The document discusses the benefits of physical exercise on cognitive function in older adults and patients with Alzheimer's disease or mild cognitive impairment. It provides evidence from multiple reviews and studies that both aerobic and resistance training can improve executive function and delay cognitive decline. The document also describes results from trials conducted by the author showing that regular physical exercise interventions led to sustained or improved cognitive performance and functional abilities in MCI patients and helped maintain cognitive skills longer in Alzheimer's patients compared to control groups without exercise.

1. Physical activities and Cognitive function Magda Tsolaki, MD, PhD Neuropsychiatrist Professor of Aristotle University of Thessaloniki Chair of Greek Alzheimer Federation www.alzheimer-hellas.gr

3. Age is #1 Dementia Risk Factor

4. Numbers in Greece 1. Prevalence , 9% in subjects more than 70 in Pylea, Thessaloniki 2. In Great Alexander municipality 3,6% >65 Tsolaki M. et al, AJAD, 1999 Tsolaki M. et al, ADI2010 Family Ε4 (11% vs 32% ) Olive oil 06/01/11

5. Alzheimer's disease

12. MIND YOUR BODY and YOUR BRAIN

13. Alzheimer Disease Progression Deterioration Time in years From S GAUTHIER 1996  Clinical Phase ? Mood disturbances Cognitive impairments Impaired activities of daily living ADL Behavioural disturbances Motor disorders

14. LITERATURE P articipation in both aerobic and resistance training exercises alone, and in combination, leads to sustained improvements in cognitive performance, particularly for executive control tasks ( MEDICINE & SCIENCE IN SPORTS & EXERCISE , 2009 ; 1510-1530)

15. Guidelines for Physical Activities

16. Physical Exercise: Mechanisms of action 1.CNS neuronal apoptosis is a consequence of exercise in the adult rat and suggests that this process is a potential mediator of rapid exercise-induced plasticity. Exercise in mouse models causes neurogenesis in the dentate gyrus. Alzheimers Res Ther. 2011 Feb

17. Physical Exercise: Mechanisms of action 2.Exercise engages arousal mechanisms in the reticular-activating system, which involves a big number of neurotransmitter systems. 3. Exercise, also, disengages the higher-order functions of the prefrontal cortex. 4. Improvement of blood circulation and brain oxygen supply J. Am Geriatr. Soc., 38, 123-128, 1990.

18. Possible effect of interventions which delay the onset of dementia Prevalence in USA Delay (years)

19. ANIMAL MODELS ( Combination of physical and cognitive exercise )

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22. Other MECHANISMS The current experiment assessed levels of apoptosis , angiogenesis , and neurogenesis during the first week of an exercise regimen in the adult rat. The results indicate that exercise rapidly induces these processes in the hippocampus and cerebellum Behav Neurosci. 2011 Feb

23. TRIALS IN HUMANS ( ONLY PHYSICAL EXERCISE )

24. ACSM (American College of Sports Medicine), 2009 At least 3 times a week for two weeks ~ 1 hour Warm-up period 5-10 min. Main Part 40-50 min. Stretching 8-10 min. Strength (upper body) 10-15 min Flexibility - Aerobic 8-10 min. Balance – Strength (lower body) 15 min. Cool down period 5 min

25. FFA, Scientific issues Organized interventions of Increased difficulty Assessment Subjective criteria : Heart rate and blood pressure Subjective criteria : Borg Scal e Borg Scale

26. Physical exercise and cognitive function Multiple results of physical exercise on cognitive function 3 reviews -meta-analysis and 7 studies Principles Scientific model of improvement of cognitive functions – clear methodology and target Severity of exercise according the abilities of participants. – step by step changes of exercises Every patient can do different activities Balance between duration of exercise and frequency

27. Physical exercise and Cognitive function Principles of body exercise Medical follow up Organization of the program according abilities Use of experience Encourage of independence Characteristics of exercise : Simple , preparation – main part - relaxation Socialization

28. Physical exercise and Cognitive function Suggestions Duration (31 – 45 mins ) Bigger improvement ( more than 6 months) . Moderate aerobic exercise

29. Authors Year Participants Intervention Results Molloy et al 1988 N= 15, MMSE: 24 1 st group : mild aerobic exercise 45΄/ once a week for two weeks 2 nd group : no intervention Improvement in verbal fluency Mulrow et al 1994 N= 194, MMSE: 21 1 st group ασκήσεις ενδυνάμωσης, ισορροπίας, κινητικότητας. 2 η ομάδα: φιλικές επισκέψεις. 45΄/ 3 φορές την εβδομάδα/ 16 εβδομάδες Moderate motor improvement Baum et al 2003 N= 20 MMSE: 21 1 η ομάδα: εύρος κινητικότητας καθισμένου 2 η ομάδα: ψυχαγωγικές δραστηριότητες 60΄/ 3 φορές την εβδομάδα/ 6 μήνες Improvement in physical status and MMSE Stevens et al 2006 N= 75 MMSE: 9 - 23 1 η ομάδα: σωματική άσκηση 2 η ομάδα: κοινωνικές επισκέψεις 30΄/ 3 φορές την εβδομάδα/ 12 εβδομάδες 2 η ομάδα: καμία παρέμβαση Delay of cognitive and physical deterioration

31. Physical Exercise Proximal F/U Hillman et al. Nature Reviews Neuroscience (2008)

32. RCT of PE x in MCI with Longitudinal FU

33. RCT of PE x in MCI with Longitudinal FU Lautenschlager et al. 2008

34. RCT of PE x in MCI with Longitudinal FU

35. RCT of PE x in MCI with Longitudinal FU

36. PEx Reorganises Hippocampal Synaptic Connectivity Joyce Siette In preparation

37. What about combining cBT and PEx?

39. TRIALS IN HUMAN (PROTECTIVE)

40. Can Physical Exercise Prevent Cognitive Decline?

41. PHYSICAL EXERCISE AND DEMENTIA P hysical activity or exercise can prevent or delay the onset of age-related cognitive impairment or dementia ( Middleton K.R., 2007) P ositive effects of physical activity on attention, memory, communication, executive functions and global mental functioning, in older people with dementia. ( Eggermont L., Swaab D., et al, 2005; Fang Yu, Kolanowski A. M., 2006)

43. TRIALS IN HUMAN (THERAPEUTIC)

47. OUR EXPERIENCE RHEA, a non pharmacological cognitive training intervention in patients with Mild Cognitive Impairment ( MCI): A Pilot Study Kounti F, 1, 2 Bakoglidou E, 1, 2 Agogiatou C, 1, 2 Emerson Lombardo NB, 5 Serper LL, 4 Tsolaki M 1, 2, 3

48. PARTICIPANTS 58 MCI patients with MMSE= 27.69 , assigned to 2 groups of 29 each (experimental, 20-weekly RHEA sessions, and no-therapy control), matched for age, gender, education, cholinesterase inhibitors, cognitive abilities.

49. NEUROPSYCHOLOGICAL TESTS MMSE [ Mini Mental State Examination - MMSE ( Roth , Huppert , Tum , & Mouthjoy , 1988)] TEA [ Test of Every Day Attention( Robertson et al., 1989)] RBMT [Rivermead Behavioural Memory Test ( Wilson et al., 1989) ] ROCFT [Rey Osterreith Complex Figure Test (Rey, 1941) ]

50. NEUROPSYCHOLOGICAL TESTS FUCAS [ Functional Cognitive Assessment Scale - FUCAS ( Kounti , Efklides, Tsolaki , & Kiosseoglou , 200 6 )] WCST [Wisconsin Card Sorting Test ( Berg , 1948) ] ΧΣΑ [Verbal fluency (Kosmidis , Vlachou , Panagiotaki , & Kiosseoglou , 2004) ] FRSSD [ Functional Rating Scale of Symptoms of Dementia - FRSSD ( Hutton , 1990) ]

51. RHEA Intervention Design and Rationale The RHEA intervention was 90 minutes duration, once a week, for 20 weeks. The tasks are ecological. The stimuli that are used are shapes, colours, sizes, and numbers. The technical materials include wreath, boards with letters, cards with colours, shapes and numbers, corridors with numbers, balls, wands, rings, and cones.

52. RHEA Intervention Design and Rationale Each session includes 5 exercises lasting approximately 15 minutes each. The program has tasks with an increasing degree of difficulty varying according to the cognitive and kinetic performance of the participants

53. 1 st Exercise (Free movements)

54. 1 st Exercise (Free movements)

55. 2 nd Exercise: Walking

56. 2 nd Exercise (Walking)

57. 3 rd Exercise (Balance)

58. 3 rd Exercise (Balance)

59. 4 th Exercise (mild movement abilities)

60. 4 th Exercise (mild movement abilities)

61. 5 th Exercise (Free voluntary movements)

62. 5 th Exercise (Free voluntary movements)

63. Results (MCI) The benefit of the experimental group was in Attention (p=0.002), Language(p=0.015), Visual-spatial (p=0.013), MMSE (p=0.047), ADL(p=0.009). Experimental participants improved cognitive and functional performances while control participants remained stable.

64. OUR EXPERIENCE EFFECTS OF AN EXERCISE INTERVENTION ON COGNITIVE FUNCTION OF ALZHEIMER’S DISEASE PATIENTS C.A. Mouzakidis, M.Tsolaki

65. METHODS 2 4 AD patients Exercise Group (n=1 2 ). Mean Age = 65 . 70 , SD = 7 . 73, Education = 9 . 33 , SD = 2 . 90. Control Group (n=1 2 ). Mean Age = 6 8.5 0 , SD = 3.8 7, Education = 8.92, SD = 4.72 . Assessment Cognitive Functions (MMSE) Psychomotor Measures

66. Equipment Colored easy controlled balls, sticks, hoops of different sizes, plastic bottles, soda cans, tennis balls, chairs, dumbbells. Duration 36 weeks (3 times/week) 90 minutes/time Description of Exercise Program Warm up Period (30’). Aerobic & range of motion exercises Main Exercise Period (50’). flexibility, strength of upper and lower limbs, endurance, dexterity, balance, agility, speed, attention and accuracy, co-ordination, orientation, memory, self-control, and co-operation Cool down Period (10’). Main purpose to allow the heart rate to return to normal and the body to relax.

67. RESULTS The patients of the exercise group managed to maintain their cognitive and functional abilities, while the patients of the control group deteriorated. * p < 0.05 Exercise Group ( n = 12) Control Group ( n = 12) Before Mean ( SD ) After Μ ean ( SD ) Before Μ ean ( SD ) After Μ ean ( SD ) MMSE 18,50 (8,85) 18,33 (9,02) 16,25 (5,64) 12,83 (5,57)*

68. NS = non-significant Soda Pop Test 12 16.50 ( ± 11.79) 13.20 ( ± 11.20) NS Finger Dexterity 12 29.75 ( ± 31.00) 25.85 ( ± 23.26) NS Hand Tapping 12 62.00 ( ± 19.00) 70.00 ( ± 11.67) NS Reaction Time (cm) 12 38.50 (±15.51) 29.70 (±13.75) p = 0.001 Repetitive Arm and Hand Movements Right Hand 12 3.21 (±0.97) 2.75 (±0.74) p = 0.001 Left Hand 12 3.44(±0.97) 3.00 (±0.78) p = 0.010 Grip Test (kg) Right Hand 12 27.58 (±6.37) 30.00 (±7.29) p = 0.007 Left Hand 12 24.33 (±7.40) 26.50 (±8.10) p = 0.007 Sequential Arm and Hand Movements 12 1.75 (±2.05) 0.83 (±2.00) p = 0.050 Reeling String on a Stick 11 17.17 (±11.93) 15.22 (±11.00) p = 0.001 Bounce a Ball 12 2.17 ( ± 2.21) 1.08 ( ± 2.06) NS Throw a B all to a target 12 2.08 (±1.24) 0.92 (±1.24) p = 0.004 Bowling 12 2.17 ( ± 2.33) 3.50 ( ± 2.71) NS Gait Control 11 0.45 ( ± 1.21) 0.09 ( ± 0.30) NS Static Balance 12 25.17 (±22.61) 33.81 (±23.57) p = 0.008 Step Into and Out of a Hoop 12 0.83 ( ± 1.64) 1.58 ( ± 2.35) NS Sit and Reach Test 12 49.25 (±13.50) 52.17 (±15.35) p = 0.006 Agility 12 7.00 ( ± 4.26) 8.25 ( ± 5.67) NS

70. OUR EXPERIENCE (MCI) Tsolaki M , Kounti F , Agogiatou C , Poptsi E , Bakoglidou E , Zafeiropoulou M , Soumbourou A , Nikolaidou E , Batsila G , Siambani A , Nakou S , Mouzakidis C , Tsiakiri A , Zafeiropoulos S , Karagiozi K , Messini C , Diamantidou A , Vasiloglou M . Effectiveness of Nonpharmacological Approaches in Patients with Mild Cognitive Impairment . Neurodegener Dis. 2010 Dec 3

71. ΝΟΣΟΣ ALZHEIMER Μάγδα Τσολάκη, MD, PhD Νευρολόγος-Ψυχίατρος, Θεολόγος, Αναπληρώτρια Καθηγήτρια, Α.Π.Θ. Πρόεδρος της Ελληνικής Ομοσπονδίας Νόσου Alzheimer

73. CLINICAL TRIALS ( Combination of physical and cognitive exercise )

75. What is LLM ? Long Lasting Memories (LLM) is an integrated ICT platform which: combines state-of-the-art cognitive exercises with physical activity in the framework of an advanced ambient assisted living environment. 2011

76. Component 1: Effects of Physical Exercise in the Elderly Regular physical exercise, significantly improves physical functioning of individuals at any age Engagement of elderly individuals in regular physical exercise programs has demonstrated improvement in aerobic capacity, muscular strength, muscular endurance, flexibility, balance, motor control and performance, skill acquisition, coordination, cognition and psychological well being ( www.who.int/hpr/ageing/heidelberg_eng.pdf ) 2011

77. LLM Design Idea 2011

78. The Pilots Pilots in 5 countries Austria Spain France Greece Cyprus 2011

79. Expected Results pre post Cognitive Function Theory Expected Results Results from Konstanz: 10 weeks physical training 2 x 45 min/week Hertzog et al., 2009 LLM Control 2011

80. ΓΙΑΤΙ ΟΧΙ AKOMH ΣΤΟ ΑΙΜΑ;

82. Σας ευχαριστώ Thank you very much for your attention