James F. Sumowski, PhD
`Maria A. Rocca, MD
`Victoria M. Leavitt, PhD
`Gianna Riccitelli, PhD
`Giancarlo Comi, MD
`John DeLuca, PhD
`Massimo Filippi, MD
`
`Correspondence to
`Dr. Sumowski:
`jsumowski@kesslerfoundation.org
`
`Brain reserve and cognitive reserve in
`multiple sclerosis
`What you’ve got and how you use it
`
`ABSTRACT
`Objective: We first tested the brain reserve (BR) hypothesis in multiple sclerosis (MS) by examining
`whether larger maximal lifetime brain volume (MLBV; determined by genetics) protects against
`disease-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 leisure was measured as a source of CR. We assessed cognitive status with tasks of cognitive
`efficiency and memory. Hierarchical regressions were used to investigate whether higher BR (ICV)
`protects against cognitive impairment, and whether higher CR (leisure) independently protects
`against cognitive impairment over and above BR.
`Results: Cognitive status was positively associated with ICV (R2 5 0.066, p 5 0.017). An ICV 3
`disease burden interaction (R2 5 0.050, p 5 0.030) revealed that larger ICV attenuated the
`impact of disease burden on cognition. Controlling for BR, higher education (R2 5 0.047, p 5
`0.030) and leisure (R2 5 0.090, p 5 0.001) predicted better cognition. A leisure 3 disease
`burden interaction (R2 5 0.037, p 5 0.030) showed that leisure independently attenuated the
`impact of disease burden on cognition. Follow-up analyses revealed that BR protected against
`cognitive inefficiency, not memory deficits, whereas CR was more protective against memory
`deficits than cognitive inefficiency.
`Conclusion: We provide evidence of BR in MS, 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 one’s control. Neurologyâ 2013;80:2186–2193
`
`GLOSSARY
`AD 5 Alzheimer disease; BR 5 brain reserve; CR 5 cognitive reserve; GM 5 gray matter; ICV 5 intracranial volume; MLBV 5
`maximal lifetime brain volume; MS 5 multiple sclerosis; WM 5 white matter.
`
`Many persons with multiple sclerosis (MS) have cognitive impairment, whereas others withstand
`considerable disease burden without cognitive decline.1,2 A similar cognitive-pathologic dissocia-
`tion in Alzheimer disease (AD)3 prompted theories of “brain reserve”4 and “cognitive reserve.”5
`The brain reserve hypothesis posits that larger maximal lifetime brain volume (MLBV) (estimated
`with head size or intracranial volume [ICV]) protects against cognitive decline.4 That is, cognitive
`impairment emerges when brain volume falls beneath a critical threshold; persons with larger
`MLBV withstand greater disease burden before reaching this threshold. Indeed, elders with
`larger MLBV have better cognition6–10 and lower risk of dementia.11,12 Herein, we investigate
`whether MLBV (brain reserve) protects patients with MS from cognitive impairment.
`Brain reserve (MLBV) is determined almost entirely by genetics.13,14 In contrast, the cognitive
`reserve hypothesis posits that enriching experiences (e.g., education, cognitive leisure) protect
`
`From Neuropsychology and Neuroscience (J.F.S., V.M.L., J.D.), Kessler Foundation Research Center, West Orange; Departments of Physical
`Medicine and Rehabilitation (J.F.S., V.M.L., J.D.), and Neurology and Neurosciences (J.D.), UMDNJ–New Jersey Medical School, Newark, NJ;
`and Neuroimaging Research Unit (M.A.R., G.R., M.F.) and Department of Neurology (M.A.R., G.C., M.F.), San Raffaele Scientific Institute,
`Vita-Salute San Raffaele University, Milan, Italy.
`Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
`
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`against dementia.5 Indeed, educational attain-
`ment attenuates the effect of AD neuropathol-
`ogy on cognition.15,16 We have extended the
`cognitive reserve hypothesis to MS,17–20 showing
`that lifetime intellectual enrichment attenuates
`the effect of disease burden on cognition.17,19
`Importantly, brain reserve and cognitive reserve
`have been investigated separately, so it remains
`unclear whether enriching life experiences pro-
`tect against cognitive decline independently of
`genetically determined MLBV. Given the mod-
`erate but
`robust correlation between brain
`reserve and cognitive reserve (brain size and
`intelligence21),
`it
`is unknown whether
`the
`protective effect of enriching experiences is
`explained through concomitantly higher brain
`reserve. Herein, we investigate whether early-life
`cognitive leisure (source of cognitive reserve)
`independently protects against cognitive impair-
`ment over and above MLBV (brain reserve) in
`patients 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 43.7 6 11.1 years
`with 13.1 6 3.4 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
`13.2 6 6.9 years, with a mean Expanded Disability Status Scale
`score of 3.2 6 2.1. 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 (n 5 4), glatiramer acetate (n 5 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 patient
`consents. 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 MS.1 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 were
`calculated for both tasks,23 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 z
`scores comprised our memory composite. A norm-referenced
`overall cognitive status score was derived as the mean of cognitive
`efficiency and memory composites. Analyses first investigated the
`impact of brain reserve and cognitive reserve on overall cognitive
`status, and then separately for cognitive efficiency and memory.
`
`Lesion load and brain atrophy. Using a 3.0-tesla Philips Intera
`scanner (Philips Healthcare, Guildford, UK), the following brain
`sequences were acquired: a) dual-echo turbo spin echo (repetition
`time/echo time 5 3,500/24–120 milliseconds; fractional anisot-
`ropy 5 150°; field of view 5 240 mm2; matrix 5 256 3 256; 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 4.6 milliseconds; fractional anisot-
`ropy 5 30°; 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 0.89 3 0.89 mm2). T2 lesion load was measured on
`dual-echo scans using a local thresholding segmentation technique
`(Jim 5.0, Xinapse System, www.xinapse.com). Brain atrophy
`was measured as normalized volumes of gray matter (GM) and
`white matter (WM) obtained using SIENAX (version 2.6, part
`of FSL 4.1), 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 the MNI 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-
`ment,24 and ICV is strongly correlated with brain size in healthy
`persons (e.g., r 5 0.8625). ICV has been used as an estimate of
`brain reserve in previous research (e.g., 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 5.62, p , 0.001), 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 (r 5 20.02, p 5 0.88) or
`T2 lesion load (r 5 0.08, p 5 0.55), nor was there a difference
`between disease phenotypes (t[60] 5 0.81, p 5 0.41).
`
`Estimate of cognitive reserve: Cognitive leisure activity.
`As described previously,20 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 18.8 6 5.7). 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
`
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`Table 1
`
`Means and SDs for the current sample and matched pilot sample on each of the 7 cognitive leisure
`activities, as well as the total cognitive leisure scorea
`
`Pilot sample (n 5 124),b
`mean 6 SD
`
`Sample (n 5 62),
`mean 6 SD
`
`Difference,
`p values
`
`Cognitive leisure activities
`
`Read books
`
`Read magazines or newspapers
`
`Produce art (e.g., painting, poetry,
`sculpture, song writing, ballet)
`
`Produce nonartistic writing (e.g., diary,
`newsletter, essay, blog)
`
`Play a musical instrument
`
`Play structured games (e.g., cards,
`board games, crossword puzzles)
`
`Participate in hobbies (e.g., gardening,
`model building, Web design)
`
`3.1 6 1.4
`
`3.9 6 1.2
`
`2.5 6 1.3
`
`2.3 6 1.3
`
`2.1 6 1.4
`
`2.8 6 1.2
`
`2.5 6 1.4
`
`3.2 6 1.5
`
`3.8 6 1.4
`
`2.2 6 1.3
`
`2.3 6 1.5
`
`2.0 6 1.5
`
`2.7 6 1.1
`
`2.6 6 1.3
`
`0.80
`
`0.62
`
`0.24
`
`0.80
`
`0.54
`
`0.67
`
`0.59
`
`0.71
`
`Total cognitive leisure activity
`
`19.0 6 4.8
`
`18.7 6 5.6
`
`a There were no differences between the current sample and the larger pilot sample on any items.
`b The pilot sample did not differ in age (42.0 6 10.3 years, p 5 0.29), disease duration (13.2 6 8.4 years, p 5 0.97),
`education (13.6 6 3.2 years, p 5 0.36), or Expanded Disability Status Scale score (3.1 6 1.9, p 5 0.70). There was a
`marginally higher proportion of women (60.5%, p 5 0.076) and patients with relapsing-remitting multiple sclerosis
`(78.2%, p 5 0.076) within the pilot sample.
`
`disease.20 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 0.14, p 5
`0.28) or T2 lesion load (r 5 20.06, p 5 0.67), nor was there a
`difference between disease phenotypes (t[60] 5 0.61, p 5 0.55).
`
`Statistical analyses. Brain reserve. We 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
`moderates/attenuates 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 moderates/attenu-
`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 reserve
`analyses are presented in table 2.
`Overall cognitive status. After controlling for age, sex,
`and phenotype (block 1), T2 lesion load (the only
`estimate of disease burden retained) was negatively
`associated with cognitive status (block 2). There was
`a medium-sized positive relationship between ICV
`and cognitive status (block 3), such that patients with
`larger ICVs had better cognitive status (figure 1A).
`
`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
`
`0.236
`
`0.089
`
`0.066
`
`0.050
`
`p Value
`
`0.001
`
`0.008
`
`0.017
`
`0.030
`
`ΔR2
`
`0.203
`
`0.040
`
`0.100
`
`0.087
`
`p Value
`
`0.004
`
`0.090
`
`0.005
`
`0.005
`
`ΔR2
`
`0.180
`
`0.119
`
`0.012
`
`0.005
`
`p Value
`
`0.009
`
`0.003
`
`0.335
`
`0.528
`
`Age, sex, phenotype
`
`T2LL
`
`ICV
`
`T2LL 3 ICV
`
`Abbreviations: ICV 5 intracranial volume; T2LL 5 T2 lesion load.
`
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`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.
`
`The interaction between ICV and disease burden (T2
`lesion load) was also significant (block 4), such that
`greater
`ICV moderated/attenuated the negative
`impact of disease burden (T2 lesion load) on cogni-
`tive status (figure 1B).
`
`Cognitive efficiency and memory. There was a large
`positive relationship between ICV and cognitive effi-
`ciency (block 3), such that patients with larger ICVs
`showed better cognitive efficiency. There was also an
`interaction whereby greater ICV moderated/attenu-
`ated the negative impact of T2 lesion load on cogni-
`tive efficiency. In contrast, there was no relationship
`between ICV and memory (block 3), nor was the
`interaction significant (block 4). Brain reserve pro-
`tected against disease-related cognitive inefficiency,
`not memory problems.
`
`Cognitive reserve. The results of cognitive reserve anal-
`yses are presented in table 3.
`Overall cognitive status. After accounting for the
`brain reserve analysis (block 1: age, sex, phenotype,
`T2 lesion load, ICV, ICV 3 T2 lesion load), there
`was a positive relationship between cognitive status
`and education (block 2). There was also a large inde-
`pendent positive relationship between cognitive lei-
`sure and cognitive status (block 3), such that patients
`who engaged in more early-life cognitive leisure had
`better cognitive status (figure 2A). The interaction
`between T2 lesion load and cognitive leisure was sig-
`nificant (block 4), with greater cognitive leisure mod-
`erating/attenuating the negative impact of T2 lesion
`load on cognitive status (figure 2B).
`Cognitive efficiency and memory. Cognitive efficiency
`was unrelated to education (block 2) but positively
`related to cognitive leisure (block 3). The interaction
`between T2 lesion load and cognitive leisure on cog-
`nitive efficiency was small and nonsignificant (block
`4). Memory was strongly and positively related to
`both education (block 2) and cognitive leisure (block
`3), and there was a significant small- to medium-sized
`interaction between T2 lesion load and cognitive lei-
`sure (block 4) such that greater cognitive leisure mod-
`erated/attenuated the negative impact of T2 lesion
`load on memory. In summary, cognitive leisure inde-
`pendently contributed to both cognitive efficiency
`and memory over and above brain reserve, but the
`interaction between cognitive leisure and disease bur-
`den was only significant for memory. The cognitive
`
`Table 3
`
`Results for the hierarchical regression analyses investigating the independent protective effect of
`cognitive reserve (leisure) on overall cognitive status, cognitive efficiency, and memory
`
`Overall cognitive status
`
`Cognitive efficiency
`
`Memory
`
`BR analysis
`
`Education
`
`Leisure
`
`T2LL 3 leisure
`
`ΔR2
`
`0.441
`
`0.047
`
`0.090
`
`0.037
`
`p Value
`
`,0.001
`
`0.030
`
`0.001
`
`0.030
`
`ΔR2
`
`0.368
`
`0.012
`
`0.061
`
`0.021
`
`p Value
`
`,0.001
`
`0.278
`
`0.014
`
`0.136
`
`ΔR2
`
`0.315
`
`0.086
`
`0.083
`
`0.040
`
`p Value
`
`0.001
`
`0.007
`
`0.005
`
`0.042
`
`Abbreviations: BR 5 brain reserve; T2LL 5 T2 lesion load.
`
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`Figure 2
`
`Cognitive reserve independently protects against disease-related
`cognitive 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 cognitive
`leisure and T2 lesion load whereby greater engagement in cognitive leisure moderates the
`negative impact of T2 lesion load on cognitive status. These results demonstrate the inde-
`pendent protection afforded by cognitive reserve over and above brain reserve (intracranial
`volume).
`
`reserve hypothesis was upheld for memory, but less so
`for cognitive efficiency.
`
`Supplemental analyses. We entered brain reserve into
`regression models before cognitive reserve, as MLBV
`is established before education and leisure. Given a
`correlation between education and ICV (r 5 0.25,
`p 5 0.05), we examined whether the relationship
`between brain reserve (ICV) and cognitive efficiency
`is explained by the relationship between education
`and 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 0.064, p 5 0.022) and the ICV 3 T2 lesion
`load interaction (ΔR2 5 0.075, p 5 0.009) remained,
`indicating that brain reserve provides independent
`protection from cognitive inefficiency over and above
`
`education. Although there was no link between ICV
`and leisure (r 5 0.03, p 5 0.84), to be thorough we
`reran the regression analysis controlling for education
`and leisure (block 1). There were relatively no
`changes to the effect of ICV (ΔR2 5 0.067, p 5
`0.014) or the ICV 3 T2 lesion load interaction
`(ΔR2 5 0.067, p 5 0.010). Similar to education,
`premorbid intelligence is a common proxy of cogni-
`tive reserve, and correlated with maximal
`lifetime
`brain size.21 Verbal intelligence (an estimate of pre-
`morbid intelligence) was only available for a subsam-
`ple of patients (n 5 36), but was strongly correlated
`with education (r 5 0.62, p , 0.001), indicating that
`they measure similar constructs. Note that verbal
`intelligence was only weakly related to cognitive lei-
`sure (r 5 0.16, p 5 0.350), so the protective effects of
`cognitive leisure reported herein are not explained by
`higher intelligence.
`Consistent with the MS population, half of our
`sample was diagnosed with MS before age 30. As such,
`for some patients, cognitive leisure was performed after
`disease onset. We investigated whether the protective
`effect of cognitive leisure differed based on age of diag-
`nosis. A cognitive leisure 3 disease burden (T2 lesion
`load) 3 age at diagnosis interaction term (controlling
`for 2-way interactions) was not significant for models
`predicting overall cognitive status (ΔR2 5 0.011, p 5
`0.217), cognitive efficiency (ΔR2 5 0.008, p 5 0.361),
`or memory (ΔR2 5 0.010, p 5 0.300). That is, the
`protective effect of cognitive leisure did not differ based
`on age of diagnosis.
`
`DISCUSSION Larger MLBV moderated/attenuated
`the negative impact of disease burden on cognitive sta-
`tus, thereby supporting the brain reserve hypothesis in
`MS. Given the moderate but robust correlation between
`estimates of cognitive reserve and brain reserve,21 the
`protective effect of higher cognitive reserve in previous
`research may be partially or fully explained by concom-
`itantly higher brain reserve. Our results demonstrate
`that early-life intellectual enrichment (cognitive reserve)
`protects patients from disease-related cognitive impair-
`ment independently of MLBV (brain reserve), thereby
`supporting 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 aging/AD literature linking larger head
`size or ICV to better cognition in elders6–10 and lower
`risk of dementia11,12; however, closer examination of
`these aging/AD studies confirms that larger head size
`or ICV predicts cognitive efficiency, not memory.6,8,9
`Furthermore,
`longitudinal studies link age-related
`brain atrophy to declines in cognitive efficiency, not
`memory.26,27 Other aging/AD studies link larger ICV
`or head size to better Mini-Mental State Examination
`
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`scores,7,10 but the Mini-Mental State Examination
`makes minimal memory demands. Finally, some
`studies show that larger head size protects against
`dementia,11,12 but other studies do not.28,29 Although
`memory impairment is the hallmark of dementia, all
`elders with dementia also have a decline in nonme-
`mory cognition. It is conceivable that higher brain
`reserve protects against nonmemory cognitive decline
`associated with conversion from amnestic mild cog-
`nitive impairment to dementia. Indeed, cognitive
`inefficiency is among the best predictors of conver-
`sion from mild cognitive impairment to dementia.30
`In summary, the aging/AD literature appears to be
`largely consistent with our finding that brain reserve
`is protective against declines in cognitive efficiency,
`not memory.
`The specific link between brain reserve and cogni-
`tive efficiency is consistent with the strong heritability
`of both MLBV13,14 and cognitive efficiency (much
`more than memory).31,32 Strong heritability may con-
`traindicate rehabilitation efforts
`to bolster brain
`reserve and cognitive efficiency. However, rather than
`building brain reserve, persons may be able to pre-
`serve their remaining brain reserve (and protect cog-
`nitive efficiency) through effective disease-modifying
`therapies (which may slow brain volume loss) and by
`maintaining a “brain healthy” lifestyle (e.g., aerobic
`exercise). Indeed, cardiorespiratory fitness is posi-
`tively correlated with brain volume and cognitive effi-
`ciency in healthy persons33 and patients with MS.34 In
`contrast to brain reserve, cognitive reserve is devel-
`oped through enriching life experiences. The stronger
`protective impact of life experience on memory rela-
`tive to cognitive efficiency in the current study is
`consistent with lower heritability of memory relative
`to cognitive efficiency,31,32 which is further aligned
`with lower heritability of hippocampal volume (esti-
`mated genetic variance 5 0.40) relative to ICV
`(0.81).35 That is, 60% of the variance in hippocampal
`volume seems to be attributable to environmental
`factors (relative to 19% for ICV). Indeed, enriching
`cognitive experiences may have a positive impact on
`hippocampal volume in humans.36,37
`Cognitive reserve may protect against cognitive
`decline through superior/optimal neurocognitive pro-
`cessing.5 Consistent with this notion, functional MRI
`research has revealed differences in cerebral processing
`among patients with MS who have greater lifetime intel-
`lectual enrichment,
`including greater activation (or
`lesser deactivation) within the brain’s default network.18
`The default network consists largely of limbic structures,
`including the hippocampus,38 and has been implicated
`in memory.39 We have subsequently demonstrated that
`default network activity during functional MRI predicts
`performance on neuropsychological tasks of memory
`(but not cognitive efficiency) on a separate day.40 These
`
`links among cognitive reserve, default network activity,
`and memory are consistent with our current finding that
`cognitive reserve is specifically protective against mem-
`ory decline; however,
`future research should more
`directly investigate whether differences in default net-
`work activity mediate the relationship between intellec-
`tual enrichment and memory. Although the current
`study provides less support for the role of intellectual
`enrichment in protection against cognitive inefficiency,
`there was a positive correlation between cognitive leisure
`and cognitive efficiency. We have previously shown that
`higher cognitive reserve protects against cognitive inef-
`ficiency in MS,17 although we did not control for brain
`reserve in that study. Taken together, the protective
`impact of cognitive reserve appears to be more pro-
`nounced for memory than for cognitive efficiency, at
`least for patients with MS.
`Given that larger MLBV (estimated with ICV)
`protects against disease-related cognitive inefficiency
`in MS, clinical consideration of patient ICV may
`improve identification of patients at risk for cognitive
`impairment, and efforts to maintain cardiorespiratory
`fitness may help preserve brain reserve and cognitive
`efficiency. As discussed, the specific link between
`brain reserve and cognitive efficiency (not memory)
`in this study is consistent with results from aging
`studies, and should be further explored in aging,
`AD, and other neurologic populations. The current
`study also demonstrates that a cognitively enriching
`lifestyle (a source of cognitive reserve) independently
`protects against cognitive impairment
`(especially
`memory decline) over and above brain reserve. This
`is critical, because estimates of cognitive reserve and
`brain reserve are correlated, and the protective effects
`of higher cognitive reserve in previous research may
`have been at least partially attributable to concomi-
`tantly higher brain reserve. Our finding that early-life
`cognitive leisure protects against memory decline
`more than cognitive inefficiency is consistent with
`lower heritability of memory and hippocampal vol-
`ume relative to cognitive efficiency and ICV. Cogni-
`tive rehabilitation efforts targeting memory in MS
`stand to be most beneficial as the hippocampus is
`more affected by experience than other brain regions.
`Future prospective
`and/or
`experimental
`studies
`should investigate whether intellectual enrichment is
`associated with larger/increased hippocampal volume
`(or lesser/reduced hippocampal atrophy) in patients
`with MS. Finally, the positive link between intellec-
`tual enrichment and cognition in the current and pre-
`vious studies is observational, and cognitive leisure
`activity is almost always sampled from a period before
`disease onset. Longitudinal research is needed to
`investigate whether
`cognitive
`leisure moderates
`decline within MS patients as disease progresses,
`and randomized controlled trials of
`intellectual
`
`Neurology 80 June 11, 2013
`2191
`© 2013 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
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`link
`enrichment are required to establish a causal
`between enrichment and protection from disease-
`related cognitive decline in patients already diagnosed
`with MS. Such evidence is needed to support a pre-
`scription of intellectual enrichment as a therapeutic
`intervention to minimize or prevent disease-related
`cognitive decline.
`
`AUTHOR CONTRIBUTIONS
`James F. Sumowski, PhD, drafted the manuscript for content, contrib-
`uted to the study concept and design and analysis/interpretation of the
`data, and performed statistical analyses. Maria A. Rocca, MD, assisted
`in drafting the manuscript for content and analysis/interpretation of data,
`as well as acquisition of data and study supervision/coordination. 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 FUNDING
`This project was funded in part by the NIH (R00HD060765 to J.F.S.).
`
`DISCLOSURE
`J.F. Sumowski reports no disclosures. M.A. Rocca received speakers’
`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. V.M. 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-Dompé as a consul-
`tant, speaker, or scientific advisory board member. J. DeLuca received
`salary support through comp