Physical Activity Prevents Progression for Cognitive
Impairment and Vascular Dementia
Results From the LADIS (Leukoaraiosis and Disability) Study
Ana Verdelho, MD; Sofia Madureira, PsyD; José M. Ferro, MD, PhD; Hansjörg Baezner, MD, PhD;
Christian Blahak, MD; Anna Poggesi, MD; Michael Hennerici, MD; Leonardo Pantoni, MD, PhD;
Franz Fazekas, MD; Philip Scheltens, MD, PhD; Gunhild Waldemar, MD, DMSc;
Anders Wallin, MD, PhD; Timo Erkinjuntti, MD, PhD; Domenico Inzitari, MD;
on behalf of the LADIS Study
Background and Purpose—We aimed to study if physical activity could interfere with progression for cognitive impairment
and dementia in older people with white matter changes living independently.
Methods—The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of
white matter changes on the transition of independent elderly subjects into disability. Subjects were evaluated yearly
during 3 years with a comprehensive clinical protocol and cognitive assessment with classification of cognitive impairment
and dementia according to usual clinical criteria. Physical activity was recorded during the clinical interview. MRI was
performed at entry and at the end of the study.
Results—Six hundred thirty-nine subjects were included (74.1±5 years old, 55% women, 9.6±3.8 years of schooling, 64%
physically active). At the end of follow-up, 90 patients had dementia (vascular dementia, 54; Alzheimer disease with
vascular component, 34; frontotemporal dementia, 2), and 147 had cognitive impairment not dementia. Using Cox
regression analysis, physical activity reduced the risk of cognitive impairment (dementia and not dementia: β=−0.45,
P=0.002; hazard ratio, 0.64; 95% CI, 0.48–0.85), dementia (β=−0.49, P=0.043; hazard ratio, 0.61; 95% CI, 0.38–0.98),
and vascular dementia (β=−0.86, P=0.008; hazard ratio, 0.42; 95% CI, 0.22–0.80), independent of age, education, white
matter change severity, medial temporal atrophy, previous and incident stroke, and diabetes.
Conclusions—Physical activity reduces the risk of cognitive impairment, mainly vascular dementia, in older people living
independently. (Stroke. 2012;43:3331–3335.)
Key Words: cognition ◼ cognitive impairment ◼ dementia ◼ magnetic resonance ◼ physical activity
◼ white matter disease
P
hysical activity can prevent functional decline associated with age and promote global health status. Recent
reports suggested that physical activity can prevent cognitive
decline and progression for dementia, including Alzheimer
disease,1–6 and the explanation for this relation still remains
a matter of debate.7 Several reasons can explain the protective effect of physical activity on the evolution for cognitive
impairment. Beneficial effects of physical exercise can be
observed in mental and social stimulation and can be integrated in a healthier life status to explain the association.8
More biological explanations have been proposed: physical
activity can improve cerebral blood flow, reduce vascular risk
factors, decrease secretion of stress hormones, and stimulate
plasticity.9 Recently physical activity has been associated with
enhancement of endothelial function, counteracting the loss
of vasodilatory function associated with aging.10,11 Some data
support a decreased progression of intima-media thickness
associated with physical activity.12
In this study we aimed to study the impact of physical
activity on the evolution for cognitive impairment and dementia
Received April 20, 2012; final revision received July 27, 2012; accepted August 1, 2012.
From the Department of Neurociences, University of Lisbon, Santa Maria Hospital, Lisbon, Portugal (A.V., S.M., J.M.F.); the Department of Neurology,
University of Heidelberg, Klinikum Mannheim, Mannheim, Germany (H.B., C.B., M.H.); the Department of Neurological and Psychiatric Sciences,
University of Florence, Florence, Italy (A.P., L.P., D.I.); the Department of Neurology and MRI Institute, Karl Franzens University Graz, Graz, Austria
(F.F.); the Department of Neurology, VU Medical Center, Amsterdam, The Netherlands (P.S.); the Memory Disorders Research Unit, Department of
Neurology, Copenhagen University Hospital, Copenhagen, Denmark (G.W.); the Institute of Clinical Neuroscience, Göteborg University, Göteborg,
Sweden (A.W.); and the Memory Research Unit, Department of Clinical Neurosciences, Helsinki University, Helsinki, Finland (T.E.).
Costantino Iadecola, MD, was the Guest Editor for this article.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.
661793/-/DC1.
Correspondence to Ana Verdelho, MD, Department of Neurosciences, University of Lisbon, Santa Maria Hospital, Av Prof Egas Moniz 1649-028
Lisbon, Portugal. E-mail [email protected]
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.112.661793
3331
3332 Stroke December 2012
in a cohort of old people with white matter changes (WMC)
living independently who were followed prospectively during
3 years with comprehensive cognitive evaluation and careful
control of concomitant factors implicated in disability.
Materials and Methods
The LADIS (Leukoaraiosis and Disability) study is a prospective multinational European project investigating the independent impact of
WMC on the transition to disability in the elderly. The rationale, methodology, and baseline assessment have been described previously.13,14
Inclusion criteria for the study were: (1) 65 to 84 years of age; (2)
changes in WMC on MRI of any degree, according to the scale of
Fazekas;15 and (3) no disability, as determined by the Instrumental
Activities of Daily Living scale.16 Patients were enrolled because of
minor neurological, cognitive, mood, or motor complaints or incidental findings on cranial imaging caused by nonspecific events, without
impact on daily living activities, as detailed elsewhere.12 Subjects were
evaluated at baseline and yearly during 3 years with a comprehensive
clinical and functional protocol that included registry of demographic
factors, vascular risk factors including stroke and diabetes, comorbidities, depression, quality of life, and neuropsychological evaluation.12
During the interview physical activity was assessed and defined according to the American Heart Association Scientific Position (at least
30 minutes of activity on at least 3 days per week).17 Patients were
classified as physically active or inactive according to this definition.
For those patients who could not attend the clinical visit, a phone
interview was performed.14 Investigators were provided with a specifically developed handbook with guidelines for applying criteria and
tools and trained medical personnel used a structured and comprehensive questionnaire together with review of the available records.13
Neuropsychological Evaluation and Cognitive
Criteria
The LADIS neuropsychological battery has been described in detail
elsewhere.14 References from the battery neuropsychological tests are
given in Supplemental Appendix I. In short, the neuropsychological
battery included the Mini-Mental State Examination as a global measure of cognitive function; the Vascular Dementia Assessment Scale
cognitive subscale (VADAS-Cog) as a comprehensive instrument to
assess orientation, language, ideational and constructional praxis, immediate memory and delayed recall, attention and speed of mental
processing; and the Stroop and Trail Making tests as measures of executive function. Additionally, in the follow-up clinical visits, patient
cognitive status was classified into the following groups: (1) dementia; (2) cognitive impairment not dementia; or (3) no cognitive impairment. For this purpose, we used the following criteria and definitions
(references are given in Supplemental Appendix I). We considered 2
types of cognitive impairment not dementia: (1) amnestic mild cognitive impairment, according to Petersen RC, Doody R, Kurz A, Mohs
RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive
impairment. Arch Neurol. 2001;58:1985–1992. (defined as memory complaint, preferably corroborated by an informant; impaired
memory function for age and education, preserved general cognitive
function, intact activities of daily living and no dementia); or (2) vascular cognitive impairment without dementia (defined as evidence of
cognitive impairment and clinical consensus to identify significantly
related vascular features, exclusion of dementia when impairments
were not sufficiently severe to interfere with social or occupational
functioning or when impairments were more focal than the global
requirement for a diagnosis of dementia). We considered the following clinical criteria for subtypes of dementia: Alzheimer disease according to the National Institute of Neurological and Communicative
Disorders and Stroke–Alzheimer’s Disease and Related Disorders
Association (NINCDS-ADRDA) Work Group, vascular dementia according to National Institute of Neurological Disorders and
Stroke (NINDS) Association Internationale pour la Recherche et
l'Enseignement en Neurosciences (AIREN) criteria, subtype of
subcortical vascular dementia according to Erkinjuntti T, Inzitari
D, Pantoni L, Wallin A, Scheltens P, Rockwood K, et al. Research
criteria for subcortical vascular dementia in clinical trials. J Neural
Transm Suppl. 2000;59:23–30. and frontotemporal dementia according to McKhann GM, Albert MS, Grossman M, Miller B, Dickson
D, Trojanowski JQ; Work Group on Frontotemporal Dementia and
Pick's Disease. Clinical and pathological diagnosis of frontotemporal
dementia: report of the Work Group on Frontotemporal Dementia and
Pick's Disease. Arch Neurol. 2001;58:1803–1809. The criteria for
Alzheimer disease with vascular component were considered when
the investigator judgment considered that the clinical picture was due
simultaneously to Alzheimer disease and vascular dementia.
Progression for cognitive impairment (or cognitive decline) during
the study was defined clinically as a change in the clinical cognitive
diagnosis in the different times of follow-up. That is, decline was determined by: (1) transition from no cognitive impairment to cognitive
impairment no dementia; or (2) transition from cognitive impairment
no dementia to dementia; or (3) transition from no cognitive impairment to dementia.
MRI Study
MRI was performed at entry and at the end of the study following
a protocol previously described.13 The degree of WMC severity was
rated on fluid-attenuated inversion recovery sequences by central
readers blind to the clinical data using the 3 classes (mild, moderate,
and severe) in the revised version of the visual scale of Fazekas and
colleagues.15 Medial temporal lobe atrophy was assessed on coronal
T1-weighted sequences using the medial temporal atrophy scale.18
Statistical Analysis
The influence of physical activity (recorded at baseline) on the cognitive status during follow-up was assessed using Cox proportional hazard
models that relied on a noninformative censoring process. We considered as a dependent variable the last cognitive evaluation as described
in the Methods section, and progression for cognitive impairment was
considered as described in Methods section, with a change between
baseline and last follow-up. We performed different models considering
the cognitive diagnosis at the end of follow-up: any cognitive impairment (dementia and cognitive impairment not dementia); or diagnosis
of dementia, Alzheimer disease, and vascular dementia. We considered
the following independent variables: age, education, medial temporal
atrophy, and WMC severity. Age and educational level were considered continuous variables. Medial temporal atrophy and WMC severity
were considered categorical variables. We controlled analysis for the
variables found relevant in predicting cognitive impairment in previous
publications (diabetes and previous stroke)19 and for global cognitive
status at baseline using Mini-Mental State Examination because it was
found in our sample to be sensitive to the evolution for cognitive impairment and dementia.20 Data were analyzed using SPSS 16.0 software.
Results
Six hundred thirty-eight subjects were included (74.1 years, SD
5; 55% women; 9.6 years of educational level, SD 3.8). Baseline
characteristics, including vascular risk factors of the study population, were already described;19 in short, concerning relevant risk
factors for the present study, 29.6% of the study population had previous stroke and 14.6% were diabetic at baseline (Table 1). WMC
severity at baseline was as follows: mild, 44%; moderate, 31%;
and severe, 25%. At entry, 63.8% of subjects performed physical activity. At the end of follow-up, vital status or Instrumental
Activities of Daily Living scale was possible to ascertain in 633
patients (99.1% of initial sample). Fifty-one patients missed complete cognitive evaluation in any follow-up clinical visit; for those
51 patients, no cognitive diagnosis was attributed.
Considering the cognitive diagnosis ascertained in the
last clinical visit, dementia was diagnosed in 90 patients
Verdelho et al Physical Activity Reduces Risk for Vascular Dementia 3333
Table 1. Baseline Patient Characteristics (N=639)
Age, y, mean±SD
Female/male
Educational level,
y of schooling
Table 3. Cox Proportional Hazards Model
HR
P Value
0.033
1.034
0.163
0.987
1.084
–0.016
0.985
0.600
0.929
1.044
0.899
0.650
0.569
1.421
0.731
0.596
2.093
0.017
1.127
3.463
With Physical
Activity (64%)
No Physical
Activity (36%)
74.1±5
73.9±5
74.5±5
0.2
Educational level
55%/45%
53%/46%
57%/43%
0.4
Sex
–0.106
9.6±3.8
10.1±3.6
8.7±3.9
0.000
WMC severity
0.005
WMC severity
(moderate vs mild)
0.110
1.117
WMC severity
(severe vs mild)
0.681
1.976
WMC severity
P
Value
β
Total
Age
95% CI
0.033
Mild
283 (44%)
191/407
93/231
Moderate
197 (31%)
133/407
64/231
Severe
158 (25%)
83/407
74/231
MTA score
1.1±0.8
1.1±0.8
1.2±0.9
0.04
MTA (1 vs 0)
0.397
1.488
0.362
0.633
3.496
27.36±2.4
27.6±2.2
26.9±2.7
0.000
MTA (2 vs 0)
1.363
3.907
0.002
1.666
9.160
MTA (3 vs 0)
1.738
5.686
0.000
2.205 14.663
MTA (4 vs 0)
2.520
12.430
0.000
3.263 47.348
Physical activity
–0.492
0.611
0.043
0.380
MMSE score,
mean±SD
MTA
WMC indicates white matter changes; MTA, medial temporal atrophy;
MMSE, Mini-Mental State Examination.
(vascular dementia, 54; Alzheimer disease with vascular component, 34; frontotemporal dementia, 2), and 147
patients had cognitive impairment not dementia (vascular
cognitive impairment without dementia, 86; mild cognitive
impairment, 61).
Using Cox regression analysis we found that physical activity measured at baseline was an independent protective factor
for cognitive impairment overtime (dementia and cognitive
impairment not dementia; Table 2). The preventive effect of
physical activity for the progression for cognitive impairment was unchanged when controlling for diabetes (β=−0.35,
P=0.021; hazard ratio, 0.71; 95% CI, 0.524–0.949).
• Considering dementia irrespective of pathogenesis, physical activity reduced the risk of dementia (Table 3)
• Considering patients with criteria for Alzheimer disease
(N=34), physical activity did not influence evolution for
dementia (Table 4).
Table 2. Cox Proportional Hazards Model
Age
β
HR
P Value
0.000
0.984
Dependent variable: dementia in last clinical evaluation (90 subjects).
CI indicates confidence interval; HR, hazard ratio; MTA, medial temporal
atrophy; WMC, white matter changes.
• Considering patients with criteria for vascular dementia
(N=54) we found that physical activity reduced in more
than half the risk for vascular dementia (Table 5), even
controlling for incident stroke (β=−0.80, P=0.015; hazard ratio, 0.45; 95% CI, 0.236–0.858).
Because the impact of physical activity over time could be
due to cognitive differences already at baseline, we repeated
the analysis considering Mini-Mental State Examination at
baseline. Even so, physical activity at baseline remained an
independent predictor of vascular dementia, reducing in half
the risk for future vascular dementia (β=−0.71, P=0.032; hazard ratio, 0.49; 95% CI, 0.257–0.940; Supplemental Table VI
in Appendix II). Considering other outcomes, we controlled
Table 4. Cox Proportional Hazards Model
95% CI
β
HR
P Value
95% CI
0.026
1.026
0.070
0.998
1.055
Age
0.060
1.062
0.142
0.980
1.151
–0.050
0.951
0.007
0.917
0.986
Educational level
–0.049
0.952
0.347
0.860
1.055
0.184
1.202
0.186
0.915
1.580
Sex
–0.823
0.439
0.043
0.197
0.976
WMC severity
(moderate vs mild)
0.353
1.423
0.039
1.017
1.991
WMC severity
(moderate vs mild)
–0.661
0.517
0.228
0.176
1.512
WMC severity
(severe vs mild)
0.411
1.508
0.020
1.066
2.134
WMC severity
(severe vs mild)
0.358
1.431
0.415
0.605
3.383
Educational level
Sex
WMC severity
0.038
MTA
WMC severity
0.023
0.179
MTA
0.010
MTA (1 vs 0)
0.080
1.083
0.689
0.733
1.600
MTA (1 vs 0)
–0.976
0.377
0.113
0.113
1.259
MTA (2 vs 0)
0.416
1.516
0.057
0.987
2.328
MTA (2 vs 0)
0.785
2.192
0.144
0.765
6.283
MTA (3 vs 0)
0.642
1.901
0.019
1.109
3.256
MTA (3 vs 0)
0.880
2.411
0.186
0.655
8.873
MTA (4 vs 0)
1.135
3.112
0.040
1.055
9.185
MTA (4 vs 0)
1.381
3.979
0.134
0.655
24.187
Physical activity
–0.447
0.640
0.002
0.482
0.849
Physical activity
0.089
1.093
0.823
0.504
2.369
Dependent variable: cognitive decline (dementia and cognitive decline not
dementia in last clinical evaluation (237 subjects).
CI indicates confidence interval; HR, hazard ratio; MTA, medial temporal
atrophy; WMC, white matter changes.
Dependent variable: Alzheimer disease with vascular component in last
clinical evaluation (34 subjects).
CI indicates confidence interval; HR, hazard ratio; MTA, medial temporal
atrophy; WMC, white matter changes.
3334 Stroke December 2012
Table 5. Cox Proportional Hazards Model
β
HR
P Value
95% CI
Age
0.029
1.029
0.352
0.969
1.093
Educational level
0.008
1.008
0.835
0.937
1.084
Sex
0.320
1.377
0.300
0.752
2.519
WMC severity
0.041
WMC severity
(moderate vs mild)
0.624
1.867
0.156
0.787
4.425
WMC severity
(severe vs mild)
1.029
2.798
0.012
1.255
6.240
MTA (1 vs 0)
1.960
7.102
0.058
0.936
53.890
MTA (2 vs 0)
2.654
14.208
0.011
1.861
108.484
MTA (3 vs 0)
3.125
22.751
0.003
2.807
184.406
MTA (4 vs 0)
4.184
65.599
0.001
5.297
812.370
Physical activity
–0.864
0.421
0.008
0.223
0.797
MTA
0.002
Dependent variable: vascular dementia in last clinical evaluation (54
subjects).
CI indicates confidence interval; HR, hazard ratio; MTA, medial temporal
atrophy; WMC, white matter changes.
also results for Mini-Mental State Examination score, and
results remained unchanged considering cognitive impairment
(dementia and not dementia altogether; Supplemental Table
VII in Appendix II) and were lost for dementia, probably due
to the different types of predictors of the dementias included
(Supplemental Table VIII in Appendix II).
Discussion
Our results showed that among nondisabled old people with
WMC, physical activity reduced the risk for cognitive impairment and vascular dementia, independently of the severity of
WMC even controlling for educational level, age, and temporal
atrophy and for risk factors found to be predictive of dementia.
Previous studies suggested a beneficial impact of physical activity on the progression for cognitive impairment and
dementia, even for subjects with Alzheimer disease and a
reduced amount of exercise.1–6 Recently, a panel reviewed
evidence on the prevention for Alzheimer disease; although
globally physical activity (particularly high levels) have been
associated with decreased risk of Alzheimer disease, associations were not always significant after adjusting for confounding factors risk and in some studies the risk estimates were in
the direction indicating increased risk of Alzheimer disease.21
A recent meta-analysis addressed the preventive effect of
physical activity for vascular dementia, but among the 5 studies
included, only 1 showed a significant association between
physical activity and risk for vascular dementia. Several
studies reported no association between physical activity
and all dementias or vascular dementia.22 Moreover, those
studies, with 1 exception,23 did not control for imaging data,
namely WMC or medial temporal atrophy, and most of them
did not control for cognitive status at inclusion.23–27 Our study
has some limitations, mostly related with sample selection,
which does not represent the community. Participants were
selected due to minor complaints and probably represent the
first moment when nondisabled elderly with cerebral WMC
seek medical attention. Other limitations consist of length
of the study (3 years) that was probably short to allow a
larger number of conversions for cognitive impairment and
dementia and interfere with the power of the study. However,
longer follow-up would implicate more missing values and
compromise also statistical approach. Nevertheless, our
study has several strengths providing a unique opportunity
to evaluate prognostic factors of cognitive impairment and
subtypes of dementia over time when evaluating older people
with a particular vascular profile and living independently
and allowed a very comprehensive control for risk factors and
comorbidities implicated in disability, including brain imaging
variables.19 In the LADIS study, severe WMC were associated
with worse motor performance using simple clinical measures
of balance and gait28 and with an increase risk of falls,29 and
at that time, it seemed conceivable that exercise could have
a protective effect in delaying transition to disability. In the
present study we looked for the particular effect of physical
activity on the transition for cognitive impairment. We already
described that severe WMC predicted evolution for cognitive
impairment and vascular dementia. We found now that, even
taking into consideration the effect of severe WMC, physical
activity implicated a reduced risk for the transition to vascular
dementia. Among the reasons that could explain the protective
effect of physical activity on the transition for cognitive
impairment, reduced physical activity could be a subtle
manifestation of an incipient cognitive impairment. Although
we cannot exclude premild cognitive impairment in our
sample, we controlled results for a global cognitive measure
at baseline (Mini-Mental State Examination) and found that
physical activity remained protective, reducing in half the
risk to develop vascular dementia. The same consistency of
results was found when controlling for cognitive impairment
(dementia and cognitive impairment not dementia together),
but was lost for dementia, because this group includes
Alzheimer disease and vascular dementia, and, as published
previously, the cognitive predictors were quite different.19
In the LADIS sample, among all vascular risk factors studied, diabetes was the only independent predictor of cognitive
decline (including dementia and cognitive decline not dementia) independent of the effect of WMC and medial temporal
lobe atrophy, and stroke was a prognostic factor for vascular
dementia. For this reason we controlled our findings for both
diseases, and the protective effect of physical activity remained
unchanged. Our data support the conviction that older subjects
with vascular risk factors and evidence for vascular cerebral
damage benefit from regular physical activity. We think that
relation between physical activity and cognitive impairment
should be further studied by interventional studies.
Sources of Funding
The LADIS Study was supported by the European Union within the
Vth European Framework Program Quality of life and management
of living resources (1998–2002), contract No. QLRT-2000-00446.
Disclosures
One of the authors (Dr Fazekas) received 1 individual modest research grant.
Verdelho et al Physical Activity Reduces Risk for Vascular Dementia 3335
References
1.Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane
P, Kukull W. Exercise is associated with reduced risk for incident
dementia among persons 65 years of age and older. Ann Intern Med.
2006;144:73–81.
2. Weuve J, Kang JH, Manson JE, Breteler MM, Ware JH, Grodstein F.
Physical activity, including walking, and cognitive function in older
women. JAMA. 2004;292:1454–1461.
3. Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J,
Soininen H, Nissinen A, Kivipelto M. Leisure-time physical activity at
midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol.
2005;4:705–711.
4. Wang L, Larson EB, Bowen JD, van Belle G. Performance-based physical function and future dementia in older people. Arch Intern Med.
2006;166:1115–1120.
5. Forbes D, Forbes S, Morgan DG, Markle-Reid M, Wood J, Culum
I. Physical activity programs for persons with dementia. Cochrane
Database Syst Rev. 2008;3:CD006489.
6. Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S,
Tang MX, Stern Y. Physical activity, diet, and risk of Alzheimer disease.
JAMA. 2009;302:627–637.
7. Miller DI, Taler V, Davidson PS, Messier C. Measuring the impact of
exercise on cognitive aging: methodological issues. Neurobiol Aging.
2012;33:622.e29–622.e43.
8. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol.
2004;3:343–353.
9. Kramer AF, Colcombe SJ, McAuley E, Scalf PE, Erickson KI. Fitness,
aging and neurocognitive function. Neurobiol Aging. 2005;26(suppl
1):124–127.
10. Clarkson P, Montgomery HE, Mullen MJ, Donald AE, Powe AJ, Bull T,
Jubb M, World M, Deanfield JE. Exercise training enhances endothelial
function in young men. J Am Coll Cardiol. 1999;33:1379–1385.
11. Vona M, Codeluppi GM, Iannino T, Ferrari E, Bogousslavsky J, von
Segesser LK. Effects of different types of exercise training followed by
detraining on endothelium-dependent dilation in patients with recent
myocardial infarction. Circulation. 2009;119:1601–1608.
12. Seals DR, Desouza CA, Donato AJ, Tanaka H. Habitual exercise and
arterial aging. J Appl Physiol. 2008;105:1323–1332.
13.Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J,
Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O’brien
J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari
D. Impact of age-related cerebral white matter changes on the transition to disability—the LADIS study: rationale, design and methodology.
Neuroepidemiology. 2005;24:51–62.
14. Madureira S, Verdelho A, Ferro J, Basile AM, Chabriat H, Erkinjuntti T,
Fazekas F, Hennerici M, O’Brien J, Pantoni L, Salvadori E, Scheltens
P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D; LADIS
Study Group. Development of a neuropsychological battery for the
Leukoaraiosis and Disability in the Elderly Study (LADIS): experience
and baseline data. Neuroepidemiology. 2006;27:101–116.
15. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal
abnormalities at 1.5T in Alzheimer’s dementia and normal aging. AJNR
Am J Neuroradiol. 1987;8:421–426.
16. Lawton MP, Brody EM. Assessment of older people: self-maintaining and
instrumental activities of daily living. Gerontologist. 1969;9:179–186.
17. Fletcher GF, Balady G, Blair SN, Blumenthal J, Caspersen C, Chaitman
B, Epstein S, Sivarajan Froelicher ES, Froelicher VF, Pina IL, Pollock
ML. Statement on exercise: benefits and recommendations for physical
activity programs for all Americans. A statement for health professionals
by the Committee on Exercise and Cardiac Rehabilitation of the Council
on Clinical Cardiology, American Heart Association. Circulation.
1996;94:857–862.
18. Scheltens P, Leys D, Barkhof F, Huglo D, Weinstein HC, Vermersch P,
Kuiper M, Steinling M, Wolters EC, Valk J. Atrophy of medial temporal lobes on MRI in ‘probable’ Alzheimer’s disease and normal ageing:
diagnostic value and neuropsychological correlates. J Neurol Neurosurg
Psychiatry. 1992;55:967–972.
19. Verdelho A, Madureira S, Moleiro C, Ferro JM, Santos CO, Erkinjuntti
T, Pantoni L, Fazekas F, Visser M, Waldemar G, Wallin A, Hennerici
M, Inzitari D; LADIS Study. White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Neurology.
2010;75:160–167.
20. Madureira S, Verdelho A, Moleiro C, Ferro JM, Erkinjuntti T, Jokinen H,
Pantoni L, Fazekas F, Van der Flier W, Visser M, Waldemar G, Wallin A,
Hennerici M, Inzitari D. Neuropsychological predictors of dementia in a
three-year follow-up period: data from the LADIS study. Dement Geriatr
Cogn Disord. 2010;29:325–334.
21. Daviglus ML, Plassman BL, Pirzada A, Bell CC, Bowen PE, Burke JR,
Connolly ES Jr, Dunbar-Jacob JM, Granieri EC, McGarry K, Patel D,
Trevisan M, Williams JW Jr. Risk factors and preventive interventions for
Alzheimer disease: state of the science. Arch Neurol. 2011;68:1185–1190.
22. Aarsland D, Sardahaee FS, Anderssen S, Ballard C; Alzheimer’s Society
Systematic Review group. Is physical activity a potential preventive
factor for vascular dementia? A systematic review. Aging Ment Health.
2010;14:386–395.
23. Podewils LJ, Guallar E, Kuller LH, Fried LP, Lopez OL, Carlson M,
Lyketsos CG. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am J Epidemiol.
2005;161:639–651.
24. Abbott RD, White LR, Ross GW, Masaki KH, Curb JD, Petrovitch
H. Walking and dementia in physically capable elderly men. JAMA.
2004;292:1447–1453.
25. Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical
activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001;58:498–504.
26. Ravaglia G, Forti P, Lucicesare A, Pisacane N, Rietti E, Bianchin M,
Dalmonte E. Physical activity and dementia risk in the elderly: findings
from a prospective Italian study. Neurology. 2008;70:1786–1794.
27. Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K,
Ohmori S, Nomiyama K, Kawano H, Ueda K. Incidence and risk factors of
vascular dementia and Alzheimer’s disease in a defined elderly Japanese
population: the Hisayama Study. Neurology. 1995;45:1161–1168.
28. Baezner H, Blahak C, Poggesi A, Pantoni L, Inzitari D, Chabriat H,
Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O’Brien J, Scheltens P,
Visser MC, Wahlund LO, Waldemar G, Wallin A, Hennerici MG; LADIS
Study Group. Association of gait and balance disorders with age-related
white matter changes: the LADIS study. Neurology. 2008;70:935–942.
29. Blahak C, Baezner H, Pantoni L, Poggesi A, Chabriat H, Erkinjuntti T,
Fazekas F, Ferro JM, Langhorne P, O’Brien J, Visser MC, Wahlund LO,
Waldemar G, Wallin A, Inzitari D, Hennerici MG; LADIS Study Group.
Deep frontal and periventricular age related white matter changes but
not basal ganglia and infratentorial hyperintensities are associated with
falls: cross sectional results from the LADIS study. J Neurol Neurosurg
Psychiatry. 2009;80:608–613.