Neuroscience and Behavioral Physiology, Vol. 41, No.

8, October, 2011

Memory Disorders in Multiple Sclerosis

K. S. Meshkova1 and I. V. Damulin2

Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 110, No. 9, 8–13, September,
2010.

Short-term memory disorders are the earliest and most frequently seen changes to cognitive functions in
multiple sclerosis (MS). Complex neuropsychological investigations and MRI brain scans were performed
in 100 patients with MS. The results showed that memory disorders were encountered in MS patients
regardless of the duration and type of disease. The main pathophysiological mechanism of cognitive dis-
orders in MS consists of interruption of projection, commissural, and long associative fibers, which leads
to impairment of the integrative activity of the brain and activation of the cortex by deep structures.

Keywords: multiple sclerosis, memory disorders, MRI.

The clinical picture of multiple sclerosis (MS) has
been well studied. Neurologists have traditionally paid
attention to the motor, sensory, and visual impairments as
the clearest and most disabling manifestations, while stud-
ies of neuropsychological status have taken a secondary
role. The appearance of new neuroimaging methods,
extending the potential of immunomodulatory therapy
modifying the course of illness, has led to increased interest
in cognitive impairments in MS.
The phenomenology of impairments to higher mental
functions in MS has been the subject of a number of stud-
ies in recent years. These have shown that mild cognitive
deficit in the form of impairments to short-term memory
and attention can be detected as early as the time of dis-
ease onset; these changes are increasingly apparent as the
condition progresses [1, 20, 30]. The sequence of the clin-
ical manifestations of cognitive deficit remains unclear, as
do the influences of the extent of neurological defect and
the type of disease course on its severity and the interac-
tion between individual measures of cognitive tests with
the clinical features of the disease and its morphological
characteristics.
1 Department of Fundamental and Clinical Neurology,
N. I. Pirogov Russian State Medical University.
2 Department of Nervous Diseases, I. M. Sechenov
Moscow Medical Academy.
871
0097-0549/11/4108-0871 ©2011 Springer Science+Business Media, Inc.
The aim of the present work was to assess memory
function in patients with MS and compare them with neu-
roimaging data.
MATERIALS AND METHODS
A total of 100 patients (39 men and 61 women) aged
16–61 (median 37, mean 37.4 ± 10.8) years with MS were
studied in neurological out-patient conditions. The study
included patients with confirmed diagnoses of MS estab-
lished in accordance with the criteria of McDonald et al.
[26]. Exclusion criteria were the inability or refusal to accept
all the experimental conditions and use of medications influ-
encing cognitive functions (neuroleptics, antidepressants).
The severity of neurological deficit was assessed objec-
tively using a quantitative neurological status assessment
scale (Neurologic Rating Scale, NRS) [33]. Patient’s func-
tional capacities were evaluated using the Kurtzke Expanded
Disability Status Scale (EDSS) [24].
The type of disease course and the stage of the patho-
logical process were identified on the basis of patients’ his-
tories and clinical pictures in accordance with the criteria of
Lublin et al. [25]. A majority (51%) of the study group con-
sisted of patients with the remitting type of MS, while 41%
had the progressive type (25% with primary progressive and
16% with secondary progressive). Patients with disease
onset, remitting MS, and secondary progressive MS under-
872
went neuropsychological assessment during complete or
partial remission.
Memory functions were assessed using a method
allowing assessment of visual, auditory, and motor memo-
ry: a spoken list of 10 unconnected words (the 10 words
test) and naming of six abstract figures using the Luriya
method [4], along with methods facilitating information
processing on remembering (the semantic coding test).
Immediate (just after presentation) and delayed (at 1 h)
reproduction were tested.
When signs of dementia were present in the patients,
diagnoses were established on the basis of the correspon-
dence between signs and the ICD-10 and DSM-IV criteria
for dementia [7]. Cognitive functions were assessed using
the Mini Mental Scale Examination (MMSE) [21].
MRI brain scans were performed using standard proto-
cols for MS [10, 11, 26, 35] using a Toshiba-Opart (Japan)
open scanner with a magnetic field strength of 0.35 T.
T1 and T2 weighted images were obtained, along with T2
weighted images with free water signal suppression
(FLAIR). Tomograms were analyzed visually with assess-
ment of the state of the gray and white matter of the brain,
the ventricular system, and the subarachnoid space; focal
changes in the white matter were assessed quantitatively,
i.e., the extent of demyelination was determined. Images
were analyzed morphometrically using the tomograph work-
station and programs from Toshiba-Opart, including a set of
scan sequences and programs for image editing and analysis.
Data were analyzed statistically using SPSS 10.0.
Differences between pairs of independent sets were identi-
fied using Student’s test and the nonparametric Mann–
Whitney test. Pairs of dependent sets were compared using
the t test for paired sets and the Wilcoxon test. Comparative
analysis of more than two dependent sets was performed
using the Friedman test. Relationships between different
numerical measures were identified by Spearman rank cor-
relation. Differences were regarded as significant at p < 0.05.
RESULTS
The effects of MS on the formation of cognitive disor-
ders were addressed by ranking all subjects into three
groups on the basis of results obtained from screening with
the MMSE. Group 1 included 81 patients without cognitive
impairments (mean MMSE score 29.7 ± 0.6); group 2 con-
sisted of 12 patients with mild and moderate cognitive
impairments (25.9 ± 1.1); group 3 consisted of seven
patients with more severe cognitive disorders (20.7 ± 1.9)
(Table 1).
Most of the subjects were patients without significant
cognitive impairments. There were no intergroup differ-
ences in age, degree of disability, and severity of neurolog-
ical symptomatology as assessed using neurological scales.
Although patients with severe cognitive impairments allow-
Meshkova and Damulin
Fig. 1. Quantitative results of the 10-word remembering test: 5 trials and
delayed reproduction (DR). The abscissa shows trials; the ordinate shows
the number of words. *Significant differences compared with other groups
(p < 0.05).
ing diagnoses of mild dementia (MMSE scores of less
than 24) were older than other patients, these showed a later
onset of disease and a longer mean duration of illness,
though these differences did not reach significance.
Quantitative assessment of auditory, visual, and motor
memory in patients with cognitive deficit of different
extents is shown in Table 2 and Fig. 1.
These data show that patients with MS did not have
difficulty with either verbal or nonverbal materials and no
significant intergroup differences were seen, while the fixi-
ty of memory differed significantly between patients with
different levels of cognitive impairment.
Quantitative analysis of test results assessing auditory
memory showed that MS patients, regardless of the severi-
ty of cognitive deficit, selected inert strategies for remem-
bering, with slow build-up; these patients showed impair-
ments in the selectivity of reproduction in the form of
actualization of homophonic but unnecessary words,
semantic substitutions, frequent repeats, and narrowing of
acoustic attention (differences between groups were not sig-
nificant). Patients made analogous errors in reproducing
visual images and in grouping visual images, where there
were perceptual substitutions and uncorrected omissions.
Despite the fact that analysis of measures of motor
memory revealed no statistically significant differences,
patients with MMSE scores of less than 24 points per-
formed this test less successfully, with increases in the
latent periods of performing series of movements with each
hand, and often with occasional errors on transferring to the
other hand, in some cases with spontaneous correction.
Relationships between cognitive impairments detected
on neuropsychological testing and structural changes in the
brain seen on MRI scans were assessed by comparing results
from memory evaluation tests and neuroimaging results.
The results of this analysis, presented in Table 3, iden-
tify moderate correlational relationships between measures
obtained in memory tests and increases in the ventricles and
demyelination foci in these areas. The volumes of immedi-
ate and delayed reproduction in the semantic coding test
were related to the severity of atrophy and the extent of
enlargement of the cerebral ventricles, the tightest relation-
Memory Disorders in Multiple Sclerosis 873

TABLE 1. Clinical Characteristics of Patients Depending on the Severity of Cognitive Deficit

Group
Measure
1 2 3

Number of patients 81 12 7

Mean cognitive deficit, MMSE points 29.7 ± 0.6* 25.9 ± 1.1* 20.7 ± 1.9*

Mean age, years 36.8 ± 10.9 35.3 ± 8.3 48.0 ± 8.47

Mena age at onset of MS, years 30.2 ± 10.4 30.2 ± 10.1 36.4 ± 11.0

Mean duration of disease, years 6.7 ± 6.6 5.3 ± 2.9 12.3 ± 7.6

Mean points on NRS 78.1 ± 9.9 71.7 ± 13.0 70.3 ± 12.3

Mean points on EDSS 2.8 ± 1.0 3.2 ± 1.1 3.3 ± 0.9

Note. *Significant difference between groups, p < 0.05.

TABLE 2. Memory Function on Testing in Patients with MS

Group
Neuropsychological tests
1 2 3

10-word remembering test (number of words reproduced)

Volume of memory 8.77 ± 1.06 8.08 ± 1.08 7.86 ± 1.07

Fixity of memory 6.62 ± 2.22 5.75 ± 2.18* 3.57 ± 0.98*

Semantic coding test (number of words reproduced)

Immediate reproduction 6.57 ± 1.97 5.50 ± 2.02 4.29 ± 2.06*

Delayed reproduction 6.33 ± 2.18 5.75 ± 1.60* 5.29 ± 1.70*

Reproduction with prompt 9.11 ± 1.57 9.00 ± 1.35 6.71 ± 2.56*

Remembering and recognition of visual images (number of images recognized)

Immediate reproduction of object images 5.13 ± 1.00 5.00 ± 0.63 4.80 ± 1.10

Immediate reproduction of abstract images 4.47 ± 1.12 4.55 ± 1.13 3.80 ± 0.84

Delayed reproduction of object images 4.67 ± 1.35 4.36 ± 0.67 3.40 ± 0.89*

Motor memory, points 0.29 ± 0.44 0.46 ± 0.58 0.33 ± 0.41

Note. *Significant difference from group 1, p < 0.05.

ships being between the volume of immediate reproduction
and the indexes of the right (r = 0.33; p < 0.05) and left (r =
= 0.44; p < 0.01) lateral ventricles and the index of the third
ventricle (r = –0.40; p < 0.05). Similar correlations were
detected by comparing measures of motor memory with the
cortical index (r = 0.36; p < 0.05) and the indexes of the
anterior horns (r = 0.33; p < 0.05), third ventricle (r = 0.33;
p < 0.01), and right lateral (r = –0.39; p < 0.05) ventricles
of the brain.
At the same time, remembering and naming visual
images showed a moderate link with the demyelinating pro-
cess in these same areas (see Table 3). Reproduction of
object images was moderately significantly affected by foci
in the posterior periventricular areas on both the right (r =
= –0.33; p < 0.05) and left (r = –0.33; p < 0.05) sides, while
memory for abstract images was moderately associated
with foci in the anterior periventricular areas on the right
side (r = –0.40; p < 0.01).
874 Meshkova and Damulin

TABLE 3. Correlations between Memory Test Results and MRI Scan Data

10-word remembering
Semantic coding test Remembering and recognition of visual objects
test
Immediate Immediate Delayed
Measure Immediate Delayed Reproduc- reproduc- reproduc- reproduc-
Volume of Fixity of Motor
reproduc- reproduc- tion with tion of tion of tion of
memory memory memory
tion tion prompt object abstract abstract
images images images
r = –0.348 r = 0.364
Cortical index
p = 0.032 p = 0.029

r = 0.331
Index of anterior horns
p = 0.048

r = –0.397 r = 0.331
Index of third ventricle
p = 0.014 p = 0.049

r = 0.331 r = –0.387
Index of right lateral ventricle
p = 0.042 p = 0.020

r = 0.437 r = 0.325
Index of left lateral ventricle
p = 0.001 p = 0.047

r = –0.424 r = 0.343
Periventricular foci on the right
p = 0.009 p = 0.043

Periventricular foci along the bodies r = 0.371*

of the lateral ventricles on the right p = 0.022

Periventricular foci close to the ante- r = 0.401

rior horn on the right p = 0.015

Periventricular foci close to the pos- r = –0.334

terior horn on the right p = 0.035

Periventricular foci close to the r = –0.325

posterior horn on the left p = 0.047

r = –0.402
Foci in the left parietal region
p = 0.015

r = 0.417 r = –0.338
Foci in the cerebellum
p = 0.009 p = 0.044

r = 0.334
Foci in the brainstem
p = 0.040

r = 0.385
Foci in the corpus callosum
p = 0.020

Note. The Table shows only statistically significant correlation coefficients.

DISCUSSION ory is the preservation and maintenance of active voluntary

Memory impairments, especially of short-term memo-
ry, along with impairments to attention, represent one of the
main cognitive dysfunctions in MS. Memory is one of the
central mental functions, operating as an integrative system
involving other mental processes (thought, speech, etc.).
Memory is the basis of behavior, thought, and conscious-
ness, i.e., mental activity in general. The main component
of memory supporting information storage, operating in a
changing environment, and recourse to past experience and
long-term memory consists of short-term memory. A neces-
sary condition for the normal operation of short-term mem-
attention and visuospatial concepts. Profound memory
impairments are extremely rare in MS; short-term memory
is the most often affected. In our study, memory impair-
ments appeared phenomenologically as mode-nonspecific
disturbances in the form of decreases in the volumes of
immediate and delayed reproduction, increases in the influ-
ences of interference, decreases in the volume of delayed
reproduction even in the absence of impairments to imme-
diate memory, and changes in the selectivity of memory.
A number of studies on short-term and working mem-
ory have shown that the processes of retention and repro-
duction of verbal and nonverbal material are supported by
Memory Disorders in Multiple Sclerosis
different anatomical brain structures [34]. Data obtained
using neuroimaging methods indicate that performance of
tasks based on the delayed reproduction of verbal stimuli
activates the posterior parietal areas (Brodman field 40),
Broca’s area (field 44), the left premotor area, and the sup-
plementary motor cortex (field 6). Broca’s area and the sup-
plementary motor cortex are involved in the processes of
repetition and pronunciation, while the posterior parietal
areas store verbal material during the delay period.
Visuospatial memory is supported by the functioning and
activation of connections in the right hemisphere – the pos-
terior parietal areas (field 40), the anterior visual cortex
(field 19), and the premotor (field 6) and inferior prefrontal
areas (field 47). The equivalent of repetition for nonverbal
material is the process of computation of the spatial coordi-
nates of the object presented, for which the premotor cortex
and superior posterior parietal areas are responsible [9, 19].
Various areas of the frontal cortex also have an important
role in the process of the reproduction and storage of mate-
rial in verbal memory; thus, the anterior areas in particular
are responsible for repetition of verbal material and the pos-
terior temporal-occipital for storage of material in the active
state [28]. The prefrontal areas, along with the inferolateral
temporal area, are also involved in supporting semantic
memory [23].
Reproduction of verbal series requires a successive
(linear) strategy of addressing traces in which each succes-
sive element has a linear associative link with the preceding
and succeeding elements. Speech mediation is important for
the reproduction of verbal stimuli, as each element in the
series is pronounced. In nonverbal tests, each element is
presented sequentially (successive strategy), though the
scheme of organization of the material is simultaneous in
nature, such that the material is presented simultaneously in
the visuospatial and sequential forms. There is no reliance
on speech mediation and the leading role in reproducing
traces is played by the spatial configuration (simultaneous
scheme). This leads to the suggestion that inclusion of the
supplementary functions of speech mediation and reliance
on the verbally mediated successive strategy should allow
patients to remember verbal material better. However, this
was not observed; furthermore, even the semantic organiza-
tion of memory in the semantic coding test did not increase
the productivity of reproduction, regardless of the level of
the cognitive defect. The results of delayed reproduction
of nonverbal material showed that coding of stimuli in the
visuospatial form was significant for patients with MS
with minimal cognitive dysfunction, while this was not of
decisive importance for performing the test in patients with
mild dementia.
A major characteristic of short-term memory is its vol-
ume, determined by the number of elements simultaneous-
ly stored in it, which is limited to 5–9 units, the elementary
unit of information being a letter, a phrase, or a word, i.e.,
that which is perceived as a single meaningful image.
875
The volume remembered in the patients studied here was no
different from normal, though there were impairments to
reproduction in conditions of retention of memory traces,
which is supported by the effectiveness of categorial
prompts in the semantic coding test.
Of the relationships identified here, particular attention
should be paid to the moderately strong correlational rela-
tionships between demyelination foci in the cerebellum and
the volume of delayed reproduction in the semantic coding
test (r = 0.42; p < 0.01) and motor memory (r = –0.40; p <
< 0.05). Impairments to cerebellar function in the form of
disturbances to coordination in patients with MS are the
clearest and earliest manifestations of the disease. The cere-
bellum was long regarded as a structure supporting nothing
more than coordination and movement. The development of
high-resolution neuroimaging methods such as positron
emission tomography and MRI imaging allowed the role of
the cerebellum in organizing mental processes to be recog-
nized [6, 14–16, 27]. The link between cognitive impair-
ments and lesions to the posterior cranial fossa (in the cere-
bellum and brainstem) in MS has been addressed previously
[8, 32]. A number of investigators have noted a relationship
between tests assessing neurodynamic functions and the
volumes of foci of demyelination in the brainstem and cere-
bellum [13], while use of a different set of tests revealed
no such correlation [30]. The relationship between foci
of demyelination in the cerebellum and indicators in
the semantic coding test found in our studies allows the
involvement of the extensive connections of the cerebellum
with the cortex in various areas of the hemispheres, partic-
ularly the associative fields of the frontal lobes and the lim-
bic-reticular complex, to be assessed. Cerebellar neurons
are known to be connected with the cortical areas of the
cerebral hemispheres, especially the prefrontal areas of the
frontal lobes, which are functionally important for cognitive
and verbal functions [2, 3, 31]. Damage to the cerebellum
and its connections is known to lead to a wide spectrum of
cognitive disorders, including impairments of attention (dif-
ficulty with switching attention), impairments to operative
memory and learning, impairments to the planning and con-
trol of activities requiring the performance of tasks and
actions in strict sequence, and deficits in spatial functions
[15, 17, 22, 32]. As in motor acts, the cerebellum supports
rapid and smooth movement performance of mental acts,
ensuring precise interaction of cognitive operations, i.e., it
takes part in resolving tasks requiring rapid and sequential
changes and regulates mental activity on switching from
one task to another [2, 3].
Atrophy of the corpus callosum is one of the most
commonly encountered neuroimaging phenomena in
patients with MS [12, 18, 29]. The corpus callosum is a
massive commissural tract and we would expect the struc-
tural lesions within it commonly seen in MS (multiple foci
of demyelination and frequently observed signs of atrophy)
to affect cognitive functions. However, its role in realizing
876
cognitive capacities is ambiguous, and it seems unlikely
that atrophy of the corpus callosum is the main cause of the
development of cognitive deficit in people with MS. As
dementia is most commonly seen in people with long cours-
es of illness, it is possible that atrophy of the corpus callo-
sum reflects the duration of disease. In addition, clinical
symptoms of callosal disconnection in MS are quite rare.
This may have several explanations. Firstly, the number of
axons in the corpus callosum is large (about 20 million) and
decreases in the number of fibers by 20–25% (as seen in
MS) may not lead to functional impairment, especially if
information is duplicated by axon collaterals [5]. Secondly,
atrophy of the corpus callosum can result from depletion of
the myelin sheaths of fibers whose axons continue to func-
tion, supporting the conduction of nerve impulses. Further-
more, the traditionally used tests for assessing corpus callo-
sum functioning do not have high specificity and can be
performed badly even by healthy people. Our study demon-
strated a relationship between the volume of immediate
reproduction of visual images and the presence of foci in the
corpus callosum on MRI scans (r = –0.39; p < 0.05), while
atrophic changes in this area are not of decisive significance.
Results obtained by comparing tests assessing memory
functions and MRI data demonstrated the involvement of
conducting pathways supporting connections between the
associative cortex and the posterior areas and the periven-
tricular regions. This relationship, in combination with the
absence of signs of lesions (both in terms of clinical data and
on use of neuroimaging methods) to individual parts of the
brain, suggests that the main neurophysiological mechanism
of cognitive disorders in MS is interruption of projection,
commissural, and long associative fibers, leading to impair-
ments to the integrative activity of the brain and activation of
the cortex by deep structures, primarily the thalamus. It
should be recognized that cognitive deficit in MS is evident-
ly based on diffuse damage, particularly of the white matter
of the brain, major neural networks supporting cognitive
functions, and some of the axons of subcortical formations,
causing damage to intra- and interhemisphere connections.
It is clearly evident that enlargement of the ventricles, along
with the demyelinating process in the periventricular areas,
leads to secondary damage to executive functions due to
damage to conductors running in these zones and connecting
the temporal limbic and parietal-occipital structures with the
frontal lobes, leading to executive disorders and memory
impairments. Thus, a neuropsychological method combined
with MRI scans identified impairment to functions in the
damaged brain.
REFERENCES
1. E. I. Gusev, I. A. Zavalishin, and A. N. Boiko, Multiple Sclerosis and
Other Demyelinating Diseases [in Russian], Mitkosh, Moscow
(2004).
Meshkova and Damulin
2. Yu. V. Zueva, Impairments to Cognitive Processes in Isolated
Cerebellar Infarcts: Author’s Abstract of Master’s Thesis in Psycho-
logical Sciences, Moscow (2003).
3. L. A. Kalashnikova, A. S. Kadykov, E. M. Kashina, et al., “Impair-
ments to higher brain functions in cerebellar infarcts,” Nevrol. Zh.,
No. 1, 15–21 (2000).
4. A. R. Luriya, Basic Neuropsychology [in Russian], Akademiya,
Moscow (2002).
5. F. Aboitiz, A. B. Scheibel, R. S. Fisher, and E. Zaidel, “Fiber com-
position of the human corpus callosum,” Brain Res., 598, 143–153
(1992).
6. N. A. Akshoomoff and E. A. Courchesne, “A new role for the cerebel-
lum in cognitive operations,” Behav. Neurosci., 106, 731–738 (1992).
7. Diagnostic and Statistical Manual of Mental Disorders, 4th edition
(DSM-IV). American Psychiatric Association, Washington (1994),
pp. 143–147.
8. C. J. Archibald, X. Wei, J. N. Scott, et al., “Posterior fossa lesion vol-
ume and slowed information processing in multiple sclerosis,”
Brain, 127, 1526–1534 (2004).
9. A. Awh and J. Jonides, “Spatial selective attention and spatial work-
ing memory,” in: The Attentive Brain [in Russian], E. Parasuraman
(ed.), MIT Press, Cambridge (1996), pp. 353–380.
10. E. Barkhof, “The role of magnetic resonance imaging in diagnosis of
multiple sclerosis,” in: Multiple Sclerosis: Clinical Challenges and
Controversies, A. J. Thompson, C. Polman, and R. Hohlfeid (eds.),
Martin Dunitz, (1997), pp. 43–64.
11. F. Barkhof, M. Filippi, and D. H. Miller, “Comparison of MRI crite-
ria at first presentation to predict conversion to clinically definite
multiple sclerosis,” Brain, 120, 2059–2069 (1997).
12. R. O. Bernard and M. Triggs, “Corpus callosum in multiple sclero-
sis,” J. Neurol. Neurosurg. Psychiat., 37, 1259–1264 (1974).
13. R. W. Baumhefner, W. W. Tourtellotte, K. Syndulko, et al.,
“Quantitative multiple sclerosis plaque assessment with magnetic
resonance imaging. Its correlation with clinical parameters, evoked
potentials, and intra-blood–brain barrier IgG synthesis,” Arch.
Neurol., 47, 19–26 (1990).
14. P. C. Berquin, J. N. Giedd, L. K. Jacobsen, et al., “Cerebellum in
attention-deficit hyperactivity disorders: a morphometric MRI,”
Neurology, 50, 1087–1093 (1998).
15. T. Botez-Marquard and M. Botez, “Cognitive behavior in heterode-
generative ataxias,” Eur. J. Neurosci., 8, 347–353 (2001).
16. T. Botez-Marquard C. Bard, L. Léveillé, and M. I. Botez, “A severe
frontal-parietal lobe syndrome following cerebellar damage,” Eur. J.
Neurosci., 8, 347–353 (2001).
17. A. G. Canavan, R. Sprengelmayer, and H. C. Diener, “Conditional
associative learning is impaired in cerebellar disease in humans,”
Behav. Neurosci., 275, 1940–1943 (1994).
18. G. Comi, M. Filippi, V. Martinelli, et al., “Brain magnetic resonance
imaging correlates of cognitive impairment in multiple sclerosis,”
J. Neurol. Sci., 115, S66–S73 (1993).
19. S. M. Courtney, L. Petit, J. M. Maisog, et al., “An area specialized
for spatial working memory in human frontal cortex,” Science, 279,
No. 5355, 1347–1351 (1998).
20. A. Feinstein, L. D. Kartsounis, D. H. Miller, et al., “Clinically isolated
lesions of the type seen in multiple sclerosis: a cognitive, psychiatric
and MRI follow up study,” J. Neurol. Neurosurg. Psychiat., 55,
869–876 (1992).
21. M. F. Folstein, S. E. Folstein, and P. R. McHugh, “Mini-Mental
State: a practical guide for grading the mental state of patients for the
clinician,” J. Psychiat. Res., No. 1, 189–198 (1975).
22. J. Grafman, I. Litvan, S. Massaquoi, et al., “Cognitive planning deficit
in patient with cerebellar atrophy,” Neurology, 42, 1493–1496 (1992).
23. J. R. Hodges, N. Graham, and K. Patterson, “Charting the progres-
sion in semantic dementia: Implications for the organization of
semantic memory,” Memory, 3, 463–495 (1995).
Memory Disorders in Multiple Sclerosis
24. J. F. Kurtzke, “Rating neurological impairment in multiple sclerosis: an
expanded disability status scale,” Neurology, 33, 1444–1452 (1983).
25. F. D. Lublin and S. C. Reindold, “The National Multiple Sclerosis
Society (USA) Advisory Committee on clinical trials in multiple
sclerosis. Defining the clinical course of multiple sclerosis: results of
an international survey,” Neurology, 46, 907–911 (1996).
26. W. I. McDonald, A. Compston, G. Edan, et al., “Recommended
diagnostic criteria for multiple sclerosis: guidelines from the
International Panel of the diagnosis of multiple sclerosis,” Ann.
Neurol., 50, 121–127 (2001).
27. E. Paulesu, A. Connelly, and C. D. Frith, “Functional MRI correla-
tions with PET: Initial experience using a cognitive activation
paradigm on verbal working memory,” Neuroimag. Clin. North Am.,
4, 207–225 (1995).
28. M. I. Posner and A. Pavese, “Anatomy of word and sentence meaning,”
Proc. Natl. Acad. Sci. USA, 95, 899–905 (1998).
29. C. Pozzilli, S. Bastianello, A. Padovani, et al., “Anterior corpus cal-
877
losum atrophy and verbal fluency in multiple sclerosis,” Cortex, 27,
441–445 (1991).
30. S. M. Rao, G. J. Leo, L. Bernardin, and F. Unverzagt, “Cognitive
dysfunction in multiple sclerosis. Frequency, patterns and prediction,”
Neurology, 41, 685–691 (1991).
31. J. Schmahmann, “An emerging concept. The cerebellar contribution
to higher function,” Arch. Neurol., 48, 1178–1187 (1991).
32. J. Schmahmann, “The cerebellar cognitive affective syndrome,”
Brain, 121, 561–579 (1998).
33. J. C. Spie, R. L. Knobler, S. L. Braheny, et al., “A neurological rating
scale (NRS) for use in multiple sclerosis,” Neurology, 34, 1368–1372
(1984).
34. E. Smith and J. Jonides, “Neuroimaging analyses of human working
memory,” Proc. Natl. Acad. Sci. USA, 95, 12061–12068 (1998).
35. M. Tintore, A. Rovira, M. Martinez, et al., “Comparison of different
MR imaging criteria to predict conversion to clinically definite mul-
tiple sclerosis,” Am. J. Neuroradiol., 21, 702–706 (2000).