الفهرس 
Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Summary
85
Neuropsychological studies available reveal a
considerably high prevalence of abnormal intelligence quotient
(IQ), not correlating, however, to factors such as hypoxia or
iron overload. It is proposed that factors associated to severe
chronic illness, rather than the disease per se, could be
responsible for these findings (Zafeiriou et al., 2006).
Our study is a part of a continum of a previously done
study in (2013) by Badir on the same group of patients where
they studied 60 child diagnosed with β-TM (on basis of
transfusion dependent microcytic hypochromic anemia early in
life with elevated hemoglobin F level).They were recruited
from Hematology Outpatient Clinic Ain Shams University in
the period from April 2011 to January 2012. They were divided
according to their compliance to iron chelating therapy
(receiving ≥ 70 % of previosly planned iron chelating therapy
protocol for 6 months prior to the study) . A ccordingly ,
patients were divided into into 2 groups; Group A: compliant to
iron chelating therapy and Group B: Non-compliant to iron
chelating therapy. Those with auditory problems, neurological
complaints, thyroid hormone dysfunction, or Vitamin B12
deficiency were excluded from the study. They were compared
to 40 age and sex matched apparently healthy controls.
Summary
86
After obtaining a verbal consent from the included
subjects they were subjected to careful history taking and a
through physical examination in addition to serum ferritin level
in the last three months and evaluating the ferritin trend in the
past three years. All studied groups were subjected to
Neuropsychological Testing using: Wechsler Intelligence Scale
for Children forth edition (WISC IV): (Wechsler, 1991),
Benton Visual Retention Test: (Benton, 1963) and Wisconsin
Card Sort Test: (Wisconsin, 1987) and their results revealed
that different neurophysiological functions studied were
significantly impaired in non compliant patients compared to
compliant patients as well as the controls with significant
impairment in those receiving desferrioxamine (DFO) and
significant correlation was observed with serum ferritin,
suggesting that BTM is associated with neuropsychological
impairment involving multiple cognitive domains and argue for
a potential role of hemosiderosis and DFO on cognitive
functioning.
Hence we aimed at uncovering the relation between
neurocognitive impairment, serum fetritin and different iron
chelators with cerebral intracellular metabolites by doing MRS
to those patients.
Summary
87
The major peaks of the proton MRS, corresponding to Nacetylaspartate
(NAA), creatine (Cr), have been previously
used to evaluate neuronal loss and active neurons breakdown.
The ratio of NAA to Cr (NAA/Cr) is considered a metabolic
marker reflecting the functional status of neurons and axons in
the brain, with a decrease indicating neuronal or axonal loss or
dysfunction (Watanabe et al., 2004).
NAA / Cr ratio has been useful in predicting the degree
of injury and potential recoverability of brain damage following
head injury (Moffett et al., 2007). Reduction of cerebral
NAA/Cr ratio may be reversible; thus, it can be used as a
dynamic marker of neuronal dysfunction and integrity and
cognitive functions (Demougeot, 2001).
However, the relation between NAA/Cr ratio and neuro
cognitive tests in BTM patients needs to be further elucidated.
So we were especially interested in studying NAA/Cr ratio in
our cases and compare it with previously mentioned variables.
NAA is a free amino acid that is synthesized
fromacetyl coenzyme A and aspartate by D-aspartate Nacetyltransferase
in the mitochondria of neurons (Neale
et al., 2000).
Summary
88
NAA is believed to be almost exclusively located
in neurons and neuronal processes such axons and
dendrites. Thus, NAA is expected to be a marker of
neuro/axonal integrity at 1H MRS (Miller,
1991).Pathologies that cause neuronal loss or
neuro/axonal dysfunction decrease the level of NAA at
1HMRS. Chenga et al. (2002) demonstrated that NAA
level in brain is correlated with neuronal density. It has
also been shown that increased neuro/axonal activity in
pathological and physiological conditions might increase
NAA level (Aydin et al., 2005)
In white matter, NAA is predominantly present in
axons. Therefore, the NAA concentration in white matter
is related to the structural and functional integrity of the
myelinated axonal fibers (Appenzeller et al., 2005;
Bjartmar et al., 2002; chard et al., 2002a, 2002b; Lentz
et al., 2005).
The correlation of NAA concentration with IQ scores
might indicate a variation in axonal density between the
subjects that affects intellectual performances. Higher
NAA concentration in frontal lobe might reflect a higher
number of axonal fibers connecting cerebral
hemispheres. (Aydin et al.,2012)
Summary
89
NAA level in white matter is correlated and
associated with the progression and maturation of
myelination process. It is well known that myelin
increases axonal conduction velocity, Thus, a variation in
the degree of myelination of neuronal fibers between the
subjects might lead to the significant differences in the
IQ test performances. Higher axonal density and/or
greater degree of axonal myelination lead to more
efficient inter-hemispheric data transfer that may
enhance intellectual performance. (Aydin et al.,2012)
In out study , reduced NAA/Cr was observed in only
78.3% of cases with normal NAA/Cr in all control group
subjects. Its reduction reflects neuronal loss, lower neuronal
density, atrophied dendrites and axons, and/or deranged
neuronal metabolism (Ross &Bluml ., 2001).
Hasegawa et al. in (2011) investigated the effects of
ferritin overexpression in the brain by H-MRS on the mices
there was significantly altered some metabolic markers in mice
brains, such as decrease in myo-inositol and glutamine, an
increase in lactate were observed with no specific changes in
NAA, creatine, choline & alanine and this is in accordance to
our findings.
Summary
90
The relationship between frontal lobe NAA/Cr ratio and
neuropsychological tests associated with frontal lobe function
was confirmed in a study on healthy children in (2009) by
Ozturk et al.
Further more, in (2012) Aydin et al. studied metabolite
concentrations in the brain and intelligence among 30
adolescents using the Wechsler Intelligence Scale for Children
(verbal, performance and full-scale IQ) test, and they found a
significant positive correlation between performance IQ and
full-scale IQ scores and NAA concentration. In the same
domain, Grazioli et al. (2008) studied patients with multiple
sclerosis and found that patients with lowest frontal lobe
NAA/Cr ratio performed significantly worse on the memory
test..
In our study, there was a significant positive correlation
between NAA/Cr and Wechsler Intelligence Scale for Children,
and patients with reduced NAA /Cr ratio had a significantly
higher abnormal scores on Benton Visual Retention Test
(BVRT) with a significant negative correlation between
NAA/Cr and BVRT. Also, Wisconsin Card Sort Test scores
were significantly lower in patients with reduced NAA/Cr ratio
and WCST showed a significant positive correlation with
NAA/Cr ratio
Summary
91
Additionally reduced NAA/Cr ratio is a marker of
cortical neuronal loss and dysfunction in schizophrenia. In 2009
Pedersen et al they correlated the level NAA/Cr with
performance on the dynamic WCST in patients with
schizopherenia as well as healthy subjects. And a significant
correlation was observed between NAA/Cr and learning
potential on WCST. ALSO Galińska et al.( 2007) found that
Cognitive impairment related to dysfunction of the prefrontal
cortex in first-episode schizophrenia is associated with
reduction of NAA /Cr in the frontal lobe. AND NAA/Cr in the
frontal lobe were significantly related to poorer WCST
performance.
Also, Reduced NAA/Cr ratio is a marker of cortical
neuronal loss and dysfunction in amyotrophic lateral sclerosis
(ALS). Moreover, NAA levels in the motor area and frontal
lobe correlate with the clinical features ALS, including frontal
lobe function (Abe et al., 2001). As per their study in 2001,
Abe et al. found that the NAA/Cr ratio was reduced in the
motor area and frontal lobe of the brain of 14 patients with
clinically definite (ALS) compared to controls with a
significant correlations between the NAA/Cr ratio and the
number of categories achieved in the Wisconsin Card Sorting
test, implying frontal lobe dysfunction