack: Spektrum der Neurorehabitilation, 1993 Placebo (n = 70) Memantine (n = 72) Score SCAG factor: cognitive impairment 0 15 16 17 18 19 20 86162432404856 Improvement Treatment/weeks End of double-blind phase

74. Efficacy of memantine in everyday practice 531 patients Rüther E. et al., Pharmacopsychiatry 33, 103-108, 2000 Unchanged 17% Worse 6% Improved 77%

75. 100 % 75 % 50 % 25 % 0 % Patients Treatment period (month) 01234From 5 onwards Poor Moderate Good Very good Use of memantine in everyday practice - I Rieke J, medwelt 47, 251–4, 1996. (n = 1420) Evaluation of memory

76. 100 % 75 % 50 % 25 % 0 % Patients Treatment period (month) 01234From 5 onwards Poor Moderate Good Very good Use of memantine in everyday practice - II Rieke J, medwelt 47, 251–4, 1996. (n = 1420) Evaluation of mood

77. Poor Moderate Good Very good Treatment period (month) 01234From 5 onwards 100 % 75 % 50 % 25 % 0 % Patients Use of memantine in everyday practice - III Rieke J, medwelt 47, 251–4, 1996. (n = 1420) Evaluation of motor function

78. Tolerability of memantine Rieke J, medwelt 47, 251–4, 1996. (n = 1420) No data (2.1 %) Poor (2.1 %) Moderate (2.0 %) Very good 56.5% Good 37.3%

79. Interactions with memantine Potential enhancing effect on: Barbiturates CNS depression: mild sedation  coma) Neuroleptics antipsychotic Anticholinergics anti-parasympathetic L-dopa und dopaminergic agonists (e.g. bromocriptine) anti-Parkinsonian Amantadine Modifying effect on: Dantrolene antispasmodic Baclofen antispasmodic Memantine Structure chemically closely related to that of memantine  Risk of pharmacopsychosis

80. Conclusions - I Dementia is a disease! Stop regarding dementia as a taboo Start treating dementia as early as possible Tx of all stages of dementia: An ethical obligation A doctor’s duty

81. Conclusions - II Counsel & support caregivers/relatives Keep patient in familiar environment as long as possible Determine Tx goal by severity of disease Bear in mind that slowed-down progression represents Tx success

82. Conclusions - III 70% of the excitatory synapses in the CNS are glutamatergic ones. In AD and VaD, the glutamatergic signaling pathway via NMDA receptors is impaired. The neuroprotective NMDA antagonist memantine is clinically effective in the treatment of dementia. Appropriate therapy has socioeconomic impact by reducing the costs of nursing and care.