Computerized Medical Imaging and Graphics

PERGAMON
Computerized Medical Imaging and Graphics 25 (2001) 299326 www.elsevier.com/locate/compmedimag

Diffusion MRI: apparent diffusion coefcient (ADC) values in the normal brain and a classication of brain disorders based on ADC values
R.N. Sener*
Department of Radiology, Ege University Hospital, Bornova, Izmir 35100, Turkey Received 18 July 2000; accepted 30 October 2000

Abstract Diffusion-weighted imaging, dependent on motion of water molecules, provides information regarding tissue integrity. Apparent diffusion coefcient (ADC) values in the normal brain parenchyma, and those in a variety of lesions were studied by echo-planar diffusion MRI in 310 cases. Brain disorders were classied based on their ADC values, taking the ADC values of the normal brain white matter as the principal category. In the normal white matter ADC ranges were 0.601.05 10 23 mm 2/s, and the mean ADC value was 0.84 ^ 0.11 10 23 mm 2/s. It was possible to distribute brain disorders, as well as artefacts on diffusion MRI to ve major categories: category 1, ADC similar to normal white matter; category 2, ADC lower than normal white matter; category 3, ADC higher than normal white matter; category 4, ADC similar to CSF; and category 5, markedly low or high ADC. Further studies can provide addition of different lesions as well as renements of these categories. q 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Diffusion-weighted MR imaging; Apparent diffusion coefcient; Normal brain, diffusion MRI; Classication of brain disorders, diffusion MRI

1. Introduction Diffusion-weighted MR imaging is a relatively new sequence reecting molecular motion of water within the tissue, so providing data on tissue integrity. In conventional MR imaging, diffusion of water molecules in the tissues has an extremely small contribution to the MR signal. In diffusion MRI, powerful magnetic gradients with echo planar sequence are used. This enables images that are dependent on water diffusion. A diffusion coefcient called apparent diffusion coefcient (ADC) value can be calculated, and ADC maps can be generated. Diffusion MRI has mainly been used for detection of acute ischemia (cytotoxic edema), and for distinction of cytotoxic and vasogenic edema [110], and its role in other brain diseases such as neurodegenerative and metabolic conditions, infections, tumors, and others has been investigated [1115]. This article is a preliminary report from our prospective study on diffusion MRI in an attempt to establish normal ADC values in the brain, and in a variety of disorders.

2. Subjects and methods In this study, 310 cases (166 males, 144 females) are included covering 52 normal individuals, and 258 patients with brain lesions, out of our ongoing studies on diffusion MRI since 1998. There were 26 infants (age range: 1 day 2 years; mean 8 months), 74 children (218 years; mean 6.3 years), and 210 adults (1881 years; mean 47.8 years). Conventional MR imaging and echo planar diffusion weighted imaging were performed on a 1.5 T MR unit (Magnetom Vision, Siemens, Erlangen, Germany). Diffusion MRI was obtained by an automated software. Three protocols were used, labeled as: (1) b-0-1000 (TR 4700, TE 118 ms) taking 23 s; (2) b-0-5001000-slice-read-phase-ADC (TR 4000, TE 110.07 ms) taking 32 s; and (3) trace-0-500-1000-ADC (TR 6700, TE 139.03 ms) taking 22 s. A standard slice thickness of 5 mm was used in all these diffusion imaging sequences. In the last two protocols, automated ADC (apparent diffusion coefcient maps) were available. The ADC values from the normal or diseased brain parenchyma were calculated directly from these automatically generated ADC maps with region of interest (ROI) and/or `pixel lens' evaluation. The pixel lens could be electronically adjusted for 1, 4, 9 and 16 pixels, and usually the last size was used. For the numeric

* Tel.: 190-232-388-1390; fax: 190-232-342-0001. E-mail address: rnsener@hotmail.com (R.N. Sener).

0895-6111/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S 0895-611 1(00)00083-5

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Fig. 1. Normal ADC values are shown on ADC maps in six cases. 2-month-old boy: ADC values in the myelinated regions of the internal capsula and perirolandic areas are 0.95, 0.98, and 1.02 10 23 mm 2/s (a, b), while those of the unmyelinated regions are quite high: 1.84 and 2.02 10 23 mm 2/s (b). 3-year-old boy: Compared to the normal white matter ADC values from the normal corpus callosum are relatively low: 0.63 and 0.55 10 23 mm 2/s. That of hypomyelinated posterior periventricular area is relatively high: 1.19 10 23 mm 2/s. That of normal white matter is 0.93 10 23 mm 2/s (c). 17year-old girl: normal ADC values at different regions of the brain parenchyma are shown (pixel values 37) ranging from 0.65 to 0.95 10 23 mm 2/s, however, again those of the normal corpus callosum (pixel values 1, 2) are low: 0.49 and 0.46 10 23 mm 2/s, comparable to cytotoxic edema, and this is an artefact due to anisotropy effects (d). 14-year-old boy: ADC values from the midbrain are shown. ROI evaluation from the right side is normal: 0.73 10 23 mm 2/s, however pixel lens evaluation shows a relatively low value in the nucleus ruber: 0.58 10 23 mm 2.s, due to paramagnetic effects of iron deposition (e). 63-year-old woman: ROI evaluation of the white matter shows a normal ADC value of 0.77 10 23 mm 2/s. That of CSF is 3.42 10 23 mm 2/s (f). 74-year-old man: an ADC value from the right internal capsula is 0.82 10 23 mm 2/s. That of white matter hyperintensities (leukoariasis) is quite high: 1.61 10 23 mm 2/s (g).

ADC value, the obtained pixel value on the ADC map is divided by 100, and is multiplied by 1023 mm 2/s. Three diffusion sensitivity values (i.e. b value) were used: b 0 or 50 mm 2/s, b 500 and 1000 mm 2/s. In the third protocol, `trace' imaging, obtained with averaging of the three (x, y, z) gradients (maximum 20 images for each b value, and ADC map; total: 80 images), whereas in the second protocol, images were generated in each sectionselect, phase-encoding, and readout (x, y, z) gradients (maximum 20 images for each b value, and ADC map: total 160 images). Images with b 0 or 50 (b 50 in trace imaging) provided sets of T2-weighted images, and those with b 500 mm 2/s had

Table 1 Protocols for diffusion imaging 1. b-0-1000 (TR 4700, TE 118 ms), acquisition 23 s. ADC by formula; StejskalTanner equation. 2. b-0-500-1000-slice-read-phase-ADC (TR 4000, TE 110.07 ms), acquisition 32 s. ADC from automated ADC maps. 3. trace-0-500-1000-ADC (TR 5700, TE 139.03 ms), acquisition 22 s (averaging data in x, y, z gradients). ADC from automated ADC maps.

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Fig. 1. (continued)

Table 3 ADC values ( 10 23 mm 2/s) in the normal brain ROI Infants Unmyelinated white matter Myelinated white matter Paracentral cortices Basal ganglia, thalami Brainstem Cerebellar parenchyma Children and adults White matter Corpus callosum Cortex Thalamus Caudate nucleus, putamen Globus pallidus Midbrain Pons Cerebellar parenchyma Hypomyelinated posterior periventricular regions ADC value ( 10 23 mm/s) 1.64 ^ 0.17 0.90 ^ 0.12 0.83 ^ 0.14 0.98 ^ 0.11 1.00 ^ 0.10 0.97 ^ 0.13 0.84 ^ 0.11 0.75 ^ 0.15 0.75 ^ 0.16 0.83 ^ 0.14 0.82 ^ 0.13 0.74 ^ 0.19 0.76 ^ 0.18 0.84 ^ 0.15 0.83 ^ 0.17 1.25 ^ 0.14

Table 2 Calculation of ADC values A. From automatically generated ADC maps with region of interest (ROI) and/or `pixel lens' evaluation: *The pixel lens can be electronically adjusted for 1, 4, 9, and 16 pixels. *ROI can cover larger areas as desired. *For the numeric ADC value, the obtained pixel value on the ADC map is divided by 100, and is multiplied by 10 23 2/s. B. From the StejskalTanner equation with region of interest (ROI) and/or `pixel lens' evaluation: *StejskalTanner equation: ADC 2 (1/b)ln(S/S0): *S0 is signal intensity with the gradient factors b 0 *S is the signal intensity with the gradient factors b 1000 mm 2/s *ln is natural logarithm *b in 1/b is 1000

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Fig. 1. (continued)

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3. Results 3.1. ADC values in the normal brain The mean ADC values ( 10 23 mm 2/s) in the normal brain belonging to the rst group, covering infants up to 2 years of age were as follows: unmyelinated white matter, 1.64 ^ 0.17; myelinated white matter, 0.90 ^ 0.12; paracentral cortices, 0.83 ^ 0.14; basal ganglia, thalami, 0.98 ^ 0.11; brainstem, 1.00 ^ 0.10; and cerebellar parenchyma, 0.97 ^ 0.13. The mean ADC values in the normal brain belonging to the second group, covering children and adults from 2 to 81 years of age were as follows: white matter, 0.84 ^ 0.11; corpus callosum, 0.75 ^ 0.15; cortex, 0.75 ^ 0.16; thalamus, 0.83 ^ 0.14; caudate nucleus, putamen, 0.82 ^ 0.13; globus pallidus, 0.74 ^ 0.19; midbrain, 0.76 ^ 0.18; pons, 0.84 ^ 0.15; cerebellar parenchyma, 0.83 ^ 0.17; and when present hypomyelinated posterior periventricular regions, 1.25 ^ 0.14. These are shown in Table 3. ADC calculations of the normal brain are illustrated in Fig. 1. 3.2. ADC values in different conditions There were apparent differences among the ranges of ADC values of the normal cerebral white matter, normal CSF, acute infarct (cytotoxic edema), vasogenic edema, and other brain disorders (Table 4). Therefore, we attempted to classify brain diseases based on their ADC values. For this, the ranges of ADC values of the normal white matter were considered as the rst category. Thus, it was possible to distribute brain disorders, as well as artefacts on diffusion MRI to ve major categories: category 1, ADC similar to normal white matter (ADC ranges: 0.601.05 10 23 mm 2/ s); category 2, ADC lower than normal white matter (ADC values: less than 0.60 10 23 mm 2/s); category 3, ADC higher than normal white matter (ADC ranges: more than 1.05 10 23 mm 2/s, and less than CSF); category 4, ADC similar to CSF (ADC ranges of CSF: 2.40 4.40 10 23 mm 2/s); and category 5, markedly low or high ADC (Table 5). In the rst category (ADC similar to normal white matter) the following were included: atrophy, neuronal migrational disorders, lipoma, intraparenchymal dermoid, calcied giant cell tumor of tuberous sclerosis, some metastatic tumors with hemorrhage, glutaric aciduria type 1, nonketotic hyperglycinemia, and pontine myelinolysis due to gluten enteropathy (Fig. 2). In the second category (ADC lower than normal white matter) the following were contained: ischemia and acute infarct (cytotoxic edema), subacute hemorrhage (extracellular methemoglobin), venous thrombosis (in superior sagittal sinus), metachromatic leukodystrophy (deep white matter), epidermoid, ischemic portions of tumors, and ischemia associated with herpes encephalitis, areas of normal

Fig. 1. (continued)

T2 information in part, called T2 shine-through. Those with b 1000 mm 2/s provided true diffusion images. On the other hand, in the rst protocol the diffusion sensitivity values were: b 0, and b 1000 mm 2/s. Images with b 0 provided a set of T2-weighted images, wherease those with b 1000 mm 2/s provided three sets of true diffusion images in the x, y, and z directions (maximum 20 images for each b value; total: 80 images). In this sequence automated map was not available, so ADC were calculated according to the StejskalTanner equation: ADC 2 (1/b)ln(S/S0), where S0 is signal intensity (mean) obtained in the regions of interest (ROI) with the gradient factors b 0, and S is the signal intensity (mean) obtained with the gradient factors b 1000 mm 2/s. `ln' is natural logarithm (Tables 1 and 2). The ADC values in the normal brain were calculated in two major groups, one covering infants up to 2 years of age, and the other children and adults from 2 to 81 years. ADC calculations were easier with automated ADC maps compared to the formula.

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Fig. 2. An example from category 1 (ADC similar to normal white matter): Neuronal migration disorder: 5.5-year-old boy: FLAIR image shows thickened, and infolded cortex representing cortical dysplasia (a). ADC map shows normal values at this region, and at the contralateral normal parenchyma ranging from 0.88 to 0.93 10 23 mm 2/s (b).

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Fig. 3. An example from category 2 (ADC lower than normal white matter): Acute infarct (cytotoxic edema). 68-year-old man. True diffusion (b 1000 mm 2/ s) image shows high signal in the left occipital lobe, corpus callosum, and left thalamus (a). ADC map shows low ADC values in the infracted regions: 0.42 and 0.47 10 23 mm 2/s. Note that there is extensive white matter hyperintensities (leukoariasis) ADC value of which is 1.52 10 23 mm 2/s (b).

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Fig. 4. An example from category 2 (ADC lower than normal white matter). Venous thrombosis in superior sagittal sinus. 25-year-old man. MR angiography shows nonlling of the proximal parts of the sinus (a). ADC map shows thrombus in the sinus (arrow) with an ADC value of 0.35 10 23 mm 2/s. Also note that there are low-signal ischemic changes in the right frontal tip (venous infarction), and high-signal edema at the contralateral site (b).

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Fig. 5. An example from category 2 (ADC lower than normal white matter). Herpes virus type 1 infection. 46-year-old man. b 1000 mm 2/s image shows high-signal ischemic changes (a). ADC map reveals low ADC values in the affected regions: 0.33 and 0.39 10 23 mm 2/s. Also, normal ADC values from the right posterior temporal region, cerebellum, and midbrain 0.82, 0.75, and 0.66 10 23 mm 2/s (b).

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Fig. 6. An example from category 2 (ADC lower than normal white matter). Metachromatic leukodystrophy. 1.5-year-old boy. FLAIR image shows high-signal changes in the deep white matter (a). b 1000 mm 2/s image shows high-signal changes similar to cytotoxic edema. Since these lesions apparently are not ischemia, such high-signal may reect presence of gel state of water instead of the usual sol state in such neurometabolic conditions (b). ADC map reveals a low value in the deep white matter: 0.47 10 23 mm 2/s, similar to ischemia. However, the peripheral white matter has a relatively high ADC value: 1.10 10 23 mm 2/s, suggesting high molecular motion of water, compared to that of normal individuals (c).

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Fig. 7. An example from category 2 (ADC lower than normal white matter). Epidermoid tumor. 31-year-old woman. CISS (constructive interference of steady state) image shows the mass with a `muddy' appearance (a). b 0 image, which actually is a T2-weighted image, shows high signal in the lesion. The mean pixel value is 1044 (b). b 100 mm 2/s image, which is the true diffusion image, shows high signal in the lesion, which could suggest presence of gel status of water. The mean pixel value is 622 (c). The ADC value, calculated by the StejskalTanner equation: ADC 2 (1/b)ln(S/S0), is 0.51 10 23 mm 2/s.

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R.N. Sener / Computerized Medical Imaging and Graphics 25 (2001) 299326 Table 6 Disorders contained in ve categories Category 1. ADC similar to normal white matter Atrophy Lipoma Dermoid Neuronal migrational disorders Glutaric aciduria type 1 Nonketotic hyperglycinemia Pontine myelinolysis due to gluten enteropathy Calcied giant cell tumor of tuberous sclerosis Some metastatic tumors with hemorrhage Category 2. ADC lower than normal white matter Ischemia and acute infarct (cytotoxic edema) Subacute hemorrhage (extracellular methemoglobin) Venous thrombosis (in superior sagittal sinus) Metachromatic leukodystrophy (deep white matter) Epidermoid Ischemic portions of tumors Ischemia associated with herpes encephalitis Normal iron deposition (globus pallidus, red nucleus, substantia nigra) Localized areas in corpus callosum, and subcortical white matter Category 3. ADC higher than normal white matter Vasogenic edema Enlarged VirchowRobin spaces White matter hyperintensities (leukoariasis) Transependymal resorption of water Matrix of tumors Radiation necrosis Periventricular leukomalacia Microcystic encephalomalacia Hamartomas in tuberous sclerosis and NFI Rasmussen encephalitis Herpes infection without ischemia Multiple sclerosis Acute disseminated encephalomyelitis Leigh's disease Alexander's disease Mucopolysaccharidosis Metachromatic leukodystrophy (peripheral white matter) Xanthogranuloma of the choroid plexus Category 4. ADC similar to CSF Arachnoid cyst Hydatid cyst Cystic tumor Tumor necrosis Macrocystic encephalomalacia Category 5. Markedly low or high ADC Low ADC 0 Calcication Hemosiderin Lipoma (due to a misregistration on ADC maps, actually in category 1). Large veins (superior sagittal sinus) with normal ow Air High ADC 5.0010.00 10 23 mm 2/s motion effects in Cystic tumors Tumor necrosis Macrocystic encephalomalacia Enlarged ventricles (5.00 10 23 mm 2/s) Very bright artefacts related with motion, and ADC map creation (10.00 10 23 mm 2/s)

Fig. 7. (continued)

Table 4 ADC value differences in four conditions (ranges and mean) 10 3 mm 2/s Acute infarct (cytotoxic edema) Normal cerebral white matter Vasogenic edema CSF 0.140.50 (0.32 ^ 0.09) 0.601.05 (0.84 ^ 0.11) 1.282.20 (1.68 ^ 0.27) 2.404.40 (3.40 ^ 0.45)

Table 5 Classication of brain disorders according to ADC values ( 10 23 mm 2/s) Categories 1. ADC similar to white matter 2. ADC lower than normal white matter 3. ADC higher than normal white matter 4. ADC similar to CSF 5. Markedly low or high ADC Ranges 0.601.05 Less than 0.60 More than 1.05, less than CSF 2.404.40 0, and 510

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Fig. 8. An example from category 2 (ADC lower than normal white matter). Cavernoma with subacute hemorrhage (extracellular methemoglobin). 3-year-old boy. T1-weighted (a), and T2-weighted (b) images show a high-signal round lesion. b 1000 mm 2/s image shows high signal in the cavernoma (c). ADC map reveals a low value: 0.36 10 23 mm 2/s in the hemorrhagic region, and a high value in the surrounding edema: 1.26 10 23 mm 2/s (d).

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Fig. 8. (continued)

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Fig. 9. An example from category 3 (ADC higher than normal white matter). Radiation necrosis. 5-year-old boy. FLAIR image shows widespread high-signal in this patient following irradiation for an anaplastic astrocytoma of the oculomotor nerve nucleus (a). ADC map reveals high-signal changes in the corresponding regions with high values: 1.42 and 1.39 10 23 mm 2/s. Normal ADC value is shown from the right frontal region: 0.78 10 23 mm 2/s (b).

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Fig. 10. An example from category 3 (ADC higher than normal white matter). Pons glioma 6-year-old-girl. b 50 T image, which actually is a T2-weighted image, shows enlarged pons with diffuse high signal (a). ADC map reveals a high value: 1.28 10 23 mm 2/s. Normal ADC value is shown from the crebellum: 0.85 10 23 mm 2/s (b).

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Fig. 11. An example from category 3 (ADC higher than normal white matter). Acute disseminated encephalomyelitis. 10-year-old girl. FLAIR image shows patchy high-signal in both hemispheres (a). ADC map reveals high values in the white matter lesions ranging from 1.16 to 1.41 10 23 mm 2/s. A low value from the unaffected (normal) corpus callosum is also shown: 0.55 10 23 mm 2/s (b).

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Fig. 12. An example from category 3 (ADC higher than normal white matter). Mucopolysaccharidosis. 11-month-old girl. FLAIR image shows high-signal changes in deep white matter (a). ADC map reveals a high value in deep matter: 1.26 10 23 mm 2/s. A normal value from the unaffected peripheral white matter is also shown: 0.84 10 23 mm 2/s (b).

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Fig. 13. An example from category 3 (ADC higher than normal white matter). Leigh's disease. 4-year-old girl. FLAIR image shows high-signal changes in caudate nuclei, and putamina (a). ADC map reveals high values in the putaminal lesions: 1.33 10 23 mm 2/s (b).

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Fig. 14. An example from category 3 (ADC higher than normal white matter). Multiple sclerosis. 35-year-old woman. FLAIR image shows high-signal plaques of multiple sclerosis (a). ADC map reveals high values in the lesions: 1.741.78 10 23 mm 2/s. A value of 0.82 10 23 mm 2/s is also shown from the normal parenchyma (b).

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Fig. 15. An example from category 3 (ADC higher than normal white matter). Two patients, 7- and 9-year-old boys, with tuberous sclerosis. FLAIR image shows high-signal hamartomas (a). ADC map reveals values of 1.41 and 1.32 10 23 mm 2/s in the hamartomas (b). ADC map from the second patient shows the value of a subependymal calcication as `zero'. Therefore, this ADC value belongs to category 5 (markedly low or high ADC). ADC value of the normal thalamus is 0.88 10 23 mm 2/s.

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hemosiderin, and lipoma, on automated ADC maps. Also, the ADC value for lipoma ( 0) possibly was a misregistration due to chemical-shift effects on automated ADC maps, as it ranged from 0.85 to 1.04 10 23 mm 2/s by multiple measurements using the StejskalTanner formula, which is similar to that of normal white matter (Fig. 18). In the second subcategory (markedly high ADC) of the fth category higher ADC values (i.e. 5.60 10 23 mm 2/s) than normal CSF were noted in cystic tumors, tumor necrosis, macrocystic encephalomalacia, and within enlarged ventricles, possibly due to motion effects. Also, small, bright artefactual objects had markedly high ADC values (as high as 10.00 10 23 mm 2/s) by pixel lens evaluation, on automated ADC maps (Fig. 19). These are listed in Table 6. 4. Discussion Random motion of water molecules is referred to as Brownian motion or `translational molecular diffusion', and it is relatively free in homogeneous uid-containing structures. This type of water diffusion is called isotropic diffusion. On the other hand, in the tissues (e.g. brain parenchyma), water motion is restricted by the presence of cellular structures which provide barriers to free diffusion. This restriction may be more in one direction than in another (e.g. around axons). This type of water diffusion is called anisotropic diffusion. In conventional MRI, diffusion of water molecules in the tissues has an extremely small contribution to the MR signal. With the development of diffusionweighted MRI pulse sequences in which powerful magnetic gradients coupled with echo planar data acquisition techniques are used, it is possible to obtain images that are dependent on water diffusion. The gradients are applied in x, y, and z directions resulting in irreversible signal attenuation of moving water molecules. Thus, water diffusion becomes the dominant, intrinsic image contrast mechanism. A diffusion coefcient called apparent diffusion coefcient (ADC) value can be calculated within each image voxel, and ADC maps can be generated on a pixel-by-pixel basis. Because diffusion coefcients are high in uids where diffusion is free, low signal is observed on diffusion imaging at b 1000 mm 2/s (high signal on corresponding ADC maps). Normal CSF is an example of this. On the other hand, if the mobility of water molecules is restricted such as in ischemia (cytotoxic edema) high signal is observed on diffusion imaging at b 1000 mm 2/s (low signal on corresponding ADC maps). In the presence of vasogenic edema high signal is seen on ADC maps, however, this is apparently lower than CSF. ADC values can be calculated either from automatically generated ADC maps with `ROI' and/or `pixel lens' evaluation, or from the StejskalTanner equation. Besides true diffusion images (i.e. b 1000 mm 2/s images), calculation of ADC values is signicant, as both provide information regarding tissue integrity in a variety of brain lesions [110].

Fig. 15. (continued)

iron deposition (globus pallidus, red nucleus, substantia nigra), and localized areas in the corpus callosum, and subcortical white matter (Figs. 38). In the third category (ADC higher than normal white matter) the following were noted: vasogenic edema, transependymal resorption of water, enlarged VirchowRobin spaces, white matter hyperintensities (leukoariasis), multiple sclerosis, matrix of tumors, radiation necrosis, periventricular leukomalacia, microcystic encephalomalacia, hamartomas of tuberous sclerosis and neurobromatosis type 1 (NF1), edema associated with herpes encephalitis, Rasmussen's encephalitis, acute disseminated encephalomyelitis Leigh's disease, mucopolysaccharidosis, metachromatic leukodystrophy (peripheral white matter), and xanthogranuloma of the choroids plexus (Figs. 916). In the fourth category (ADC similar to CSF) the following were included: arachnoid cyst, hydatid cyst, cystic tumor, tumor necrosis, and macrocystic encephalomalacia (Fig. 17). On the other hand, in the fth category (markedly low or high ADC) the following were noted: in the rst subcategory (markedly low ADC) ADC was zero with calcication,

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Fig. 16. An example from category 3 (ADC higher than normal white matter). Periventricular leukomalacia. 2.5-year-old girl. FLAIR image shows high-signal, gliotic, periventricular changes (a). ADC map reveals high values in the gliotic lesions: 1.391.60 10 23 mm 2/s (b).

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Fig. 17. An example from category 4 (ADC similar to CSF). Hydatid cyst. 3-year-old boy. T2-weighted image shows a round cyst with low-signal walls (a). b 0 image, which actually is a T2-weighted image, shows high signal in the cyst. The mean pixel is 1100 (b). b 1000 mm 2/s image, which is the true diffusion image, shows low signal in the cyst, suggesting free molecular movement of water. The mean pixel value is 55. Note that the cyst walls show black signal (c). The ADC value, calculated by the StejskalTanner equation: ADC 2 (1/b)ln(S/S0), is 2.99 10 23 mm 2/s. That for CSF herein is 3.22 10 23 mm 2/s.

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Fig. 17. (continued)

In this preliminary study on diffusion MRI, we noticed that a variety of normal conditions as well as brain lesions can be classied into certain groups based on ADC value determinations. Therefore lists of ve categories are created: category 1, ADC similar to normal white matter; category 2, ADC lower than normal white matter; category 3, ADC higher than normal white matter; category 4, ADC similar to CSF; and category 5, markedly low or high ADC. Brain lesions are distributed to these categories. It should be noted that further studies can enable addition of different lesions as well as renements of these categories, and can provide subcategories. Therefore, the listings in these tables can be accepted as prospectively expandable in further studies. Our major conclusions based on diffusion MRI, and on the classications of normal conditions, and brain disorders by ADC values are as follows. For ischemia (cytotoxic edema) visual evaluation of b 1000 mm 2/s images may be more reliable than visual evaluation of automated ADC maps, as small lesions appear very bright on b 1000 mm 2/ s images. In such lesions, ADC value calculations can be performed by correlation with b 1000 mm 2/s images.

Also, it should be noted that trace diffusion MRI is better in this regard than diffusion MRI giving images in each of the x, y, z gradients, because in the latter certain brain structures such as corticospinal tracts, and corpus callosum have differing brightnesses depending on the gradient directions (anisotropy effects), some of which may resemble ischemic lesions in a certain gradient direction. On diffusion MRI major visual and qualitative (ADC values) differences are between acute infarct (cytotoxic edema), normal cerebral white matter, vasogenic edema, and CSF, and these belong to four major categories according to our classication. ADC values of the normal cerebral white matter is the basis of this classication. A number of diverse conditions fell in this normal category, consistent with normal molecular motion of water molecules. It was important that some normal tissues of the brain parenchyma such as corpus callosum, subcortical white matter, and regions with iron deposition (globus pallidus, red nucleus, substantia nigra) have low ADC values comparable to cytotoxic edema. The former two conditions were probably due to anisotropy effects, and the latter due to paramagnetic effects. These probably Therefore, ADC maps need to be correlated with b 1000 mm 2/s images, especially for exclusion of suspected cytotoxic edema. Acute ischemia (cytotoxic edema) is the frequently encountered, main lesion of the second category (ADC lower than normal white matter). According to the widely accepted explanation of signal changes on diffusion MRI there is apparent restriction of movement of water molecules with cytotoxic edema, hence high signal on b 1000 mm 2/s images, and low ADC values [110]. However, in a recent experiment by Branco [16], it was shown that transition of water from the sol to the gel state, can contribute to the signal on diffusion MRI, and in gel state high signal is observed on b 1000 mm 2/s images. Our ndings in metachromatic leukodystrophy (high signal of deep white matter on b 1000 mm 2/s images, and low ADC values) may support Branco's suggestion, as there was no ischemia associated with the condition (Fig. 6). Subacute hemorrhage was in the second category (ADC lower than normal white matter). ADC values of hemosiderin, however, was zero, therefore we categorized it to the fth group (markedly low or high ADC). Thrombus demonstration was possible in major dural sinuses, and this was in the second category (Fig. 4). Parenchymal changes associated with metachromatic leukodystrophy were both in the second and third categories. Low ADC values of the deep white matter in metachromatic leukodystrophy suggested apparently restricted molecular motion of water in these regions or a transformation of water from sol to gel state. On the other hand, peripheral white matter changes in metachromatic leukodystrophy, changes associated with Leigh's disease, and mucopolysaccharidosis were in the third category, suggesting increased molecular motion at lesion sites. Glutaric aciduria type 1 was in the rst category (i.e. normal molecular motion).

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Fig. 18. An example from category 5 (markedly low or high ADC). Lipoma. 3-year-old boy. T1-weighted image reveals a pericallosal lipoma (a). ADC map reveals a value of `zero' (b), which apparently is a misregistration artefact due to chemical-shift effects, as the ADC value of this lipoma calculated by the formula [StejskalTanner equation: ADC 2 (1/b)ln(S/S0)] ranged from 0.85 to 1.04 10 23 mm 2/s by multiple careful measurements, which is similar to that of normal white matter (category 1).

This was also true with another amino acid disorder, nonketotic hyperglycinemia. With respect to both of these amino acid disorders, again, there was high signal on the true diffusion (b 1000 mm 2/s images), although the ADC values were contained in the rst (normal) category, but at lower ranges, suggesting a possible contribution from gel state of water, consistent with Branco's suggestion [16]. Autoimmune and infectious conditions such as multiple sclerosis, Rasmussen's encephalitis, and early herpes virus type 1 infection associated with edema were in the third category, reecting relatively high molecular motion of water with these. When ischemic changes developed in herpes infection ADC values fell in the second category. It appeared that discrimination of active and inactive multiple sclerosis lesions was not possible. Epidermoid tumor was in the second category, while intraparenchymal dermoid, and lipoma in the rst, suggesting relatively normal molecular motion in the latter, and restricted motion in the former. Gel status of water may

also account for the low ADC value of the epidermoid tumor (high signal on b 1000 mm 2/s images). A `muddy' appearance of the epidermoid tumor on FLAIR (uid attenuated inversion recovery), and CISS (constructive interference of steady state) images could support this (Fig. 7). ADC values of enlarged VirchowRobin spaces, white matter hyperintensities (leukoariasis), transependymal resorption of water, and vasogenic edema, were close to each other, and these were contained in the third category (ADC higher than normal white matter). This category also covered hamartomas, tumors, radiation necrosis, some leukoencephalopathies, acute disseminated encephalomyelitis, and others. It appeared that discrimination between tumor and radiation necrosis was not possible. Although ADC values of tumor parenchyma usually fell in the third category, changes associated with these, as well as metastatic tumors (ischemia, hemorrhage, cystic, necrotic component) were in all categories.

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(markedly high ADC) artefacts due to motion effects in liquid containing structures, and small, bright apparently artefactual objects were contained. 5. Summary Apparent diffusion coefcient (ADC) values are studied in the normal brain parenchyma, and in a variety of brain lesions. Echo-planar diffusion-weighted imaging, using either a three-axis or trace approach, were performed on a 1.5 T MR unit (Magnetom Vision) in 310 patients, ages ranging from 1 day to 81 years. ADC calculations were performed either from automated ADC maps or from the StejskalTanner formula. ADC values ( 10 23 mm 2/s) in normals were: unmyelinated white matter, 1.64 ^ 0.17: myelinaetd white matter, 0.90 ^ 0.12; and paracentral cortices, 0.83 ^ 0.14, in infants. The values in normal children and adults were: white matter, 0.84 ^ 0.11; corpus callosum, 0.75 ^ 0.15; cortex, 0.75 ^ 0.16; thalamus, 0.83 ^ 0.14; caudate nucleus, and putamen, 0.82 ^ 0.13; globus pallidus, 0.74 ^ 0.19; midbrain, 0.76 ^ 0.18; pons, 0.84 ^ 0.15; cerebellar parenchyma, 0.83 ^ 0.17; and hypomyelinated regions posterior to lateral ventricles, 1.25 ^ 0.14. Obtained ADC values in various diseases are classied into ve groups: (1) ADC similar to normal white matter; (2) ADC lower than normal white matter; (3) ADC higher than normal white matter; (4) ADC similar to CSF; (5) markedly low or high ADC. Diffusion MRI and ADC values provide information on tissue integrity in the brain. Evaluations of ADC values reveal signicant results not only in distinction between cytotoxic and vasogenic edema, but also in a variety of lesions including tumors, cysts, hamartomas, leukodystrophies, infections and others. References
[1] Beaulieu C, D'Arceuil H, Hedehus M, de Crespigny A, Kastrup A, Moseley ME. Diffusion-weighted magnetic imaging: theory and potential applications to child neurology. Semin Pediatr Neurol 1999;6:87100. [2] Rowley HA, Grant PE, Roberts TP. Diffusion MR imaging. Theory and applications. Neuroimaging Clin N Am 1999;9:34361. [3] Jones DK, Horseld MA, Simmons A. Optimal strategies for measuring diffusion in anisotropic systems by magnetic resonance imaging. Magn Reson Med 1999;42:51525. [4] Finsterbusch J, Frahm J. Diffusion-weighted single-shot line scan imaging of the human brain. Magn Reson Med 1999;42:7728. [5] Li TQ, Takahashi AM, Hindmarsh T, Mosely ME. ADC mapping by means of a single-shot spiral MRI technique with application in acute cerebral ischemia. Magn Reson Med 1999;41:1437. [6] Kuroiwa T, Nagaoka T, Ueki M, et al. Correlations between the apparent diffusion coefcient, water content, and ultrastructure after induction of vasogenic brain edema in cats. J Neurosurg 1999;90:499503. [7] Barzo P, Marmarou A, Fatouros P, Hayasaki K, Corwin F. Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging. J Neurosurg 1997;87:9007.

Fig. 19. An example from category 5 (markedly low or high ADC). Postoperative changes after excision of a glial tumor. 5-year-old boy. ADC map reveals a very high value (5.00 10 23 mm 2/s) within CSF, apparently due to motion effects. Other calculations from CSF are in normal ranges: 2.81 and 2.96 10 23 mm 2/s. Also, it should be noted that bright artefacts, related with head motion and map creation, cause even higher ADC values (b).

Chronic infarct (macrocystic encephalomalacia), and cystic lesions were obviously in the fourth category (ADC similar to CSF). Also included were arachnoid cysts, hydatic cyst, and tumor cysts. Microcystic encephalomalacia, on the other hand, was in the third category (ADC higher than normal white matter), reecting relatively low molecular motion compared to macrocystic encephalomalacia. Some lesions, and artefacts were in the fth category (markedly low or high ADC). Those with markedly low ADC (ADC 0) included calcication, hemosiderin, and lipoma, on automated ADC maps. The ADC value for the lipoma, carefully calculated by the StejskalTanner formula with multiple measurements, was similar to that of normal white matter. This paradox for ADC values of the lipoma can be explained by a misregistration due to chemical-shift effects on automated ADC maps. In the other subcategory

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R.N. Sener / Computerized Medical Imaging and Graphics 25 (2001) 299326 [12] Tien RD, Felsberg GJ, Friedman H, Brown M, MacFall J. MR imaging of high-grade cerebral gliomas: value of diffusion-weighted echoplanar pulse sequences. AJR 1994;162:6717. [13] Sugahara T, Korogi Y, Kochi M, et al. Usefulness of diffusionweighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging 1999;8:5360. [14] Sener RN. Rasmussen's encephalitis: proton MR spectroscopy and diffusion MR ndings. J Neuroradiol 2000 (in press). [15] Sener RN. van der Knaap syndrome: MR imaging ndings including FLAIR, diffusion imaging, and proton MR spectroscopy. Eur Radiol 2000 (in press). [16] Branco G. An alternative explanation of the origin of the signal in diffusion-weighted MRI. Neuroradiology 2000;42:9698.

[8] Altieri M, Metz RJ, Muller C, Maeder P, Meuli R, Bogousslavsky J. Multiple brain infarcts: clinical and neuroimaging patterns using diffusion-weighted magnetic resonance. Eur Neurol 1999;42:7682. [9] Ulug AM, Moore DF, Bojko AS, et al. Clinical use of diffusion-tensor imaging for diseases causing neuronal and axonal damage. AJNR 1999;20:10448. [10] Burdette JH, Ricci PE, Petitti N, Elster AD. Cerebral infarction: time course of signal intensity changes on diffusion-weighted MR images. AJR 1998;171:7915. [11] Ay H, Buananno FS, Schaefer PW, et al. Posterior leukoencephalopathy without severe hypertension: utility of diffusion-weighted MRI. Neurology 1998;51:136976.