2. MORFOLOGÍA
2.4. SELECCIÓN DE LOS MARCOS DE REFERENCIA Y DETERMI-
3.3.4. JUNTAS DEL HOMBRO
The use o f bolus tracking perfusion data is now routine in many institutions, and studies
have shown that these perfusion measurements can add information o f use in the clinical
setting. However, few studies within the paediatric population have been reported. As
discussed in section 5.1, paediatric perfusion measurement using bolus tracking methods
can potentially be confounded by several factors in comparison to adult data:
• The small volumes o f contrast agent administered to young subjects, which make
the signal intensity time-course more difficult to characterise accurately;
• Increased partial volume effects due to the smaller size o f the cerebral structures;
• The effects o f age on perfusion measures.
The large paediatric population undergoing neurological investigation at Great Ormond
Street Hospital for Children enabled the identification o f a cohort o f 13 normal infants less
than 30 months old who have undergone a bolus tracking perfusion study. These data were
used to investigate the reliability o f perfusion measurements in very young children, and to
investigate whether there is significant age dependence in the measured MR perfusion
values.
The paediatric perfusion measurements were found to be dependent upon age, with
perfusion increasing with age over the age range studied. After correction for this age
dependence, the variability in the paediatric measurements was no different to that in the
adult group. This suggests that the factors that can potentially confound the analysis o f data
collected in young children are not significant effects, and do not prevent the resolution o f
the age dependence o f the perfusion measurements. Thus, it appears that regional bolus
tracking perfusion measurements can be made as robustly in infants as they are in adults. In
the following sections, the issues o f characterisation o f the bolus passage and partial
volume effects are briefly discussed, before the observed age dependence is discussed
CHAPTER 5 : BOLUS TRACKING PERFUSION MEASURMENT IN INFANTS 151
5.4.1 Characterisation of the bolus passage
The administration o f smaller contrast agent volumes to paediatric subjects when compared
to adults results in the passage o f a narrower bolus through the vascular system, and
therefore the collection o f fewer data points during its first pass (if the time resolution
remains constant). Although the use o f slower injection rates in children (necessary due to
the smaller cannulas used) does compensate this effect to some extent by widening the
bolus, the paediatric CAirit) and CRoi(t) curves were found to be much narrower than those measured in the adult cases in this study. This potentially leads to a less robust curve fitting
since fewer data points can be provided for the fit. However, all curve fitting in the present
study was performed interactively, so that the quality o f the fit could be visually assessed in
each case. The ability o f the gamma-variate model to accurately represent the input data
was not observed to be systematically poorer in the paediatric data on qualitative visual
assessment.
The fact remains, however, that less data points are available for the deconvolution in the
paediatric case; the effect o f this is difficult to predict, and requires further investigation.
One means by which the bolus can be widened is to increase the dose o f contrast agent.
However, there exist strict maximum dosage limitations. Alternatively, the time resolution
for paediatric data collection could be improved. This can be achieved either by reducing
the number o f slices acquired, which reduces brain coverage, or by using a gradient echo
EPI sequence to achieve a shorter TR. However, gradient echo sequences are more
sensitive to large vessels. Therefore none o f the approaches mentioned is satisfactory.
5.4.2 Partial volume effects
Care was taken to minimise partial volume effects in this study by careful ROI drawing,
and the selection o f homogeneous tissue regions within the paediatric data was not found to
be more difficult than the equivalent selections in the adult data. Some partial volume
averaging with other tissue types in both the adult and paediatric data is somewhat
inevitable due to the sizes o f the cerebral structures relative to the 2x2x5mm voxel size.
CHAPTER 5 : BOLUS TRACKING PERFUSION MEASURMENT IN INFANTS 152
partial volume contribution from vessels (W eisskoff et al., 1994, Boxerman et al., 1995,
Kennan et al., 1994).
Partial volume averaging o f the AIE leads to a global overestimation o f perfusion values.
Since this effect is expected to be larger in paediatric data, this is a potential source o f extra
variability in the paediatric perfusion measurements. However, our data suggest that this is
not the case. Furthermore, the age dependence observed cannot be a result o f increasing
AIF partial volume averaging in the youngest subjects since this would result in a decrease
in perfusion with age, rather than the increase observed.
5.4.3 Age dependence
The youngest subject in the study was considered to be an outlier and excluded from the
statistical analysis o f the data since the perfusion values measured in this subject were
approximately 3-4 times higher than children o f a similar age. The remaining paediatric
data showed a trend for increasing CBFapp with age, which was significant in 3 out o f the 4
tissue categories. However, the form o f the relationship between age and measured CBFapp
cannot be clearly determined due to the limited amount o f data available.
This increase in CBFapp with age is consistent with previous studies in normal children.
Chiron et al. (1992) used [^^^Xe]-SPECT to measure CBF values in 42 normal children
aged 2 days to 19 years (29 were <30 months old), and also obtained reference values in 32
adults. The mean CBF was found to rise from birth to a maximum that was maintained
between approximately 4 and 8 years o f age, before decreasing towards adult values. Over
the age range used in the present study, their data showed a significant increase (o f -30% )
in CBF values. This increase is smaller than that found in our study (50-80%). These
differences may arise because SPECT and bolus tracking techniques are based on different
principles, each having its own limitations, and these two techniques are therefore not
necessarily expected to produce the same results. The increase in perfusion values is further
supported by transcranial doppler measurements o f blood flow in the major arteries
CHAPTER 5 : BOLUS TRACKING PERFUSION MEASURMENT IN INFANTS 153
years, which is sustained until a decline from approximately 7 years towards adult values
(Newell and Aaslid, 1992).
The increase in perfusion values has been speculated to be related to an increase in cerebral
metabolic demand as the brain matures, as demonstrated using FDG PET (Chugani et al.,
1987). That study, involving 29 normal children, o f whom 11 were under 30 months old,
showed an increase in cerebral metabolic rates for glucose within grey matter from 5 days
old to a maximum at around 3 or 4 years. High rates were maintained until approximately 9
years, when they began to decline towards adult values. This time-course o f metabolic
changes matches that describing the process o f initial overproduction and subsequent
elimination o f excessive neurons and synapses known to occur in the developing brain
(Huttenlocher and Dabholkar, 1997).
The scarcity o f reported studies o f perfusion (and perfusion-related) changes with age in the
normal infant population is a reflection o f the ethical restrictions inherent in obtaining these
data. Like the children in the present study, the 42 children in Chiron et al.’s SPECT study
and the 29 children in Chugnai et al.’s FDG PET study were all originally scanned for
clinical reasons; all had suffered transient neurological events that were not found to
significantly affect normal neurodevelopment. It is therefore necessary to have access to a
particularly large cohort o f children within the age range o f interest, in order that a
sufficiently large number o f children who can be regarded as normal can be identified. This
severely restricts the number o f institutions at which such a study can be carried out, and
explains the limited number o f reported studies.
The referencing o f the measured perfusion values to cerebellar values was found to remove
the age dependency, and therefore the referencing o f values may be the most appropriate
CHAPTER 5 : BOLUS TRACKING PERFUSION MEASURMENT IN INFANTS 154
5.4.4 Further considerations
It is important to note that several other factors can affect MR bolus tracking perfusion
measurements, namely subject sedation, changes in brain density, and changes in
haematocrit levels. Each o f these is considered below.
There have been a number o f studies investigating the effects o f sedation on CBF (mostly
using animal models). There appears to be a consensus that the administration o f sedative
drugs generally leads to a reduction in CBF values, though the effects are dependent on the
specific drug used. Details regarding the effects on CBF o f the particular drugs used in this
study are not available. However, since all o f the paediatric subjects in the study received
the same drugs and the same dose per bodyweight o f those drugs, it is expected that any
effect on the CBF values would have influenced the measurements in all subjects in a
similar way.
It can be seen from Eq. [5.1] that bolus tracking perfusion measures are dependent upon
both brain density and haematocrit levels. Therefore, changes in both o f these parameters
with age will have a direct effect on the measured perfusion values. Haematocrit levels
have been reported to be fairly constant over the age range studied (Nelson 1996), and the
effects o f haematocrit levels are therefore assumed negligible. Understanding the effects o f
changes in brain density, however, is less straightforward. It is well known that the total
water content o f the brain decreases during brain maturation; Dobbing and Sands (1973)
showed that the percentage o f water in the whole brain falls from -90% at birth to -80% at
adulthood, with the majority o f this change occurring over the first year o f life. However,
the parameter o f importance in perfusion quantification using bolus tracking is the density
o f brain tissue, not the density o f brain water. The effect o f the reduction in total water
content during maturation on the brain tissue density has not been reported to the best o f
our knowledge, and therefore the effect on the measured perfusion values is difficult to
estimate.
Finally, the outlying paediatric subject is worthy o f further discussion. Although the exact
cause o f the high measured values could not be identified, this subject was also found to
CHAPTER 5: BOLUS TRACKING PERFUSION MEASURMENT IN INFANTS 155
using the area beneath the tissue curves (normalised to the AIF area) in each case, this
calculation does not require deconvolution, and the elevated CBFapp in the youngest subject
is therefore not caused by errors in the deconvolution. Therefore, it is possible that these
data reflect a higher CBF in very young (<6 months) children, although there is insufficient
data available in the current study to address this further. It is worth noting, however, that
no alternative technique for measuring CBF has indicated that such a large increase might
be expected.
Further data collection is required in order to ascertain whether the age dependence in the
studied range is linear, and to enable further analysis o f regional changes in more detail.
However, suitable data seldom become available due to the ethical issues involved.
Nonetheless, as discussed, it is important for studies in the very young that the age
dependence o f MR perfusion measures is characterised, and this study is a step towards this
goal.