Brain reserve and cognitive reserve in multiple sclerosis: What you've got and how you use it

DOI 101212WNL0b013e318296e98b2013802186-2193 Published Online before print May 10 2013Neurology

James F Sumowski Maria A Rocca Victoria M Leavitt et al youve got and how you use it

Brain reserve and cognitive reserve in multiple sclerosis What

This information is current as of May 10 2013

httpwwwneurologyorgcontent80242186fullhtmllocated on the World Wide Web at

The online version of this article along with updated information and services is

Neurology All rights reserved Print ISSN 0028-3878 Online ISSN 1526-632Xsince 1951 it is now a weekly with 48 issues per year Copyright copy 2013 American Academy of

reg is the official journal of the American Academy of Neurology Published continuouslyNeurology

James F Sumowski PhDMaria A Rocca MDVictoria M Leavitt PhDGianna Riccitelli PhDGiancarlo Comi MDJohn DeLuca PhDMassimo Filippi MD

Correspondence toDr Sumowskijsumowskikesslerfoundationorg

Brain reserve and cognitive reserve inmultiple sclerosisWhat yoursquove got and how you use it

ABSTRACT

ObjectiveWe first tested the brain reserve (BR) hypothesis in multiple sclerosis (MS) by examiningwhether larger maximal lifetime brain volume (MLBV determined by genetics) protects againstdisease-related cognitive impairment and then investigated whether cognitive reserve (CR)gained through life experience (intellectually enriching leisure activities) protects against cogni-tive decline independently of MLBV (BR)

Methods Sixty-two patients with MS (41 relapsing-remitting MS 21 secondary progressive MS)received MRIs to estimate BR (MLBV estimated with intracranial volume [ICV]) and disease burden(T2 lesion load atrophy of gray matter white matter thalamus and hippocampus) Early-life cog-nitive leisurewasmeasured as a source of CRWe assessed cognitive statuswith tasks of cognitiveefficiency and memory Hierarchical regressions were used to investigate whether higher BR (ICV)protects against cognitive impairment and whether higher CR (leisure) independently protectsagainst cognitive impairment over and above BR

Results Cognitive status was positively associated with ICV (R2 5 0066 p 5 0017) An ICV 3

disease burden interaction (R2 5 0050 p 5 0030) revealed that larger ICV attenuated theimpact of disease burden on cognition Controlling for BR higher education (R2 5 0047 p 5

0030) and leisure (R2 5 0090 p 5 0001) predicted better cognition A leisure 3 diseaseburden interaction (R2 5 0037 p 5 0030) showed that leisure independently attenuated theimpact of disease burden on cognition Follow-up analyses revealed that BR protected againstcognitive inefficiency not memory deficits whereas CR was more protective against memorydeficits than cognitive inefficiency

ConclusionWeprovide evidence of BR inMS and show that CR independently protects against dis-ease-related cognitive decline over and above BR Lifestyle choices protect against cognitive impair-ment independently of genetic factors outside of onersquos control Neurology 2013802186ndash2193

GLOSSARYAD5 Alzheimer disease BR5 brain reserve CR5 cognitive reserve GM5 gray matter ICV5 intracranial volumeMLBV5maximal lifetime brain volume MS 5 multiple sclerosis WM 5 white matter

Many persons with multiple sclerosis (MS) have cognitive impairment whereas others withstandconsiderable disease burden without cognitive decline12 A similar cognitive-pathologic dissocia-tion in Alzheimer disease (AD)3 prompted theories of ldquobrain reserverdquo4 and ldquocognitive reserverdquo5

The brain reserve hypothesis posits that larger maximal lifetime brain volume (MLBV) (estimatedwith head size or intracranial volume [ICV]) protects against cognitive decline4 That is cognitiveimpairment emerges when brain volume falls beneath a critical threshold persons with largerMLBV withstand greater disease burden before reaching this threshold Indeed elders withlarger MLBV have better cognition6ndash10 and lower risk of dementia1112 Herein we investigatewhether MLBV (brain reserve) protects patients with MS from cognitive impairment

Brain reserve (MLBV) is determined almost entirely by genetics1314 In contrast the cognitivereserve hypothesis posits that enriching experiences (eg education cognitive leisure) protect

From Neuropsychology and Neuroscience (JFS VML JD) Kessler Foundation Research Center West Orange Departments of PhysicalMedicine and Rehabilitation (JFS VML JD) and Neurology and Neurosciences (JD) UMDNJndashNew Jersey Medical School Newark NJand Neuroimaging Research Unit (MAR GR MF) and Department of Neurology (MAR GC MF) San Raffaele Scientific InstituteVita-Salute San Raffaele University Milan Italy

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

2186 copy 2013 American Academy of Neurology

against dementia5 Indeed educational attain-ment attenuates the effect of AD neuropathol-ogy on cognition1516 We have extended thecognitive reserve hypothesis toMS17ndash20 showingthat lifetime intellectual enrichment attenuatesthe effect of disease burden on cognition1719

Importantly brain reserve and cognitive reservehave been investigated separately so it remainsunclear whether enriching life experiences pro-tect against cognitive decline independently ofgenetically determined MLBV Given the mod-erate but robust correlation between brainreserve and cognitive reserve (brain size andintelligence21) it is unknown whether theprotective effect of enriching experiences isexplained through concomitantly higher brainreserve Herein we investigate whether early-lifecognitive leisure (source of cognitive reserve)independently protects against cognitive impair-ment over and above MLBV (brain reserve) inpatients with MS

METHODS Subject enrollment Subjects were 62 patients

with definite MS22 (30 women) without an exacerbation in the

last 4 weeks no current corticosteroid use and no history of

serious psychiatric illness substance abuse learning disability

or other neurologic condition Mean age was 437 6 111 years

with 131 6 34 years of education Given that a) patients retro-

spectively reported cognitive leisure from their early 20s and b)

we wanted formal education completed before participation all

patients were at least 25 years old Mean disease duration was

132 6 69 years with a mean Expanded Disability Status Scale

score of 32 6 21 MS phenotypes included relapsing-remitting

(n 5 41) and secondary progressive (n 5 21) Current disease-

modifying drug treatments included interferon b-1a (n 5 26) or

interferon b-1b (n5 4) glatiramer acetate (n5 19) azathioprine

(n 5 3) cyclophosphamide (n 5 2) natalizumab (n 5 2)

mitoxantrone (n 5 1) or no treatment (n 5 5)

Standard protocol approvals registrations and patientconsents Approval was received from the local ethical standards

committee on human experimentation and written informed

consent was obtained from all subjects participating in the study

Cognitive functioning Cognitive inefficiency and memory

problems are the most prevalent cognitive deficits among patients

with MS1 Cognitive efficiency was measured with the Symbol

Digit Modalities Test (oral version) and the Paced Auditory Serial

Addition Task (3-second version) Norm-referenced z scores werecalculated for both tasks23 and the mean of these z scores com-

prised our cognitive efficiency composite Memory was assessed

with the Selective Reminding Test and Spatial Recall Test

Norm-referenced z scores were calculated for the Selective Re-

minding Test (Total Learning Delayed Recall) and Spatial Recall

Test (Total Learning Delayed Recall)23 and the mean of these zscores comprised our memory composite A norm-referenced

overall cognitive status score was derived as the mean of cognitiveefficiency and memory composites Analyses first investigated the

impact of brain reserve and cognitive reserve on overall cognitivestatus and then separately for cognitive efficiency and memory

Lesion load and brain atrophy Using a 30-tesla Philips Interascanner (Philips Healthcare Guildford UK) the following brain

sequences were acquired a) dual-echo turbo spin echo (repetition

timeecho time 5 350024ndash120 milliseconds fractional anisot-

ropy5 150deg field of view5 240mm2 matrix5 2563 256 echo

train length 5 5 44 contiguous 3-mm-thick axial slices) and b)

3-dimensional T1-weighted fast field echo (repetition time 5

25 milliseconds echo time 5 46 milliseconds fractional anisot-

ropy 5 30deg field of view 5 230 mm2 matrix 5 256 3 256

slice thickness 5 1 mm 220 contiguous axial slices in-plane res-

olution 5 089 3 089 mm2) T2 lesion load was measured on

dual-echo scans using a local thresholding segmentation technique

(Jim 50 Xinapse System wwwxinapsecom) Brain atrophy

was measured as normalized volumes of gray matter (GM) and

white matter (WM) obtained using SIENAX (version 26 part

of FSL 41) whereas normalized volumes of the thalamus and

hippocampus were obtained using FIRST then applying the

same scaling factor calculated with SIENAX To correct for the

misclassification of WM lesions all pixels classified as GM but

lying neither in the cortical GM nor in the subcortical GM were

reassigned to the WM before volume calculation The scaling

factor within SIENAX is derived from the transformation that

matches the extracted brain and skull to standard-space brain and

skull images (derived from the MNI152 standard image) values

higher than one were obtained for heads with small ICV and values

lower than one for ICVs larger than theMNI atlas An advantage of

this approach is that it does not require that CSF be robustly

estimated as it is difficult to distinguish between CSF and skull

voxels in T images Lesion load and brain atrophy were used as

estimates of MS disease burden in subsequent analyses

Estimate of brain reserve ICV ICV is an estimate of MLBV

as brain growth corresponds to increased ICV during develop-

ment24 and ICV is strongly correlated with brain size in healthy

persons (eg r 5 08625) ICV has been used as an estimate of

brain reserve in previous research (eg references 6 and 9) The

aforementioned scaling factor within SIENAX is a measurement

of ICV however we reversed the direction of values such that

larger values represent larger ICVs (for ease of presentation)

Given that men have larger ICVs than women as in our sample

(t[60] 5 562 p 0001) we adjusted ICV measurements for

sex The brain reserve hypothesis states that persons with higher

brain reserve withstand more severe disease burden before expe-

riencing cognitive decline not that higher brain reserve slows

disease progression As expected therefore there was no relation-

ship between ICV and disease duration (r52002 p5 088) or

T2 lesion load (r 5 008 p 5 055) nor was there a difference

between disease phenotypes (t[60] 5 081 p 5 041)

Estimate of cognitive reserve Cognitive leisure activityAs described previously20 patients were surveyed to quantify par-

ticipation in 7 cognitive leisure activities during their early 20s

(table 1) Frequency of participation in each activity was endorsed

as 1) once or less per year 2) several times per year 3) several

times per month 4) several times per week or 5) daily Total

frequency across items was our estimate of early-life cognitive

leisure (mean 5 188 6 57) This score was interpolated for

patients missing 1 (n 5 3) or 2 (n 5 4) items There was no

difference in leisure frequency between our sample and a larger

independent matched pilot sample of 124 patients with MS aged

25 years or older (table 1) indicating that early-life cognitive

leisure within our sample was representative of MS patients gen-

erally We have previously shown no difference between item

endorsement between patients with MS and healthy persons

indicating that cognitive leisure was unaffected by preclinical

Neurology 80 June 11 2013 2187

disease20 The cognitive reserve hypothesis states that lifetime

enrichment helps patients better withstand disease without cog-

nitive impairment not that enriching lifestyles slow disease pro-

gression As expected therefore there was no relationship

between cognitive leisure and disease duration (r 5 014 p 5

028) or T2 lesion load (r 5 2006 p 5 067) nor was there a

difference between disease phenotypes (t[60] 5 061 p 5 055)

Statistical analyses Brain reserveWe performed a hierarchical

regression to investigate the protective effect of brain reserve on

overall cognitive status After controlling for age sex and pheno-

type (block 1) estimates of disease burden (T2 lesion load brain

atrophy normalized volumes of cerebral GM cerebral WM thal-

amus and hippocampus) were entered in a stepwise fashion (block

2) ICV was entered within block 3 to test whether MLBV predicts

cognitive status (Stepwise entry of disease burden estimates within

block 2 allowed us to assess the contribution of brain reserve over

and above the estimate of disease burden most associated with cog-

nitive status) Finally the interaction between ICV and disease bur-

den (estimate retained within block 2) was evaluated in block 4 If

brain reserve protects against cognitive decline there should be an

interaction between ICV and disease burden such that greater ICV

moderatesattenuates the deleterious impact of disease burden on

cognitive status This hierarchical regression was repeated to predict

cognitive efficiency and memory separately

Cognitive reserve We then investigated whether cognitive

reserve independently protects against disease-related cognitive

decline even after controlling for brain reserve A hierarchical

regression was again performed to predict overall cognitive status

After controlling for the previous brain reserve analysis (block 1)

education (block 2) and early-life cognitive leisure (block 3) were

entered followed by the interaction between disease burden and

cognitive leisure (block 4) If cognitive reserve independently pro-

tects against disease-related cognitive decline there will be an

interaction whereby greater cognitive leisure moderatesattenu-

ates the deleterious impact of disease burden on cognitive status

This hierarchical regression was repeated to predict cognitive effi-

ciency and memory separately

RESULTS Brain reserve The results for brain reserveanalyses are presented in table 2

Overall cognitive status After controlling for age sexand phenotype (block 1) T2 lesion load (the onlyestimate of disease burden retained) was negativelyassociated with cognitive status (block 2) There wasa medium-sized positive relationship between ICVand cognitive status (block 3) such that patients withlarger ICVs had better cognitive status (figure 1A)

Table 1 Means and SDs for the current sample and matched pilot sample on each of the 7 cognitive leisureactivities as well as the total cognitive leisure scorea

Cognitive leisure activitiesPilot sample (n 5 124)b

mean 6 SDSample (n 5 62)mean 6 SD

Differencep values

Read books 31 6 14 32 6 15 080

Read magazines or newspapers 39 6 12 38 6 14 062

Produce art (eg painting poetrysculpture song writing ballet)

25 6 13 22 6 13 024

Produce nonartistic writing (eg diarynewsletter essay blog)

23 6 13 23 6 15 080

Play a musical instrument 21 6 14 20 6 15 054

Play structured games (eg cardsboard games crossword puzzles)

28 6 12 27 6 11 067

Participate in hobbies (eg gardeningmodel building Web design)

25 6 14 26 6 13 059

Total cognitive leisure activity 190 6 48 187 6 56 071

aThere were no differences between the current sample and the larger pilot sample on any itemsb The pilot sample did not differ in age (420 6 103 years p 5 029) disease duration (132 6 84 years p 5 097)education (136 6 32 years p 5 036) or Expanded Disability Status Scale score (31 6 19 p 5 070) There was amarginally higher proportion of women (605 p 5 0076) and patients with relapsing-remitting multiple sclerosis(782 p 5 0076) within the pilot sample

Table 2 Results for the hierarchical regression analyses investigating the protective effect of brain reserve(ICV) on overall cognitive status cognitive efficiency and memory

Overall cognitive status Cognitive efficiency Memory

ΔR2 p Value ΔR2 p Value ΔR2 p Value

Age sex phenotype 0236 0001 0203 0004 0180 0009

T2LL 0089 0008 0040 0090 0119 0003

ICV 0066 0017 0100 0005 0012 0335

T2LL 3 ICV 0050 0030 0087 0005 0005 0528

Abbreviations ICV 5 intracranial volume T2LL 5 T2 lesion load

2188 Neurology 80 June 11 2013

The interaction between ICV and disease burden (T2lesion load) was also significant (block 4) such thatgreater ICV moderatedattenuated the negativeimpact of disease burden (T2 lesion load) on cogni-tive status (figure 1B)

Cognitive efficiency and memory There was a largepositive relationship between ICV and cognitive effi-ciency (block 3) such that patients with larger ICVsshowed better cognitive efficiency There was also aninteraction whereby greater ICV moderatedattenu-ated the negative impact of T2 lesion load on cogni-tive efficiency In contrast there was no relationshipbetween ICV and memory (block 3) nor was theinteraction significant (block 4) Brain reserve pro-tected against disease-related cognitive inefficiencynot memory problems

Cognitive reserve The results of cognitive reserve anal-yses are presented in table 3

Overall cognitive status After accounting for thebrain reserve analysis (block 1 age sex phenotypeT2 lesion load ICV ICV 3 T2 lesion load) therewas a positive relationship between cognitive statusand education (block 2) There was also a large inde-pendent positive relationship between cognitive lei-sure and cognitive status (block 3) such that patientswho engaged in more early-life cognitive leisure hadbetter cognitive status (figure 2A) The interactionbetween T2 lesion load and cognitive leisure was sig-nificant (block 4) with greater cognitive leisure mod-eratingattenuating the negative impact of T2 lesionload on cognitive status (figure 2B)

Cognitive efficiency and memory Cognitive efficiencywas unrelated to education (block 2) but positivelyrelated to cognitive leisure (block 3) The interactionbetween T2 lesion load and cognitive leisure on cog-nitive efficiency was small and nonsignificant (block4) Memory was strongly and positively related toboth education (block 2) and cognitive leisure (block3) and there was a significant small- to medium-sizedinteraction between T2 lesion load and cognitive lei-sure (block 4) such that greater cognitive leisure mod-eratedattenuated the negative impact of T2 lesionload on memory In summary cognitive leisure inde-pendently contributed to both cognitive efficiencyand memory over and above brain reserve but theinteraction between cognitive leisure and disease bur-den was only significant for memory The cognitive

Figure 1 Brain reserve protects against disease-related cognitive decline

Graphical depiction of (A) the positive correlation between intracranial volume (ICV) (brain reserve)and overall cognitive status and (B) the interaction between ICV and T2 lesion load (T2LL)whereby larger ICV moderates the negative impact of T2LL on cognitive status

Table 3 Results for the hierarchical regression analyses investigating the independent protective effect ofcognitive reserve (leisure) on overall cognitive status cognitive efficiency and memory



BR analysis 0441 0001 0368 0001 0315 0001

Education 0047 0030 0012 0278 0086 0007

Leisure 0090 0001 0061 0014 0083 0005

T2LL 3 leisure 0037 0030 0021 0136 0040 0042

Abbreviations BR 5 brain reserve T2LL 5 T2 lesion load


reserve hypothesis was upheld for memory but less sofor cognitive efficiency

Supplemental analyses We entered brain reserve intoregression models before cognitive reserve as MLBVis established before education and leisure Given acorrelation between education and ICV (r 5 025p 5 005) we examined whether the relationshipbetween brain reserve (ICV) and cognitive efficiencyis explained by the relationship between educationand ICV We reran the brain reserve regression pre-dicting cognitive efficacy now controlling for educa-tion in block 1 (before ICV) The main effect of ICV(ΔR2 5 0064 p 5 0022) and the ICV 3 T2 lesionload interaction (ΔR2 5 0075 p5 0009) remainedindicating that brain reserve provides independentprotection from cognitive inefficiency over and above

education Although there was no link between ICVand leisure (r 5 003 p 5 084) to be thorough wereran the regression analysis controlling for educationand leisure (block 1) There were relatively nochanges to the effect of ICV (ΔR2 5 0067 p 5

0014) or the ICV 3 T2 lesion load interaction(ΔR2 5 0067 p 5 0010) Similar to educationpremorbid intelligence is a common proxy of cogni-tive reserve and correlated with maximal lifetimebrain size21 Verbal intelligence (an estimate of pre-morbid intelligence) was only available for a subsam-ple of patients (n 5 36) but was strongly correlatedwith education (r5 062 p 0001) indicating thatthey measure similar constructs Note that verbalintelligence was only weakly related to cognitive lei-sure (r5 016 p5 0350) so the protective effects ofcognitive leisure reported herein are not explained byhigher intelligence

Consistent with the MS population half of oursample was diagnosed with MS before age 30 As suchfor some patients cognitive leisure was performed afterdisease onset We investigated whether the protectiveeffect of cognitive leisure differed based on age of diag-nosis A cognitive leisure 3 disease burden (T2 lesionload) 3 age at diagnosis interaction term (controllingfor 2-way interactions) was not significant for modelspredicting overall cognitive status (ΔR2 5 0011 p 50217) cognitive efficiency (ΔR25 0008 p5 0361)or memory (ΔR2 5 0010 p 5 0300) That is theprotective effect of cognitive leisure did not differ basedon age of diagnosis

DISCUSSION Larger MLBV moderatedattenuatedthe negative impact of disease burden on cognitive sta-tus thereby supporting the brain reserve hypothesis inMS Given the moderate but robust correlation betweenestimates of cognitive reserve and brain reserve21 theprotective effect of higher cognitive reserve in previousresearch may be partially or fully explained by concom-itantly higher brain reserve Our results demonstratethat early-life intellectual enrichment (cognitive reserve)protects patients from disease-related cognitive impair-ment independently of MLBV (brain reserve) therebysupporting the independent role of enriching experien-ces in protecting against cognitive decline

Brain reserve protected against cognitive ineffi-ciency not memory decline This may seem inconsis-tent with the agingAD literature linking larger headsize or ICV to better cognition in elders6ndash10 and lowerrisk of dementia1112 however closer examination ofthese agingAD studies confirms that larger head sizeor ICV predicts cognitive efficiency not memory689

Furthermore longitudinal studies link age-relatedbrain atrophy to declines in cognitive efficiency notmemory2627 Other agingAD studies link larger ICVor head size to better Mini-Mental State Examination

Figure 2 Cognitive reserve independently protects against disease-relatedcognitive decline over and above brain reserve

Graphical depiction of (A) the positive correlation between early-life cognitive leisure (cogni-tive reserve) and overall cognitive status and (B) the interaction between early-life cognitiveleisure and T2 lesion load whereby greater engagement in cognitive leisure moderates thenegative impact of T2 lesion load on cognitive status These results demonstrate the inde-pendent protection afforded by cognitive reserve over and above brain reserve (intracranialvolume)


scores710 but the Mini-Mental State Examinationmakes minimal memory demands Finally somestudies show that larger head size protects againstdementia1112 but other studies do not2829 Althoughmemory impairment is the hallmark of dementia allelders with dementia also have a decline in nonme-mory cognition It is conceivable that higher brainreserve protects against nonmemory cognitive declineassociated with conversion from amnestic mild cog-nitive impairment to dementia Indeed cognitiveinefficiency is among the best predictors of conver-sion from mild cognitive impairment to dementia30

In summary the agingAD literature appears to belargely consistent with our finding that brain reserveis protective against declines in cognitive efficiencynot memory

The specific link between brain reserve and cogni-tive efficiency is consistent with the strong heritabilityof both MLBV1314 and cognitive efficiency (muchmore than memory)3132 Strong heritability may con-traindicate rehabilitation efforts to bolster brainreserve and cognitive efficiency However rather thanbuilding brain reserve persons may be able to pre-serve their remaining brain reserve (and protect cog-nitive efficiency) through effective disease-modifyingtherapies (which may slow brain volume loss) and bymaintaining a ldquobrain healthyrdquo lifestyle (eg aerobicexercise) Indeed cardiorespiratory fitness is posi-tively correlated with brain volume and cognitive effi-ciency in healthy persons33 and patients withMS34 Incontrast to brain reserve cognitive reserve is devel-oped through enriching life experiences The strongerprotective impact of life experience on memory rela-tive to cognitive efficiency in the current study isconsistent with lower heritability of memory relativeto cognitive efficiency3132 which is further alignedwith lower heritability of hippocampal volume (esti-mated genetic variance 5 040) relative to ICV(081)35 That is 60 of the variance in hippocampalvolume seems to be attributable to environmentalfactors (relative to 19 for ICV) Indeed enrichingcognitive experiences may have a positive impact onhippocampal volume in humans3637

Cognitive reserve may protect against cognitivedecline through superioroptimal neurocognitive pro-cessing5 Consistent with this notion functional MRIresearch has revealed differences in cerebral processingamong patients withMSwho have greater lifetime intel-lectual enrichment including greater activation (orlesser deactivation) within the brainrsquos default network18

The default network consists largely of limbic structuresincluding the hippocampus38 and has been implicatedin memory39 We have subsequently demonstrated thatdefault network activity during functional MRI predictsperformance on neuropsychological tasks of memory(but not cognitive efficiency) on a separate day40 These

links among cognitive reserve default network activityandmemory are consistent with our current finding thatcognitive reserve is specifically protective against mem-ory decline however future research should moredirectly investigate whether differences in default net-work activity mediate the relationship between intellec-tual enrichment and memory Although the currentstudy provides less support for the role of intellectualenrichment in protection against cognitive inefficiencythere was a positive correlation between cognitive leisureand cognitive efficiency We have previously shown thathigher cognitive reserve protects against cognitive inef-ficiency in MS17 although we did not control for brainreserve in that study Taken together the protectiveimpact of cognitive reserve appears to be more pro-nounced for memory than for cognitive efficiency atleast for patients with MS

Given that larger MLBV (estimated with ICV)protects against disease-related cognitive inefficiencyin MS clinical consideration of patient ICV mayimprove identification of patients at risk for cognitiveimpairment and efforts to maintain cardiorespiratoryfitness may help preserve brain reserve and cognitiveefficiency As discussed the specific link betweenbrain reserve and cognitive efficiency (not memory)in this study is consistent with results from agingstudies and should be further explored in agingAD and other neurologic populations The currentstudy also demonstrates that a cognitively enrichinglifestyle (a source of cognitive reserve) independentlyprotects against cognitive impairment (especiallymemory decline) over and above brain reserve Thisis critical because estimates of cognitive reserve andbrain reserve are correlated and the protective effectsof higher cognitive reserve in previous research mayhave been at least partially attributable to concomi-tantly higher brain reserve Our finding that early-lifecognitive leisure protects against memory declinemore than cognitive inefficiency is consistent withlower heritability of memory and hippocampal vol-ume relative to cognitive efficiency and ICV Cogni-tive rehabilitation efforts targeting memory in MSstand to be most beneficial as the hippocampus ismore affected by experience than other brain regionsFuture prospective andor experimental studiesshould investigate whether intellectual enrichment isassociated with largerincreased hippocampal volume(or lesserreduced hippocampal atrophy) in patientswith MS Finally the positive link between intellec-tual enrichment and cognition in the current and pre-vious studies is observational and cognitive leisureactivity is almost always sampled from a period beforedisease onset Longitudinal research is needed toinvestigate whether cognitive leisure moderatesdecline within MS patients as disease progressesand randomized controlled trials of intellectual


enrichment are required to establish a causal linkbetween enrichment and protection from disease-related cognitive decline in patients already diagnosedwith MS Such evidence is needed to support a pre-scription of intellectual enrichment as a therapeuticintervention to minimize or prevent disease-relatedcognitive decline

AUTHOR CONTRIBUTIONSJames F Sumowski PhD drafted the manuscript for content contrib-

uted to the study concept and design and analysisinterpretation of the

data and performed statistical analyses Maria A Rocca MD assisted

in drafting the manuscript for content and analysisinterpretation of data

as well as acquisition of data and study supervisioncoordination Victoria

M Leavitt PhD assisted in drafting the manuscript for content and con-

tributed to the interpretation of the data Gianna Riccitelli PhD assisted

in the analysis of data and acquisition of data Giancarlo Comi MD

assisted with interpretation of the data John DeLuca PhD assisted in

drafting the manuscript for content Massimo Filippi MD assisted in

drafting the manuscript for content and interpretation of data as well

as acquisition of data study supervision and obtaining funding

STUDY FUNDINGThis project was funded in part by the NIH (R00HD060765 to JFS)

DISCLOSUREJF Sumowski reports no disclosures MA Rocca received speakersrsquo

honoraria from Biogen Idec and Serono Symposia International Founda-

tion and receives research support from the Italian Ministry of Health

and Fondazione Italiana Sclerosi Multipla VM Leavitt and G Riccitelli

report no disclosures G Comi has received personal compensation for

activities with Teva Neuroscience Merck Serono Bayer Schering No-

vartis Sanofi-Aventis Pharmaceuticals and Biogen-Dompeacute as a consul-

tant speaker or scientific advisory board member J DeLuca received

salary support through compensation to the Kessler Foundation Research

Center from Biogen-Idec He is also a consultant for Biogen M Filippi

serves on scientific advisory boards for Teva Pharmaceutical Industries

Ltd and Genmab AS has received funding for travel from Bayer Scher-

ing Pharma Biogen-Dompeacute Genmab AS Merck Serono and Teva

Pharmaceutical Industries Ltd serves as a consultant to Bayer Schering

Pharma Biogen-Dompeacute Genmab AS Merck Serono and Teva Phar-

maceutical Industries Ltd serves on speakersrsquo bureaus for Bayer Schering


maceutical Industries Ltd and receives research support from Bayer

Schering Pharma Biogen-Dompeacute Genmab AS Merck Serono Teva

Pharmaceutical Industries Ltd and Fondazione Italiana Sclerosi Multi-

pla Go to Neurologyorg for full disclosures

Received November 13 2012 Accepted in final form March 7 2013

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11 Schofield PW Logroscino G Andrews HF Albert S

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Gazzaniga MS Brain size head size and intelligence quo-

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modifies the relation of AD pathology to level of cognitive

function in older persons Neurology 2003601909ndash1915

16 Roe CM Mintun MA DrsquoAngelo G Xiong C Grant EA

Morris JC Alzheimer disease and cognitive reserve varia-

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nitive reserve moderates the negative effect of brain atro-

phy on cognitive efficiency in multiple sclerosis J Int

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18 Sumowski JF Wylie GR Deluca J Chiaravalloti N Intel-

lectual enrichment is linked to cerebral efficiency in mul-

tiple sclerosis functional magnetic resonance imaging

evidence for cognitive reserve Brain 2010133362ndash374

19 Sumowski JF Wylie GR Chiaravalloti N DeLuca J

Intellectual enrichment lessens the effect of brain atrophy

on learning and memory in multiple sclerosis Neurology

2010741942ndash1945

20 Sumowski JF Wylie GR Gonnella A Chiaravalloti N

Deluca J Premorbid cognitive leisure independently con-

tributes to cognitive reserve in multiple sclerosis Neurology

2010751428ndash1431

21 Deary IJ Penke L Johnson W The neuroscience of

human intelligence differences Nat Rev Neurosci 2010

11201ndash211

22 Polman CH Reingold SC Banwell B et al Diagnostic cri-

teria for multiple sclerosis 2010 revisions to the McDonald

criteria Ann Neurol 201169292ndash302

23 Amato MP Portaccio E Goretti B et al The Raorsquos Brief

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age education and gender corrections in an Italian popu-

lation Mult Scler 200612787ndash793


24 Courchesne E Chisum HJ Townsend J et al Normal brain

development and aging quantitative analysis at in vivo MR

imaging in healthy volunteers Radiology 2000216672ndash782

25 Mori E Hirono N Yamashita H et al Premorbid brain size

as a determinant of reserve capacity against intellectual decline

in Alzheimerrsquos disease Am J Psychiatry 199715418ndash24

26 Rabbitt P Mogapi O Scott M et al Effects of global atro-

phy white matter lesions and cerebral blood flow on age-

related changes in speed memory intelligence vocabulary

and frontal function Neuropsychology 200721684ndash695

27 Kramer JH Mungas D Reed BR et al Longitudinal MRI

and cognitive change in healthy elderly Neuropsychology

200721412ndash418

28 Edland SD Xu Y Plevak M et al Total intracranial vol-

ume normative values and lack of association with Alz-

heimerrsquos disease Neurology 200259272ndash274

29 Jenkins R Fox NC Rossor AM Harvey RJ Rossor MN

Intracranial volume and Alzheimer disease evidence against

the cerebral reserve hypothesis Arch Neurol 200057220ndash224

30 Tabert MH Manly JJ Liu X et al Neuropsychological

prediction of conversion to Alzheimer disease in patients

with mild cognitive impairment Arch Gen Psychiatry

200663916ndash924

31 Pedersen NL Plomin R Nesselroade JR McClearn GE A

quantitative genetic analysis of cognitive abilities during the

second half of the life span Psychol Sci 19923346ndash353

32 McClearn GE Johansson B Berg S et al Substantial

genetic influence on cognitive abilities in twins 80 or more

years old Science 19972761560ndash1563

33 Hillman CH Erickson KI Kramer AF Be smart exercise

your heart exercise effects on brain and cognition Nat

Rev Neurosci 2008958ndash65

34 Prakash RS Snook EM Motl RW Kramer AF Aerobic

fitness is associated with gray matter volume and white

matter integrity in multiple sclerosis Brain Res 2010

134141ndash51

35 Sullivan EV Pfefferbaum A Swan GE Carmelli D Her-

itability of hippocampal size in elderly twin men equiva-

lent influence from genes and environment Hippocampus

200111754ndash762

36 Maguire EA Gadian DG Johnsrude IS et al Navigation-

related structural change in the hippocampi of taxi drivers

Proc Natl Acad Sci USA 2000974398ndash4403

37 Draganski B Gaser C Kempermann G et al Temporal

and spatial dynamics of brain structure changes during

extensive learning J Neurosci 2006266314ndash6317

38 Greicius MD Supekar K Menon V Dougherty RF Rest-

ing-state functional connectivity reflects structural connec-

tivity in the default mode network Cereb Cortex 200919

72ndash78

39 Kim H A dual-subsystem model of the brainrsquos default

network self-referential processing memory retrieval pro-

cesses and autobiographical memory retrieval Neuro-

image 201261966ndash977

40 Sumowski JF Wylie GR Leavitt VM Chiaravalloti ND

Deluca J Default network activity is a sensitive and spe-

cific biomarker of memory in multiple sclerosis Mult Scler

201219199ndash208

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James F Sumowski Maria A Rocca Victoria M Leavitt et al you use it

Brain reserve and cognitive reserve in multiple sclerosis What youve got and how


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Supplementary Material

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References

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Citations

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CORRECTIONBrain reserve and cognitive reserve in multiple sclerosis What yoursquove got and how you use it

In the article ldquoBrain reserve and cognitive reserve in multiple sclerosis What yoursquove got and how you use itrdquo by JF Sumowski et al (Neurologyreg

2013802186ndash2193) there is an error in figures 1 and 2 where the lines are switched The corrected figures are below The editorial staff regrets the error

Figure 1 Brain reserve protects against disease-relatedcognitive decline

Graphical depiction of (A) the positive correlation between intracra-nial volume (ICV) (brain reserve) and overall cognitive status and (B)the interaction between ICV and T2 lesion load (T2LL) wherebylarger ICV moderates the negative impact of T2LL on cognitivestatus

Figure 2 Cognitive reserve independently protectsagainst disease-related cognitive declineover and above brain reserve

Graphical depiction of (A) the positive correlation between early-lifecognitive leisure (cognitive reserve) and overall cognitive status and(B) the interaction between early-life cognitive leisure and T2 lesionload whereby greater engagement in cognitive leisure moderatesthe negative impact of T2 lesion load on cognitive status These re-sults demonstrate the independent protection afforded by cognitivereserve over and above brain reserve (intracranial volume)


James F Sumowski PhDMaria A Rocca MDVictoria M Leavitt PhDGianna Riccitelli PhDGiancarlo Comi MDJohn DeLuca PhDMassimo Filippi MD

Correspondence toDr Sumowskijsumowskikesslerfoundationorg

Brain reserve and cognitive reserve inmultiple sclerosisWhat yoursquove got and how you use it

ABSTRACT

ObjectiveWe first tested the brain reserve (BR) hypothesis in multiple sclerosis (MS) by examiningwhether larger maximal lifetime brain volume (MLBV determined by genetics) protects againstdisease-related cognitive impairment and then investigated whether cognitive reserve (CR)gained through life experience (intellectually enriching leisure activities) protects against cogni-tive decline independently of MLBV (BR)

Methods Sixty-two patients with MS (41 relapsing-remitting MS 21 secondary progressive MS)received MRIs to estimate BR (MLBV estimated with intracranial volume [ICV]) and disease burden(T2 lesion load atrophy of gray matter white matter thalamus and hippocampus) Early-life cog-nitive leisurewasmeasured as a source of CRWe assessed cognitive statuswith tasks of cognitiveefficiency and memory Hierarchical regressions were used to investigate whether higher BR (ICV)protects against cognitive impairment and whether higher CR (leisure) independently protectsagainst cognitive impairment over and above BR

Results Cognitive status was positively associated with ICV (R2 5 0066 p 5 0017) An ICV 3

disease burden interaction (R2 5 0050 p 5 0030) revealed that larger ICV attenuated theimpact of disease burden on cognition Controlling for BR higher education (R2 5 0047 p 5

0030) and leisure (R2 5 0090 p 5 0001) predicted better cognition A leisure 3 diseaseburden interaction (R2 5 0037 p 5 0030) showed that leisure independently attenuated theimpact of disease burden on cognition Follow-up analyses revealed that BR protected againstcognitive inefficiency not memory deficits whereas CR was more protective against memorydeficits than cognitive inefficiency

ConclusionWeprovide evidence of BR inMS and show that CR independently protects against dis-ease-related cognitive decline over and above BR Lifestyle choices protect against cognitive impair-ment independently of genetic factors outside of onersquos control Neurology 2013802186ndash2193

GLOSSARYAD5 Alzheimer disease BR5 brain reserve CR5 cognitive reserve GM5 gray matter ICV5 intracranial volumeMLBV5maximal lifetime brain volume MS 5 multiple sclerosis WM 5 white matter

Many persons with multiple sclerosis (MS) have cognitive impairment whereas others withstandconsiderable disease burden without cognitive decline12 A similar cognitive-pathologic dissocia-tion in Alzheimer disease (AD)3 prompted theories of ldquobrain reserverdquo4 and ldquocognitive reserverdquo5

The brain reserve hypothesis posits that larger maximal lifetime brain volume (MLBV) (estimatedwith head size or intracranial volume [ICV]) protects against cognitive decline4 That is cognitiveimpairment emerges when brain volume falls beneath a critical threshold persons with largerMLBV withstand greater disease burden before reaching this threshold Indeed elders withlarger MLBV have better cognition6ndash10 and lower risk of dementia1112 Herein we investigatewhether MLBV (brain reserve) protects patients with MS from cognitive impairment

Brain reserve (MLBV) is determined almost entirely by genetics1314 In contrast the cognitivereserve hypothesis posits that enriching experiences (eg education cognitive leisure) protect

From Neuropsychology and Neuroscience (JFS VML JD) Kessler Foundation Research Center West Orange Departments of PhysicalMedicine and Rehabilitation (JFS VML JD) and Neurology and Neurosciences (JD) UMDNJndashNew Jersey Medical School Newark NJand Neuroimaging Research Unit (MAR GR MF) and Department of Neurology (MAR GC MF) San Raffaele Scientific InstituteVita-Salute San Raffaele University Milan Italy

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article











































































































































Differencep values

Read books 31 6 14 32 6 15 080



25 6 13 22 6 13 024


23 6 13 23 6 15 080



28 6 12 27 6 11 067


25 6 14 26 6 13 059







T2LL 0089 0008 0040 0090 0119 0003

ICV 0066 0017 0100 0005 0012 0335

T2LL 3 ICV 0050 0030 0087 0005 0005 0528













BR analysis 0441 0001 0368 0001 0315 0001

Education 0047 0030 0012 0278 0086 0007

Leisure 0090 0001 0061 0014 0083 0005

T2LL 3 leisure 0037 0030 0021 0136 0040 0042







































































20028448ndash460















2012331758ndash1768













1997120(pt 2)257ndash269






















2010741942ndash1945




2010751428ndash1431



11201ndash211





















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints



















































































































































Differencep values

Read books 31 6 14 32 6 15 080



25 6 13 22 6 13 024


23 6 13 23 6 15 080



28 6 12 27 6 11 067


25 6 14 26 6 13 059







T2LL 0089 0008 0040 0090 0119 0003

ICV 0066 0017 0100 0005 0012 0335

T2LL 3 ICV 0050 0030 0087 0005 0005 0528













BR analysis 0441 0001 0368 0001 0315 0001

Education 0047 0030 0012 0278 0086 0007

Leisure 0090 0001 0061 0014 0083 0005

T2LL 3 leisure 0037 0030 0021 0136 0040 0042







































































20028448ndash460















2012331758ndash1768













1997120(pt 2)257ndash269






















2010741942ndash1945




2010751428ndash1431



11201ndash211





















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints




















































Differencep values

Read books 31 6 14 32 6 15 080



25 6 13 22 6 13 024


23 6 13 23 6 15 080



28 6 12 27 6 11 067


25 6 14 26 6 13 059







T2LL 0089 0008 0040 0090 0119 0003

ICV 0066 0017 0100 0005 0012 0335

T2LL 3 ICV 0050 0030 0087 0005 0005 0528













BR analysis 0441 0001 0368 0001 0315 0001

Education 0047 0030 0012 0278 0086 0007

Leisure 0090 0001 0061 0014 0083 0005

T2LL 3 leisure 0037 0030 0021 0136 0040 0042







































































20028448ndash460















2012331758ndash1768













1997120(pt 2)257ndash269






















2010741942ndash1945




2010751428ndash1431



11201ndash211





















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints




















BR analysis 0441 0001 0368 0001 0315 0001

Education 0047 0030 0012 0278 0086 0007

Leisure 0090 0001 0061 0014 0083 0005

T2LL 3 leisure 0037 0030 0021 0136 0040 0042







































































20028448ndash460















2012331758ndash1768













1997120(pt 2)257ndash269






















2010741942ndash1945




2010751428ndash1431



11201ndash211





















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints














































































20028448ndash460















2012331758ndash1768













1997120(pt 2)257ndash269






















2010741942ndash1945




2010751428ndash1431



11201ndash211





















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints



































































20028448ndash460















2012331758ndash1768













1997120(pt 2)257ndash269






















2010741942ndash1945




2010751428ndash1431



11201ndash211





















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints



























































20028448ndash460















2012331758ndash1768













1997120(pt 2)257ndash269






















2010741942ndash1945




2010751428ndash1431



11201ndash211





















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints






















200721412ndash418










200663916ndash924













134141ndash51




200111754ndash762










72ndash78








201219199ndash208

















References


Citations






Errata





Reprints


















References


Citations






Errata





Reprints


















Documents

Brain reserve and cognitive reserve in multiple sclerosis: What you've got and how you use it