Review
The measurement and clinical relevance of brain atrophy in
Lancet Neurol 2006; 5: 158–70
Department of Neurology,
Cleveland Clinic Foundation,
Cleveland, OH, USA
(R A Bermel MD); and Center for
Neurological Imaging, Partners
Multiple Sclerosis Center,
Departments of Neurology and
Radiology, Brigham and
Women’s Hospital, Harvard
Medical School, Boston, MA,
USA (Rohit Bakshi MD)
Correspondence to:
Dr Rohit Bakshi, Brigham &
Women’s Hospital, Harvard
Medical School, 77 Avenue Louis
Pasteur, HIM 730 Boston,
MA 02115, USA
rbakshi@bwh.harvard.edu
158
multiple sclerosis
Robert A Bermel, Rohit Bakshi
Brain atrophy has emerged as a clinically relevant component of disease progression in multiple sclerosis.
Progressive loss of brain tissue bulk can be detected in vivo in a sensitive and reproducible manner by MRI.
Clinical studies have shown that brain atrophy begins early in the disease course. The increasing amount of data
linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is an important
determinant of disease progression to a greater extent than can be explained by conventional lesion assessments.
In this review, we will summarise the proposed mechanisms contributing to brain atrophy in patients with
multiple sclerosis. We will critically discuss the wide range of MRI-based methods used to quantify regional and
whole-brain-volume loss. Based on a review of current information, we will summarise the rate of atrophy among
phenotypes for multiple sclerosis, the clinical relevance of brain atrophy, and the effect of disease-modifying
treatments on its progression.
Historical background Focal-tissue loss within overt white-matter lesions is
Brain-volume loss was reported as a component of probably a major contributor to brain atrophy due to loss
multiple sclerosis in early descriptions of the pathology. of myelin and axonal density.10,14 But is there a relation
In 1938, Robert Carswell discussed multiple sclerosis in between lesion load and brain atrophy, even remote to
an article on atrophy in his Atlas of Pathology.1 In 1963, lesion development? One group studied 29 patients with
German pathologist Eduard Rindfleisch reported focal a clinically isolated demyelinating syndrome over
atrophy of brain tissue in his description of the 14 years.15 Progression of T2-hyperintense lesion load in
perivascular nature of multiple sclerosis lesions.2 With the first 5 years after disease onset was the best predictor
advances in technology,3 structural neuroimaging of whole-brain atrophy 14 years later, suggesting that
provides increasingly sensitive methods of monitoring lesions partly contribute to the development of global
brain atrophy in vivo. In this review we will focus on atrophy. However, most studies examining the relation
brain atrophy, referring the readers to separate reviews between T2-hyperintense lesions and whole-brain
on atrophy of the optic nerve and spinal cord in multiple atrophy reported that lesion load accounts for at most
sclerosis.4–8 10% of the variance in atrophy in patients with
relapsing-remitting multiple sclerosis, and has limited
Pathogenesis predictive value for the subsequent development of
Although brain atrophy is probably an endpoint of atrophy.16–18 An increasing amount of data show that
irreversible tissue loss in multiple sclerosis, it is not whole-brain grey-matter volume is moderately
pathologically specific. The underlying mechanisms for correlated with lesion volume, suggesting that remote
brain atrophy are diverse and complex. Some proposed effects of white-matter lesions are partly responsible for
mechanisms are directly related to the multifocal grey-matter degeneration.16,19–23 However, this
inflammatory disease process, whereas others are association might not extend to atrophy in deep grey-
indirectly related to or are independent from traditional matter nuclei, in which atrophy is poorly related to such
measures of overt lesions.9 lesions.24
Gadolinium-enhancing lesions partly predict the
Overt lesions development of whole-brain atrophy in early relapsing-
Multiple sclerosis lesions are dynamic and progress remitting multiple sclerosis in some studies.14,25–33 One
through distinct stages on MRI scans. Lesions that are study26 reported that the number of enhancing lesions
enhanced with intravenous-gadolinium contrast on T1- was moderately correlated with ventricular enlargement
weighted images represent active areas of inflammation in 16 patients with relapsing-remitting multiple
and dysfunction of the blood–brain barrier.10,11 Most sclerosis. Three other studies of patients with similar
gadolinium-enhancing lesions become permanent characteristics lend support to this association.27–29 Two
hyperintense lesions on T2-weighted images and groups showed that ring-enhancing lesions might be
represent a range of pathological changes (eg, oedema, particularly predictive of brain atrophy.26,30 However,
gliosis, inflammation, demyelination, remyelination, results from two studies17,31 suggest that gadolinium-
and axonal loss). About half of gadolinium-enhancing enhancing lesions do not predict whole-brain atrophy.
lesions will ultimately persist as severe hypointensity on Overall, the relation between enhancing lesion volume
T1-weighted images (T1 black holes).11 These persistent and brain atrophy seems to disappear in later disease
lesions represent irreversible tissue destruction and stages.32 Even with near complete pharmacological
axon loss.10,12,13 suppression of gadolinium-enhancing lesions in
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 Review

patients with secondary progressive multiple sclerosis,
brain atrophy continues to progress.33
The association between T1-black holes and brain
atrophy however, is unclear.14,17,34,35 One study34 recorded a
relation between T1-black holes and supratentorial brain
atrophy (r=0·48) in a cross-sectional study of patients
with relapsing-remitting multiple sclerosis (n=55).
Results from our group supported this finding in 78
patients with multiple sclerosis (r=0·35),35 and we also
reported an association between subcortical atrophy and
volume of T1-black holes.36 This finding contrasts with
studies showing that the volume of T1-black holes at
baseline does not predict the development of
longitudinal whole-brain atrophy in relapsing-remitting
multiple sclerosis.17
Are multiple sclerosis lesions and brain atrophy linked,
or are they unique results of different pathological
processes? On the basis of the above results, there seems
to be a partial link between lesions and brain atrophy.
One key mechanism linking MRI lesion load to brain
atrophy is the remote effect of axonal injury on neuronal
loss (Wallerian degeneration). A study of the pathology37
has shown the abundance of transected axons in the brain
of patients with multiple sclerosis (more than 11 000 per
mm3 of lesional tissue). Wallerian degeneration can be
detected at the earliest stage of multiple sclerosis (in
patients with a clinically isolated demyelinating
syndrome).38 However, the slight predictive value of
lesion volumes suggests that other mechanisms might be
contributing to volume loss.14 There has been a recent
effort to correlate diffuse damage in the normal-
appearing brain tissue with brain atrophy. One group
used MR spectroscopy to quantify N-acetyl aspartate as a
marker of neuronal integrity and showed that decreased
whole-brain N-acetyl aspartate preceded global-
parenchymal loss in 42 patients with relapsing-remitting
multiple sclerosis.39 Another group, measuring whole-
brain N-acetyl aspartate and diffusivity, showed these
markers (but not any lesion-load volumes) were
associated with whole-brain atrophy.40 These studies
provide evidence to show that in addition to overt lesion
formation, global dysfunction or degeneration of neurons
might be occuring, and perhaps preceding brain atrophy.
Alternative mechanisms
The absence of a strong association between lesion load
and brain atrophy suggests that other mechanisms
contribute to atrophy. There has been evidence of a
genetic predisposition to brain atrophy or
neurodegeneration in multiple sclerosis. Specifically,
patients who carry the APOE 4 allele have up to five
times greater annual rate of brain atrophy than do
patients who do not have the allele.41 Patients with this
genotype are also at risk for developing persistent T1-
black holes.41 Brain atrophy has also been associated
with damage in grey matter, as measured by T2
hypointensity of subcortical structures, and is thought to
represent pathological iron deposition18,42,43 (figure 1).
Localisation of brain atrophy
Brain atrophy seems to be widespread in multiple
sclerosis, affecting all brain regions, including all the
cerebral lobes, the compact white-matter tracts,
brainstem, and cerebellum.44 Both grey-matter and
white-matter compartments are affected. Several groups
have assessed grey-matter versus white-matter volume
loss using various segmentation tools, and selective
grey-matter atrophy has been documented in patients
with a clinically isolated demyelinating syndrome or
relapsing-remitting multiple sclerosis.16,20,21,23,24,45–47

Patient A Patient B

Baseline T2 intensity values: Baseline T2 intensity values:

Mean thalamus=0·44 Mean thalamus=0·59
Mean caudate=0·48 Mean caudate=0·63
Left putamen=0·42 Left putamen=0·59
Right putamen=0·42 Right putamen=0·59
Left globus pallidus=0·28 Left globus pallidus=0·44
Right globus pallidus=0·32 Right globus pallidus=0·44
Mean red nucleus=0·39 Mean red nucleus=0·46

Baseline BPF=0·82 Baseline BPF=0·85

Year 2 BPF=0·77 Year 2 BPF=0·85

Figure 1: Midthalamic T2-weighted axial images from two placebo patients at baseline
We did a post-hoc analysis of patients with MS from a 2-year clinical trial of interferon beta-1a (30g IM weekly) or placebo.18 We determined deep grey-matter T2
hypointensity, brain parenchymal fraction (BPF), and total T2-, gadolinium-enhancing-, and T1-lesion volumes. T2 hypointensity was chosen in regression modeling
as the best predictor of BPF change at the 1 year (R2=0·23, p=0·002) and 2 year (R2=0·33, p0·001) time points after accounting for all MRI variables. Mid-thalamic
T2-weighted axial images from two placebo patients at baseline are shown, relating visual to quantitative findings, showing a range of T2 intensity and BPF values.
Patient A (left) had relative baseline T2 hypointensity and atrophy, with marked atrophy progression. Patient B (right) had higher baseline T2 intensity and BPF
values, with no atrophy progression. Thus, grey matter T2-hypointensity predicts the progression of brain atrophy in patients with early relapsing-remitting multiple
sclerosis. This predictive effect is seen as early as the first year. We hypothesise that brain atrophy may involve iron deposition as a mediator of neurotoxicity or as a
disease epiphenomenon. Reproduced with permission from the American Medical Association.18

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 Review

matter volume loss, which could have been the result of

8000
atrophy, was offset by inflammation or oedema-related
increases in tissue bulk. These data suggest that
decreases in grey-matter volume can identify progressive
7000 neurodegeneration more sensitively than can decreases
in white matter or whole-brain volumes.
Atrophy of the deep grey nuclei also seems to happen
Caudate volume (mm3)

6000 in multiple sclerosis (figures 2 and 3). Tissue loss from

the thalamus52,53 and the caudate nucleus24 has been
measured with MRI segmentation. There was
5000 substantial neuron loss, with neuronal density decreased
by 22%, in the thalamus of patients with multiple
sclerosis.52 This pathological evidence for
neurodegeneration in the grey matter highlights the
4000
underlying causes of damage detected non-invasively by
imaging studies, such as hypometabolism,54 decreased
neuronal activation,55,56 increased diffusivity,57 and
3000
Normal MS decreased N-acetyl aspartate.52
n=10 n=24
Methods used to measure brain atrophy
Figure 2: Box plot of normalised caudate volumes Qualitative measures
We tested whether caudate atrophy occurs in MS, and whether it correlates with
Clinically, brain atrophy can be identified from
conventional MRI or clinical markers of disease progression. Caudate nuclei of
24 patients with MS and ten age-matched healthy controls were traced, qualitative images by the recognition of an increase in
normalised, reconstructed, and visualised from high-resolution MRI scans. cerebrospinal fluid spaces or a reduction in size of
Normalised bicaudate volume was 19% lower in MS vs controls (p0·001), an parenchymal structures compared with the normal
effect that persisted after adjusting for whole-brain atrophy (p0·008).
Caudate volume did not correlate with total brain T2 hyperintense or
appearance for age (figure 4). Upon review of serial
T1-hypointense lesion load (both p0·05). Reproduced with permission from studies, progressive atrophy can be detected by
Lippincott, Williams & Wilkins.24 comparison of images (figure 5). Such relatively simple
determinations are easy to implement in routine patient
Cortical atrophy happens early in the course of multiple care or for semiquantitative analysis,44 and can help to
sclerosis45,48,49 and can be localised to specific regions of assess disease severity and disease progression.
the brain. One group measured cortical thickness in
20 patients with multiple sclerosis and noted the Quantitative two-dimensional measures
presence of focal atrophy in the bilateral frontal and Because of the limited reproducibility and precision of
temporal cortices early in the disease course, and visually based atrophy measures, quantitative
additionally in the motor cortex in patients with more
advanced disease.49 Evidence from other groups, I cm
however, suggests that atrophy similarly affects both
grey and white-matter compartments20,50 or preferentially
affects the white-matter compartment.19 The similarity of
the patient populations, small sample sizes, and
differences in techniques might explain, in part, the
conflicting conclusions of these studies.
Data show that the grey matter, although affected by
the disease, has relatively less inflammation51 compared
with white matter, which is more prominently affected.
This process could potentially cause increases in white-
matter volume and mask ongoing atrophy. Consistent
with this hypothesis, in a 3 year longitudinal study,16
patients with early-onset multiple sclerosis had large
decreases in grey-matter volume but small increases in
white-matter volume. Additionally, those with a Figure 3: Deep grey-matter damage might be an important component of
clinically isolated demyelinating syndrome had loss of the MS disease process
grey-matter volume, but there were no changes in white- Superior view of three-dimensional caudate reconstructions from a patient with
MS (green) and a normal control (pink), both age 50 years old, normalised for
matter volume. Both groups of patients had large head size. Surfaces were reconstructed from volume acquisition coronal MR
increases in white-matter lesions during the observation images using a manual parcellation technique, normalised for head size, and co-
period, prompting the authors to speculate that white- registered using Visualization Toolkit.24

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Healthy control RRMS RRMS SPMS

BPF 0·89 BPF 0·84 BPF 0·80 BPF 0·70

Figure 4: Whole brain atrophy in MS as measured by a normalised proportional method

Representative midventricular axial non-contrast T1-weighted MRI scans are shown from age-matched individuals in the sixth decade. Note the progressive decrease
in brain parenchyma, increase in cerebrospinal fluid spaces, and decrease in brain parenchymal fraction (BPF) among the scans from left to right. The first patient with
relapsing-remitting multiple sclerosis (RRMS) has an EDSS score of 1·5 and disease duration of 5 years. The next patient with relapsing-remitting multiple sclerosis
has an EDSS score of 4·0 and disease duration of 10 years. The patient with secondary-progressive multiple sclerosis has an EDSS score of 6·5 and disease duration of
18 years. Reproduced with permission from the American Society for Experimental NeuroTherapeutics.11

techniques are preferred. Quantitative two-dimensional hardcopy films).29,35,36,58–63 Although two-dimensional

measures of atrophy include linear measures, which can measures have the advantage of relative ease of
be quantified on a single-image section with a distance implementation in the clinical setting, the main
tool on a computer workstation (or even a ruler on disadvantage is the absence of reproducibility compared

Figure 5: Progressive brain atrophy in a 41-year-old man with RRMS imaged at baseline and 4 years later
Non-contrast T1-weighted images show progressive enlargement of the ventricles and subarachnoid spaces consistent with diffuse brain volume loss. Top row is at
baseline, bottom row is at 4 year follow-up. Reproduced with permission from the American Society for Experimental NeuroTherapeutics.11

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Figure 6: Two-dimensional measures of brain atrophy

Third ventricle width (A), maximum lateral ventricle width (B; arrows), brain width (C; arrows), corpus callosum area (D), and bicaudate ratio (E; minimum intercaudate distance [solid line] divided by
the brain width along the same line [dashed line]). Measurement of third ventricular width is done by measuring the width along the anteriorposterior midpoint of the third ventricle. Lateral ventricular
width is determined along a plane corresponding to the anteroposterior midpoint of the ventricle on an anatomical level from an axial slice at which the septum pellucidum remains thin. Brain width is
the distance between two points on the cortical surface, measured at the same level and along the same line as the lateral ventricle width. Corpus callosum area is determined by outlining the margins
of the structure from the best available midsagittal section The bicaudate ratio, also known as the intercaudate nucleus ratio, is measured from an axial section on which the heads of the caudate
nuclei are most visible and closest together. These two dimensional measures of brain atrophy have shown longitudinal sensitivity to disease progression,29 meaningful correlations with clinical
findings,29,36 and strong associations with three dimensional measures of whole brain atrophy.64 Both the third ventricle width and bicaudate ratio show associations with cognitive impairment, even
after accounting for other MRI biomarkers including whole-brain atrophy and lesion load.36,60 A–D reproduced with permission from Lippincott, Williams & Wilkins29

with three-dimensional measures. Figure 6 shows
examples of two-dimensional measures.
Quantitative three-dimensional measures
Quantitative measures of whole-brain atrophy, acquired
by automated or semiautomated methods,64 have
become the most powerful methods for assessing
patients with multiple sclerosis over time because of
their reproducibility, sensitivity, and potential to capture
global disease effects.65,66
Segmentation-based techniques include separation of
intracranial contents into parenchymal and non-
parenchymal classes, thereby arriving at an expression
of what proportion of space is occupied by brain tissue at
any given time. The most popular terminology for this
“proportional method” is brain parenchymal fraction
(BPF) (figures 4 and 7).17,35,64,67,68 Other examples of
techniques which use segmentation-based methods
include 3DVIEWNIX,69 SIENAX,70, index of brain
atrophy,71 whole brain ratio,72 brain to intracranial cavity
ratio,73 brain to intracranial volume ratio,74 fuzzy
connectedness,75 the Alfano method,76 MIDAS,77 and
ILAB4.78 Segmentation-based techniques can also
separately quantify the volume of grey matter, white
matter, and cerebrospinal fluid compartments
(figure 7).23 The abnormal signal intensity of multiple
sclerosis lesions presents a potential source of voxel
misclassification. Lesions in the white matter tend to be
misclassified as grey matter,20 and misclassified volumes
should be corrected to avoid confounding clinical
correlations.23
Registration-based techniques are designed to follow
patients longitudinally over time.79 These methods align
two serial scans from a patient and find areas of signal-
intensity change after accounting for changes in head
position or slice plane. The result is a number such as
percent brain volume change. Examples of such
measures include SIENA,80 voxel-based morphometry,81
statistical parametric mapping (figure 7),23,64,67,82,83
template-driven segmentation,84 and brain boundry shift
integral.79 The advantages of registration-based methods
are that they are sensitive to longitudinal changes and
(because they are mostly automated) need little operator
input and time. The main disadvantage is the need for
additional steps in image processing.
Thus, there are a multitude of techniques now
available to measure brain atrophy. However, the main
limitation of the use of brain atrophy in clinical trials is
that different measures can produce conflicting results.
Differing results might be valid,85 but as a result of the
low specificity of brain atrophy, techniques can quantify
different physiological observations.
Atrophy and disease course
Clinically isolated syndrome
There is increasing evidence that brain atrophy is not
restricted to the later progressive stages, but begins in
the earliest stages of multiple sclerosis.6 In patients with
clinically isolated demyelinating syndrome, whole-brain
atrophy is detectable in those who go on to develop
multiple sclerosis.86,87 Patients who meet the
international panel criteria for multiple sclerosis88 (but
who have had only a single demyelinating event) had
detectable ventricular enlargement over the subsequent
year (median enlargement=0·3 cm3, n=27) compared
with those who do not meet the criteria (median
enlargement=0·05 cm3, n=28, p=0·03).77 In another
study of patients with clinically isolated demyelinting
syndrome followed up over 3 years, the group that
developed multiple sclerosis during the study period
had detectable grey-matter atrophy, but no white-matter
atrophy.16 In the placebo group of a randomised
controlled trial of subcutaneous interferon beta-1a in
clinically isolated demyelinating syndrome,
investigators measured a mean decrease in brain-
parenchymal volume of 1·68% over 2 years.89 In

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Figure 7: Representative slices from a T1-weighted gradient echo series and obtained grey, white, and CSF tissue compartments after automated skull-
stripping and segmentation by SPM99 for a normal control (top row) and a patient with MS (bottom row)
Images from left to right are: raw T1-weighted image; white matter only (bright areas); grey matter only (bright areas); CSF only (bright areas) with background brain
parenchyma (inner dark areas). Note the misclassification of white-matter lesions that have been classified as grey matter. This procedure can be used to quantify the
volumes separately, or determine residual or proportion-based measures of normalised whole-brain atrophy. BPF=total parenchymal volume divided by total
intracranial volume. Applying this method we studied 41 patients with MS and 18 age and sex-matched healthy controls. We also measured lesion load (total T1-
hypointense and FLAIR hyperintense lesion volume), third ventricular width and bicaudate ratio. Disability was assessed by the EDSS and timed 25-foot walk. Patients
with MS had lower grey matter (3·9%, p=0·003) and total parenchymal volume (3·8%, p=0·003), but only a trend for lower white-matter volume (3·7%,
p=0·052) relative to normal controls. Grey-matter atrophy was most closely related to clinical status as compared to all other MRI measures (see figure 8 and table for
more information). Reproduced with permission from Academic Press.23

summary, when brain atrophy occurs in clinically Secondary-progressive multiple sclerosis

isolated demyelinating syndrome it seems to be related
to the underlying multiple sclerosis disease process, as
pathological brain atrophy is more common in patients
who go on to develop multiple sclerosis than in those
who do not.
Relapsing-remitting multiple sclerosis
Brain atrophy has been well documented in relapsing-
remitting multiple sclerosis, and seems to happen
rapidly in early stages of the disease.6 Overall, the rate of
brain-parenchymal volume loss in relapsing-remitting
multiple sclerosis is 0·6–1·35% per year. In the pivotal
trial of weekly intramuscular interferon-beta 1a, patients
with early relapsing-remitting multiple sclerosis (mean
disease duration 6·2 years) and only mild disability
(mean expanded disability status scale (EDSS] 2·3) had a
lower whole-brain volume than age-matched normal
controls (5 SD below the normal control group) and a
higher annual rate of brain-volume loss than controls
over 2 years (0·6% per year vs 0·1% per year for
healthy controls).17 Another study measured brain
parenchymal volume in 53 patients with early untreated
relapsing-remitting multiple sclerosis (disease duration
1–5 years, EDSS5) and reported that volume loss
averaged 2·7% over 2 years.90 Other groups have
observed the rates of brain atrophy in either untreated
patients31,68,79,91–95 or those in clinical trials.74,89,96–100
Studies which have assessed both patients with
relapsing-remitting multiple sclerosis and those with
secondary-progressive multiple sclerosis have reported
that the annual rates of atrophy are similar between the
two groups, with rates between 0·6% and 0·8% per
year.6,79,91,98 In a clinical trial of an immunomodulatory
drug in secondary-progressive multiple sclerosis, the
placebo group (n=31) had a mean brain-volume loss of
3·86% over 3 years.32 Other studies showed that brain
atrophy occurred at a lower rate in secondary-progressive
multiple sclerosis than in relapsing-remitting multiple
sclerosis,92,101 suggesting that the most aggressive rates of
atrophy happen early on in the disease course,
coincident with rapid accumulation of lesion burden.33
Primary-progressive multiple sclerosis
In a multicentre study of progressive multiple
sclerosis,102 137 patients with primary-progressive
disease averaged 1·3% loss of brain-parenchymal
volume over 1 year. Another group103 assessed
41 patients with primary-progressive multiple sclerosis
and showed a mean reduction in brain-parenchymal
volume of 3·7% over 5 years. In the placebo group of a
therapeutic trial in this type of multiple sclerosis,
ventricular volume increased over 2 years.104 Therefore
brain atrophy happens in patients with primary-
progressive multiple sclerosis at a rate greater than in

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those with secondary-progressive multiple sclerosis, but
not as aggressively as reported in some studies of
relapsing-remitting multiple sclerosis.6
Clinical correlations
Physical disability
Lesion-load measures on MRI are associated only weakly
with physical disability in cross-sectional studies, which
has led to the traditional “clinical-imaging paradox” of
multiple sclerosis.105 Lesions can appear on MRI without
any progression in physical disability, and conversely,
patients can progress in disability without the appearance
of new lesions. Whole-brain atrophy has a stronger, yet
moderate, imaging association with physical disability,
and is a stronger predictor of future disability than T1-
hypointense and T2-hyperintense lesion load.6 Many
groups have tested the relation between whole-brain
atrophy and EDSS score. One study showed that the rate
of progression of brain atrophy over 18 months was
significantly heightened in patients with deterioration of
disability, whereas only trends were seen between
disability change and progression of T2-hyperintense
lesions.96 Another group reported significant correlations
between EDSS score and ventricular volume, but no
association between lesion loads and EDSS.106 Our group
and others have recorded similar associations between
brain atrophy and measures of physical disability
(figure 7, figure 8, table).22,23,35
Early atrophy seems to predict the subsequent
development of physical disability to a better extent than
lesion-load measures. A longitudinal study107 reported
that patients with more atrophy during the first 2 years
had greater disability 8 years later. Furthermore, the
change in brain parenchymal fraction over the first
2 years was the best MRI predictor of 8 year disability
after accounting for the 2 year change in all MRI-lesion
measures. At 8 years, patients with the largest amount of
brain atrophy were about four times more likely to have a
disability level needing assistance with walking, or worse.
Thus, brain atrophy is emerging as a clinically relevant
measure of multiple sclerosis disease progression,
supported by its association with physical disability.
Spinal cord atrophy seems to show particularly strong
relations with physical disability, as reviewed separately.4
25-foot timed walk (residual)
EDSS score (residual)
Whole grey-matter volume (residual) Whole grey-matter volume (residual)
Figure 8: Correlation of whole-brain normalised grey-matter volume with physical disability
Left: corrected whole grey-matter volume with EDSS scores (partial r=0·46, p=0·004). Right: corrected whole-
grey matter volume with the 25-foot timed walk (partial r=0·52, p=0·002). Reproduced with permission from
Academic Press.23
164
Neuropsychological impairment
Multiple neuropsychological domains are affected by
multiple sclerosis, including cognition, mood,
personality, fatigue, and quality of life.108–117 An early
study118 identified an association between third
ventricular width and cognition. Multiple subsequent
studies have confirmed the link between brain atrophy
and neurobehavioural status.36,48,60,62,74,90,108,110,119–125 Our
group60 reported that third ventricular width was the
most significant MRI predictor of cognitive dysfunction
in patients with multiple sclerosis. In this same study,
whole-brain atrophy (ie, brain parenchymal fraction)
was the next significant predictor, and notably both
atrophy measures predicted more variance in
neuropsychological function than did MRI-lesion
measures. Another study90 noted a strong correlation
between whole-brain parenchymal volume (but not
lesion loads) and cognitive function in early relapsing-
remitting multiple sclerosis (r=0·51, p=0·0003). Many
studies suggest that subcortical atrophy is well
correlated with cognition, to a greater extent than whole-
brain atrophy or lesion load.36,60,124 Grey-matter atrophy48
and lobar atrophy125 have also shown correlations with
cognitive dysfunction, to a greater extent than seen with
lesion-load measures.
From the studies on brain atrophy and neuropsycho-
logical impairment we conclude that subcortical atrophy
has a stronge association with general cognitive
dysfunction, which can be explained by a disruption of
frontal-subcortical circuits. Regional or cortical atrophy
measures might provide insight into impairment of
more specific functional domains in some patients.
Effect of technical or other factors on volume
measurement
A prerequisite for the use of brain volume as a surrogate
marker for irreversible tissue damage and neuro-
degeneration in patients with multiple sclerosis is the
need to understand the potential effect of other factors
such as MRI-related technical error and biological
factors that can affect brain volume independent of
tissue destruction.
Effect of MRI protocol and analysis approach
Changes in the position of the patient’s head or slice
plane between scans are potential sources of error when
measuring serial changes in brain volume. Either a
normalisation or co-registration procedure should
address these concerns. Normalised measures of whole-
brain volume (eg, expressed as a ratio to head size) show
a higher degree of reproducibility and sensitivity than do
those expressed as absolute volumes and have about
twice the statistical power.65 This degree of difference
might improve the ability to detect treatment effects in
clinical trials.
In studying the longitudinal reproducibility of brain
parenchymal fraction, investigators did two serial MRI
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n Parenchymal Grey matter White matter Third ventricle Bicaudate T1 black hole FLAIR lesion
volume volume volume width ratio lesion volume volume
EDSS 40 0·34* 0·46† 0·06 0·20 0·32* 0·41† 0·34*
25-foot timed walk 35 0·45† 0·52† 0·20 0·43* 0·32 0·46† 0·38*
Disease duration 41 0·46† 0·44† 0·31 0·48† 0·44† 0·34* 0·32*
Third ventricle width 41 0·80§ 0·71§ 0·60§ .. 0·80‡ 0·50† 0·47†
Bicaudate ratio 41 0·75§ 0·66§ 0·56§ .. .. 0·56‡ 0·49†
T1 black hole lesion volume 41 0·45† 0·46† 0·27 .. .. .. 0·89‡
FLAIR lesion volume 41 0·39* 0·43† 0·18 .. .. .. ..

Partial correlations (df=n4) are based on whole-brain data and express associations after adjusting for intracranial volume and age. FLAIR=fluid-attenuated inversion-recovery and
ellipses. *p0·05 †p0·01 ‡p0·001 §p0·0001. Note that grey-matter atrophy correlates most highly with measures of physical disability (more so than lesion load or white-matter-
volume measures). Reproduced with permission Academic Press.23

Table: Correlations between MRI measures (atrophy and lesion loads) and physical disability in patients with multiple sclerosis

scans (30 min apart) on 30 patients with multiple
sclerosis and calculated their brain parenchymal
fraction. The authors reported that a change of brain
parenchymal fraction of 0·0056% carries 95% certainty
that this measure has actually changed (given a standard
error of 0·0020%).126 Thus, brain parenchymal fraction is
a sensitive measure and is an appealing method to serve
as a supportive outcome measure in clinical trials.
The ability to pool results from different imaging
hardware is essential to help with multicentre clinical
trials. One group127 studied the effect of brain
parenchymal fraction acquired on different scanners
and different pulse sequences. They showed that this
quantity can be accurately measured using a variety of
MRI pulse sequences where there is a marked contrast
between cerebrospinal fluid and brain parenchyma. Our
group64 reported no effect of pulse sequences (spin echo
vs gradient echo) on the ability to accurately measure
brain parenchymal fraction using both semiautomated
and automated methods; both protocols yielded robust
clinical correlations. Another group identified that good
reproducibility of brain parenchymal fraction can be
achieved across scanners when using the same pulse
sequence at the same field strength.128
Reversible biological effects on brain volume
Another factor thought to confound brain volume
measures in multiple sclerosis is acute inflammation
and oedema in white matter that might transiently
increase brain volume and offset decreases related to
tissue destruction.16 Corticosteroids have been associated
with reduced brain volume in patients treated for
neurological and non-neurological diseases.129 Proposed
mechanisms include steroid-induced protein catabolism
and reduction of water volume in the brain as a result of
decreased vascular permeability. Corticosteroids also
affect brain volume in patients with multiple sclerosis,
although the relation is complex. An acute effect of
intravenous corticosteroids on brain volume has been
shown by several groups.130–132 One group132 looked at the
effects of a typical course of intravenous
methylprednisolone. The researchers identified a
significant decrease in brain parenchymal fraction in
patients with secondary-progressive multiple sclerosis
but not in those with relapsing-remitting multiple
sclerosis. This decrease peaked at about a 1% change 2
weeks after the steroids were first given and only in part
resolved over 8 weeks in patients with secondary-
progressive multiple sclerosis.
By contrast, steroids might have a protective effect on
brain atrophy in the long term in patients with multiple
sclerosis. In a phase II placebo-controlled study of
patients with relapsing-remitting multiple sclerosis,
intravenous pulsed steroids reduced cerebral atrophy
over 5 years.133 Furthermore, the effect of one disease-
modifying therapy on brain atrophy measured in a
clinical trial of patients with relapsing-remitting
multiple sclerosis seemed to be unaffected by steroid
dose near the time of MRI.134 Another study135 showed
that pulses of intravenous methylprednisolone injected
every 4–6 weeks did not accelerate (but rather slowed)
the rate of brain atrophy in 11 patients with primary-
progressive multiple sclerosis. In conclusion,
intravenous steroids seem to have a dual effect on brain
volume, but in the long term might protect against brain
atrophy in relapsing-remitting forms of the disease.
Effect of disease-modifying treatments
Brain atrophy, because of its clinical relevance and
ability to serve as a sensitive, reproducible quantitative
measure of irreversible tissue destruction, is now
commonly used as a secondary therapeutic outcome
measure in clinical trials for multiple sclerosis.5,136
Interferon beta-1a
In the pivotal phase III trial of once-weekly intramuscular
interferon beta-1a,17 whole-brain atrophy (by brain
parenchymal fraction) was measured in patients with
relapsing-remitting multiple sclerosis randomised to
interferon beta-1a and patients randomised to placebo.17
There was a 55% reduction in brain atrophy with
interferon therapy in the second year of treatment
(0·233% reduction in brain parenchymal fraction in
interferon beta-1a vs 0·521% in placebo), but no effect
during the first year of treatment. In a larger study of
patients who were treated with the same medication,

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 Review
rates of decline in brain parenchymal fraction were
0·686% in the first year, 0·377% in the second year, and
0·378% in the third year, again suggesting, delayed, but
significant slowing of the rate of brain atrophy.137
A large-scale randomised placebo-controlled
prospective trial of once-weekly subcutaneous interferon
beta-1a showed a beneficial effect on whole-brain
atrophy after 2 years of treatment in patients with
clinically isolated demyelinating syndrome.89 The rate of
brain-parenchymal volume decrease for patients on
placebo was 0·83% during the first year and 0·67%
during the second year. Respective values for treated
patients were 0·62% and 0·61%, with a treatment effect
seen after 2 years (p=0·0031). This is in contrast with a
post-hoc analysis of the initial large phase III trial of the
same medication dosed at three times a week in patients
with relapsing-remitting multiple sclerosis which
reported no effect of treatment on the loss of brain
volume (measured as whole brain ratio) over 2 years.72
Another group100 did a post-hoc analysis of an open label,
randomised dose comparison trial of subcutaneous
interferon beta-1a (11 g vs 33 g subcutaneously three
times per week) in 52 patients with relapsing-remitting
multiple sclerosis, and showed that there was a
significant decline in brain volume in both groups
during the 2 years of the study, and no difference in
change in brain volume between doses. Two subset
analyses of 38 patients (with a mix of patients with
relapsing-remitting or secondary-progressive multiple
sclerosis) in two trials138,139 showed no significant
treatment effect on upper cervical spinal cord area,140 but
a slowing in the rate of brain atrophy (measured as brain
parenchymal volume) over 18 months.98 Thus data are
conflicting for the effects of subcutaneous interferon
beta-1a on CNS atrophy.
Data obtained over 3 years in an open-label study of
interferon beta-1b in 30 patients with relapsing-
remitting multiple sclerosis showed a significant but
delayed reduction in the rate of cerebral atrophy.141
Brain volumes at baseline decreased by 1·35% during
the first year of the study, then remained relatively
stable during the second (1·48% lower than at baseline)
and third (1·68% lower than baseline) years. A trial of
interferon beta-1b in 95 patients with secondary-
progressive multiple sclerosis32 showed no significant
treatment effect overall on brain volumes; however, the
authors identified a significant effect in the subgroup of
patients who had gadolinium-enhancing lesions at
study entry.
When interferon beta is given once a week it seems to
have a partial delayed beneficial effect on brain atrophy,
irrespective of formulation. The treatment effect is
delayed by at least several months. This delay might
indicate the fact that the atrophy occurring in the first
months is the culmination of a cascade of events that
began before the onset of therapy. Alternatively, the
ongoing loss of brain volume might be the result of
166
“pseudoatrophy”, such as that due to treatment-related
resolution of brain oedema and inflammation.142
Whether interferon beta three times a week or every-
other-day limits the rate of brain atrophy is unclear.
Proposed mechanisms by which interferon might limit
brain atrophy include: increasing nerve growth factors;143
limiting immune-mediated destructive inflammation;144
or by limiting toxic mechanisms such as pathological
iron deposition.18
Glatiramer acetate
Trials of daily subcutaneous glatiramer acetate suggest
that it also limits brain atrophy. One group97 recorded a
reduction in the amount of whole-brain volume loss
between 14 patients treated with glatiramer acetate and
13 treated with placebo over 2 years (0·6% per year vs
1·8% per year, p=0·0078). In a larger scale trial of
shorter duration, brain volume was measured in
113 patients treated with glatiramer acetate for
18 months and 114 patients on placebo for the first
9 months (then switched to active treatment in the
second 9 months) using a central seven-slice brain-
atrophy absolute-volume measurement technique.28
Despite a reduction in inflammatory lesions there was
no detecatble difference in brain-volume loss between
groups. However, in a post-hoc analysis of the same
study with a more reproducible normalised whole-
brain volume measurement technique, the rate of brain
atrophy was lower in the fully treated group in the last
9 months than in the placebo.65 Thus, glatiramer
acetate might have a partial and delayed, but significant
effect on limiting the rate of brain atrophy in relapsing-
remitting multiple sclerosis.
Conclusions
Brain atrophy has emerged as a clinically relevant
component of the multiple sclerosis disease process.
Progressive loss of brain tissue bulk can be identified
in-vivo in a sensitive and reproducible manner by MRI.
Brain atrophy begins early in the disease course. The
increasing amount of data linking brain atrophy to
clinical impairments suggest that irreversible tissue
destruction is a major determinant of disease
progression to a greater extent than can be explained by
conventional lesion assessments. Whole-brain atrophy
is an appealing method to monitor patients for the
destructive aspects of the disease in clinical trials.
Measures of regional brain atrophy might be
particularly useful in helping to understand
neuropsychological dysfunction or other specific
clinical findings. Confounding factors must be
considered when assessing whether loss of brain
volume directly indicates tissue atrophy. Although the
mechanisms that contribute to brain atrophy are
unclear, degenerative processes that underlie brain
atrophy will hopefully provide novel therapeutic targets
to help patients.
http://neurology.thelancet.com Vol 5 February 2006

Search strategy and selection criteria
References for this review were identifed by searches of
PubMed from 1985 to October 2005 with the terms “brain
atrophy” or “spinal cord atrophy” and “multiple sclerosis”.
Articles resulting from that search as well as references cited
in those articles were considered for this review of brain
atrophy. Articles were also identifed through searches of the
authors’ own files. Only papers published in English were
reviewed.
Acknowledgments
RB was supported by research grants from the National Institutes of
Health (NIH-NINDS 1 K23 NS42379-01), National Multiple Sclerosis
Society (RG 3258A2/1; RG 3574A1), and National Science Foundation
(DBI-0234895). We thank Sophie Tamm for assistance with manuscript
preparation.
Authors’ contributions
RAB contributed to the literature search, and both RB and RAB
contributed to the overall paper design, writing, and editing.
Conflicts of interest
RB discloses the following relationships in the past 3 years with
companies involved in the production or sales of pharmaceutical
treatments for multiple sclerosis: consultancies (Biogen Idec, Serono,
Teva Neuroscience), speaker’s fees (Berlex, Biogen Idec, Serono, Teva
Neuroscience), and research funding (Biogen Idec, Pfizer, Serono, Teva
Neuroscience, Pepgen). RAB has no conflicts of interest.
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