SUPPLEMENTARY MATERIAL
Supplemental Methods
Below more detailed information regarding the CSF MRI sequence and the qualitative imaging scales (the global cortical atrophy (GCA) scale and the medial temporal lobe atrophy
(MTA) scale are included.
Extended explanation of the CSF MRI
The CSF MRI sequence (voxel 3x3x6 mm 3 , TR 7917 ms, scan time 1:11 min) 1 exploits the long T
2
properties of the CSF to obtain a pure CSF map. The sequence chart of the CSF MRI sequence is shown in Figure 1. The basic sequence consists of three parts: a magnetization reset, a T
2
-preparation, and a readout part. First, in the magnetization reset part of the pulse sequence a global non-selective saturation pulse is applied. This ensures consistent magnetization recovery before each T
2
-preparation. After a time delay of 6000 ms, the second part (T
2
-preparation) starts which aims at encoding the T
2
into the z-magnetization. In between the second and third part an optional 180 degree inversion pulse can be applied which can correct for slice-timing differences. This optional inversion pulse will be discussed in detail below. The third and final part of the sequence is the readout for which a multi-slice echo planar imaging (EPI) is used. To achieve the T
2
-preparation (the second part) the sequence is repeated four times, each with a different effective echo time (eTE) which is obtained by adapting the number of refocusing pulses in a Malcolm Levitt’s CPD (MLEV) scheme
2
. Our scan parameters were set to a τ
CPMG
of 70 ms and 0, 4, 8 or 16 refocusing pulses from which we got eTE’s of 0, 280, 560, and 1120ms. From the readouts performed at the different eTE’s, signal decay curves could be obtained for each voxel allowing to estimate the T
2
of the CSF voxelwise by means of the following formula:

S
 eTE


 eTE
A
 e
T
2 , CS F
A

M
0



1


T s e
T
1 , CS F


Eq.1
Here S(eTE) is the signal obtained at each eTE, the constant A is the recovered magnetization at time T s
after the non-selective saturation pulse (part 1 of the sequence), T
1,CSF
and T
2,CSF
are the longitudinal and transverse relaxation of the CSF, respectively. However, the above formula is only valid in the case where the readout is performed instantaneously after the T
2
preparation e.g. by using a 3D-GRASE readout
1
. When a multi-slice readout is used instead, each slice has a different acquisition time T a
causing additional T
1
recovery of both tissue and
CSF which is not related to the T
2
-preparation. This can be dealt with in different ways. One can fit a voxel-wise constant offset, which however would introduce a third fitting parameter making it unreliable with only 3 encodings as used here (eTE=0 is not added to the fit as it still contains tissue signal). For this approach, additional encodings using longer MLEV trains should be added with an increased specific absorption rate as a consequence. This is because the next MLEV trains include 32, 64, 128 etc. echoes or refocusing pulses with increased power deposition by the many RF pulses. Alternatively, one can measure the actual recovery effect by letting T s
=0 and skipping the T
2
-preparation module. By subtracting the image obtained with this experiment from the images from the previous eTE encoded experiments, the offset can be ignored, thereby reducing it to the initial two parameter fit. The signal difference can then be shown to have the form:
S
 eTE ,
A

T a

T a

A
 e
 eTE
T
2 , CS F
M
0


1


T s e
T
1 , CS F




T a e
T
1 , CS F
Eq.2 where S(T a
) is the signal recovery at time T a
. A third approach which was used in this work, relies on the addition of an inversion pulse right after the T
2
-preparation module (Figure 1).

Acquiring the different eTE encodings both with and without a subsequent inversion pulse allows doubling the dynamic range (A) while still avoiding the offset. The complex subtracted signal difference can then be shown to have the form:
S
 eTE , 0
  eTE , 180


 eTE
A
 e
T
2 , CS F
A

2

M
0


1


T s e
T
1 , CS F




T a e
T
1 , CS F
Eq.3 where S(eTE,0) and S(eTE,180) are the signals/images from the non-inverted and inverted experiments, respectively.
With this approach a CSF volume fraction map and an R
2,CSF
(= the inverse of the T
2,CSF
) map are obtained, example images of these are shown in Figure 2. The actual volume fraction of
CSF is than obtained by relating the M
0
of an observed voxel to the M
0
of a reference voxel which contains pure CSF. For this, the T
2
of the CSF is used to extrapolate to the intersect eTE = 0 which is where we have the CSF fraction when compared to a voxel filled with CSF extracted from the ventricles. This reference voxel is selected within the ventricles by means of an automatic localizer tool. The CSF volume fraction within a voxel (CSF
VF
) can then be estimated using the following equation:
CSF
VF

S
S ref
 eTE
 eTE


0

0
 Eq.4
Based on the first echo (eTE = 0) of the CSF MRI sequence which include both parenchymal and CSF signal, the intracranial volume (ICV) was measured. The overall CSF volume in the brain (V
CSF
) is than expressed as a percentage of the ICV. The ventricles can be extracted by searching for the largest interconnected CSF space within the brain. Both steps can be calculated within two minutes making it feasible to be performed as an automated routine processing step on the scanner in the future. Based on the ventricle mask, region-of-interest analyses (Figure 2C) are performed to obtain the peripheral subarachnoidal and the

ventricular CSF volumes. Similar regions are used to obtain the mean overall T
2,CSF
and the mean peripheral subarachnoidal and ventricular T
2,CSF
. All these analyses are performed using
IDL 6.1 for Windows (ITT Visual Information Solutions, Boulder, CO, U.S.A.).
Extended explanation of the qualitative imaging scales
Qualitative imaging scales (Table 1) were used to score brain atrophy. This scoring was performed by Jeroen Hendrikse, an experienced neuroradiologist with 10 years of experience and Jill De Vis, 4 years of experience. The scoring was performed blinded and the first reader performed the scoring twice with an interval of one year in between. Based on the transverse
T
2
-FLAIR images, global cortical atrophy throughout the complete cerebrum was scored
(GCA scale)
3
(Table 1). To score medial temporal lobe atrophy (MTA scale), the 3D T
1
weighted images were reconstructed in a plane perpendicular to the hippocampus. A slice through the corpus of the hippocampus, at the level of the anterior pons, was selected, and on this slice the width of the choroid fissure, the width of the temporal horn, and the height of the hippocampal formation was scored
4
(Table 1).

Supplemental Figures
Figure 1
GCA, global cortical atrophy; MTA, medial temporal lobe atrophy. Relative peripheral subarachnoidal CSF volume (V (PS), peripheral subarachnoidal CSF volume expressed as a percentage of ICV) increases with an increased GCA and MTA score (p < 0.001). Relative ventricular CSF volume (V (V), ventricular CSF volume expressed as a percentage of ICV) increases with an increased GCA and MTA score (p < 0.001)

Figure 2
GCA, global cortical atrophy; MTA, medial temporal lobe atrophy.
The T
2
of the peripheral subarachnoidal CSF (T
2
(PS)) increases with increased GCA and
MTA score (p < 0.001 and < 0.01). The T
2
of the ventricular CSF (T
2
(V)) increases with increased GCA and MTA score (p < 0.01 and < 0.05).

References
1.
Qin Q. A simple approach for three-dimensional mapping of baseline cerebrospinal fluid
2.
volume fraction. Magn Reson Med 2011;65:385-391.
Brittain JH, Hu BS, Wright GA et al. Coronary angiography with magnetization-prepared T2 contrast. Magn Reson Med 1995;33:689-696.16. Smith SM,
Jenkinson M, Woolrich MW,Beckmann CF, Behrens TE, Johansen-Berg H, et al.
Advances in functional and structural MR imaga analysis and implementation as FSL.
Neuroimage 2004;23 Suppl 1:S208-S219.
3.
Scheltens P, Pasquier F, Weerts JG, Barkhof F et al.. Qualitative assessment of cerebral atrophy on MRI: inter- and intra-observer reproducibility in dementia and normal aging.
Eur Neurol 1997;37:95-99.
4.
Scheltens P, Leys D, Barkhof F et al. Atrophy of medial temporal lobes on MRI in
"probable" Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992;55:967-972.