1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis

OBJECTIVES: To test the hypothesis that irrecoverable neurological deficit in multiple sclerosis is associated with axonal loss. METHODS: 1H magnetic resonance spectroscopy (MRS) was carried out in a group of patients with clinically definite multiple sclerosis (n=31). Using this technique, the apparent concentration of NA ([NA] the sum of N-acetyl aspartate (NAA), a neuronal marker, and N-acetylaspartylglutamate has been compared in four groups of patients with multiple sclerosis classified as relapsing-remitting, secondary progressive, primary progressive, benign, and a control group. RESULTS: In the patients with relapsing-remitting disease (n=9) there was a highly significant reduction of apparent NA (median 8.73 mM, range 6.86 mM-10.74 mM, P=0.0008) from an area of high signal compared with the control group (median 11.97 mM, range 10.55 mM-14.5 mM). In the patients with secondary progressive disease (n=10), there was again a highly significant reduction of apparent NA (median 7.82 mM, range 3.5 mM-10.3 mM, P=0.0003) from an area of high signal compared with the control group. In the patients with primary progressive disease (n=6) there was once again a highly significant reduction of apparent NA (median 8.83 mM, range 6.95 mM-9.89 mM, P<0.002) from an area of high signal compared with the control group. In the patients with benign disease, however, there was no significant difference in the apparent NA (median 10.5 mM, range 8.53 mM-12.8 mM, P>0.05) from an area of high signal compared with the control group. In the patients with benign disease (n=5) there was also no significant difference in the apparent NA (median 10.74 mM, range 8.58 mM-13.4 mM, P>0.3) from an area of normal appearing white matter compared with the control group. In the patients with primary progressive disease, however, there was a significant reduction of apparent NA from an area of normal appearing white matter (median 8.78 mM, range 8.7 mM-12.38 mM, P< 0.025) compared with the control group. There was a significant inverse correlation between [NA] from lesions in the patients with multiple sclerosis and disability as measured on the Kurtzke expanded disability scale score (r= -0.364, 0.05>P>0.02). CONCLUSION: These findings support the hypothesis that axonal loss is important in the development of disability in multiple sclerosis. They also provide evidence for axonal loss in normal appearing white matter in patients with primary progressive disease.     

In vivo localized NMR proton spectroscopy of normal appearing white matter in patients with multiple sclerosis

Single photon emission computed tomography (SPECT) using I-123 metaiodobenzylguanidine (MIBG) was evaluated for the detection of doxorubicin (DXR) cardiomyopathy in seven patients with malignant lymphoma receiving DXR doses ranging from 70 to 530 mg (DXR group), and 20 normal subjects without hypertension, diabetes mellitus or electrocardiographic abnormalities (control group). The ratio of the heart to mediastinal counts (H/M) and the washout rate (WR) in MIBG SPECT images were compared between the two groups. Correlation of total doses of DXR with H/M and the relationship of H/M to WR were investigated. The H/M of the DXR group was lower than that of the control group (3.00 +/- 0.97 vs 4.90 +/- 1.08, p < 0.001). The WR of the DXR group was higher than that of the control group (30.9 +/- 10.5% vs 16.5 +/- 9.1%, p < 0.001). Total DXR doses were inversely correlated with H/M (r = -0.86), H/M correlated inversely with the WR (r = -0.83) only in the DXR group. Pathological findings of one patient, who died of DXR cardiomyopathy, showed atrophic and fibrotic nerve fibers in the apical inferior segment of the left ventricle where MIBG uptake was reduced markedly. DXR cardiomyopathy can be detected with MIBG SPECT as cardiac sympathetic nervous dysinnervation. The pathological findings correspond to the MIBG SPECT findings.     

Insulin-like growth factor-I expression in normal and diseased endometrium

While the role of steroid hormones in the regulation of endometrial proliferation and differentiation is well established, the effects of growth factors and their receptors in normal and neoplastic endometrium remain a matter of debate. Previous studies have documented the positive effects of insulin-like growth factor-I (IGF-I) on epithelial cell proliferation and the active production of this growth factor in endometrial tissues. In view of decreased expression of transforming growth factor-beta1 (TGF-beta1), an antagonist of IGF-I, in endometrial carcinoma, we investigated the expression of IGF-I, at both the mRNA and protein levels, and the immunoreactivity for type I IGF-I receptor in 30 formalin-fixed, paraffin-embedded tissue samples of normal and neoplastic endometrium, in order to possibly clarify the role of IGF-I in endometrial proliferation and differentiation. Our results demonstrate a reduced expression of IGF-I mRNA in endometrial carcinomas compared with non-neoplastic tissues, despite equivalent immunohistochemical expression of IGF-I and IGF-I receptor. Our data suggest that IGF-I and its corresponding receptor may not be directly involved in endometrial cancer cell proliferation and differentiation in vivo, though other components of the IGF-I system (e.g., IGF binding proteins) may affect endometrial malignant transformation and tumor progression.     

Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis

Serial monthly magnetization transfer (MT) imaging was performed to evaluate whether a change of the normal appearing white matter (NAWM), which precedes the appearance of enhancing lesions, is seen in patients with multiple sclerosis (MS). Every 4 weeks for 3 months, 10 patients with relapsing-remitting MS were scanned with a T1-weighted sequence, 20 minutes after injection with 0.3 mmol/kg gadolinium-DTPA (Gd-DTPA). During each of the monthly sessions, MT and dual echo scans were also performed before Gd-DTPA injection. On coregistered images, the MT ratio (MTR) was measured in NAWM subsequently involved by enhancing lesions, in NAWM areas on the same slices but outside any present or future MR abnormality, and in enhancing lesions at the time of their appearance. Forty-eight new enhancing lesions with no corresponding abnormalities on previous scans were identified. Their average MTR was 33.1% (+/-8.4%). Three, 2, and 1 month before enhancement appearance, the mean MTR in NAWM, measured from areas corresponding to future enhancing lesions, was significantly lower than the mean MTR in NAWM outside enhancing areas; the MTR decreased steadily as the time when the enhanced lesion approached. These results suggest that changes in the NAWM of patients with MS occur before lesions become evident on conventional MRI scans.     

Insulin-like growth factor-I in men with idiopathic osteoporosis

The etiology of osteoporosis in most men without a history of alcohol abuse, hypogonadism, or glucocorticoid excess is unknown. Several histomorphometric reports have demonstrated a reduction in indices of bone formation. We tested the hypothesis that the putative reduction in bone formation in men with idiopathic osteoporosis may be related to deficiencies in skeletal mechanisms that are mediated by insulin-like growth factor I (IGF-I). Twenty-four middle-aged men (50.5 +/- 1.9 yr) with severe idiopathic osteoporosis (mean lumbar spine T-score -3.5 +/- 0.16) were studied. The following biochemical indices were all normal: serum calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, testosterone, osteocalcin, carboxyterminal propeptide of type I collagen, bone specific alkaline phosphatase, urinary calcium, and collagen crosslinks. Parathyroid hormone level was in the lower range of normal, 25 +/- 2 pg/mL (nl: 10-65). Mean serum IGF-I level was also in the lower range of normal, 157.9 +/- 7.6 ng/mL (normal age-matched range, 140-260 ng/mL). Eight men had IGF-I levels that were below 140 ng/mL. The mean IGF-IZ score was -0.75, significantly different from the expected mean of zero (P = 0.0002). IGF-I was correlated negatively with age (r = -0.49, P < 0.02). With age held constant, serum IGF-I accounted for 15% of the variance in lumbar bone mineral density (BMD; P < 0.001). The osteocalcin concentration correlated well with bone density at the distal 1/3 radius (r = +0.44; P < 0.002). Histomorphometric analysis of bone biopsy specimens showed significant reductions in cancellous bone volume (31%; P < 0.001), cortical width (28%; P < 0.05), osteoid surface (33%; P < 0.01), and bone formation rate (54%; P < 0.01) when results were compared with age-matched control subjects. Percent eroded surface was normal and was correlated inversely with serum IGF-I levels (r = -0.5; P < 0.04). These results suggest that serum IGF-I levels are reduced in men with idiopathic osteoporosis and that IGF-I correlates with and may contribute to the reduction in lumbar spine bone mass density (BMD). The low IGF-I levels may reflect the reduction in bone formation demonstrated by histomorphometry. Insights into the etiology of idiopathic osteoporosis in men may be revealed by further studies of the IGF-I axis.     

Insulin-like growth factor-I rapidly activates multiple signal transduction pathways in cultured rat cardiac myocytes

In response to insulin-like growth factor-I (IGF-I), neonatal rat cardiac myocytes exhibit a hypertrophic response. The elucidation of the IGF-I signal transduction system in these cells remains unknown. We show here that cardiac myocytes present a single class of high affinity receptors (12,446 +/- 3,669 binding sites/cell) with a dissociation constant of 0.36 +/- 0.10 nM. Two different beta-subunits of IGF-I receptor were detected, and their autophosphorylation was followed by increases in the phosphotyrosine content of extracellular signal-regulated kinases (ERKs), insulin receptor substrate 1, phospholipase C-gamma1, and phosphatidylinositol 3-kinase. IGF-I transiently activates c-Raf in cultured neonatal cardiac myocytes, whereas A-raf is activated much less than c-Raf. Two peaks of ERK activity (ERK1 and ERK2) were resolved in cardiac myocytes treated with IGF-I by fast protein liquid chromatography, both being stimulated by IGF-I (with EC50 values for the stimulation of ERK1 and ERK2 by IGF-I of 0.10 and 0. 12 nM, respectively). Maximal activation of ERK2 (12-fold) and ERK1 (8.3-fold) activities was attained after a 5-min exposure to IGF-I. Maximal activation of p90 S6 kinase by IGF-I was achieved after 10 min, and then the activity decreased slowly. Interestingly, IGF-I stimulates incorporation of [3H]phenylalanine (1.6-fold) without any effect on [3H]thymidine incorporation. These data suggest that IGF-I activates multiple signal transduction pathways in cardiac myocytes some of which may be relevant to the hypertrophic response of the heart.     

Insulin-like growth factor system in serum and cerebrospinal fluid in patients with multiple sclerosis

Perforation during attempted gas-enema reduction of intussusception is more common than during a barium enema. In a review of 650 consecutive attempted gas enemas, perforation occurred in 7 infants (1.1%). Gross abdominal distension from the pneumoperitoneum may be rapid and cause splinting of the diaphragm, which leads to acute respiratory distress. This complication is readily recognised at the time of the gas enema, and may require immediate intervention by paracentesis using a 14-gauge needle. A review of 7 children with intussusception in whom perforation occurred revealed that all had radiologic evidence of bowel obstruction (air-fluid levels) prior to the enema, and the patients had had a relatively long history since the onset of symptoms. No perforation occurred during a delayed repeat enema reduction. Perforation during gas enema produces minimal peritoneal contamination. No pathological lesion at the lead point of the intussusception was identified in any of the children in whom perforation occurred.     

Insulin-like growth factor-I in growth hormone-deficient adults: relationship to population-based normal values, body composition and insulin tolerance test

BACKGROUND: Although an insulin tolerance test (ITT) is the most commonly used method for detecting growth hormone (GH) deficiency (GHD) in adults, measurements of serum insulin-like growth factor-I (IGF-I) may also be of value. OBJECTIVE: To validate the use of serum IGF-I concentration in the diagnosis of GHD in adults. DESIGN: A cross-sectional study. PATIENTS: One hundred and four patients, 60 men and 44 women, with known pituitary disease and verified GHD based on ITT. MEASUREMENTS: Serum IGF-I was determined by radioimmunoassay after acid-ethanol extraction. Body composition was estimated with total body potassium combined with total body water assessments. RESULTS: According to age- and sex-adjusted population-based references values, 51 patients had serum IGF-I concentrations below -2 SD of the predicted values and 53 had concentrations within 2 SD. Fifty-seven per cent of the patients aged 41 years (25th percentile) or below and 39% of the patients aged 57 years (75th percentile) or above had serum IGF-I concentrations below -2 SD. Women had lower mean IGF-I SD scores than men (P < 0.01). Serum IGF-I was correlated with peak GH response during ITT (r = 0.40; P < 0.001), age (r = -0.27; P < 0.01), duration of hypopituitarism (r = -0.52; P < 0.001), number of pituitary hormonal deficiencies (r = -0.35; P < 0.001), body cell mass (r = 0.30; P < 0.01) and serum insulin (r = 0.21; P < 0.05). The peak GH response during ITT correlated with spontaneous GH secretion, duration (P = -0.48; P < 0.001) and number of deficiencies (r = -0.50; P 0.001). CONCLUSION: The measurement of serum IGF-I concentrations is not suitable as a single diagnostic test for growth hormone deficiency in adults. Even as a screening test, its use appears to be limited, especially in elderly subjects. The serum level of IGF-I was influenced by several factors in addition to GH, such as age, gender, anthropodometry and serum insulin level. The peak GH response during the insulin tolerance test appears to be influenced to a lesser degree by these factors.     

Insulin-like growth factor-I and binding protein-3 in relation to childhood leukaemia

The aetiology of most cases of childhood leukaemia remains unknown, but several studies have indicated that increased birthweight and height are risk factors for the disease. Since insulin-like growth factor-I (IGF-I) mediates the effect of growth hormone and has been positively associated with prostate cancer, we have evaluated the role of this hormone and its principal binding protein, IGFBP-3, in the aetiology of childhood leukaemia. Incident cases of childhood leukaemia from those recorded by a national network of childhood oncologists were enrolled in our study. Controls were children hospitalised for acute conditions of no more than moderate severity with matching for gender, age and maternal place of residence. Blood measurements of IGF-I and IGFBP-3 were undertaken using commercially available radioimmunoassays. Serum IGF-I values decreased by about 1.7% per month, and the rate of decline was higher, though not significantly so, among cases (2.1% per month) than among controls (1.4%). There was no significant association between IGF-I and the likelihood of childhood leukaemia, but an increment of 1 microg/ml of IGFBP-3 was associated with a substantial and statistically significant reduction of childhood leukaemia by 28% (95% confidence interval 7% to 45%). Because IGFBP-3 is essentially a binding protein, we interpret our findings as indicating that bioavailable IGF-I may play an important role in the aetiology of childhood leukaemia. The much smaller quantities and the inherent instability of IGF-I in the blood in comparison to those of IGFBP-3 are likely to hinder documentation of an underlying positive association of IGF-I with the disease.     

Insulin-like growth factor receptors and binding proteins

The insulin-like growth factor receptors are integral membrane proteins and demonstrate separate, but important effects on the regulation of cellular processes. The IGF-I receptor signals multiple cascades via its inherent tyrosine kinase activity. The IGF-II/M-6-P receptor on the other hand is primarily involved in targeting of enzymes to various subcellular compartments. In contrast, the insulin-like binding proteins are secreted by the cells and accumulate in the extracellular matrix or on the external surface of the cell. They are also involved in regulating cellular processes more indirectly. They modulate the interactions of the IGFs with their receptors, and in addition, may have some IGF-independent effects probably by direct interaction with integrin and other cell membrane receptor proteins. The recent studies, as outlined in this review, strongly suggest an important, if not essential role for the IGF system in normal physiology and disease states. The challenge now is to define the mechanisms involved in these effects. More studies are required to fully understand the post-receptor mechanism involved in IGF-I receptor signal transduction and the mechanisms whereby the IGFBPs exert their interesting effects. Understanding these mechanisms will enable investigators to create new therapeutic modalities for diseases that are affected by the IGF system.     

Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice

Vincristine is a commonly used antitumor agent whose major dose-limiting side-effect is a mixed sensorimotor neuropathy. To assess whether insulin-like growth factor-I (IGF-I), a neurotrophic agent that supports the survival of motoneurons and enhances regeneration of motor and sensory neurons, could prevent the peripheral neuropathy produced by vincristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 x /week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mice treated with vincristine alone, there was evidence of a mixed sensorimotor neuropathy as indicated by changes in behavior, nerve conduction and histology. Caudal nerve conduction velocity was significantly slower in mice treated with vincristine alone as compared with vehicle-treated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but not toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristine-treated mice prevented the neurotoxic effects of vincristine as measured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I partially ameliorated the neuropathy induced by vincristine as this dose only prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. These results suggest that IGF-I prevents both motor and sensory components of vincristine neuropathy and may be useful clinically in preventing the neuropathy induced by vincristine treatment.     

Insulin-like growth factor-I (IGF-I) plasma concentrations are increased in depressed patients

There is some evidence that the somatotrophic system in depression, as assessed by basal growth hormone (GH) concentrations and by GH releasing hormone (GHRH) challenge, might be dysfunctional. However, the rather limited data have been inconclusive so far and plasma concentrations of both insulin-like growth factor-1 (IGF-I) and binding proteins (IGFBP 1 to IGFBP-6) have not been measured simultaneously in depressed patients. We studied 24 severely depressed patients and 33 healthy controls and estimated 24-hour mean plasma cortisol, six-hour evening mean plasma growth hormone (GH), morning plasma IGF-I, IGFBP 2 and 3 and GH-binding protein (GH-BP). Twenty-four-hour mean cortisol (306 +/- 69 vs. 196 +/- 30 nmol/l, p < .001) and IGF-I (157 +/- 40 vs. 120 +/- 33 micrograms/l, p < .01) plasma concentrations were found to be significantly increased in depressed patients, while there was no difference in GH or binding proteins between both groups. MANOVA analysis revealed age and diagnosis to have main effects upon plasma IGF-I. Especially young age and a diagnosis of major depression are associated with higher plasma IGF-I. After treatment only patients in remission had attenuated IGF-I plasma concentrations. We conclude that plasma IGF-I is increased in acutely depressed patients similar to other states of hypercortisolemia.     

MR identification of white matter abnormalities in multiple sclerosis: a comparison between 1.5 T and 4 T

BACKGROUND AND PURPOSE: Although MR spectroscopy and functional MR imaging of the brain have been successful at 4 T, conventional fast spin-echo imaging of the brain at 4 T has not been adequately evaluated. The purpose of this study was to compare the detection of white matter abnormalities in multiple sclerosis (MS) at 1.5 T and 4 T. METHODS: Fifteen patients with clinically definite MS were imaged at both 1.5 T and 4 T within a 1-week period. Comparison was made between fast spin-echo long-TR images at both field strengths. Pulse sequences were tailored to maximize resolution and signal-to-noise ratio in clinically relevant imaging times (< 7 min). Four interpreters independently reviewed the images obtained at both field strengths in separate sessions and evaluated them for lesion identification, size, characterization, and subjective resolution. Differences in interpretations at 1.5 T and 4 T were subsequently recorded. RESULTS: Images obtained at 4 T showed a mean of 88 more lesions as compared with images obtained at 1.5 T. All the lesions measured less than 5 mm and were typically aligned along perivascular spaces. Twenty-five consensually identified lesions on 4-T images were not seen at all on 1.5-T images. Moreover, 4-T images showed 56 additional consensually identified lesions, which were indistinct and seen only in retrospect on 1.5-T images. These lesions were frequently (n = 48) identified in large confluent areas of white matter signal intensity abnormality at 1.5 T. All observers also agreed that 4-T images subjectively enhanced the perception of normal perivascular spaces and small perivascular lesions. CONCLUSION: MR imaging at 4 T can depict white matter abnormalities in MS patients not detectable at 1.5 T through higher resolution with comparable signal-to-noise ratio and imaging times.     

Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging

The goals of the current study were threefold: first, to confirm previous single volume proton (1H) magnetic resonance spectroscopy results of reduced N-acetyl aspartate (NAA, a putative marker of neurons) in multiple sclerosis (MS) white matter lesions using multiple volume 1H magnetic resonance spectroscopic imaging (MRSI); second, to measure the phospholipid metabolites phosphomonoesters and phosphodiesters in such lesions using phosphorus (31P) MRSI; and third, to test the hypothesis that biochemical changes occur in the normal-appearing (on spin echo T2-weighted magnetic resonance images) white matter in patients with MS. Thirteen subjects with clinically definite MS were studied with both 1H and 31P MRSI, and 19 controls were studied with either 1H MRSI, 31P MRSI, or both. MS lesion, MS normal-appearing white matter, and region-matched control spectra from the centrum semiovale were analyzed. The major findings of this study were that in both white matter lesions and normal-appearing white matter in patients with MS, the metabolite ratio NAA/creatine and the total 31P peak integrals were significantly reduced compared with controls. In addition, in MS lesions NAA/choline and phosphodiesters/total 31P were significantly reduced compared with controls, and in MS normal-appearing white matter there was a trend for NAA/choline to be reduced compared with controls. In normal-appearing white matter in patients with MS, total creatine and phosphocreatine were significantly increased compared to controls, as detected with both 1H (total creatine peak integrals) and 31P (phosphocreatine/total 31P) MRSI techniques. These results suggest reduced neuronal density and altered phospholipid metabolites in white matter lesions in patients with MS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective measurement of white matter and gray matter diffusion trace values in normal human brain

The trace of the diffusion tensor (or simply the trace) is diagnostically valuable for detecting acute ischemic lesions. A number of studies indicate that the trace of human gray matter (GM) and white matter (WM) are quite similar. This is somewhat surprising considering the different cellular environments of GM and WM. It is possible that partial volume averaging (PVA) effects between GM and WM, inherent in many of the ultrafast imaging sequences used for diffusion measurements, are responsible for this observation. In order to minimize PVA effects, the trace values of GM and WM have been selectively measured by implementing double inversion recovery (DIR) echo planar imaging (EPI) pulse sequences. Results on six normal volunteers indicate that the trace values of WM and GM are not statistically different.     

Expression of insulin-like growth factor-I gene in normal and diabetic rat eye

The expression of insulin-like growth factor I (IGF-I) gene was studied in both normal and diabetic rat eyes via in situ hybridization. The results revealed the regional expression of IGF-I gene in the rat eyes. The expression of IGF-I mRNA in the internal nuclear layer and ganglion cell layer is strong, in choroid, retinal pigment epithelium and external nuclear layer is moderate, in sclera is weak in degree and no such mRNA is detected in the cornea. The abundance of IGF-I mRNA in diabetic eye tissues is significantly (P < 0.05 or P < or = 0.01) higher than that in normal eye. These findings suggest that (1) functionally, the eye ball be considered to be an "IGF-I paracrine-autocrine system", and (2) the high expression of IGF-I indicate its initiation of diabetic retinopathy and its promotion of the progression of the lesion.     

Insulin-like growth factor-I modulation of cerebellar cell populations is developmentally stage-dependent and mediated by specific intracellular pathways

Although development of transgenic animals overexpressing insulin-like growth factor-I has allowed the establishment of a role of this trophic factor in brain growth, detailed knowledge of the action of insulin-like growth factor-I on different brain areas is still lacking. We now provide evidence for a pleiotrophic role of this growth factor on cerebellar development. Insulin-like growth factor-I produced by cerebellar cultures is a survival factor for Purkinje cells and a mitogen/differentiation factor for cerebellar glioblasts. Trophic effects of insulin-like growth factor-I were observed only during specific developmental stages. In addition, insulin-like growth factor-I increased intracellular Ca2+ levels in Purkinje cells and c-Fos in dividing glioblasts. Survival-promoting effects of insulin-like growth factor-I on Purkinje cells required activation of protein kinase C, while glioblast division induced by insulin-like growth factor-I depended on phosphatidylinosytol 3-kinase activation. We conclude that insulin-like growth factor-I is a paracrine/autocrine pleiotrophic factor for both glia and neurons in the cerebellum. Its effects are mediated by distinct intracellular signals and appear to be specific to the developmental stage of the target cell. Since development of the different cell populations that compose a specific brain territory is not synchronized, the pleiotrophic action of growth factors such as insulin-like growth factor-I may be essential to ontogenetic processes underlying normal brain growth.     

Histopathologic correlates of white matter changes on MRI in Alzheimer''s disease and normal aging

Human lipoproteins after their intestinal or hepatic synthesis undergo within vascular compartment important remodeling through the agency of endothelial lipases, Lecithin: Cholesterol Acyl Transferase and lipid transfer proteins, Cholesteryl Ester Transfer Protein (CETP) and Phospholipid Transfer Protein (PLTP). Following CETP and PLTP characteristics presentation, transfer proteins activities and role were described specifying notably mechanism and kinetic models of cholesteryl ester transfer reaction (shuttle and ternary collision complex mechanisms). Comparative study of Phospholipid Transfer Activities mediated by CETP and PLTP has shown that phospholipid transfer activities of PLTP and CETP are different and might rely on distinct mechanisms. PLTP mediated phospholipid transfers modulate cholesteryl ester transfer activity of CETP. In vivo PLTP is responsible for the net mass transfer of phospholipid from triglyceride rich lipoprotein towards HDL. Whereas PLTP has no intrinsic cholesteryl ester transfer activity, it enhances the transfer of cholesteryl ester from HDL to VLDL and LDL. Thus PLTP might be a determinant factor in modulating the CETP mediated redistribution of cholesteryl esters between pro-(LDL) and anti-(HDL) atherogenic lipoproteins.