Iron stores and cerebral veins in MS studied by susceptibility weighted imaging.
ABSTRACT In this paper, we seek to determine whether the iron deposition as seen by susceptibility weighted imaging (SWI) in the basal ganglia and thalamus of patients with multiple sclerosis is greater than the iron content measured in normal subjects (individuals unaffected by multiple sclerosis). As increased iron content may result from increased venous pressure, such information would add credence to the concept of Zamboni et al (1) that MS is caused by chronic cerebrospinal venous insufficiency.
Fourteen MS patients were recruited for this study with a mean age of 38 years ranging from 19 to 66 year-old. A velocity compensated 3D gradient echo sequence was used to generate SW images with a high sensitivity to iron content. We evaluated iron in the following structures: substantia nigra, red nucleus, globus pallidus, putamen, caudate nucleus, thalamus and pulvinar thalamus. Each structure was broken into two parts, a high iron content region and a low iron content region. The measured values were compared to previously established baseline iron content in these structures as a function of age.
Twelve of fourteen patients had an increase in iron above normal levels and with a particular pattern of iron deposition in the medial venous drainage system that was associated with the confluence of the veins draining that structure.
Iron may serve as a biomarker of venous vascular damage in multiple sclerosis. The backward iron accumulation pattern seen in the basal ganglia and thalamus of most MS patients is consistent with the hypothesis of venous hypertension.
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ABSTRACT: PurposeTo study iron deposition in the substantia nigra (SN) and red nuclei (RN), in patients with clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS) and healthy controls (HC).Materials and Methods Iron deposition was assessed using susceptibility maps and T2*-w images acquired at high resolution MRI at 7 Tesla (T). Mean intensities were calculated within circular regions of interest in the SN (d/v, dorsal/ventral) and RN on high resolution T2*-w, quantitative susceptibility maps and their product for: RRMS, CIS and HC (N = 14, 21, 27, respectively).ResultsMagnetic susceptibility was significantly greater in SNd and RN in RRMS compared with HC (P = 0.04 [0.001, 0.48] and P = 0.01 [0.005, 0.05]), with intermediate values for the CIS group. 1/T2*-w did not show significant inter-group differences (for SNv, SNd, RN, respectively: P = 0.5 [−0.352, 0976], P = 0.35 [−0.208, 0.778], P = 0.16 [−0.114, 0.885] for RRMS versus HC) and the T2*-susceptibility product maps showed the difference only for RN (P = 0.01, [0.009, 0.062]). Changes were independent of EDSS and disease duration.ConclusionMR changes consistent with iron accumulation occurring in the SN and RN of CIS patients can be identified using susceptibility mapping; this may provide an additional method of monitoring early MS development.J. Magn. Reson. Imaging 2014. © 2014 Wiley Periodicals, Inc.Journal of Magnetic Resonance Imaging 05/2014; · 2.57 Impact Factor
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ABSTRACT: Restless legs syndrome (RLS) is a sleep-related sensory-motor disorder characterized by an irresistible urge to move the legs accompanied by unpleasant sensations in the lower extremities. According to many recent studies patients with multiple sclerosis (MS) suffer frequently from symptoms of RLS. The prevalence of RLS in MS patients varies 13.3%-65.1%, which is higher than the prevalence of RLS in people of the same age in the general population. MS patients with RLS have higher scores in the Expanded Disability Status Scale compared to MS patients without RLS. Presence of RLS has a negative impact on sleep quality and fatigue of MS patients. Iron deficiency and chronic inflammation may be factors contributing to development of RLS in MS. The relationship between the course and treatment of MS and RLS requires further prospective studies. Copyright © 2014 Elsevier Ltd. All rights reserved.Sleep Medicine Reviews 10/2014; · 9.14 Impact Factor
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ABSTRACT: This study aimed to investigate age-related iron deposition changes in healthy subjects and Alzheimer disease patients using susceptibility weighted imaging. The study recruited 182 people, including 143 healthy volunteers and 39 Alzheimer disease patients. All underwent conventional magnetic resonance imaging and susceptibility weighted imaging sequences. The groups were divided according to age. Phase images were used to investigate iron deposition in the bilateral head of the caudate nucleus, globus pallidus and putamen, and the angle radian value was calculated. We hypothesized that age-related iron deposition changes may be different between Alzheimer disease patients and controls of the same age, and that susceptibility weighted imaging would be a more sensitive method of iron deposition quantification. The results revealed that iron deposition in the globus pallidus increased with age, up to 40 years. In the head of the caudate nucleus, iron deposition peaked at 60 years. There was a general increasing trend with age in the putamen, up to 50-70 years old. There was significant difference between the control and Alzheimer disease groups in the bilateral globus pallidus in both the 60-70 and 70-80 year old group comparisons. In conclusion, iron deposition increased with age in the globus pallidus, the head of the caudate nucleus and putamen, reaching a plateau at different ages. Furthermore, comparisons between the control and Alzheimer disease group revealed that iron deposition changes were more easily detected in the globus pallidus.Archives of gerontology and geriatrics 04/2014; · 1.36 Impact Factor
Iron stores and Cerebral Veins in MS Studied by Susceptibility Weighted Imaging (SWI)
E. Mark Haackea, James Garberna, Yanwei Miaob, Charbel Habiba, Manju Liua.
aDepartment of Radiology, Wayne State University, Detroit, MI 48202, USA
bDepartment of Radiology, the First Affiliated Hospital, Dalian Medical University, Dalian,
Liaoning 116011, China
E. Mark Haacke, PhD
Wayne State University
MR Research Facility
Department of Radiology
HUH—MR Research G030/Radiology
3990 John R Road
Detroit, MI 48201
Tel. (313) 745-1395
Fax (313) 745-9182
Aim: Multiple sclerosis (MS) is a disease whose etiology until recently has remained a mystery.
A possible explanation for MS has been put forward by Zamboni et al 1 that it is caused by a
chronic cerebrospinal venous insufficiency (CCSVI). In this paper, we show that the iron
deposition as seen by susceptibility weighted imaging (SWI) in the basal ganglia and thalamus is
consistent with this interpretation.
Methods: 14 MS patients were recruited for this study with a mean age of 38 ranging from 19
to 66 years old. A velocity compensated 3D gradient echo sequence was used to generate
susceptibility weighted images (SWI) with a high sensitivity to iron content. We evaluated iron
in the following structures: substantia nigra, red nucleus, globus pallidus, putamen, caudate
nucleus, thalamus and pulvinar thalamus. Each structure was broken into two parts, a high iron
content region and a low iron content region. The measured values were compared to previously
established baseline iron content in these structures as a function of age.
Results: Of the 14 cases, 12 revealed an increase in iron above normal levels and with a
particular pattern of iron deposition in the medial venous drainage system.
Conclusion: The backward iron accumulation pattern seen in the basal ganglia, thalamus and
midbrain of most MS patients is consistent with the hypothesis of venous hypertension.
Key words: brain iron deposition, susceptibility weighted imaging, iron changes in multiple
It has been suggested recently that multiple sclerosis (MS) may develop as a neurodegenerative
disease because of a venous vascular insufficiency 1 and the resulting venous hypertension
related directly to abnormalities (narrowing and restricted flow) in the jugular and azygous veins.
Although evidence of venous involvement has been known for a long time 2-4, pioneering efforts
in this direction have basically been ignored until Zamboni et al 1 demonstrated the presence of
stenoses in MS patients. This is truly a paradigm shift, where one must look outside the brain, in
this case the cardiovascular system, to understand the source of the brain’s problem in MS.
Evidently, the venous hypertension that leads to multiple sclerosis can have a damaging effect on
the vessel wall 5,6. This is best understood from research related to chronic venous disease where
it has been shown that changes in venous hemodynamics leads to a disruption of flow, a
reduction of the shear stress in the vessel wall, an inflammatory degenerative response and,
subsequently, a deterioration of the venous wall 7-9. Similar effects are known in atherosclerosis
when normal flow is disrupted. And even in multiple sclerosis research dating back to the work
of Adams 2, and later Trojano 10, venous wall breakdown in multiple sclerosis has been well
Following this argument a bit further, one might expect then local iron increases from the
damaged vessel wall, loss of vessel function, reduced transit times and reduced local blood flow
in the chronic stages of the disease. One might also expect that the vascular pathways most
closely associated with the hypertension and local reflux (especially in the areas of the internal
cerebral veins and vein of Galen) associated with obstructed venous flow would in turn lead to
local venous damage in multiple sclerosis 11-13. The areas most affected by this might well be the
thalamus and basal ganglia since they are associated with the medial venous drainage system 14.
With this philosophy in mind, we investigated the local iron content in the basal ganglia and
thalamus using susceptibility weighted imaging (SWI) to see if there were any evidence of such
microbleeding or vascular breakdown that followed a pathway reverse to that of the draining
veins as noted by Fog in 1964 3 and later espoused by Schelling 4.
SWI is a gradient echo MR imaging technique that uses phase as an alternate source of
information to enhance contrast 15. It uses the susceptibility differences between tissues to
generate this contrast. Susceptibility is very different than the usual spin density, T1 and T2
properties. It is represented indirectly by the phase images and in this case by the SWI filtered
phase images that are used to remove background field inhomogeneities. These phase images
produce the same image, whether acquired at 1.5T, 3T or any other field strength as long as the
product of BoTE is a constant. Thus, while other tissue properties change from field strength to
field strength, phase properly adjusted for TE will not. That is because susceptibility does not
change from one field strength to another. The early applications of SWI stemmed from the
signal changes that took place in the SWI images for veins 16. The presence of deoxygenated
blood leads to both a T2* effect and a change in phase in the veins since deoxyhemoglobin is
paramagnetic. Combining these two characteristics into SWI data led to a beautiful perspective
of the venous system in the brain. Similar to how the blood oxygenation level dependent
(BOLD) effect is used in functional brain imaging, SWI shows veins with less deoxyhemoglobin
as less suppressed and those with more deoxyhemoglobin as more suppressed. Several examples
of the venograms that are possible with SWI at 3T are shown in Figure 1. In this paper, our
interest is to combine the venous vascular information in SWI processed data with the putative
iron content seen in SWI high pass filtered phase data. These two pieces of information can then
be used to assess the state of the venous vasculature in multiple sclerosis patients. Some example
SWI filtered phase images good for visualizing iron are shown in Figure 2.
To this end, we compared the iron in a series of 14 multiple sclerosis patients with that in a set of
100 normal subjects using SWI. Our goal was to look for iron abnormalities and evaluate
whether these could be integrated into this new theory of cerebral spinal venous insufficiency.
Materials and Methods
Fourteen (14) clinically defined MS patients were imaged with mean age of 38 ranging from 19
to 66 years old. All patients signed a consent form approved by the Internal Review Board (IRB-
approved). A velocity compensated 3D gradient echo sequence was used to generate
susceptibility weighted images (SWI) with a high sensitivity to iron content. All SWI images
were acquired at 1.5T Sonata [Siemens, Erlangen, Germany] with a resolution of 0.5x0.5x2mm3.
Imaging parameters were TR=57ms, TE=40ms; FA=20°; and BW=80 Hz/pixel. A 64x64 low
spatial frequency kernel was used to complex-divide into the original data to create an effective
high pass filtered phase image. The resulting SWI filtered phase images were used as a means to
quantify iron content in vivo. The following 7 deep gray matter structures were studied for iron
content including: the globus pallidus (GP), the caudate nucleus (CN), the putamen (PUT), the
thalamus (THA), the substantia nigra (SN), the red nucleus (RN) and the pulvinar thalamus (PT).
A two region analysis concept was used where each structure was separated into two regions-of-
interest (ROI): the normal iron content region (RI) and the high iron content region (RII). These
regions were differentiated using threshold values cited in previous work by Haacke et al. in
2007 17. The measured values were compared to a previously established baseline of iron content