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Journal of Alzheimer’s Disease 39 (2014) 833–839 DOI 10.3233/JAD-131808 IOS Press

Physical Activity Reduces the Risk of Dementia in Mild Cognitive Impairment Subjects: A Cohort Study Giulia Grandea,b , Nicola Vanacorec , Laura Maggiorea , Valentina Cucumoa , Roberta Ghirettia , Daniela Galimbertid , Elio Scarpinid , Claudio Mariania,b and Francesca Clericia,b,∗ a Centre

for Research and Treatment on Cognitive Dysfunctions, Institute of Clinical Neurology, “Luigi Sacco” Hospital, Milan, Italy b Department of Biomedical and Clinical Sciences “Luigi Sacco” Hospital, University of Milan, Milan, Italy c National Centre for Epidemiology, Surveillance and Health Promotion, National Institute of Health, Rome, Italy d Department of Pathophysiology and Transplantation, University of Milan, Fondazione C` a Granda, IRCCS Ospedale Policlinico, Milan, Italy

Accepted 16 October 2013

Abstract. Background: Leisure activities, particularly exercise, play a protective role against dementia in healthy people, but it is unknown if this protective effect could be generalized to subjects with mild cognitive impairment (MCI). Objective: To investigate the influence of leisure activities on the risk of progression of MCI to dementia. Methods: 176 MCI subjects attending a memory clinic underwent a standardized lifestyle questionnaire between October 2007 and May 2010. Social, cognitive, and physical scores were derived based on the assiduity of interpersonal contacts and on the frequency of participation in individual leisure activities. Subjects were requested to return every 12 months for dementia surveillance. The outcome measure was the risk of dementia associated with social, cognitive, and physical scores. Results: Over a median follow-up time of 2.59 year, 92 (52.2%) MCI subjects developed dementia. Subjects with physical scores in the highest third had a lower risk (HR 0.44; 95% CI 0.23–0.85) of dementia compared with those in the lowest third. No association was found between cognitive or social scores and the risk of dementia. Conclusion: To our knowledge, this is the first prospective clinical study which demonstrates that high levels of participation in physical leisure activities are associated with reduced risk of dementia in subjects with MCI. In line with findings coming from community-based studies on healthy elderly, our finding suggests that the protective role of exercise against the development of dementia can be generalized to MCI subjects seen in clinical practice. Clinicians should encourage MCI subjects to participate in physical leisure activities. Keywords: Dementia, exercise, leisure activities, lifestyle, mild cognitive impairment

INTRODUCTION

∗ Correspondence to: Francesca Clerici, Center for Research and Treatment on Cognitive Dysfunctions, Institute of Clinical Neurology, Department of Biomedical and Clinical Sciences, “Luigi Sacco” Hospital, University of Milan, Via G.B. Grassi, 74, I-20157 Milan, Italy. Tel.: +39 02 3904 2761; Fax: +39 02 50319869; E-mail: [email protected]

Along with global aging, age-related diseases, including neurodegenerative dementias like Alzheimer’s disease (AD), will increase dramatically in the coming years and will have a strong impact on both individuals and society. Given the increasing evidence that neurodegenerative processes develop over many years or even decades as well as

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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the current difficulty in identifying disease-modifying treatments [1], there has been growing interest in identification of effective strategies for AD prevention [2]. In particular, it is becoming a major public health priority to identify modifiable risk and protective factors as targets for preventing dementia [3]. Increasing attention has been paid to the influence of healthy lifestyle, including leisure activities, on dementia occurrence. Leisure activities can be defined as the voluntary use of free time for activities outside the daily routine, and are part of the huge group of modifiable protective factors. There are three main components of leisure activities: cognitive, social, and physical. A recent systematic review [4] of populationbased studies reported the protective role of these lifestyle components on the risk of developing cognitive impairment and dementia. Particularly, physical activity is the component of a healthy lifestyle that collects the strongest evidence [5] as being a protective factor against dementia. An observational study [6] reports that regular physical activity may reduce the risk or delay the onset of dementia and AD, especially among genetically susceptible individuals. A similar study [7], conducted on elderly people, demonstrates that physical activity is associated with a lower risk of vascular dementia. Finally, a meta-analysis [5] of prospective studies suggested a significant and consistent protection for all levels of physical activity against the occurrence of cognitive decline among non-demented subjects. In contrast to the evidence linking leisure activities and improvement of cognition in healthy people, little is known whether this also occurs in individuals at risk for dementia such those who meet the diagnostic criteria of mild cognitive impairment (MCI). The latter is defined as a cognitive dysfunction that exceeds what would be expected for an individual’s age and level of education, but yet non-interfering with the main activities of daily living, even if a minimal impairment in complex instrumental functions may be present [8, 9]. MCI is considered a risk condition for the development of dementia [8], so it represents a window of opportunity to test promising strategies to fight cognitive decline. To date, no clinical study has investigated the role of the social and cognitive components of lifestyle on the progression of cognitive impairment in MCI subjects. By contrast, two 6-months randomized controlled trials [10, 11] have demonstrated that physical exercise has positive effects on cognition, without providing results on the risk of progression to dementia. In this study we aim to investigate, from the perspective of a memory clinic, whether lifestyle can modulate

the trajectory of evolution of MCI using a strong outcome, i.e., progression to dementia. Specifically, we intend to check whether high levels of cognitive, social, and physical activity are associated with a decreased dementia risk in MCI subjects.

MATERIALS AND METHODS Between 1 October 2007 and 30 May 2010, 798 consecutive subjects were examined at the Centre for Research and Treatment of Cognitive Dysfunctions of the University of Milan. Out of these, 179 (22.4%) satisfied the Petersen’s revised diagnostic criteria of MCI [8] and were included in the study. MCI was diagnosed according to standard criteria [8] and operationalized as follows: 1) Subjective cognitive complaint as reported by subjects and corroborated by an informant; 2) Objective cognitive impairment, defined as scoring below 1.5 standard deviation (SD) from the mean (according to age and education specific norms) on at least one task of an extensive neuropsychological assessment; 3) Essentially preserved daily functioning defined as full scores in both basic [12] and instrumental [13] activities of daily living; 4) Essentially preserved general cognitive functioning, defined as a score = 0.5 on the Clinical Dementia Rating scale (CDR) [14]; and 5) Absence of dementia as defined by the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria [15]. MCI cases were classified into the following subtypes [8]: amnestic MCI, if there was impairment in memory alone; single domain MCI, if there was impairment in one cognitive domain other than memory; multiple domains MCI, if there was impairment in at least two cognitive domains. Exclusion criteria for MCI were: 1) dementia as defined by the DSM-IV [15]; 2) other psychiatric disorders [15]; 3) organic brain pathology or organic illness affecting the brain according to the ICD-10; 4) significant history of head injury; 5) major systemic illnesses or medical complications, including vitamin deficiency states, thyroid disorders, and sensory disorders (i.e., blindness or deafness); 6) history of drug or alcohol dependence; and 7) structural brain alterations that included mass lesions and hydrocephalus. At baseline, all study participants underwent an extensive in-person evaluation following a previously described [16] standardized diagnostic protocol, which included medical and neurological examinations, laboratory testing, APOE genotyping, neuroimaging, and neuropsychological assessments. In particular, global

G. Grande et al. / Physical Activity Reduces the Risk of Dementia in Mild Cognitive Impairment Subjects

cognition was assessed by the Mini-Mental State Examination (MMSE) [17] and mood by the 30-items Geriatric Depression Scale (GDS) [18]. Multimorbidity was assessed using the Cumulative Illness Rating Scale [19]. Lifestyle assessment At baseline all subjects underwent a structured lifestyle questionnaire. The questionnaire was composed of two main sections: the first concerned the frequency of leisure time activities, whereas the second one concerned interpersonal contacts. Subjects were required to answer according to the lifestyle they were conducting at the time of submission of the questionnaire. First, at baseline, subjects were interviewed about sixteen cognitive activities (reading either books or newspaper, attending courses, painting, playing an instrument, doing puzzles, watching TV, collecting stamps, playing cards alone, engaging in cultural or political interests, participating in group discussions, writing, following listed markets, playing chess or cards, listening to the radio, engaging in church activities, playing bingo), four physical activities (playing sports, walking, traveling, gardening), and four social activities (going on holiday, going to the theatre or concerts, going to museum, singing). In accordance with Verghese et al. [20], for each activity subjects received 7 points for daily participation, 4 points for weekly participation, 1 point for monthly or once a year participation, and 0 point for participating occasionally or never (range 0–168). Then, we quantified the frequency of contacts with children, sons/daughters in law, grandchildren, siblings, friends, professional caregivers, or others (such as domestic help, parish priest, relatives not included in the previous questions). For each interpersonal contact, we assigned 7 points for daily contacts, 4 points for weekly contacts, 1 point for monthly or once a year contacts, and 0 point for meeting the subjects occasionally or never: the range of the interpersonal contact score is 0–49. Finally, based on these two sections of the questionnaire, we coded three different scales: a Cognitive, a Physical, and a Social Activity Scale. The Cognitive Activity Scale score (range 0–112) comes from the sum of the sixteen cognitive activities scores. The Physical Activity Scale score (range 0–28) derives from the sum of the four physical activities scores. Finally, the Social Activity Scale score (range 0–77) is the sum of the interpersonal contact score and the scores of the four social activities.

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Follow-up Subjects were requested to return every 12 months in order to evaluate the clinical course of MCI, by both clinical and neuropsychological assessments. The follow-up ended at the diagnosis of dementia [15] or death. May 2011 was chosen as the end date for dementia surveillance. The subjects who did not show up at the scheduled control examination were contacted by phone in order to make a new appointment. Whenever the clinical and neuropsychological follow-up examination indicated a progression toward dementia, the laboratory testing and the CT scan of the brain were repeated. The diagnosis of dementia was based on standard criteria [15] and required evidence of cognitive decline on the neuropsychological test battery, as well as evidence of impairment on social or occupational function (CDR >0.5). AD was diagnosed according to NINCDS-ADRDA criteria [21], Lewy body dementia according to McKeith criteria [22], frontotemporal dementia according to Lund and Manchester criteria [23], and vascular dementia according to NINDSAIREN criteria [24]. Fourteen subject refused or were unable to undergo the follow-up visit: in these cases the information on clinical status was collected by phone from an informant and the dementia screening was performed using the CDR, as previously described [25]. The phone call was performed by the same neurologist (FC) who assigned the CDR score. These patients were diagnosed as having dementia if the CDR score moved from 0.5 to greater than or equal to 1 [25]. Statistical analysis Three out of 179 subjects (1.6%) were not included in the statistical analysis because they prematurely discontinued the follow-up. The follow-up duration was calculated as follows: for the subjects who did not develop dementia, it corresponds to the interval between the date of baseline examination and the last annual follow-up examination; for the individuals who developed dementia, it corresponds to the time interval between the date of the baseline examination and the date of the dementia diagnosis. Continuous measures were compared with either the independent-samples t test or the Mann–Whitney when necessary. Categorical variables were compared with the Pearson chi square test. We studied the association of baseline cognitive, physical, and social activity scores in tertiles, with risk of dementia using one Cox

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proportional-hazards regression analysis to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). This Cox model also included variables statistically significant at univariate analysis as covariates. The Kaplan Meier method was used to show the pattern in time of the variable statistically significant identified in the Cox model. All statistical analyses were twosided, with an alpha value of 0.05 and were performed with SPSS software (Version 20.0) RESULTS During a mean follow-up time of 2.59 ± 1.86 years, 92 out of 176 (52.2%) MCI subjects progressed toward dementia, including 75 (81.5%) with AD [21]. In the remaining cases, the following diagnosis were made: seven patients with vascular dementia [24], five patients with Lewy body dementia [22], one patient with frontotemporal dementia [23], and one patient with severe dementia of unspecified origin. Finally, three (3.3%) subjects were diagnosed as having dementia by phone interview [25]. As shown in Table 1, at baseline subjects who progressed toward dementia were older (p = 0.001) and more educated (p = 0.03) with respect to subjects who did not develop dementia. Moreover, they showed lower global cognition and mood as assessed by MMSE (p = 0.002) and GDS (p = 0.02) scores, respectively. Subjects with memory impairment at baseline were overrepresented in the group which progressed to dementia, as confirmed by their significantly higher progression rates (p = 0.006). Finally, APOE ␧4 genotype was more frequent in subjects who progressed

to dementia, as compared to subjects who were still in the MCI status at the end of dementia surveillance (p = 0.045). No statistically significant differences were found between subjects who progressed toward dementia with respect to subjects who did not develop dementia in the Cognitive Activity Scale (9.88 ± 5.47 versus 8.58 ± 4.81; p = 0.10), Physical Activity Scale (3.51 ± 2.55 versus 3.98 ± 2.82; p = 0.25), and Social Activity Scale (16.36 ± 7.74 versus 14.54 ± 7.79; p = 0.12). Nevertheless, in the Cox proportional-hazards regression analysis, subjects with Physical Activity scores at baseline in the highest third had a lower risk of dementia (HR = 0.36, 95% CI 0.18 to 0.75) compared with subjects in the lowest third adjusted for age, gender, education, MMSE score, GDS score, MCI subtype, APOE genotype, Cognitive Activity Score, and Social Activity Score (Table 2). The risk of development of dementia in the follow-up according to tertiles on baseline Physical Activity Scale scores was shown in Fig. 1. DISCUSSION The present study has demonstrated a 64% reduction of risk of developing dementia in MCI subjects with high levels of participation in physical leisure activities. The protective effect of physical activity against the occurrence of cognitive decline in healthy elderly subjects is widely described [5], but very little is known whether this also occurs in people with MCI.

Table 1 Baseline characteristics of the whole mild cognitive impairment (MCI) sample and by outcome at follow-up MCI n = 176 Age y, mean (sd) Female, n (%) Education y, mean (sd) MMSE score, mean (sd) GDS score, mean (sd) APOE ␧4* ≥ 1 allele, n (%) MCI subtypes, n (%) Amnestic single domain Non-amnestic single domain Amnestic multiple domains CIRS, mean (sd) Hypertension, n (%) Diabetes mellitus type II, n (%) Hypercholesterolemia, n (%) Current smoking, n (%)

74.0 (7.4) 102 (58) 7.8 (8.2) 25.4 (2.6) 9.5 (6.2) 50 (37) 39 (22.2) 28 (15.9) 109 (62.9) 1.9 (0.3) 127 (72.2) 35 (19.9) 127 (72.2) 27 (15,3)

MCI at follow-up n = 84

dementia at follow-up n = 92

72.2 (8.2) 48 (47.1) 7.1 (3.6) 26.0 (2.5) 10.6 (6.3) 18 (36)

75.7 (6.1) 54 (52.9) 8.5 (4.6) 24.0 (2.6) 8.4 (5.9) 32 (64)

18 (46.2) 21 (75.0) 45 (41.3) 1.9 (0.4) 59 (46.5) 17 (48.5) 56 (44.1) 12 (44.4)

21 (53.8) 7 (25.0) 64 (58.7) 1.9 (0.2) 68 (53.5) 18 (51.5) 71 (55.9) 15 (55.6)

p 0.001 n.s. 0.03 0.002 0.02 0.045 0.006

n.s. n.s. n.s. n.s. n.s.

MMSE, Mini Mental State Examination; GDS, Geriatric Depression Scale; CIRS, Cumulative Illness Rating Scale. ∗ The APOE ␧4 genotype was determined in 135 subjects (76.7%).

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Table 2 A regression cox model with hazard ratios (HR) of dementia in relation to baseline cognitive, social, and physical activities score tertiles of mild cognitive impairment (MCI) subjects Physical activity score tertiles, n (%) Lowest (0–2) Middle (3–5) Highest (6–12) Cognitive activity score tertiles, n (%) Lowest (0–7) Middle (8–10) Highest (11–25) Social activity score tertiles, n (%) Lowest (0–11) Middle (12–19) Highest (20–37)

MCI at follow-up n = 84

dementia at follow-up n = 92

HR* (95% CI)

29 (40.3) 32 (53.3) 20 (50)

43 (59.7) 28 (46.7) 20 (50)

1 0.59 (0.32 to 1.10) 0.36 (0.18 to 0.75)

39 (51.3) 21 (52.5) 21 (37.5)

37 (48.7) 19 (47.5) 35 (62.5)

1 0.54 (0.26 to 1.14) 0.89 (0.45 to 1.77)

36 (58.1) 26 (42.6) 22 (41.5)

26 (41.9) 35 (57.4) 31 (58.5)

1 0.82 (0.54 to 2.15) 0.42 (0.68 to 2.56)

*Adjusted for age, gender, education, Mini-Mental State Examination score, Geriatric Depression Scale score, MCI subtype, APOE genotype, Physical activity score, Cognitive activity score, Social activity score.

Fig. 1. Kaplan Meier curves for the risk of development of dementia in subjects with MCI according to tertiles on baseline Physical Activity Scale scores.

Unfortunately, the construct of “mild cognitive impairment” is not unequivocally intended in literature, with a large heterogeneity of that definition. On one hand, there are studies, like ours, based on current diagnostic criteria [8], yet, on the other hand, there are works in which this condition is identified only on the basis of a pathological score on a single cognitive task [11, 26]. This variability weakens the possibility of comparison between our study and the current scientific literature. A meta-analysis [26] reported a medium treatment effect for combined physical, cognitive, functional, and behavioral outcomes in older patients with dementia

or cognitive impairment (intended as baseline MMSE score of less than 26 out of 30). Moreover, a 6-month single blinded controlled trial [11] conducted on senior women with probable MCI (defined by a score lower than 26 out of 30 on the Montreal Cognitive Assessment) demonstrated that a twice weekly resistance training improved selective attention/conflict resolution, associative memory, and regional patterns of functional brain plasticity compared with twice week aerobic training. Although the exact biological mechanisms underlying the protective effect of physical activities against cognitive decline have not been established, possi-

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ble explanation includes expanding cognitive reserve [27], reducing chronic stress, and promoting a healthy lifestyle [28]. Performing high levels of physical activities promotes angiogenesis, neurogenesis, and sinaptogenesis, contributing in enlarging cognitive reserve [29–31]. By expanding cognitive reserve, the brain has the ability to tolerate the age-related changes and the disease-related pathology, postponing the onset of cognitive decline or the developing of dementia in subjects with cognitive impairment. Moreover, physical, cognitive, and social activities seem to decrease brain amyloid-␤ deposition reducing burden damage from this pathway [32], and increases hippocampal synaptic immunoreactivity [33]. Finally, a protective effect could be mediated by the action that physical activities have on various vascular risk factors, such as hypertension, obesity, and diabetes mellitus [34], which have been related to an increased risk of progression from MCI to dementia [16]. To our knowledge, this is the first prospective clinical study that demonstrates a protective effect of physical activity on the risk of progression to dementia in subjects with MCI. The main strength of this study lies in the use of a hard endpoint, as the progression to dementia, and not surrogates, such as modifications in functional MRI [35] or cognitive scale score variations [11]. The present study found limitations related to the quality of the questionnaire submitted to the MCI subjects. Particularly, we do not have a direct evaluation of physical exercise, but an indirect assessment through the investigated leisure activities. Nevertheless, this seemed the only way to estimate physical activities in everyday life of older people. Moreover, leisure activities were categorized based on what we have considered the main component (cognitive, social, or physical), even if we are aware that many leisure activities include multiple components. Future studies investigating lifestyle activities in elderly people with MCI might help to understand which subtypes of dementia can be prevented with physical activity and whether it can also help in preventing AD. In line with findings coming from communitybased studies, our results suggest that the trajectory of cognitive decline can be modulated not only in healthy elderly but also in subjects with MCI who attend a memory clinic, through compliance of healthy lifestyles, including the practice of physical activity. Even if our results need to be replicated, we emphasize that from a public health standpoint clinicians should

encourage MCI subjects to perform physical leisure activities. ACKNOWLEDGMENTS We thank the Associazione per la Ricerca sulle Demenze ARD onlus for making this study possible. The authors are grateful to Dr. Simone Pomati for the precious contribution in the clinical assessment of patients. Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1994). REFERENCES [1]

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Physical activity reduces the risk of dementia in mild cognitive impairment subjects: a cohort study.

Leisure activities, particularly exercise, play a protective role against dementia in healthy people, but it is unknown if this protective effect coul...
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