CSF sulfatide is decreased in individuals with incipient

dementia

Xianlin Han, PhD, Anne M. Fagan, PhD, Hua Cheng, MS, John C. Morris, MD,

Chengjie Xiong, PhD, David M. Holtzman, MD

Washington University School of Medicine

Department of Medicine and Neurology

Pro

gres

sion

Time

Cognitive Function

Pre-clinical Very MildCDR 0.5 MCI

Clinical detection threshold

MildCDR1

Stage of dementia

Moderate

Severe

AD pathological burden

Onset of AD pathology

An unbiased screen of normal and AD brain tissue using ESI-mass spectrometry led to identification of marked decline in sulfatide in both gray and white matter at CDR 0.5 level of dementia due to AD. *Most other lipids were unchanged.

Han et al. J. Neurochem. 2002

Sulfatide: a sulfated galactocerebroside* synthesized by oligodendrocytes* buildup due to sulfatidase deficiency causes metachromatic leukodystrophy* present in lipoprotein particles along with apoE in the CNS

Electrospray ionization mass spectrometry: Decrease in sulfatidesin very mild AD frontal grey matter vs. control

CDR 0 CDR 0.5 p-value Subjects N=19 N=20 Male/Female 9/10 5/15 % Caucasian 95% 95% Age 70.6 +/- 1.3 73.9 +/- 1.7 0.12 Years of Education 14.21 +/- 0.71 15.1 +/- 0.82 0.44 MMSE score 29.4 +/- 0.18 26.4 +/-0.72 0.0002 Table 1. Characteristics of study subjects. (Mean +/- SEM)

Characteristics of initial group in CSF study

All CSF and plasma was collected fasting at 8AMSamples were stored at –70oC till analyzed

0

25

50

75

100

CDR 0 CDR 0.5

Su

lfat

ide

(pm

ol/

ml)

0

50

100

150

CDR 0 CDR 0.5

ph

osp

hat

idyl

ino

sito

l (P

I)pm

ol/m

l

CSF sulfatide (ST) is markedly and significantly lower inCDR 0.5 vs. CDR 0 subjects

0

5

10

15

20

25

30

CDR 0 CDR 0.5

MM

SE

sco

re

0.0

0.5

1.0

1.5

CDR 0 CDR 0.5

Su

lfat

ide/

PI

rati

o

0

500

1000

1500

CDR 0 CDR 0.5

A

42 (

pg

/ml)

0

1000

2000

3000

CDR 0 CDR 0.5

Tau

pro

tein

(p

g/m

l)Sensitivity and specificity of CSF sulfatide/PI ratio in differentiating CDR 0 from CDR 0.5 subjects is better in thissample than several other established AD biomarkers

Sens=90%Spec=100%

0

100

200

CDR 0 CDR 0.5

pT

au18

1P (

pg

/ml)

Future Questions to be addressed

1. Does sulfatide or the ST/PI ratio differentiate subjects who have a CDR score of 0 from a score of 0.5 and greater in other samples?

2. Are there storage or collection issues that are critical in assessment of this CSF biomarker?

3. Does a low ST/PI ratio increase risk of converting from CDR 0 to CDR 0.5 or from CDR 0.5 to 1?

4. Is a decrease in ST/PI ratio specific for AD vs. other neuro-degenerative diseases (e.g. Parkinson’s, fronto-temporal dementia, etc.).

control-ST AD-ST0

10

20

30

40 *

p<0.0001

CSF Sulfatide

ST

pm

ol/

ml

control: N=33AD: N=46

CSF sulfatide is decreased in a large sample of AD vs. controls subjects

(samples from Joseph Quinn, MD, PhD, Oregon Health Sciences)