Key words cerebrovascular disease - insulin-like growth factor I - ischemic stroke - outcome
- modified Rankin scale - NIHSS
Introduction
Insulin-like growth factor I (IGF-I) affects neuronal plasticity after brain injury
(for a review, see [1 ]). Circulating
serum IGF-I (s-IGF-I) is regulated by growth hormone (GH) from the pituitary, as
well as by other factors, such as age, metabolic state, and physical activity [2 ]
[3 ]. Specifically, s-IGF-I is lower in
elderly subjects, in those with metabolic syndrome or malnutrition, whereas a high
level of physical activity is associated with a higher level of s-IGF-I. With regard
to clinical outcomes after ischemic stroke (IS), higher levels of circulating
s-IGF-I have been variously associated with better outcomes 2–6 months after
IS [4 ]
[5 ], with worse 3-month outcomes [6 ], and with neutral outcomes after 1 year
[7 ]. Furthermore, the 3-month s-IGFI
levels have been reported as being independently associated with individual
improvements (i. e., changes in modified Rankin scale scores; ΔmRS)
in outcome [8 ] after IS. Furthermore,
lower levels of s-IGF-I represent a risk factor for the incidence of IS, mainly
first-ever IS [9 ], whereas an association
with the incidence of recurrent IS has not been reported to our knowledge. However,
post-stroke mortality has been reported to be increased in elderly patients with low
levels of s-IGF-I [5 ]. A drawback linked
to the latter 2 studies is that no adjustments were made for the effect of age on
s-IGF-I level, which means that the associations are uncertain. Thus, the situation
with regard to s-IGF-I and recurrent stroke and post-stroke mortality has not been
thoroughly investigated, and it is important to elucidate the effects of these
factors on recovery per se. Specifically, in our previous study, we showed an
independent association between high 3-month levels of s-IGF-I and long-term
improvement in functional outcome, as assessed by crude changes in the scores on the
modified Rankin scale (mRS) from 3 months to 2 years after IS [8 ]. Here, we present data regarding the
role of the 3-month s-IGF-I level in long-term functional outcomes and recovery over
an extended period of 2–7 years post-stroke, taking into account the
possible effects of recurrent stroke and mortality. Thus, we investigate the
associations between functional outcome and s-IGF-I with 2 different outcome
definitions: 1) functional independence (defined as mRS score of 0–2); and
2) recovery, which is defined as the direction of shifts in the mRS scores over time
(mRS shift category), categorized into deterioration, no change or improvement. As
we did not previously include an analysis of recurrent strokes, deaths, and mRS
shift categories, the present investigation can be regarded as more comprehensive
with respect to factors that are important for long-term recovery and prognosis.
Thus, we also perform a re-analysis of the previous data to include these factors
for the time period of 3 months to 2 years post-stroke.
We hypothesized that the s-IGF-I levels at 3 months post-stroke would be associated
with a beneficial change in functional outcome (mRS shift), with or without the
inclusion of recurrent stroke incidence and mortality over the 7-year follow-up.
Materials and Methods
Subjects and methods
The design of SAHLSIS has been reported elsewhere [8 ]
[10 ]. Briefly, patients (<70
years of age) with first-ever or recurrent acute IS were recruited consecutively
at 4 Stroke Units in western Sweden between 1998 and 2003 (N=600), and
investigated for functional outcome according to the modified Rankin Scale (mRS)
at 3 months, 2 and 7 years post-stroke [11 ]
[12 ]. In 407 of these subjects, the
levels of s-IGF-I were measured acutely or 3 months after the index stroke and
investigated in relation to the mRS scores at 3 months and 2 years post-stroke
[8 ]. Thus, in the group of 407
patients, there were 373 patients with complete data for the 3-month s-IGF-I
(91.6%) (Supplemental Fig. 1S ), in accordance with Strengthening
the Reporting of Observational Studies in Epidemiology (STROBE) [13 ]. As the purpose of the present
study was to study the outcomes for the patients after 7 years, we included only
those patients who had completed the follow-up for 7 years and for whom the
3-month s-IGF-I levels were available. Therefore, of the original patients with
3-month s-IGF-I levels available, 324 could be followed for 7 years, thereby
generating the study population in this report ([Table 1 ]). Initial stroke severity
was assessed based on scores in the Scandinavian Stroke Scale (SSS), which were
recalculated into the now more commonly used National Institutes of Health
Stroke Scale (NIHSS). Owing to skewness, the NIHSS scores were further
transformed into quintiles of stroke severity, defined as follows: quintile
(q)1, 0–0.74 (mild); q2, 0.74–2.03 (minor); q3,
2.03–3.75 (moderate); q4, 3.75–10.2 (major); and q5,
10.2–42 (severe). The algorithm used was:
NIHSS=25.68–0.43 × SSS [14 ]. Crude mRS data were used, as well
as the mRS shifts for the time periods of 3 months–7 years and
2–7 years (and for comparison, 3 months–2 years), as modified
from the system of Lai and coworkers [15 ]. For each time period, the mRS shifts were categorized as
deteriorated, unchanged or improved. The s-IGF-I levels of the study
participants were analyzed in 2008 in one series of experiments. For the purpose
of deriving the mRS score distributions, s-IGF-I was dichotomized as being above
or below the median level of s-IGF-I (146.7 ng/ml; [8 ]). This cut-off median was based on
the 3-month s-IGF-I in the study population of the previous study [8 ], but was identical to the present
3-month selection of patients with 7 years of follow-up. The 3-month s-IGF-I
mean values (152 ng/ml) were lower than the acute s-IGF-I
(171 ng/ml, p<0.01). However, the 3-month s-IGF-I was
very close to a smaller group of healthy sex-and age matched controls
(145 mg/ml, p=0.44). Hypertension, diabetes mellitus,
and smoking were defined as described previously [8 ]
[10 ]
[16 ], and measurements of serum
low-density lipoprotein (LDL) were performed at baseline. Recurrent strokes and
deaths were recorded throughout the period, as described elsewhere [12 ]. The data and characteristics of
this subsample resemble the characteristics described in previous reports based
on the SAHLSIS cohort [8 ]
[10 ]
[16 ], which together with details of
the study design and clinical examination can be found in the Supplementary
Information . This study was conducted in accordance with the 1964
Helsinki Declaration and subsequent amendments or comparable ethical standards.
Participants or next-of-kin provided written informed consent. This study was
approved by the Ethics Committee of the University of Gothenburg.
Table 1 Baseline data for the included patients with s-IGF-I
levels available at 3 months and those who were followed for 7
years.
3 months - 7 years
All including dead and recurr. stroke
Excluding dead and recurr. stroke
n
324
245
Sex
Male / female (N)
211 / 113
157 / 88
Male / female (fraction)
0.65
0.64
Age (index)
Years (SD)
55.3 (11)
54.5 (11)
Body Mass Index (BMI)
Mean (SD)
26.3 (4.3)
26.3 (4.2)
Missing (N)
2
2
Diabetes
Yes (N / fraction)
61 (0.19)
40 (0.16)
Missing (N)
0
0
Hypertension
Yes (N / fraction)
179 (0.55)
130 (0.53)
Missing (N)
0
0
Current smoking
Yes (N / fraction)
117 (0.36)
83 (0.34)
Missing (N)
0
0
LDL level (mmol/L)
Mean (SD)
3.3 (1.0)
3.4 (1.0)
Missing (N)
27
22
Stroke severity (NIHSS)
Mean (20%, 80%)
5.1 (0.74, 8.5)
4.85 (0.74, 7.6)
Missing (N)
0
0
Stroke outcome (mRS) 3 m
Mean (SD)
1.83 (1.03)
1.76 (1.01)
Missing (N)
6
3
Stroke outcome (mRS) 2 yr
mRS (SD)
1.81 (1.33)
1.60 (1.09)
Missing (N)
1
0
Stroke outcome (mRS) 7 yr
mRS (SD)
2.38 (1.84)
1.69 (1.18)
Missing (N)
0
0
Recurrent stroke (0–3 m)
Yes (N / fraction)
12 (0.038)
0 (0)
Missing (N)
0
0
Recurrent stroke (3m–7yr)
Yes (N / fraction)
19 (0.059)
0 (0)
Missing (N)
0
0
Recurrent stroke (2–7 yr)
Yes (N / fraction)
48 (0.15)
0 (0)
Missing (N)
0
0
Dead (3m–2yr)
Yes (N / fraction)
9 (0.028)
0 (0)
Missing (N)
0
0
Dead (2–7 yr)
Yes (N / fraction)
35 (0.11)
0 (0)
Missing (N)
0
0
s-IGF-I (3 m, ng/mL)
Mean (SD)
150.7 (53)
151.0 (52.2)
Missing (N)
0
0
SD, Standard deviation; LDL, low-density lipoprotein; IS, ischemic
stroke; m, months; NIHSS, National Institutes of Health Stroke Scale;
mRS, modified Rankin Scale; yr, years.
Statistical analysis
Statistical evaluations of the data were performed using the SPSS ver. 21.0
software (SPSS Inc., Chicago, IL). Crude correlations were analyzed by the
method of Pearson. Furthermore, the mean s-IGF-I values are presented with
respect to the mRS shift categories, crudely evaluated using t -tests with
respect to improvement vs. deterioration. In the cases with statistically
significant differences, further evaluation was made using a stepwise multiple
regression with respect to the mRS shift categories (deterioration, no change or
improvement). As in our previous publication [8 ], concentrations of s-IGF-I below
and above the median level of s-IGF-I were used to compare the distributions of
the mRS scores across time. For this purpose, the non-parametric Friedman rank
test for repeated related (paired) data was used, together with a post-hoc
pairwise comparison. The cardiovascular risk factors of smoking, hypertension,
diabetes, and LDL levels, in addition to initial stroke severity were considered
to be potential confounding factors and were entered into the multivariate
analyses. Cox proportional hazards regression models were used to assess the
associations between levels above and below the median s-IGF-I and: 1) recurrent
stroke; and 2) death [presented as hazard ratios (HR), 95% confidence
intervals (CI), and P-values]. A 2-tailed P-value<0.05 was considered
statistically significant. For further details of the study design, patient
examinations, protein measurements, and statistical analyses, see the
Supplementary Information .
Results
Baseline data
The baseline characteristics of the study cohort with 7 years of follow-up are
summarized in [Table 1 ]. 44 patients
died (14%) and 79 suffered a recurrent stroke (24%) during the
7-year follow-up. The present baseline data can be compared to the selection
with 2 years of follow-up [8 ] in
(Supplementary Table 1S ).
Relationships between the levels of serum IGF-I at 3 months post-stroke and
the outcomes at the 7-year follow-up
The distribution of the mRS scores at the 7-year follow-up for patients who had
s-IGF-I concentrations above or below the median level at 3 months post-stroke
is shown in [Fig. 1 ]. In the
above-median s-IGF-I group, there was a net improvement in the mRS score
distribution between 3 months and 7 years, and this was not present in the
below-median s-IGF-I group ([Fig. 1, a and
b ]). There were also distinct differences in the mRS score
distribution between the above-median and below-median s-IGF-I levels in the
group that included all the patients, as well as in the group without recurrent
stroke or death ([Fig. 1, a,b vs.
c,d ]).
Fig. 1 Values below or above the median serum-IGF-I concentration
at 3 months post-stroke are related to changes in mRS score
distributions for up to 7 years of follow-up. a -b .
Distributions of mRS scores 0–5 (at 3 months, 2 and 7 years
post-stroke), excluding patients with recurrent strokes and deaths, for
patients below a and above b the median 3-month s-IGF-I
level. c -d . Distributions of mRS scores 0–6 (at 3
months, 2 and 7 years post-stroke), including patients with recurrent
stroke, for patients below the median s-IGF-I level c and above
the median s-IGF-I level d . The non-parametric Friedman test for
repeated observations was used to analyze the mRS score distributions
and the post-hoc pairwise comparisons with their respective P-values are
shown (see Methods section).
There were no significant differences in s-IGF-I levels between the patients who
subsequently died or were afflicted with a recurrent stroke between 3 months and
2 years or between 2 and 7 years ([Table
2 ]). Although the levels of s-IGF-I were slightly higher in the
subjects with mRS 0–2 than in those with mRS 3–5 or mRS
3–6 (both time-points), the difference was not statistically
significant. Furthermore, neither in the unadjusted or in the age- and
sex-adjusted Cox proportional hazards regression models were there any
significant associations between the above-median s-IGF-I and recurrent stroke
(unadjusted HR=1.11, 95% CI 0.69–1.19, P=0.67;
sex- and age-adjusted HR=1.23, 95% CI 0.76–2.0,
P=0.4) or between the above-median s-IGF-I and death (unadjusted
HR=0.93, 95% CI 0.51–1.68, P=0.8; sex- and
age-adjusted HR=1.01, 95% CI 0.55–1.84, P=0.97).
Further adjustments of the cardiovascular covariates and initial stroke severity
did not change the significance levels (P>0.3 for all models, data not
shown).
Table 2 Data for 3-month s-IGF-I with regard to overall
favorable mRS (0–2) and unfavorable mRS (3–6),
deaths, and recurrent stroke at 2 and 7 years after the index
ischemic stroke.
2 years
7 years
s-IGF-I (±CI4 )
N
P3
s-IGF-I (±CI4 )
N
P3
All patients1
mRS 0–2
151.5 (6.6)
256
>0.3
153.0 (16.6)
212
>0.3
mRS 3–6
148.3 (12.3)
67
145.6 (7.0)
111
Missing mRS
1
0
Death (3–24 months)
See next column
165.4 (34.7)
9
0.275
Death (24–84 months)
See next column
142.5 (18.5)
35
Recurrent stroke (3–24 months)
See next column
162.3 (26.3)
19
0.135
Recurrent stroke (24–84 months)
See next column
139.3 (15.6)
48
Selected
mRS 0–2
152.9 (7.2)
206
>0.3
152.8 (7.2)
195
>0.3
patients2
mRS 3–5
140.9 (15.1)
39
143.9 (15.6)
50
1 The s-IGF-I values are shown with no exclusions, for all
patients; 2 The s-IGF-I values are shown with exclusion of
deaths and recurrent strokes during the time period;
3 P-values obtained using the Student’s t-test;
4 CI, 95% confidence interval.
Next, we analyzed the s-IGF-I levels in relation to intra-individual shifts in
the mRS scores of the patient group without recurrent stroke or deaths. In [Table 3 ], crude correlations between
the s-IGF-I levels and mRS shift category (top), as well as the mean s-IGF-I
level for each of the subsequent mRS shift categories are presented (bottom).
Indeed, the s-IGF-I levels correlated with the mRS shift categories from 3
months to 7 years, although the correlation was relatively modest
(r=0.12). While the correlation coefficient was retained
(r=0.121), the significance level was reduced to a tendency when deaths
and recurrent stroke were excluded. It is noteworthy that the correlation
persisted from 3 months to 7 years (left column, [Table 3 ]), whereas all of the
positive correlation was derived from the period of 3 months to 2 years (right
column). In terms of s-IGF-I levels, the data show a tendency (P=0.057)
towards significantly lower s-IGF-I levels in the group of patients who
experienced deterioration until 7 years, although there is no significant
difference in s-IGF-I levels between the different mRS shift categories of the
subjects between 2 and 7 years post-stroke. As for the crude correlations, the
s-IGF-I levels for different mRS shift categories taking place between 3 months
and 2 years post-stroke revealed a more marked difference between deterioration
and improvement.
Table 3 Data for the 3-month s-IGF-I levels and shifts in mRS
scores for patients who were followed for 7 years (cases of
recurrent strokes and death are excluded).
mRS shifts over6
Selection1
Analysis
3 months - 7 years
2–7 years
3 months - 2 years
r
N
P4
r
N
P4
r
N
P4
All data
correlation
0.120
318
0.035
−0.01
323
>0.3
0.183
317
0.001
missing
6
1
7
Alive, no recurrent stroke
correlation
0.121
242
0.061
−0.052
245
>0.3
0.19
242
0.003
missing
3
0
3
mRS shifts over
6
3 months - 7 years
2–7 years
3 months - 2 years
s-IGF-I (±CI7 )
s-IGF-I (±CI7 )
s-IGF-I (±CI7 )
Selection2
Category
by mRS 3 months
N
P5
by mRS 2 years
N
P5
by mRS 3 months
N
P5
Pooled mRS 0–5 (no recurrent stroke)
242
245
242
deterioration
136.4 (12.3)
44
0.057
154.6 (14.7)
53
>0.3
126.8 (14.4)
30
0.005
no shift
152.8 (8.7)
123
151.3 (8.1)
148
150.6 (8.0)
142
improvement
156.5 (13.9)
75
145.8 (16.9)
44
162.0 (14.4)
73
Missing regarding mRS change
3
0
3
By each initial mRS
mRS 0
deterioration
130.9 (23.0)
4
>0.3
146.0 (19.8)
13
>0.3
148.5 (37.4)
8
>0.3
no shift
151.8 (19.9)
23
145.2 (17.3)
29
148.8 (19.8)
19
mRS 1
deterioration
140.2 (16.6)
25
>0.3
155.6(20.2)
24
>0.3
125.9 (19.8)
13
0.28
no shift
147.3 (19.2)
20
158.4 (21.3)
31
149.3 (16.9)
33
improvement
138.9 (22.6)
18
151.2 (29.2)
15
140.5 (17.5)
17
mRS 2
deterioration
126.5 (26.6)
12
0.138
174.3 (46.7)
11
0.207
105.6 (17.2)
7
0.025
no shift
152.7 (11.6)
61
154.1 (11.7)
65
150.6 (11.6)
67
improvement
157.3 (21–0)
37
141.6 (26.5)
18
161.9 (20.5)
36
mRS 3
deterioration
151.7 (47.7)
3
>0.3
128.6 (40.2)
5
0.296
103.8
1
>0.3
no shift
136.8 (29.0)
9
132.7 (27.0
11
161.0 (31.7)
12
improvement
183.3 (29.9)
14
163.3 (43.3)
7
170.6 (29.4)
13
mRS 4
deterioration
N/A3
0
N/A3
N/A
0
N/A3
137.1
1
N/A3
no shift
180.8 (47.9)
10
149.5 (22.7)
12
146.7 (31.9)
11
improvement
141.5 (57.2)
6
105.6 (80.9)
3
226.4 (108.0)
4
mRS 5
improvement
N/A3
0
N/A3
137.1
1
N/A3
N/A3
0
N/A3
1 Category of shifts in mRS scores, as analyzed by crude
correlations (above); 2 Category of shifts in mRS scores, as
analyzed by differences in the absolute s-IGF-I levels (below);
3 N/A, not applicable; 4 P-values
obtained using Pearson correlation for mRS shift categories of
deterioration vs. improvement or for initial mRS=0,
deterioration vs. no shift, with rho values (r) given;
5 P-values obtained using the Student’s t-test (for
mRS shift categories of deterioration vs. improvement or for initial
mRS=0, deterioration vs. no shift); 6 Data for the mRS
score shift categories between 3 months and 7 years and between 2 and 7
years are shown. For comparison, the shifts in mRS scores for the period
3 months and 2 years period from 3 months to 2 years are shown with the
same selection of patients; 7 CI, 95% confidence
interval.
The relationship between the s-IGF-I levels at 3 months post-stroke and the
timing of recovery
To assess the potential associations, we used multiple stepwise regression
models. We expected to discover associations in line with the previously
reported independent association between the crude mRS improvements until 2
years post-stroke and measured levels of s-IGF-I [8 ]. Thus, after exclusion of cases of
death and recurrent strokes, the association between the 3-month s-IGF-I levels
and mRS shift categories between 3 months and 2 years withstood adjustments for
sex, age, and cardiovascular confounders (partial r=0.146,
P=0.01), and additionally for initial stroke severity (partial
r=0.142, P=0.036). With regard to the associations between the
3-month s-IGF-I levels and the mRS shifts from 3 months until 7 years, age
turned out to be a more important factor (partial r=−0.223,
P<0.001), reducing the partial correlation of 3-month s-IGF-I levels
with mRS shift categories from 3 months until 7 years post-stroke to
non-significant levels (partial r=0.064, P=0.33). No further
adjustments were made with regard to the mRS shift in the 7-year follow-up.
Taken together, this indicates that the 3-month s-IGF-I level is associated with
recovery (mRS shift categories) between 3 months and 2 years post-stroke, and
that no further significant association with mRS shifts are found between 2
years and 7 years post-stroke.
Discussion and Conclusions
Discussion and Conclusions
Post-stroke 3-month serum-IGF-I levels are associated with the 7-year mRS
shifts, although most of these shifts take place prior to 2 years
post-stroke
This is a 7-year follow-up of a previous study [8 ] that investigated the long-term
effects of the levels of s-IGF-I 3 months post-stroke on the actual mRS scores
and mRS shifts recorded 3 months and 2 years post-stroke. For 79.6% of
those patients, we were able to examine the functional status at 7 years
post-stroke. To the best of our knowledge, this is the first report showing data
with such a long follow-up with regard to s-IGF-I after IS. The 3-month s-IGF-I
level was neutral with respect to the 7-year mRS score, in agreement with the
neutral relationship noted between the 3-month s-IGF-I level and 2-year mRS
score (both crude correlations and mRS 0–2 vs. mRS 3–5). With
respect to the mRS score distributions, there were differences in the
time-dependent development of mRS score distributions in the above-median and
below-median s-IGF-I groups, with a more favorable projection of mRS score
distribution in the groups without deaths and recurrent stroke ([Fig. 1a ] and [b ]) and in the entire cohort ([Fig. 1c and d ]). The beneficial
association between s-IGF-I and individual mRS shift category was mostly
confined to 2 years post-stroke, although the relationship was preserved at 7
years post-stroke. The association of 3-month s-IGF-I levels with changes in mRS
scores until 2 years post-stroke is independent of age, whereas the association
between the 3-month s-IGF-I and mRS shifts from 3 months until 7 years is
primarily mediated by age (i. e., increasing age is more important than
s-IGF-I level). Although some effect of s-IGF-I is preserved at 7 years
post-stroke, the effect size is limited, with correlation coefficients for
s-IGF-I and recovery ranging from 0.12 to 0.18–0.19. Finally, there were
no significant associations between the 3-month s-IGF-I level and recurrent
strokes or deaths during the 7-year follow-up. Although direct comparisons
cannot be made due to the different study conditions, this result is discrepant
with previous reports showing a U-shaped relationship for s-IGF-I with regard to
primary all-cause mortality [meta-analysis in [17 ]. It also contrasts with a previous
report on a linkage between low s-IGF-I levels and a clearly higher incidence of
IS, presumably mainly first-ever IS [9 ]. However, we are not aware of any previous report showing
specifically the relationship between the incidence of recurrent IS and s-IGF-I.
Moreover, post-stroke mortality has been reported to be increased in patients
with low levels of s-IGF-I [5 ]. Since
in the last 2 studies no adjustments were made for the effect of age on s-IGF-I
[5 ]
[9 ], the reported associations may be
more uncertain than our data obtained from the Cox proportional hazards
regression models with adjustments for sex and age. This is supported by the
difference in HRs noted between the unadjusted models and sex- and age-adjusted
models, which suggests that adjustment for age is very important when assessing
the effects of s-IGF-I and when carrying out comparisons with previous
studies.
Methodological aspects
The reliability of the results of the present study is strengthened by the
consecutive recruitment of well-characterized and relatively young IS patients
and the high hospitalization rate (84%–95%) for stroke
patients (especially those aged<70 years) in Sweden [18 ]. As compared to our study of 2011,
there are some differences of inclusion [8 ]. The reasons for not including the acute levels of s-IGF-I in the
present study are that there was no significant association with the crude mRS
score (at either 3 months or 2 years) and that the association for acute s-IGF-I
with mRS score changes (ΔmRS) was substantially weaker than that for the
3-month s-IGF-I and ΔmRS [8 ].
Furthermore, as the initial change in s-IGF-I level was associated primarily
with the 3-month mRS score and less so with the long-term 2-year mRS score [19 ], we did not analyze this parameter
in this long-term follow-up. Although some patients were lost to follow-up
between the 2 years and 7 years, we consider the selection bias to be minimal
for the parameters included in the study ([Table 1 ], and for comparison, see Supplementary Table 1S ).
There may, however, be a bias associated with the somewhat higher retrieval of
patients who died (generating mRS score of 6), as such data can be retrieved
from cause of death registers rather than through informed-consent active
follow-up with clinical examination or interview. The longitudinal design with 3
time-points for the assessment of mRS scores allowed us to sort the patients
into 3 categories of mRS shifts (deterioration, no change and improvement), for
the respective time periods, in a modification to the previous regression
analysis of shifts in crude ΔmRS scores [15 ]. Although the frequencies of
deaths and recurrent stroke were low up to 2 years post-stroke, the overall
consideration of these events over the entire study 7-year follow-up makes the
present report more scientifically robust. Therefore, it can be stated that the
3-month s-IGF-I levels have no major associations with recurrent stroke or
mortality, although there is an association with recovery evaluated using the
mRS shifts, independent of recurrent stroke and mortality. The weaknesses of the
present study are the relatively small sample size and the lack of replication
in a different geographic area. Although the relatively young age of the
patients (mean, 55 years) makes it possible to follow patients for long periods
(partly due to the low death rates), it also restricts the generalizability to
older stroke populations. The relatively young age of the subjects also
disfavors the recurrence of stroke and occurrence of mortality.
Possible significance of mRS shifts and serum IGF-I levels
In the literature, high levels of s-IGF-I are generally considered as beneficial
with respect to cognitive functions and neuroprotection after acute stroke (for
a review, see [1 ]). Although animal
experiments with IGF-I treatments have shown robust neuroprotective effects, it
is important to bear in mind that endogenous s-IGF-I may play a different role
in functional outcome after stroke. As local levels of IGF-I in the central
nervous system have been reported to increase after experimental IS [20 ], it will be important to confirm
this by determining the cerebrospinal fluid (CSF) concentrations of IGF-I. At 3
months post-stroke, however, the s-IGF-I levels in patients with IS are
decreased to close to the levels found in healthy controls [8 ]. Therefore, the present
investigation focused on this more stabilized level of s-IGF-I. It may be of
importance that s-IGF-I appears to be dynamically regulated in the post-stroke
period [19 ]
[21 ], and this may explain why there
are different associations with functional outcomes in different studies [4 ]
[5 ]
[6 ]
[7 ]
[8 ], depending on which post-stroke
time-point was used for s-IGF-I sampling. Nevertheless, a stabilized 3-month
level of s-IGF-I is independently associated with recovery (mRS shift
categories) between 3 months and 2 years post-stroke, while the effect is less
pronounced but still significant when one compares the results at 3 months and 7
years post-stroke. The changes are also reflected in different mRS score
distributions at 3 months, and at 2 years and 7 years ([Fig. 1 ]). Taken together, these
results point to a relatively modest effect of 3-month IGF-I level with respect
to long-term (7-year) stroke outcome. It is known that s-IGF-I levels decrease
with age, which is relatively predictable [8 ]
[22 ]. However, the level of s-IGF-I
is also decreased by malnutrition, and to some degrees by physical inactivity
[2 ]
[3 ] and infectious diseases [23 ]. Therefore, the independent
associations with recovery warrant further studies with additional time-points
for blood sampling, both in the early post-stroke period with consideration of
physical activity, infections, and nutritional status and in long-term follow-up
after 2, 5 and 7 years. Our results also suggest that a specific s-IGF-I level
is a better predictor of the mRS shifts within the ensuing 1–2 years,
than in more extended time periods.
Conclusions
In summary, our study indicates that the s-IGF-I level at 3 months post-stroke is
neutrally related to the mRS scores at 2 and 7 years. However, there is
significantly better individual recovery, as evidenced by the mRS shift categories,
between 3 months and 7 years post-stroke, although most of the clinical benefit
occurs within the 2 years after the initial stroke. No significant relationships
were found between the 3-month s-IGF-I levels and recurrent stroke or deaths, and
the effects on recovery were also independent of these parameters. These data
provide the foundation for further studies with more sampling points, both early
after stroke and also at extended follow-up time-points, and the possible inclusion
of measurements of IGF-I levels in the CSF.
