1. Alzheimer Hellas 2. 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Greece 1. Alzheimer Hellas 2. 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Greece Longitudinal cognitive training changes the conversion’s rate of Mild Cognitive Impairment to dementia Kounti, F. 1, Poptsi, E. 1, Agogiatou, C. 1, Bakoglidou, E. 1, Soumpourou A. 1, Zafeiropoulos, S. 1, Batsila G. 1, Nikolaidou, E. 1, Vasiloglou, M. 1, Ouzouni, F. 1, Markou N. 1, Zafeiropoulou, M. 1, Tsolaki, M. 1, 2

Mild Cognitive Impairment MCI represents a transitional state between the cognitive changes of aging and the earliest clinical features of dementia (Petersen, 2003; Petersen et al., 2001) MCI patients are at increased risk for the development of dementia (Bruscoli & Lovestone, 2004; Petersen, 2004) MCI represents a transitional state between the cognitive changes of aging and the earliest clinical features of dementia (Petersen, 2003; Petersen et al., 2001) MCI patients are at increased risk for the development of dementia (Bruscoli & Lovestone, 2004; Petersen, 2004)

MCI patients progress to dementia at very different rates aMCImd patients appear to be at greatest risk for future dementia (Di Carlo et al., 2007; Palmer et al., 2008; Tabert et al., 2006 Ravaglia et al., 2006) Less than 20% of patients with aMCImd revert to normal aging (Loewenstein, et al., 2009) Others remain stable upon retest (Bickel et al., 2006) aMCImd patients appear to be at greatest risk for future dementia (Di Carlo et al., 2007; Palmer et al., 2008; Tabert et al., 2006 Ravaglia et al., 2006) Less than 20% of patients with aMCImd revert to normal aging (Loewenstein, et al., 2009) Others remain stable upon retest (Bickel et al., 2006)

Neurogenesis in aging (hippocampus)

ChEIs and Mild Cognitive Impairment ChEIs in patients with MCI are not associated with any delay in the onset of dementia The risks associated with ChEIs are not negligible (Raschetti et al., 2007) It is important to study the possibility of cognitive training to improve cognitive and functional performance ChEIs in patients with MCI are not associated with any delay in the onset of dementia The risks associated with ChEIs are not negligible (Raschetti et al., 2007) It is important to study the possibility of cognitive training to improve cognitive and functional performance

Aims of non pharmacological therapies Aim of cognitive therapy: Cognitive improvement Delay of conversion rate to dementia Expected results: Reactivation of atrophic neurons in patients with MCI (Swabb, 1994) Maintenance of regenerated neurons after cognitive training for a long period of time Aim of cognitive therapy: Cognitive improvement Delay of conversion rate to dementia Expected results: Reactivation of atrophic neurons in patients with MCI (Swabb, 1994) Maintenance of regenerated neurons after cognitive training for a long period of time

The study aMCImd patients Non pharmacological therapy (cognitive training) 64 sessions (in a period of 2 years) 2 groups (experimental and control) aMCImd patients Non pharmacological therapy (cognitive training) 64 sessions (in a period of 2 years) 2 groups (experimental and control)

Study hypotheses Experimental group: Improvement of targeted cognitive abilities (attention - parameters of executive function) Generalization of cognitive benefit in other cognitive domains through the consolidation of new learning Delay of conversion rate to dementia Control Group: Stability of cognitive performance, a slight deterioration or a slight improvement, two years after the initial assessment Experimental group: Improvement of targeted cognitive abilities (attention - parameters of executive function) Generalization of cognitive benefit in other cognitive domains through the consolidation of new learning Delay of conversion rate to dementia Control Group: Stability of cognitive performance, a slight deterioration or a slight improvement, two years after the initial assessment

Participants Inclusion criteria: 60 years of age Subjective cognitive complaints aMCImd diagnosis (Petersen’s criteria 2001) MMSE: points Spared language skills (speech comprehension or production) Inclusion criteria: 60 years of age Subjective cognitive complaints aMCImd diagnosis (Petersen’s criteria 2001) MMSE: points Spared language skills (speech comprehension or production)

Participants Exclusion criteria: Diagnosis of dementia (NINCDS-ADRDA criteria-McKahnn et al., 1984) Severe psychotic traits (untreated depression, agitation or behavioral problems) Other neurological disorders (stroke or ischemic lesions) Antipsychotics ChEIs Difficulties in sensory abilities Exclusion criteria: Diagnosis of dementia (NINCDS-ADRDA criteria-McKahnn et al., 1984) Severe psychotic traits (untreated depression, agitation or behavioral problems) Other neurological disorders (stroke or ischemic lesions) Antipsychotics ChEIs Difficulties in sensory abilities

Participants Outpatients of the memory and dementia clinic of “G.Papanikolaou” General Hospital and of the day care centers of Alzheimer Hellas Area of Northern Hellas Patients visited these sources voluntarily and signed an informed consent Outpatients of the memory and dementia clinic of “G.Papanikolaou” General Hospital and of the day care centers of Alzheimer Hellas Area of Northern Hellas Patients visited these sources voluntarily and signed an informed consent

Participants

No statistically significant differences between the two groups at baseline In age, education, gender, cognitive and functional performance Controls did not take part in any kind of cognitive therapy They continued their regular daily activities No statistically significant differences between the two groups at baseline In age, education, gender, cognitive and functional performance Controls did not take part in any kind of cognitive therapy They continued their regular daily activities

Sample Characteristics Characteristics/ Cognitive/Functional Performance *M (SD) Control Group (n=45) Experimental Group (n=95) p Age (8.62)60.01 (7.34).312 Gender (Male/Female) Fisher’s test.073 Education (4.11)11.17 (4.44).117 Global cognitive function (Total MMSE) (1.35)27.71 (1.77).046 Global cognitive function (Total MoCA) (2.84)23.05 (2.79).328 ADL (Total FRSSD) 4.33 (1.73)3.83 (1.92).081 ADL (Total FUCAS) (1.34)43.34 (1.33).060

Neuropsychological assessment 1 st assessment: at baseline 2 nd assessment: 2 years later, at the end of the therapy 1 st assessment: at baseline 2 nd assessment: 2 years later, at the end of the therapy

Neuropsychological battery MEMORY Rivermead Behavioral Memory test (RBMT) Rey Auditory Verbal Learning Test (RAVLT) Rey – Osterrieth Complex figure Test (ROCFT) ATTENTION Test of Everyday Attention (TEA) WAIS-R (DIDIT SYMBOL) LANGUAGE Boston Naming Test (BNT) Verbal fluency test (ΧΣΑ) MEMORY Rivermead Behavioral Memory test (RBMT) Rey Auditory Verbal Learning Test (RAVLT) Rey – Osterrieth Complex figure Test (ROCFT) ATTENTION Test of Everyday Attention (TEA) WAIS-R (DIDIT SYMBOL) LANGUAGE Boston Naming Test (BNT) Verbal fluency test (ΧΣΑ) EXECUTIVE FUNCTION Wisconsin Card Sorting Test (WCST) Trail-making Test Part B (TRAIL B) Stroop Color Word test (SCWT) Functional Cognitive Assessment Scale (FUCAS-EXECUTIVE FUNCTION) GENERAL COGNITIVE FUNCTION Mini Mental State Examination (MMSE) Montreal Cognitive Assessment (MoCA) ADL Functional Rating Scale of Symptoms of Dementia (FRSSD) Functional Cognitive Assessment Scale (FUCAS-ADL)

Therapeutic techniques Cognitive Training techniques of Attention and Cognitive Parameters of Executive Function through: Paper and pencil tasks Kinetic instructions Mental Imagery under Relaxation Musical Stimuli Reality Orientation in Currents Events Computer software Each trainee took part in a specific therapeutic combination of techniques, related to his/her residual abilities and impaired functions Cognitive Training techniques of Attention and Cognitive Parameters of Executive Function through: Paper and pencil tasks Kinetic instructions Mental Imagery under Relaxation Musical Stimuli Reality Orientation in Currents Events Computer software Each trainee took part in a specific therapeutic combination of techniques, related to his/her residual abilities and impaired functions

Statistical analysis SPSS 17.0 software program Kolmogorov-Smirnov Z-test Nonparametric tests Mann–Whitney test for 2 independent samples (Monte Carlo method) between groups comparisons Wilcoxon test for 2 related samples, within group comparisons Bonferonni correction was used in order to make our significance criterion more conservative SPSS 17.0 software program Kolmogorov-Smirnov Z-test Nonparametric tests Mann–Whitney test for 2 independent samples (Monte Carlo method) between groups comparisons Wilcoxon test for 2 related samples, within group comparisons Bonferonni correction was used in order to make our significance criterion more conservative

Study Results

Between groups comparison Experimental group in comparison to controls had better performance in: attention (p=.009) visual memory (p=.043) executive function (p≤.000) Experimental group in comparison to controls had better performance in: attention (p=.009) visual memory (p=.043) executive function (p≤.000) At the end of the intervention (2 years period)

AbilityControl Group *M (SD) (N=45)Experimental Group *M (SD) (N=95) p Global cognitive function (Total MoCA)23.64 (4.04)24.29 (3.66)NS ADL (Total FRSSD)3.83 (2.02)3.38 (1.42)NS ADL (Total FUCAS)43.71 (1.99)43.14 (1.39)NS ATTENTION Inhibition interference (STROOP) (9.00)-1.86 (7.40)NS Digit symbol (WAIS - R) (13.17)30.43 (10.35)NS Auditory sustained attention (MoCA).82 (.38).97 (.16).009 VERBAL MEMORY Learning ability (RAVLT) (2.53)11.30 (2.74)NS Delayed recall (RAVLT) 8.27 (3.21)11.30 (2.74)NS Immediate story recall (RBMT) (3.25)13.12 (3.14)NS Delayed story recall (RBMT) (3.75)12.40 (3.29)NS VISUAL MEMORY (6.29)30.50 (4.54) Complex figure delayed recall (ROCFT) (6.86)15.92 (7.00).043 VISUAL CONSTRUCTIVE ABILITIES Complex figure copy (ROCFT) (6.29)30.50 (4.54)NS LANGUAGE Naming without help (per cent %) (BNT) (16.10)78.88 (14.70)NS EXECUTIVE FUNCTION Phonemic verbal fluency (FAS) 9.82 (2.49)11.95 (3.41).000 Trail making part B (TRAIL B) (138.18) (96.45)NS Planning (FUCAS) 6.20 (.45)6.03 (.17).004 Working memory (MoCA) 2.53 (.75)2.81 (.42)NS

Within Group Comparisons between the 1 st and the 2 nd assessment abilities of attention (p≤.002) executive function (p≤.008) verbal memory (p≤.003) visual memory (p=.000) language (p=.000) global cognitive performance (p=.028) abilities of attention (p≤.002) executive function (p≤.008) verbal memory (p≤.003) visual memory (p=.000) language (p=.000) global cognitive performance (p=.028) Experimental group After two years’ participation in cognitive training Has shown improvement in:

AbilityΜ(SD)* 1 st AssessmentM (SD)* 2 nd Assessment p Global cognitive function (Total MoCA)23.05 (2.79)24.29 (3.66).000 ADL (Total FRSSD)3.83 (1.92)3.38 (1.42)NS ADL (Total FUCAS)43.34 (1.33)43.14 (1.39)NS ATTENTION Visual selective attention (TEA) (10.07)30.30 (9.53).001 Speed of selective attention (multiple choices) (TEA) 5.16 (2.05)4.81 (1.39).003 Inhibition interference (STROOP) (7.04)-1.86 (7.40).002 Digit symbol (WAIS - R) (9.50)30.43 (10.35).001 Auditory sustained attention (MoCA).93 (.25).97 (.16)NS Digit span (RAVLT) 4.94 (2.07)5.72 (2.22).002 VERBAL MEMORY Learning ability (RAVLT) (2.75)11.30 (2.74).003 Delayed recall (RAVLT) 7.14 (3.56)11.30 (2.74).000 Immediate story recall (RBMT) (3.18)13.12 (3.14)NS Delayed story recall (RBMT) (3.57)12.40 (3.29)NS VISUAL MEMORY Complex figure delayed recall (ROCFT) (6.04)15.92 (7.00).000 VISUAL CONSTRUCTIVE ABILITIES Complex figure copy (ROCFT) (4.64)30.50 (4.54)NS LANGUAGE Naming without help (per cent %) (BNT) (15.14)78.88 (14.70).000 EXECUTIVE FUNCTION Numbers of trials attempted (WCST) (20.50)88.61 (16.94).005 Perseverative responses (WCST) (8.81)9.32 (6.38).001 Phonemic verbal fluency (FAS) 9.57 (2.70)11.95 (3.41).000 Trail making part B (TRAIL B) (97.17) (96.45).002 Planning (FUCAS) 6.03 (.17) NS Working memory (MoCA) 2.80 (.45)2.81 (.42)NS

Within Group Comparisons between the 1 st and the 2 nd assessment Significant improvement in: visual memory (p=.006) attention (p=.007) Significant deterioration in: executive function (p≤.006) The rest of the cognitive abilities remained stable Significant improvement in: visual memory (p=.006) attention (p=.007) Significant deterioration in: executive function (p≤.006) The rest of the cognitive abilities remained stable After two years control group has shown:

AbilityΜ(SD)* 1 st AssessmentM (SD)* 2 nd Assessment p Global cognitive function (Total MoCA)23.23 (2.84)23.64 (4.04)NS ADL (Total FRSSD)4.33 (1.73)3.83 (2.02)NS ADL (Total FUCAS)43.00 (1.34)43.71 (1.99)NS ATTENTION Inhibition interference (STROOP) (10.56)-5.78 (9.00)NS Digit symbol (WAIS - R) (11.51)29.36 (13.17)NS Auditory sustained attention (MoCA).94 (.22).82 (.38)NS Digit span (RAVLT) 4.20 (1.50)4.92 (2.10).007 VERBAL MEMORY Learning ability (RAVLT) (2.28)10.97 (2.53)NS Delayed recall (RAVLT) 8.15 (3.23)8.27 (3.21)NS Immediate story recall (RBMT) (3.33)12.23 (3.25)NS Delayed story recall (RBMT) (3.25)11.42 (3.75)NS VISUAL MEMORY Complex figure delayed recall (ROCFT) (4.76)13.40 (6.86).006 VISUAL CONSTRUCTIVE ABILITIES Complex figure copy (ROCFT) (5.29)29.01 (6.29)NS LANGUAGE Naming without help (per cent %) (BNT) (14.17)79.65 (16.10)NS EXECUTIVE FUNCTION Phonemic verbal fluency (FAS) 9.46 (2.13)9.82 (2.49)NS Trail making part B (TRAIL B) (102.62) (138.18).000 Planning (FUCAS) 6.02 (.15)6.20 (.45)NS Working memory (MoCA) 2.86 (.34)2.53 (.75).006

Conversion to dementia 6 patients (13.33%) out of the controls converted to dementia, as they fulfilled the dysfunction criteria for dementia (performance in FUCAS’ ADL ≥ 47) NONE of the experimental group converted to dementia after two years of participation in cognitive training 6 patients (13.33%) out of the controls converted to dementia, as they fulfilled the dysfunction criteria for dementia (performance in FUCAS’ ADL ≥ 47) NONE of the experimental group converted to dementia after two years of participation in cognitive training

Conclusions

Cognitive training helped experimental patients to: Improve abilities of attention and executive function Generalize the cognitive benefit in visual memory, language & verbal memory Stabilize ADL Minimize the rate of conversion to dementia Improve abilities of attention and executive function Generalize the cognitive benefit in visual memory, language & verbal memory Stabilize ADL Minimize the rate of conversion to dementia

Further studies are needed in order to examine the longitudinal effectiveness of cognitive training in MCI

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