close

Вход

Забыли?

вход по аккаунту

?

Aturn of the sulfatide in Alzheimer's disease.

код для вставкиСкачать
2. Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG
expansion causes a novel form of spinocerebellar ataxia (SCA8).
Nat Genet 1999;21:379 –384.
3. Day JW, Schut LJ, Moseley ML, et al. Spinocerebellar ataxia
type 8. Clinical features in a large family. Neurology 2000;5:
649 – 657.
4. Nemes JP, Benzow KA, Koob MD. The SCA8 transcript is an
antisense RNA to a brain-specific transcript encoding a novel
actin-binding protein (KLHL1). Hum Mol Genet 2000;9:
1543–1551.
5. Moseley ML, Schut LJ, Bird TD, et al. SCA8 CTG repeat: en
masse contractions in sperm and intergenerational sequence
changes may play a role in reduced penetrance. Hum Mol
Genet 2000;9:2125–2130.
6. Vincent JB, Paterson AD, Strong E, et al. The unstable trinucleotide repeat story of major psychosis. Am J Med Genet (Semin Med Genet) 2000;97:77–97.
7. Sobrido M-J, Cholfin JA, Perlman S, et al. SCA8 repeat expansions in ataxia: a controversial association. Neurology 2001;57:
1310 –1312.
8. Juvonen V, Kairisto V, Hietala M, Savontaus M-L. Calculating
predictive values for the large repeat alleles at the SCA8 locus in
patients with ataxia. J Med Genet 2002;39:935–936.
9. Moseley ML, Weatherspoon M, Rasmussen L, et al. SCA8
BAC transgenic mice have a progressive and lethal neurological
phenotype demonstrating pathogenicity of the CTG expansion.
Am J Hum Genet 2002;71(suppl):176.
10. Topisirovic I, Dragasevic N, Savic D, et al. Genetic and clinical
analysis of spinocerebellar ataxia type 8 repeat expansion in Yugoslavia. Clin Genet 2002;62:321–324.
11. Worth PF, Houlden H, Giunti P, et al. Large, expanded repeats
in SCA8 are not confined to patients with cerebellar ataxia. Nat
Genet 2000;24:214 –215.
DOI: 10.1002/ana.10643
A Turn of the Sulfatide in
Alzheimer’s Disease
A Consensus Report from the Alzheimer’s Association
and the National Institute on Aging stressed the
importance of developing peripheral biomarkers to
support early and accurate diagnosis of Alzheimer’s
disease (AD).1 Appropriate surrogate markers could
also be used to predict disease risk, track disease progression, and follow response to treatment. Currently,
the most consistent biochemical measures with reasonable sensitivity and specificity for AD diagnosis are cerebrospinal fluid (CSF) levels of the 42 amino acid
form of amyloid ␤ protein (A␤42 reduced in AD), and
of tau and phosphorylated tau (elevated in AD). Nonetheless, these do not appear to have a significant impact on diagnosis or management of AD at present,
except perhaps as adjuncts in diagnostically compli-
cated cases.2 Other potential biochemical markers
for AD, based on processes in the AD brain besides
plaque and tangle formation, include measures of inflammation (eg, cytokines, glial fibrillary acidic protein), oxidative stress (isoprostanes, 3-nitrotyrosine),
and lipid metabolism (apolipoprotein E, 24S-OH
cholesterol).3
Evaluation of the neuropathological and biochemical abnormalities in AD brain has been a rich source
of strategies for developing biomarkers of AD, as illustrated in the article by Han and colleagues4 in this
issue of Annals of Neurology. The article follows up
the pathological observation that sulfatide was reduced by more than 90% in AD gray matter and
50% in AD white matter. The reduction of sulfatide
in AD brain occurred independent of dementia severity, even in the earliest stages of cognitive impairment.5 Because changes in brain metabolism often are
represented in the constituents of CSF, the authors
examined CSF sulfatide and phosphatidylinositol levels in 19 nondemented control subjects and 20 subjects with very mild dementia (Clinical Dementia
Rating score 0.5). The cases of very mild dementia
satisfied diagnostic criteria for “mild cognitive impairment” but represented a subset at particularly high
risk for progression of dementia and could be considered “incipient AD” or “early-stage AD.”6 These cases
were associated with a 40% decline in CSF sulfatide
levels relative to controls. Phosphatidylinositol, a
phospholipid preserved in AD brain, was unchanged
in the CSF. The sulfatide to phosphatidylinositol ratio was reduced by 40% in early dementia, and the
cutoff could be adapted to differentiate the early-stage
AD cases from control cases, with a sensitivity of
90% and specificity of 100%. The validity as a diagnostic marker in this cohort was more powerful than
CSF measures of A␤42, total tau, and tau phosphorylated at threonine 231. Thus, the reduced CSF sulfatide at the earliest stages of cognitive impairment
appeared to correspond to the changes observed in
postmortem AD brain.
The reduced level of sulfatide in AD brain, reflected
in CSF, provides additional evidence for disordered
lipid metabolism in AD; this extends other findings
such as the role of apolipoprotein E (APOE) allelic
polymorphisms in AD risk, the modulation of A␤ production by cholesterol, the putative effects of statin use
on AD risk, and the increasing recognition of white
matter changes in AD brain.7 Sulfatide is a class of
sulfated galactocerebrosides enriched in myelin, comprising 5% of myelin lipid.8 Sulfatide in oligodendrocytes is involved in development, axon–myelin interactions, protein trafficking, and membrane stabilization.9
Secreted sulfatide associates with high-density
lipoprotein-like particles in CSF that also transport
apolipoprotein E and A␤. The levels of sulfatide in
Irizarry: A Turn of the Sulfatide
7
brain and CSF may be modulated by the APOE genotype.10 The lipid second messenger ceramide, a potential degradation product of sulfatide, is elevated in AD
brain and has been implicated in modulation of
␤-secretase and potentiation of A␤ production.5,11
According to these data, sulfatide dysregulation is evident early in AD brain and may influence processes
associated with other AD-related proteins, including
␤-secretase and apolipoprotein E. Therefore, measurement of CSF sulfatide, whose levels may correlate with
parenchymal levels, is a compelling candidate biomarker for AD. Sulfatide in the CSF generally is considered a marker of active demyelination, myelin damage,
and myelin turnover. Variably elevated CSF sulfatide
may indicate ongoing myelin disruption in metachromatic leukodystrophy (impaired degradation of sulfatide),12 vascular dementia,13,14 HIV-1 infection,15
multiple sclerosis,16 and meningioma.17
Whether reduced CSF sulfatide represents a primary
alteration of lipid metabolism that predisposes to AD
neuropathology or is instead a reactive process reflecting chronic neuronal/axonal loss is unclear. It will be
important to demonstrate the specificity of low CSF
sulfatide, especially relative to other neurodegenerative
diseases; according to earlier studies, low CSF sulfatide
should be able to differentiate incipient AD from leukoencephalopathies associated with high CSF sulfatide.
Furthermore, the effects of aging, APOE genotype,
medications (especially cholesterol modulators), and
disease progression on CSF sulfatide levels remain to
be clarified. CSF sulfatide levels were similar in AD
and nondemented controls in a study by Fredman and
colleagues,14 emphasizing the need to further characterize the diagnostic sensitivity of sulfatide levels during
progression of mild cognitive impairment to frank Alzheimer disease. The development of robust biomarkers
for the early Alzheimer disease processes in the brain is
an exciting avenue in dementia research. The goal is to
identify measures such as CSF sulfatide levels, perhaps
in combination with other CSF and plasma markers,
that will improve the diagnostic accuracy and monitoring of AD progression and therapeutics.
Michael C. Irizarry, MD
Alzheimer Disease Research Unit, Department of
Neurology, Massachusetts General Hospital
Charlestown, MA
8
Annals of Neurology
Vol 54
No 1
July 2003
References
1. Consensus report of the Working Group on Molecular and
Biochemical Markers of Alzheimer’s Disease. The Ronald and
Nancy Reagan Research Institute of the Alzheimer’s Association
and the National Institute on Aging Working Group. Neurobiol Aging 1998;19:109 –116.
2. Growdon JH. Biomarkers of Alzheimer disease. Arch Neurol
1999;56:281–283.
3. Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C. Biochemical markers related to Alzheimer’s dementia in serum and
cerebrospinal fluid. Neurobiol Aging 2002;23:485–508.
4. Han X, Fagan AM, Cheng H, et al. Cerebrospinal fluid sulfatide is decreased in subjects with incipient dementia. Ann
Neurol 2003;53:115–119.
5. Han X, M Holtzman D, McKeel DW Jr, et al. Substantial
sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J Neurochem 2002;82:809 – 818.
6. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol
2001;58:397– 405.
7. Simons M, Keller P, Dichgans J, Schulz JB. Cholesterol and
Alzheimer’s disease: is there a link? Neurology 2001;57:
1089 –1093.
8. Rosengren B, Fredman P, Mansson JE, Svennerholm L. Lysosulfatide (galactosylsphingosine-3-O-sulfate) from metachromatic leukodystrophy and normal human brain. J Neurochem
1989;52:1035–1041.
9. Coetzee T, Suzuki K, Popko B. New perspectives on the function of myelin galactolipids. Trends Neurosci 1998;21:
126 –130.
10. Han X, Cheng H, Fryer JD, et al. Novel role for apolipoprotein
E in the central nervous system. Modulation of sulfatide content. J Biol Chem 2003;278:8043– 8051.
11. Puglielli L, Ellis BC, Saunders AJ, Kovacs DM. Ceramide stabilizes BACE1 and promotes amyloid beta-peptide biogenesis.
J Biol Chem 2003 [epub ahead of print].
12. Kaye EM, Ullman MD, Kolodny EH, et al. Possible use of
CSF glycosphingolipids for the diagnosis and therapeutic monitoring of lysosomal storage diseases. Neurology 1992;42:
2290 –2294.
13. Tullberg M, Mansson JE, Fredman P, et al. CSF sulfatide distinguishes between normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy. J Neurol Neurosurg Psychiatry 2000;69:74 – 81.
14. Fredman P, Wallin A, Blennow K, et al. Sulfatide as a biochemical marker in cerebrospinal fluid of patients with vascular
dementia. Acta Neurol Scand 1992;85:103–106.
15. Gisslen M, Fredman P, Norkrans G, Hagberg L. Elevated cerebrospinal fluid sulfatide concentrations as a sign of increased
metabolic turnover of myelin in HIV type I infection. AIDS
Res Hum Retroviruses 1996;12:149 –155.
16. Nagai Y, Kanfer JN, Tourtellotte WW. Preliminary observations of gangliosides of normal and multiple sclerosis cerebrospinal fluid. Neurology 1973;23:945–948.
17. Davidsson P, Fredman P, von Holst H, et al. Circulating glycoconjugates in CSF of meningioma patients. Acta Neurol
Scand 1990;82:203–208.
DOI: 10.1002/ana.10642
Документ
Категория
Без категории
Просмотров
1
Размер файла
42 Кб
Теги
aturn, disease, alzheimers, sulfatides
1/--страниц
Пожаловаться на содержимое документа