Keywords:
multiple sclerosis - cognition - longitudinal studies
Palavras chave:
esclerose múltipla - cognição - estudos longitudinais
Patients with multiple sclerosis (MS) clinically present with a myriad of neurologic
symptoms, including cognitive decline, regarded as having the greatest impact on key
aspects of their daily living, such as managing domestic tasks, participating in society
and holding down a job[1].
According to reviews of the scientific literature, one third of MS patients with the
relapsing-remitting (RRMS) clinical form show cognitive impairments that are often
milder than that found in the progressive subtypes of the disease[2],[3].
Cognitive impairments can vary, but an impact on episodic memory is evident in the
early stages of the disease. A 10-year longitudinal study revealed that decline in
information processing speed and verbal episodic memory (VEM) in early RRMS patients
predicted progression to the secondary progressive MS clinical form. Given that secondary
progressive MS is a more severe stage of the disease, assessing these cognitive domains
in the early stages of MS is vital[4].
A scientific review of the related literature[1] reported that episodic memory is one of the most common deficits found in MS, occurring
in 40–65% of patients. Evidence on the nature of the episodic memory disorder in MS
patients is conflicting. Some authors hold that episodic memory problems are characterized
by impairment in the retrieval of learned information over the course of time. Others
have shown reduced assimilation of new information in patients relative to controls,
yet once the information has been acquired, delayed recall and recognition ability
in patients had proven to be similar to those of healthy controls[5].
Numerous cross-sectional studies investigating the prevalence and pattern of cognitive
dysfunction in MS are available in the literature. However, there is a dearth of studies
on the evolution of the disease, from a cognitive viewpoint, over the course of time.
The results of longitudinal studies in the literature are conflicting, reporting cognitive
improvement, stability or decline in patients over time[6].
The objective of this study was to conduct a longitudinal assessment of VEM at two
time points, consisting of a baseline assessment and another at 4.5 years of disease
later, to assess the impact of RRMS on the VEM over this period. In order to characterize
the VEM in RRMS patients at baseline, results were compared against those of the healthy
controls. The characterization of sociodemographic and clinical variables, as well
as correlation between attention and executive functions and VEM, were analyzed at
the baseline assessment.
METHODS
Participants
The study sample comprised 29 patients with RRMS (19 women and 10 men), whereas the
control group comprised 26 healthy subjects (17 women and nine men). Patients were
recruited from the clinic for demyelinating diseases of the Department of Neurology
of the Clínicas Hospital of the São Paulo University School of Medicine.
The study sample included patients diagnosed with RRMS based on the McDonald criteria
(2010)[7]. All patients underwent an initial cognitive assessment to establish a baseline.
In addition, only patients with an IQ within or above the mean expected IQ for age
(mean = 106.60; SD = 7.65) were included, on the premise that patients of lower intelligence
may have worse cognitive performance. Patient IQ was determined at baseline using
the Vocabulary and Matrix Reasoning subtests of the Wechsler Adult Intelligence Scale-Revised
(WAIS-III)[8].
The exclusion criteria included: patients who had evolved to progressive clinical
subtypes, patients with deficits that prevented assessment, patients with other central
nervous system disease, patients with relapse less than 30 days before the study,
patients using corticosteroids for the last 90 days before the examination, patients
with a Mini-Mental State Examination (MMSE) score below the cut-off. Owing to the
lack of normative MMSE data for the Brazilian population for the age stratum of the
present sample, cut-off scores for the educational level were employed[9].
The control group was formed by selecting healthy participants matched for age, educational
level and gender with the patients in the study group. Volunteers using psychoactive
or neuroleptic medications or with a history of alcohol or illegal drug abuse were
excluded. Control participants scoring below the cut-off on the MMSE for educational
level[9] and above the cut-off on the Hospital Anxiety and Depression Scale (8 for symptoms
of anxiety and 9 for depression) were excluded[10].
Instruments and procedures
The patients underwent a comprehensive cognitive assessment, which included specific
tests of VEM such as the Hopkins Verbal Learning Test[11] and the Logical Memory subtest of the Memory Wechsler Scale[12] ([Table 1]). The same protocol was used for the assessments at the study baseline and endpoint.
Table 1
Neuropsychological instruments used and cognitive domains assessed.
|
Cognitive domains assessed
|
Neuropsychological instruments used
|
|
Attention
|
|
Sustained
|
Trail Making Test A
|
|
Divided
|
Trail Making Test B
|
|
Selective
|
Stroop Test Victoria – part 3
|
|
Information Processing Speed
|
Symbol Digit Modalities Test
|
|
Short-term memory (verbal and visual-spatial)
|
|
Immediate
|
Digit Span - Forward (WAIS-III)
|
|
Corsi Blocks - Forward (WMS)
|
|
Working
|
Digit Span - Backward (WAIS-III)
|
|
Letter-Number Sequencing (WAIS-III)
|
|
Corsi Blocks - Backward (WMS)
|
|
Episodic memory (verbal and visual-spatial)
|
|
Immediate Recall
|
HVLT*, BVMT, Logical Memory (WMS)*
|
|
Delayed Recall
|
HVLT*, BVMT, Logical Memory (WMS)*, ROCF
|
|
Recognition
|
HVLT* and BVMT
|
|
Executive functions
|
|
Mental Flexibility
|
Modified Wisconsin Card Sorting Test
|
|
Verbal Fluency
|
Controlled Oral Word Association Test
|
|
Visual-spatial functions
|
|
Visual-construction
|
Rey-Osterrieth Complex Figure (ROCF)
|
|
Language
|
|
Naming
|
Boston Naming Test
|
WAIS: Wechsler adult intelligence scale; WMS: Wechsler memory scale; HVLT: Hopkins
verbal learning test-revised; BVMT: brief visuospatial memory test-revised; ROCF:
Rey-Osterrieth complex figure; *Measures assessing verbal episodic memory.
The interval between the two neuropsychological assessments applied to the patient
group ranged from 3.1 to 5.7 years with a mean and standard deviation of 4.5 (0.7)
years.
The mood assessment of the patients was carried out at both baseline and follow-up
using the Beck Depression Inventory[13] and the Hospital Anxiety and Depression Scale[10].
Patients, specifically, underwent the neurologic examination at two time points to
identify the degree of physical disability by completing the Expanded Disability Status
Scale[14] applied by the neurologist.
The healthy participants from the control group were given a single neuropsychological
assessment using the same instrument that was applied to the patient group ([Table 1]).
Additional clinical data for the patients were drawn directly from medical records
held at the neurology clinic of the Clínicas Hospital (Hospital das Clínicas) of the
São Paulo University School of Medicine. All patients were using disease modifying
therapies, although there were some changes and interruptions during the follow-up
period (non-adherence to treatment) for different reasons such as the presence of
collateral effects, pregnancy and due to patients seeking alternative treatment.
All study participants signed the free and informed consent form when asked to undergo
the examinations.
Statistical analysis
Statistical analyses were carried out using the SPSS V20 for Windows 8.1 software
package. Cognitive data extracted from the sample were expressed as mean, standard
deviation, median and measures of spread. Raw scores were converted into Z-scores
to allow comparison of the data. Data on the use of medication by patients were expressed
as absolute medians.
Sociodemographic data for the control and patient groups were compared using the Student's
t-test.
The normality of cognitive data extracted from the neuropsychological tests of patients
was analyzed by the Shapiro-Wilk test. Given that most of the variables exhibited
a non-normal distribution, non-parametric statistical tests were applied.
Cognitive data collected from patients at the first and second neuropsychological
assessments were analyzed using the Wilcoxon paired statistical test. The Mann Whitney
statistical test was used to compare the cognitive data from the baseline neuropsychological
assessments of patients versus controls.
Spearman's correlation was used to better characterize patient deficits in VEM at
the baseline assessment and to determine a possible relationship or interdependence
among the clinical, sociodemographic and physical disability variables of patients
for VEM.
The following clinical variables were investigated: disease duration, time since last
relapse, number of relapses, use of disease modifying therapies, and use of antidepressants.
Sociodemographic variables were: age, education and gender. Lastly, the variable for
physical disability was assessed by the EDSS (Expanded Disability Status Scale).
Because executive functioning and attention play a role in the memorization and learning
process, instruments assessing these cognitive domains were also correlated with the
VEM tests using Spearman's correlation. Variables showing a level of significance
of p ≤ 0.05 on this statistical test were included in the covariance analysis. Thus,
it was possible to check whether differences between patient and control performances
on the VEM test persisted even after controlling for the effects of the attention
and executive functioning tests.
RESULTS
Sociodemographic data for the control and patient groups are given in [Table 2]. There was no statistically significant difference between the groups for age, educational
level or gender. Clinical and physical disability data for the patient group at the
baseline assessment are given in [Table 3]. At the follow-up, mean disease duration was 7.25 years (SD = 2.33), time since
diagnosis was 5.57 years (SD = 1.85) and the mean number of relapses was 4.10 (SD
= 2.63). Twenty-five patients were on a disease modifying drug and 13 out of the 29
patients discontinued this. Ten patients were using an antidepressant at the follow-up.
Table 2
Sociodemographic data of sample of patients and controls.
|
Variable
|
Controls (n = 26)
|
Patients at baseline (n = 29)
|
P (controls vs patients at baseline)
|
Patients at follow-up (n = 29)
|
|
Age (years)
|
|
|
0.667
|
|
|
Mean (SD)
|
30.62 (8.47)
|
29.62 (8.55)
|
|
34.34 (8.52)
|
|
Median (min-max)
|
28.00 (20.00–53.00)
|
27.00 (18.00–48.00)
|
|
33.00 (23.00–52.00)
|
|
Education (years)
|
|
|
0.291
|
|
|
Mean (SD)
|
15.46 (3.56)
|
14.55 (2.74)
|
|
15.62 (3.12)
|
|
Median (min-max)
|
15.00 (11.00–24.00)
|
15.00 (10.00–19.00)
|
|
16.00 (10.00–22.00)
|
|
Gender (female/male)
|
17/09
|
19/10
|
0.992
|
19/10
|
p: statistical significance between patient and control groups at baseline according
to the Student's t-test.
Table 3
Clinical data of patients at baseline and follow-up.
|
Variable
|
Baseline
|
Follow-up
|
|
Median (min–max)
|
Mean (SD)
|
Median (min–max)
|
Mean (SD)
|
|
Disease duration (years)
|
2.16(0.25–7.05)
|
2.64(1.94)
|
6.68(3.62–12.69)
|
7.25(2.33)
|
|
Time since diagnosis (years)
|
0.30(0.00–5.01)
|
0.96(1.30)
|
5.26(3.32–10.66)
|
5.57(1.85)
|
|
Number of relapses
|
2.00(1.00–7.00)
|
2.66(1.77)
|
4.00(1.00–11.00)
|
4.10(2.63)
|
|
Time since last relapse (months)
|
7.70(0.40–41.96)
|
13.65(12.23)
|
28.90(2.70–107.03)
|
36.08(26.85)
|
|
EDSS
|
1.00(0.00–3.00)
|
1.21(0.94)
|
1.00(0.00–4.00)
|
1.14(1.21)
|
|
Disease modifying therapies (DMTs) (y/n)
|
-
|
25/04
|
|
Interferon (Betaferon, Avonex, Rebif)
|
-
|
12
|
|
Glatiramer acetate (Copaxone)
|
-
|
9
|
|
Natalizumab (Tysabri)
|
-
|
1
|
|
Rituximab (Mabthera)
|
-
|
1
|
|
Fingolimod (Gilenya)
|
-
|
2
|
|
Antidepressants (y/n)
|
-
|
10/19
|
|
Poor adherence to DMTs (y/n)
|
-
|
13 / 16
|
Disease duration: (date of neuropsychological assessment – date of first relapse);
Time since last relapse = (date of neurologic assessment – date of last relapse);
EDSS: Expanded Disability Status Scale.
The results of the longitudinal analysis, shown in [Table 4], indicate patient stability in VEM, with statistically significant improvement on
the immediate recall of the Hopkins Verbal Learning Test (p = 0.019) and delayed recall
of the Logical Memory test (p = 0.042). In addition, there were statistically significant
improvements by patients on the tests assessing sustained attention (Trail Making
Test A) and working memory (WAIS-III Digit span), as well as on the semantic verbal
fluency (animals) and naming tasks (Boston Naming Test). At the follow-up, patient
scores on the MMSE ranged from 27 to 30 points, with a mean and standard deviation
of 29.17 (0.84).
Table 4
Data in Z-scores obtained by patients on cognitive tests – baseline vs. follow-up.
|
Neuropsychological instruments
|
Patients at Baseline
|
Patients at Follow-up
|
p-value
|
|
Median (min-max)
|
M (SD)
|
Median (min-max)
|
M (SD)
|
|
HVLT – Immediate recall
|
−0.80 (–2.20–1.00)
|
−0.97 (0.84)
|
−0.50 (–2.20–1.70)
|
−0.48 (0.94)
|
0.019*
|
|
HVLT – Delayed recall
|
−0.80 (–2.20–1.30)
|
−0.81 (0.85)
|
−0.10 (–3.00–1.10)
|
−0.48 (1.08)
|
0.092
|
|
HVLT – Recognition
|
0.60 (–2.20–0.80)
|
0.18 (0.76)
|
0.70 (–3.00–1.00)
|
−0.06 (1.19)
|
0.829
|
|
BVMT – Immediate recall
|
0.90 (–2.20–1.50)
|
0.49 (1.35)
|
0.50 (–2.00–1.70)
|
0.36 (0.98)
|
0.681
|
|
BVMT – Delayed recall
|
1.00 (–2.20–1.50)
|
0.53 (0.95)
|
1.00 (–3.00–1.50)
|
0.53 (1.10)
|
0.497
|
|
BVMT – Recognition
|
0.00 (0.00–0.00)
|
0.00 (0.00)
|
0.00 (–1.90–0.00)
|
−0.18 (0.53)
|
0.102
|
|
Letter-number sequencing
|
0.40 (–1.00–2.00)
|
0.38 (0.78)
|
0.70 (–0.70–2.00)
|
0.62 (0.75)
|
0.190
|
|
Digit span (WAIS-III)
|
0.70 (–1.00–2.50)
|
0.58(0.80)
|
1.00 (–0.30–3.00)
|
1.13(0.98)
|
0.002*
|
|
Corsi blocks (WMS-R)
|
−0.60 (–1.50–1.60)
|
−0.38 (0.67)
|
0.00 (–1.80–1.40)
|
−0.17(0.79)
|
0.175
|
|
Logical memory – immediate recall
|
−0.30 (–1.90–1.60)
|
−0.21 (0.86)
|
−0.10 (–1.80–3.50)
|
0.12(0.99)
|
0.178
|
|
Logical memory – delayed recall
|
−0.10 (–1.30–1.30)
|
−0.16 (0.66)
|
0.00 (–1.00–2.40)
|
0.22(0.87)
|
0.042*
|
|
Stroop test Victoria - part 3
|
−0.50 (–2.20–1.50)
|
−0.46 (1.07)
|
−0.20 (–2.30–1.70)
|
−0.18(0.97)
|
0.234
|
|
Trail making test A
|
−0.10 (–2.20–0.70)
|
−0.33 (0.77)
|
0.00 (–2.90–1.40)
|
0.01(0.87)
|
0.028*
|
|
Trail making test B
|
−0.10 (–2.20–0.90)
|
−0.44 (0.93)
|
0.00 (–3.00–1.00)
|
−0.52(1.20)
|
0.750
|
|
FAS form of the COWA test
|
−0.90 (–2.20–1.10)
|
−0.80 (0.78)
|
−0.80 (–2.60–0.70)
|
−0.90(0.84)
|
0.463
|
|
Animals
|
−0.60 (–1.70–1.10)
|
−0.56 (0.71)
|
0.00 (–1.40–2.20)
|
0.08(0.83)
|
<0.001*
|
|
Symbol digit modalities test
|
−0.80 (–2.40–0.60)
|
−0.79 (0.88)
|
−0.70 (–2.00–1.00)
|
−0.71(0.82)
|
0.509
|
|
Modified Wisconsin card sorting test
|
0.70 (–2.20–0.70)
|
0.17 (0.89)
|
0.70 (–3.00–0.70)
|
0.16(0.88)
|
0.726
|
|
Boston naming test
|
−0.60 (–2.20–0.10)
|
−0.90 (0.76)
|
−0.20 (–2.60–1.10)
|
−0.40(0.94)
|
0.004*
|
*p < 0.05; HVLT: Hopkins verbal learning test; BVMT: Brief visuospatial memory test;
WAIS: Wechsler adult intelligence scale; WMS: Wechsler memory scale; HVLT: Hopkins
verbal learning test-revised; BVMT: brief visuospatial memory test-revised; COWA:
controlled oral word association.
The results of the baseline assessment of control participants were statistically
better than those of the patients. The patients had worse performance than the controls
on the VEM tests for the immediate recall task of the Hopkins Verbal Learning Test
(p = 0.001; p = 0.006) and for the delayed recall of the Logical Memory test (p =
0.013; p = 0.003). The statistically significant poorer performances of patients also
occurred in the attention, semantic verbal fluency and naming processes. Comparison
of quantitative results for the sample of patients and controls on the neuropsychological
test battery is given in [Table 5].
Table 5
Cognitive data at baseline for patient vs.control groups.
|
Neuropsychological instruments
|
Patients at Baseline
|
Control
|
p-value1
|
|
Median (min–max)
|
M (SD)
|
Median (min–max)
|
M (SD)
|
|
HVLT – Immediate recall
|
−0.80 (–2.20–1.00)
|
−0.97 (0.84)
|
0.15 (–1.30–1.30)
|
−0.05 (0.82)
|
< 0.001*
|
|
HVLT – Delayed recall
|
−0.80 (–2.20–1.30)
|
−0.81 (0.85)
|
0.00 (–1.70–1.00)
|
−0.08 (0.93)
|
0.006*
|
|
HVLT– Recognition
|
0.60 (–2.20–0.80)
|
0.18 (0.76)
|
0.80 (–0.80–0.80)
|
0.29 (0.65)
|
0.495
|
|
BVMT – Immediate recall
|
0.90 (–2.20–1.50)
|
0.49 (1.35)
|
0.80 (–2.20–2.00)
|
0.69 (0.89)
|
0.826
|
|
BVMT – Delayed recall
|
1.00 (–2.20–1.50)
|
0.53 (0.95)
|
1.05 (–2.20–1.50)
|
0.78 (0.81)
|
0.314
|
|
BVMT – Recognition
|
0.00 (0.00–0.00)
|
0.00 (0.00)
|
0.00 (0.00–0.00)
|
0.00 (0.00)
|
> 0.999
|
|
Letter-number sequencing
|
0.40 (–1.00–2.00)
|
0.38 (0.78)
|
0.55 (–1.00–4.00)
|
0.81 (1.25)
|
0.300
|
|
Digit span (WAIS-III)
|
0.70 (–1.00–2.50)
|
0.58 (0.80)
|
0.70 (–1.00–4.00)
|
0.85 (1.11)
|
0.553
|
|
Corsi blocks (WMS-R)
|
−0.60 (–1.50–1.60)
|
−0.38 (0.67)
|
0.00 (–2.00–2.00)
|
−0.12 (0.98)
|
0.184
|
|
Logical memory – immediate recall
|
−0.30 (–1.90–1.60)
|
−0.21 (0.86)
|
0.35 (–1.00–1.90)
|
0.38 (0.81)
|
0.013*
|
|
Logical memory – delayed recall
|
−0.10 (–1.30–1.30)
|
−0.16 (0.66)
|
0.50 (–1.30–2.40)
|
0.47 (0.81)
|
0.003*
|
|
Stroop test Victoria – part 3
|
−0.50 (–2.20–1.50)
|
−0.46 (1.07)
|
0.55 (–2.10–2.50)
|
0.36 (0.89)
|
0.007*
|
|
Trail making test A
|
−0.10 (–2.20–0.70)
|
−0.33 (0.77)
|
0.05 (–2.20–1.60)
|
−0.05 (0.95)
|
0.227
|
|
Trail making test B
|
−0.10 (–2.20–0.90)
|
−0.44 (0.93)
|
0.20 (–3.00–2.00)
|
0.12 (1.17)
|
0.023*
|
|
FAS form of the COWA test
|
−0.90 (–2.20–1.10)
|
−0.80 (0.78)
|
−0.45 (–1.50–1.30)
|
−0.40 (0.75)
|
0.050
|
|
Animals form of the COWA test
|
−0.60 (–1.70–1.10)
|
−0.56 (0.71)
|
0.05 (–1.70–2.30)
|
0.08 (0.98)
|
0.009*
|
|
Symbol digit modalities test
|
−0.80 (–2.40–0.60)
|
−0.79 (0.88)
|
−0.40 (–1.50–1.60)
|
−0.14 (0.90)
|
0.017*
|
|
Modified Wisconsin card sorting test
|
0.70 (–2.20–0.70)
|
0.17 (0.89)
|
0.70 (–1.60–0.70)
|
0.30 (0.70)
|
0.731
|
|
Boston naming test
|
−0.60 (–2.20–0.10)
|
−0.90 (0.76)
|
−0.30 (–2.20–1.30)
|
−0.37 (0.88)
|
0.007*
|
1comparison between patient and control groups at baseline using the Mann Whitney
test.
*p < 0.05;
HVLT: Hopkins verbal learning test; BVMT: brief visuospatial memory test; WAIS: Wechsler
adult intelligence scale; WMS: Wechsler memory scale; COWA: Controlled Oral Word Association.
Also, regarding the VEM, no statistically significant difference in the recognition
phase of the Hopkins Verbal Learning Test was evident on comparison of the patient
and control groups, or comparison of the longitudinal performance of patients.
Spearman's analysis revealed a strong positive correlation between attention and executive
tasks with VEM tasks, suggesting that mnemonic impairments were accompanied by attentional
and executive deficits ([Table 6]). The executive function tests exhibiting this correlation were the Modified Wisconsin
Card Sorting Test (assessing strategy and mental flexibility) and the Letter-Number
Sequencing and Digit Span subtests of the WAIS-III (both assessing verbal working
memory). One attention test (Symbol Digit Modalities Test) correlated with the VEM
tests. The Symbol Digit Modalities Test provides a more accurate assessment of information
processing speed.
Table 6
Result of analysis of covariance between patient groups baseline vc controls corrected
by neuropsychological tests Digits, SNL, SDMT and MWCST.
|
Variable
|
Working memory
|
Information processing speed
|
Executive function
|
p group
|
|
p Dígitos
|
p SNL
|
p SDMT
|
p MWCST
|
|
HVLT - Immediate recall
|
0.112
|
0.016*
|
0.948
|
0.310
|
0.001*
|
|
HVLT - Delayed recall
|
0.911
|
0.060
|
0.596
|
0.028*
|
0.028*
|
|
Logic Memory - Immediate recall
|
0.084
|
0.094
|
0.568
|
0.068
|
0.068
|
|
Logic Memory - Delayed recall
|
0.715
|
0.172
|
0.698
|
0.017*
|
0.017*
|
SNL: Sequence of numbers and letters; SDMT: Symbol Digit Modalities Test; MWCST: Modified
Wisconsin Card Sorting Test.
*p > 0.05.
On the analysis of covariance using the attention and executive function tests cited
above (Modified Wisconsin Card Sorting Test, Letter-Number Sequencing, Digit Span,
and Symbol Digit Modalities Test), the patient group at baseline differed from the
control group on the VEM tests even when including the attention and executive functioning
measures ([Table 7]).
Table 7
Impact of the functioning of the other cognitive areas on the verbal episodic memory
of the patients in the baseline
|
Cognitive domain
|
Cognitive ability
|
Neuropsychological test
|
p/r
|
Measures of episodic verbal memory
|
|
HVLT - Immediate recall
|
HVLT - Delayed recall
|
Logic memory - Immediate recall
|
Logic memory - Delayed recall
|
|
Attention
|
Selective
|
Stroop Test Victoria
|
r
|
0.027
|
0.062
|
−0.119
|
−0.074
|
|
p
|
0.888
|
0.749
|
0.538
|
0.702
|
|
Sustained
|
TMT A
|
r
|
0.271
|
−0.024
|
0.130
|
0.094
|
|
p
|
0.155
|
0.900
|
0.501
|
0.627
|
|
Divided
|
TMT B
|
r
|
0.303
|
0.173
|
0.311
|
0.344
|
|
p
|
0.110
|
0.370
|
0.100
|
0.067
|
|
Processing speed
|
SDMT
|
r
|
0.285
|
0.350
|
0.464*
|
0.415*
|
|
p
|
0.134
|
0.063
|
0.011
|
0.025
|
|
Executive function
|
Verbal fluency to letters
|
COWAT - F.A.S
|
r
|
0.088
|
0.072
|
0.174
|
0.298
|
|
p
|
0.651
|
0.712
|
0.366
|
0.117
|
|
Verbal fluency semantic
|
COWAT - animals
|
r
|
0.165
|
0.278
|
0.115
|
0.080
|
|
p
|
0.393
|
0.144
|
0.551
|
0.680
|
|
Strategy training and mental flexibility
|
MWCST
|
r
|
0.560*
|
0.229
|
0.391
|
0.423
|
|
p
|
0.005
|
0.232
|
0.036
|
0.022
|
|
Verbal working memory
|
SNL-WAIS
|
r
|
0.560*
|
0.183
|
0.347
|
0.218
|
|
p
|
0.002
|
0.341
|
0.066
|
0.255
|
|
Dígits-WAIS
|
r
|
0.401*
|
0.260
|
0.063
|
−0.067
|
|
p
|
0.031
|
0.174
|
0.747
|
0.730
|
SNL: Sequence of numbers and letters; TMT: Trail Making Test; SDMT: Symbol Digit Modalities
Test; COWAT: Controlled Oral Word Association Test; MWCST: Modified Wisconsin Card
Sorting Test; BNT: Boston Naming Test.
*p < 0.05.
No correlation was found between VEM and sociodemographic status or clinical and physical
disability data for patients at baseline or follow-up.
With regard to mood, patients in the sample had mean scores below the cut-off point
on the scales assessing this parameter at both baseline and follow-up.
At the baseline, only three patients (3%) had mild depression while the remainder
were classified as having minimal or nonsignificant depression with a mean and standard
deviation of 6.68 (5.22), where a score of up to 10 points defines minimal depression/nonsignificant.
At the follow-up, the mean score for the sample was below the cut-off point for mood,
i.e. no significant symptoms of anxiety (mean = 7.14, SD = 3.20) or depression (mean
= 5.15, SD = 3.04).
DISCUSSION
In the present study, the group of RRMS patients showed VEM deficits at the baseline
assessment compared to the group of healthy controls. These changes were characterized
by poor patient performance on encoding (immediate recall) and retrieval (delayed
recall) of information on VEM tasks. The groups did not differ statistically on the
recognition stage assessing storage. According to a systematic review on the subject[1], this result can be expected for the neuropsychological profile of MS, but the nature
of decline in episodic memory, however, is controversial.
Chiaravalloti e DeLuca[1] discussed whether the nature of VEM impairment is characterized by ineffective performance
at the stages of information encoding, retrieval or both these stages[5]. There is evidence in the literature showing that impairments in working memory[15], processing speed[1], strategies[16] and resistance to distractibility[5] can negatively impact episodic memory functioning. Other studies have shown deficits
in delayed recall, even in patients receiving sufficient help to assimilate the information
at the encoding stage, suggesting accelerated forgetting in MS[5]. Based on the current findings of deficits at both the encoding and delayed recall
stages, the nature of the episodic memory impairment might be explained in both phases
by the brain areas affected[5].
In the present study, the results on tests assessing processing speed, strategy building
and working memory correlated with those of VEM tests at the baseline assessment,
thereby corroborating the findings in the literature outlined in the previous paragraph.
However, the covariance analysis, even when including the effects of the executive
function and attention tests on the VEM tests, revealed that the patient and control
groups differed at baseline. This finding may be explained by other attentional and
executive processes that impact episodic memory but have yet to be correlated. Another
hypothesis is that mnemonic impairments occur independently of attentional and executive
processes.
The scores obtained by patients on VEM tasks showed no correlation with sociodemographic
status or with clinical and physical disability data of patients at baseline or follow-up.
These variables have been the focus of studies to ascertain whether they impact cognitive
functioning or otherwise, although a review has shown conflicting results in the literature[2].
In the longitudinal analysis of the present study, the patients showed stabilization
or improvement in VEM performance, corroborating the findings of some longitudinal
studies[17],[18],[19],[20],[21],[22],[23],[24], yet contrasting with others showing decline[4],[6],[25],[26] in this domain. These incongruent findings have been reported in recently-published
systematic reviews on the subject[1],[2],[3].
In the longitudinal studies cited in the preceding paragraph, part of the sample that
showed a worsening of VEM over time comprised participants who evolved or were diagnosed
with more progressive clinical forms of MS. The present sample was homogenous for
the clinical form of the disease. This might explain the cognitive stability of the
patients studied, given that cognitive impairment tends to be milder in the relapsing-remitting
form of MS.
Another aspect that supports the stability and cognitive improvement of the present
sample over time is the mechanism of brain neuroplasticity. A recent systematic review
on functional magnetic resonance imaging related to the execution of neuropsychological
tasks[27] has shown that MS patients without cognitive dysfunction had different brain dynamics
from control participants. The patients had greater brain activation, widely-distributed
cortical recruitment and changes in functional connectivity in cognition-related regions.
These findings suggest that increased recruitment of important cortical networks can
attenuate the negative effect of MS on cognitive function.
On the other hand, episodic memory deficits, and likewise for other cognitive dysfunctions,
are heterogeneous in MS where their degree of severity varies significantly between
patients[5]. Based on this variability, in the present sample specifically, the patients did
not show a relevant decline in VEM.
One point to consider that may influence the detection of cognitive impairments is
the time interval between neuropsychological assessments. The short follow-up of the
present study, coupled with the low rate of VEM impairment in the patients, may explain
the longitudinal stability observed.
However, studies in the literature have shown that variation in follow-up time is
an incongruent factor in terms of the impact of evolution of cognitive impairment.
Some studies have detected cognitive impairments within follow-up periods of two years[16],[24],[26],[28],[29], reporting impairments in VEM and, particularly, attentional processes. Conversely,
a systematic review[3] found that studies with a follow-up of three to five years showed inconsistent and
slow cognitive changes, whereas a longer follow-up period (10-18 years) was needed
to detect deficits.
In summary, the incongruence of the cognitive findings in patients with MS is due
to the many different limitations inherent in longitudinal studies. These limitations
include different criteria for determining cognitive impairment parameters, possible
practice effects on the neuropsychological tests given the number of assessments administered
per time interval, the choice of tests involving different levels of difficulty, and
heterogeneous samples in terms of the clinical forms of the disease.
As outlined above, the healthy controls were not reassessed to better define the parameters
of VEM impairments in the patients over time. In addition, the high cognitive variability
among individuals with MS requires a larger sample size for greater representativeness
of the data.
In conclusion, the results of this study revealed that the patients showed ineffective
VEM relative to controls at the baseline assessment and attained improvement and stability
in this cognitive domain over time. The clinical, sociodemographic and physical disability
variables showed no correlation with patient performance on the VEM tests. An impact
of the attention and executive functioning tests on VEM in the information encoding
and retrieval stages was evident. The present sample was homogenous for the clinical
form of the disease, a factor that may have enhanced the reliability of the results.
