i(3)so3-galactosylceramide and Dementia--Vascular

Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs.. To study the diagnostic utility of CSF ST levels in SSVD.. This was a mono-center, cross-sectional study of SSVD (n = 16), Alzheimer's disease (n = 40), mixed dementia (n = 27), and healthy controls (n = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS).. CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r = 0.64, p < 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r = 0.30, p < 0.05), but it did not correlate with CSF NFL level.. Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

Topics: Aged; Alzheimer Disease; Chromatography, Liquid; Cross-Sectional Studies; Dementia, Vascular; Demyelinating Diseases; Diagnosis, Differential; Diagnostic Techniques, Neurological; Female; Humans; Magnetic Resonance Imaging; Male; Neurofilament Proteins; Procedures and Techniques Utilization; Reproducibility of Results; Sulfoglycosphingolipids; White Matter

Despite its importance as the leading cause of vascular dementia, the primary pathogenic mechanisms in subcortical ischemic vascular dementia (SIVD) have remained elusive. Because of the lack of approved therapeutic agents for SIVD, there is a pressing need to identify novel therapeutic targets. Comparative lipidomic analyses of SIVD and mixed dementia (i.e., SIVD and Alzheimer's disease, MixD) may also confer new insights pertaining to the possible interaction between neurodegenerative and vascular mechanisms in the pathogenesis of dementia. Liquid chromatography coupled to mass spectrometry was used to comprehensively analyze the lipidomes of white and gray matter from the temporal cortex of nondemented controls, SIVD, and MixD subjects. Detailed molecular profiles highlighted the pathologic relevance of gray matter sphingolipid fatty acyl chain heterogeneity in dementia. In addition, the levels of sulfatides and lysobisphosphatidic acids were progressively increased in the temporal cortex gray matter from control to SIVD to MixD. White matter phospholipid profiles indicated possible adaptive mechanisms (i.e., increased unsaturation) to chronic ischemia in SIVD and elevated membrane degradation in MixD.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Chromatography, Liquid; Chronic Disease; Dementia, Vascular; Female; Gray Matter; Humans; Lysophospholipids; Male; Mass Spectrometry; Monoglycerides; Phospholipids; Sphingolipids; Sulfoglycosphingolipids; Temporal Lobe; White Matter

Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging.. CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS).. 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015).. The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Dementia, Vascular; Demyelinating Diseases; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Leukoaraiosis; Linear Models; Magnetic Resonance Imaging; Male; Nerve Degeneration; Netherlands; Neuropsychological Tests; Predictive Value of Tests; Socioeconomic Factors; Sulfoglycosphingolipids; tau Proteins

Subcortical vascular dementia (SVD) is associated with white matter lesions and demyelination. The aim of the present study was to examine the cerebrospinal fluid (CSF) levels of TNF-alpha, a proinflammatory cytokine mediating myelin damage, in SVD patients. The intrathecal TNF-alpha levels were related to the clinical symptoms of dementia, as well as to intrathecal levels of sulfatide, a marker of white matter degradation, and of neurofilament, a marker of neuronal degeneration.. CSF levels of TNF-a, sulfatide and neurofilament were all analyzed by immunoenzymatic procedures in 17 patients with SVD and in 26 healthy controls.. The intrathecal concentration of TNF-alpha was significantly increased in SVD patients compared to healthy controls (p = 0.0001). The intrathecal levels of TNF-alpha were significantly correlated (r = 0.6, p = 0.02) to the levels of sulfatide, but not to the levels of neurofilament, (r = 0.08, NS).. We have demonstrated intrathecal production of TNF-alpha in SVD patients. The correlation between TNF-a and sulfatide levels in the CSF suggests that this apoptosis-inducing cytokine leads to the death of oligodendrocytes, thereby contributing to white matter degeneration, a hallmark of SVD.

Topics: Aged; Aged, 80 and over; Apoptosis; Brain; Case-Control Studies; Dementia, Vascular; Female; Humans; Male; Neurons; Sulfoglycosphingolipids; Tumor Necrosis Factor-alpha

To analyse the diagnostic and prognostic value of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) magnetic resonance imaging (MRI) changes and their relation to symptoms and cerebrospinal fluid (CSF) markers of demyelination (sulphatide) and axonal degeneration [neurofilament triplet protein (NFL)] in a large series of patients with normal pressure hydrocephalus (NPH) and Binswanger disease (BD).. PVH and DWMH were determined by a semi-automatic segmentation method on T2-weighted images in 29 patients with NPH and 17 patients with BD. CSF analyses, psychometric testing and quantification of balance, gait and continence were performed in all patients and also postoperatively in NPH patients.. No MRI variable could identify NPH or BD patients. Abundant PVH and DWMH preoperatively correlated with improvement in gait, balance and psychometric performance after shunt surgery (P < 0.05). CSF sulphatide correlated positively with the amount of DWMH (P < 0.05) while NFL was correlated to both PVH and DWMH (P < 0.05). Abundant PVH correlated with poor psychometric performance while DWMH correlated with gait disturbance (P < 0.05). Postoperative reduction in PVH correlated with improvement in gait, balance and psychometric performance.. In spite of a refined quantification method, NPH and BD patients exhibited similar MRI changes. MRI had a predictive value in NPH patients. DWMH might relate to demyelination and PVH to neuronal axonal dysfunction. NPH and BD share the major part of symptoms and MRI changes, indicating a common pathophysiological pattern, and we raise the question of how to treat BD patients.

Topics: Aged; Aged, 80 and over; Axons; Dementia, Vascular; Demyelinating Diseases; Female; Humans; Hydrocephalus, Normal Pressure; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Predictive Value of Tests; Sulfoglycosphingolipids

To examine the CSF concentrations of molecules reflecting demyelination, neuronal and axonal degeneration, gliosis, monoaminergic neuronal function, and aminergic and peptidergic neurotransmission in a large series of patients with normal pressure hydrocephalus (NPH) or subcortical arteriosclerotic encephalopathy (SAE), to elucidate pathogenic, diagnostic, and prognostic features.. CSF concentrations of glycosphingolipid (sulfatide), proteins (neurofilament triplet protein (NFL), glial fibrillary acidic protein (GFAP)), neuropeptides (vasoactive intestinal peptide (VIP), 4-aminobutyric acid (GABA)), and monoamines (homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG)) were analysed in 43 patients with NPH and 19 patients with SAE. The diagnoses of NPH and SAE were based on strict criteria and patients with NPH were subsequently operated on. Twelve clinical variables, psychometric tests measuring perceptual speed, accuracy, learning, and memory and a psychiatric evaluation were performed in all patients and before and after a shunt operation in patients with NPH.. The CSF sulfatide concentration was markedly increased in patients with SAE (mean 766, range 300-3800 nmol/l) compared with patients with NPH (mean 206, range 50-400 nmol/l) (p<0.001). 5-HIAA, GABA, and VIP in CSF were higher in patients with SAE than in patients with NPH. The patients with NPH with cerebrovascular aetiology had higher sulfatide concentrations and a poorer outcome after shunt surgery than patients with NPH with other aetiologies.. The pathogenesis of the white matter changes in NPH and SAE is different and ischaemic white matter changes can be a part of the NPH state. The markedly increased CSF sulfatide concentrations in patients with SAE indicate ongoing demyelination as an important pathophysiological feature of SAE. The CSF sulfatide concentration distinguished between patients with SAE and those with NPH with a sensitivity of 74% and a specificity of 94%, making it an important diagnostic marker.

Topics: Adult; Aged; Aged, 80 and over; Brain; Dementia, Vascular; Diagnosis, Differential; Female; Humans; Hydrocephalus, Normal Pressure; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Tissue Proteins; Neuropsychological Tests; Prognosis; Reference Values; Sulfoglycosphingolipids

The myelin-associated glycosphingolipid sulfatide in cerebrospinal fluid (CSF) was investigated in 20 patients with vascular dementia (VAD), 43 with Alzheimer's disease (AD) and 20 age-matched controls. The sulfatide concentration in the VAD group (307 +/- 118 nmol/l) was significantly (p less than 0.0001) higher than that in controls (145 +/- 86 nmol/l) and the AD group (178 +/- 79 nmol/l). Among the VAD patients, 8/20 had a significantly increased concentration of sulfatide (greater than mean + 2 S.D.), as compared with controls, while only 2/43 of the AD patients had a sulfatide concentration above this level. It is suggested that the elevated concentration of sulfatide in CSF from VAD patients reflects demyelination. Furthermore, sulfatide determinations, when combined with clinical findings, may be of diagnostic value, for discriminating between VAD and AD.

Topics: Aged; Alzheimer Disease; Dementia, Vascular; Diagnosis, Differential; Female; Humans; Male; Mental Status Schedule; Middle Aged; Sulfoglycosphingolipids