Extraneural Organs Research Articles

Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle.

In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer's disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.

Japanese encephalitis virus infection in meerkats (Suricata suricatta)

Japanese encephalitis virus (JEV) infection has been recognized as a serious disease in humans. Wildlife animal infections due to JEV have not been well described. This study identified JEV infection in two deceased meerkats in Thailand, with clinical signs of neurological disease. Histopathology of brains revealed severe lymphoplasmacytic necrotizing meningoencephalitis, while similar inflammation was observed in the lung and liver. Partial JEV sequences were identified from the formalin-fixed paraffin-embedded-derived brain sections of two meerkats and were found to be genetically similar to a JEV strain detected in China but not from a local strain. Using immunohistochemistry, the virus was identified in neurons and glial cells, and also found in bronchial glands, Kupffer's cells in liver, lymphocytes in the spleen and pancreatic acini, which suggests extraneural infection. Transmission electron microscopy confirmed the presence of spheroid viral particles in the lungs. These findings may suggest that infection of extraneural organs in meerkats is similar to that described in JEV-infected humans. In conclusion, this study identified the first JEV infection in meerkats as an interesting case study. The JEV should be considered as an important differential diagnosis in meerkats with encephalitis. Further surveillance on JEV infection in meerkats and other wildlife species in a large cohort is needed in the future study.

Drosophila melanogaster Models of Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the human FXN gene. FXN is evolutionarily conserved, with orthologs in essentially all eukaryotes and some prokaryotes, leading to the development of experimental models of this disease in different organisms. These FRDA models have contributed substantially to our current knowledge of frataxin function and the pathogenesis of the disease, as well as to explorations of suitable treatments. Drosophila melanogaster, an organism that is easy to manipulate genetically, has also become important in FRDA research. This review describes the substantial contribution of Drosophila to FRDA research since the characterization of the fly frataxin ortholog more than 15 years ago. Fly models have provided a comprehensive characterization of the defects associated with frataxin deficiency and have revealed genetic modifiers of disease phenotypes. In addition, these models are now being used in the search for potential therapeutic compounds for the treatment of this severe and still incurable disease.

Involvement of extraneural tissues and upregulation of inducible nitric oxide synthase after experimental infection with rabies virus in BALB/c mice and LEW/SsN rats

Rabies virus can cause fatal encephalomyelitis, but the involvement of extraneural organs has not been well characterized. In this study, we investigated the histopathological changes and the distribution of viral antigens in extraneural organs after pathogenic rabies virus infection in mouse and rat models. In histopathological examination, classical viral encephalitis and rabies-specific Negri body were observed in the brain. In addition to the central nervous system (CNS), inflammatory responses were found in other organs, such as the heart, kidney, liver, and lung. Similarly, immunohistochemical staining and reverse transcription-polymerase chain reaction revealed the presence of rabies virus in the CNS and extraneural tissues. Moreover, macrophages, especially in the lung and heart, were involved in the infection. Transcriptional analyses of the expression of inducible nitric oxide synthase (iNOS) demonstrated that rabies virus potentiated the gene expression of iNOS in the brain, lung, and heart. The immunoreactive iNOS-positive macrophages were detected adjacent to the infection. These results suggest that macrophages are involved in the extraneural infection and the expression of iNOS in macrophages contributes to the formation of tissue inflammation. Our study indicates the involvement of extraneural organs following rabies virus infection, which may aggravate the progression of this deadly disease.

Neurosarcoidosis: Clinical manifestations, diagnosis and treatment

Sarcoidosis is an idiopathic granulomatous disease affecting multiple organs. Neurosarcoidosis, involving the central and/or peripheral nervous systems, is a relatively rare form of sarcoidosis. Its clinical manifestations include cranial neuropathies, meningitis, neuroendocrinological dysfunction, hydrocephalus, seizures, neuropsychiatric symptoms, myelopathy and neuropathies. The diagnosis is problematic, especially when occurring as an isolated form without other organ involvement. Distinguishing neurosarcoidosis from other granulomatous diseases and multiple sclerosis is especially important. Although biopsy of neural tissue is the gold standard for the diagnosis of neurosarcoidosis, this is often not practical and the diagnosis must be inferred though other tests, often coupled with biopsy of extraneural organs. Corticosteroids and other immuno-suppressants are frequently used for the treatment of neurosarcoidosis. This article reviews the epidemiology, pathogenesis, pathology, clinical features, diagnosis, diagnostic tests, diagnostic criteria, and therapy of neurosarcoidosis.

Hypoxic preconditioning increases iron transport rate in astrocytes

The mechanisms involved in the neuroprotection induced by hypoxic preconditioning (HP) have not been fully elucidated. The involvement of hypoxia-inducible factor-1 alpha (HIF-1alpha) in such neuroprotection has been confirmed. There is also evidence showing that a series of genes with important functions in iron metabolism, including transferrin receptor (TfR1) and divalent metal transporter 1 (DMT1), are regulated by HIF-1alpha in response to hypoxia in extra-neural organs or cells. We therefore hypothesized that HP is able to affect the expression of iron metabolism proteins in the brain and that changes in these proteins induced by HP might be associated with the HP-induced neuroprotection. We herein demonstrated for the first time that HP could induce a significant increase in the expression of HIF-1alpha as well as iron uptake (TfR1 and DMT1) and release (ferroportin1) proteins, and thus increase tansferrin-bound iron (Tf-Fe) and non-transferrin-bound iron (NTBI) uptake and iron release in astrocytes. Moreover, HP could lead to a progressive increase in cellular iron content. We concluded that HP has the ability to increase iron transport speed in astrocytes. Based on our findings and the importance of astrocytes in neuronal survival in hypoxic/ischemic preconditioning, we proposed that the increase in iron transport rate and cellular iron in astocytes might be one of the mechanisms associated with the HP-induced neuroprotection. We also demonstrated that ferroportin1 expression was significantly affected by HIF-1alpha in astrocytes, implying that the gene encoding this iron efflux protein might be a hypoxia-inducible one.

JC Virus Latency in the Brain and Extraneural Organs of Patients with and without Progressive Multifocal Leukoencephalopathy

JC virus (JCV) is latent in the kidneys and lymphoid organs of healthy individuals, and its reactivation in the context of immunosuppression may lead to progressive multifocal leukoencephalopathy (PML). Whether JCV is present in the brains or other organs of healthy people and in immunosuppressed patients without PML has been a matter of debate. We detected JCV large T DNA by quantitative PCR of archival brain samples of 9/24 (38%) HIV-positive PML patients, 5/18 (28%) HIV-positive individuals, and 5/19 (26%) HIV-negative individuals. In the same samples, we detected JCV regulatory region DNA by nested PCR in 6/19 (32%) HIV-positive PML patients, 2/11 (18%) HIV-positive individuals, and 3/17 (18%) HIV-negative individuals. In addition, JCV DNA was detected in some spleen, lymph node, bone, and kidney samples from the same groups. In situ hybridization data confirmed the presence of JCV DNA in the brains of patients without PML. However, JCV proteins (VP1 or T antigen) were detected mainly in the brains of 23/24 HIV-positive PML patients, in only a few kidney samples of HIV-positive patients, with or without PML, and rarely in the bones of HIV-positive patients with PML. JCV proteins were not detected in the spleen or lymph nodes in any study group. Furthermore, analysis of the JCV regulatory region sequences showed both rearranged and archetype forms in brain and extraneural organs in all three study groups. Regulatory regions contained increased variations of rearrangements correlating with immunosuppression. These results provide evidence of JCV latency in the brain prior to severe immunosuppression and suggest new paradigms in JCV latency, compartmentalization, and reactivation.

Anaplastic transformation of an atypical intraventricular meningioma with metastases to the liver: case report

Malignant intraventricular meningiomas are very rare. To the best of our knowledge, only eleven cases have been reported thus far. Seven of them developed cerebrospinal fluid (CSF) metastases. We present herein the first case of a malignant intraventricular meningioma with extraneural metastases. We report a 44 year-old-man with a history of progressive headache and disorientation. Magnetic resonance imaging (MRI) revealed a 5-cm homogeneously-enhancing mass in the right trigone. The lesion was totally resected via a parietooccipital transcortical approach. Histological examination demonstrated an atypical meningioma. Thereafter, the tumor recurred twice. At first recurrence, the tumor was completely removed again and external radiotherapy was administered. At surgery at second recurrence, the tumor was more aggressive, invading the brain parenchyma. Histological examination showed anaplastic meningioma. The patient was readmitted to hospital with fever and pain in right hypochondrium. Abdominal ultrasound examination disclosed multiple hypoechoic liver lesions. Biopsy was consistent with liver metastases of a malignant meningioma. The patient died of acute liver failure seven months after initial diagnosis. Malignant intraventricular meningiomas are prone to recur and develop metastases, mainly through the CSF. Nevertheless, our case shows that extraneural metastases are also possible. Therefore, when systemic deterioration occurs in a patient with a malignant intraventricular meningioma, metastases to extraneural organs such as the liver must be ruled out.

Lagos Bat Virus in Kenya

During lyssavirus surveillance, 1,221 bats of at least 30 species were collected from 25 locations in Kenya. One isolate of Lagos bat virus (LBV) was obtained from a dead Eidolon helvum fruit bat. The virus was most similar phylogenetically to LBV isolates from Senegal (1985) and from France (imported from Togo or Egypt; 1999), sharing with these viruses 100% nucleoprotein identity and 99.8 to 100% glycoprotein identity. This genome conservancy across space and time suggests that LBV is well adapted to its natural host species and that populations of reservoir hosts in eastern and western Africa have sufficient interactions to share pathogens. High virus concentrations, in addition to being detected in the brain, were detected in the salivary glands and tongue and in an oral swab, suggesting that LBV is transmitted in the saliva. In other extraneural organs, the virus was generally associated with innervations and ganglia. The presence of infectious virus in the reproductive tract and in a vaginal swab implies an alternative opportunity for transmission. The isolate was pathogenic for laboratory mice by the intracerebral and intramuscular routes. Serologic screening demonstrated the presence of LBV-neutralizing antibodies in E. helvum and Rousettus aegyptiacus fruit bats. In different colonies the seroprevalence ranged from 40 to 67% and 29 to 46% for E. helvum and R. aegyptiacus, respectively. Nested reverse transcription-PCR did not reveal the presence of viral RNA in oral swabs of bats in the absence of brain infection. Several large bat roosts were identified in areas of dense human populations, raising public health concerns for the potential of lyssavirus infection.

High-dose chemotherapy supported by autologous stem cell transplantation in patients with primary central nervous system lymphoma: facts and opinions

The standard approach to primary central nervous system lymphomas (PCNSL), that is high-dose methotrexate (HD-MTX)-based chemotherapy followed by whole-brain irradiation (WBRT), is associated with disappointing outcome. Moreover, this strategy is heavily conditioned by increased risk of disabling neurotoxicity, mostly among elderly patients. Several drugs and strategies have been investigated to improve results and neurotolerability. Among others, some investigators focused on the use of high-dose chemotherapy supported by autologous stem cells transplant (HDC/ASCT) as consolidation after primary chemotherapy. This approach has been used as salvage therapy in patients who experienced progressive disease or relapse after conventional chemo-radiotherapy or as consolidation after primary HD-MTX-based chemotherapy, replacing or preceding WBRT. Evidence supporting the role of HDC/ASCT is growing but several questions are still unanswered. The best conditioning regimen, the role of concomitant intrathecal chemotherapy, the neurotoxicity risk of further WBRT after transplant, the best time for response assessment and late effects both on neurological performance and extraneural organs remain to be characterised. This critical review is focused on the analysis of published experiences on HDC/ASCT in PCNSL in order to provide preliminary answers to the most pressing questions in this field.

Mass spectrometric studies on brain metabolism, using stable isotopes

In fields related to biomedicine, mass spectrometry has been applied to metabolism research and chemical structural analysis. The introduction of stable isotopes has advanced research related to in vivo metabolism. Stable-isotope labeling combined with mass spectrometry appears to be a superior method for the metabolism studies, because it compensates for the shortcomings of conventional techniques that use radioisotopes. Biomolecules labeled with stable isotopes have provided solid evidence of their metabolic pathways. Labeled large molecules, however, cannot homogeneously mix in vivo with the corresponding endogenous pools. To overcome that problem, small tracers labeled with stable isotopes have been applied to in vivo studies because they can diffuse and attain a homogeneous distribution throughout the inter- and intracellular spaces. In particular, D(2)O-labeling methods have been used for studies of the metabolism in different organs, including the brain, which is isolated from other extraneural organs by the blood-brain barrier (BBB). Cellular components, such as lipids, carbohydrates, proteins, and DNA, can be endogenously and concurrently labeled with deuterium, and their metabolic fluxes examined by mass spectrometry. Application of the D(2)O-labeling method to the measurements of lipid metabolism and membrane turnover in the brain is described, and the potential advantages of this method are discussed in this review. This methodology also appears to have the potential to be applied to dynamic and functional metabolomics.

Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease.

In patients with sporadic Creutzfeldt-Jakob disease, pathologic disease-associated prion protein (PrPSc) has been identified only in the central nervous system and olfactory-nerve tissue. Understanding the distribution of PrPSc in Creutzfeldt-Jakob disease is important for classification and diagnosis and perhaps even for prevention. We used a highly sensitive method of detection--involving the concentration of PrPSc by differential precipitation with sodium phosphotungstic acid, which increased the sensitivity of Western blot analysis by up to three orders of magnitude--to search for PrPSc in extraneural organs of 36 patients with sporadic Creutzfeldt-Jakob disease who died between 1996 and 2002. PrPSc was present in the brain tissue of all patients. In addition, we found PrPSc in 10 of 28 spleen specimens and in 8 of 32 skeletal-muscle samples. Three patients had PrPSc in both spleen and muscle specimens. Patients with extraneural PrPSc had a significantly longer duration of disease and were more likely to have uncommon molecular variants of sporadic Creutzfeldt-Jakob disease than were patients without extraneural PrPSc. Using sensitive techniques, we identified extraneural deposition of PrPSc in spleen and muscle samples from approximately one third of patients who died with sporadic Creutzfeldt-Jakob disease. Extraneural PrPSc appears to correlate with a long duration of disease.

Ontogenetic development and neuroanatomical localization of growth hormone-releasing hormone (GHRH) in the brain and pituitary gland of pejerrey fish Odontesthes bonariensis

The presence and distribution of growth hormone-releasing hormone (GHRH) were studied by immunocytochemistry in adult and developing pejerrey fish, Odontesthes bonariensis (Atheriniformes). A few perikarya and fibers with immunoreactivity to GHRH (ir-GHRH) were identified in the olfactory bulbs at hatching. One week later, scattered ir-GHRH cell bodies were observed in the preoptic area and some fibers were detected entering the pituitary gland. Isolated ir-GHRH perikarya were revealed in the hypothalamus and in the medulla oblongata (MO) 3 weeks after hatching. Seven weeks after hatching, ir-GHRH cells were also identified in the nucleus of the lateral lemniscus and the cerebellum. Both nuclei presented strong ir-GHRH projections extending rostro-ventrally. At 11 weeks after hatching another group of ir-GHRH cells were revealed in the midbrain tegmentum. After that time the pattern of distribution of ir-GHRH structures remained unchanged. At 1 week after hatching and later, the pituitary gland consistently revealed ir-GHRH cells and fibers mainly in the proximalis pars distalis and in a minor proportion of the pars intermedia since week 1. The pineal gland showed ir-GHRH cells projecting into the pineal lumen, at week 6 after hatching and later. The pineal stalk and the subcomissural organ also presented ir-GHRH structures. Additionally, ir-GHRH material was found from week 3 to the adult stage in the following extraneural organs: gills, gut, kidney and hepatopancreas. These results represent the anatomical substrate for understanding the physiology of GHRH peptide in pejerrey, adding information on the ontogeny of neural structures expressing GHRH.

Distribution of Tissue Cysts in Organs of Rats Fed Toxoplasma gondii Oocysts

Toxoplasma gondii-infected rats are considered important in the epidemiology of toxoplasmosis because they can serve as a source of infection for pigs and possibly for cats. To study the distribution of tissue cysts, 10 Sprague-Dawley female adult rats were fed 1 oocyst (3 rats, group A) or 10(5) oocysts (3 rats, group B) of the VEG strain or 10(4) oocysts of the GT-1 strain (4 rats, group C) of T. gondii. All rats in a group were killed at 1 time: 76 (group A), 240 (group B), and 443 (group C) days after oocyst inoculation (DAI). Tissue cysts were seen in the brains of all 10 rats by direct microscopic examination. Portions or whole organs from heart, lung, liver, spleen, small intestines, kidneys, skeletal muscle, eyes, mesenteric lymph nodes, stomach uterus, and tongue from all rats in a group were pooled by organ, digested in acid-pepsin solution for 60 min, washed in saline, and then bioassayed in mice. Based on bioassay in mice, tissue cysts were present in 3 extraneural tissues of rats from group A, 6 extraneural organs of group B, and in 10 extraneural organs of rats of group C. Tissue cysts were present in skeletal muscles and kidneys of all 3 groups. Thus, tissue cysts are formed both in neural and extraneural tissues of rats. Therefore portions of infected rats, excluding the head, can be a source of infection for pigs and cats.

Intralesional administration of I-131 labelled monoclonal antibodies in the treatment of malignant gliomas.

The authors report their preliminary experience with the use of radiolabelled monoclonal antibodies (MAb) as an adjuvant treatment for 33 malignant gliomas. MAbs employed in this study are raised against Tenascin (TN) which is an antigen of the extracellular matrix of the tumour. It has also been found in neoplastic cells but never in normal brain tissue. This therapy is aimed to give a local high dose radiation (boost) while sparing healthy brain structures. This treatment has always been well tolerated and no adverse reactions at the level of CNS or major extraneural organs has been observed. Significant improvement of median survival has been obtained but this result should be cautiously evaluate since the study is non-randomized. Comparison with other current adjuvant technique is briefly discussed.

Amyloid precursor protein in peripheral mononuclear cells is up-regulated with cell activation.

The deposition of beta/A4 protein in extraneural organs of patients with Alzheimer disease suggests that this peptide may in part be derived from a peripheral precursor. We studied expression of amyloid precursor protein (APP) in PBMC. APP expression was detectable in resting PBMC by northern blot analysis, immunoblotting studies, and immunohistochemistry. By reverse transcription-polymerase chain reaction, the 751 and 770 APP transcripts containing the Kunitz protease inhibitor (KPI) domain were approximately 10-fold more abundant than the 695 transcript lacking the KPI domain. Activation of PBMC with the lectin PHA-P was associated with an increase in apparent intracellular APP content by cytofluorometry, and an increase in the proportion of the 695 APP transcript lacking the KPI domain. We conclude that resting and activated PBMC express APP and could contribute to a circulating pool of this protein. In addition, PBMC APP is up-regulated with mitogenic stimulation and may participate in the regulation of activation of these cells.

Primary spinal intramedullary malignant lymphoma. A case report

A rare case of primary malignant intramedullary lymphoma, localized in the cervical part of the spinal cord, is presented. The onset of clinical symptoms was associated with herpes zoster infection. Surgery led to the histological diagnosis. The clinical investigations excluded the presence of lymphoma in other sites in the central nervous system and in the extraneural organs. Postoperative irradiation and chemotherapy effected relict of neurological symptoms.

HISTOPATHOLOGICAL STUDIES OF NERVOUS SYSTEM TUMORS IN RATS INDUCED BY TRANSPLACENTAL ADMINISTRATION OF ETHYLNITROSOUREA

Sixteen pregnant rats of Donryu Strain were given intravenously with a single dose of 50 mg/ kg of Ethylnitrosourea (ENU) on the 15th day (Group I, 9 rats) and the 20th day (Group II, 7 rats) of gestation.A total of 126 tumors (Group I, 61 and Group II, 65) were produced in 92 of 117 treated offspring which had survived into tumor bearing age. The mean survival time of Group I rats with tumor developement was 317 days after brith and that of Group II rats was 276.The sites of the total of 126 tumors were formed as following : 27 were produced in the brain (Group I, 21 and Group II, 6), 21 in the spinal cord, 42 in the cranial nerve and ganglia, 8 in the spinal nerve roots, 6 in the peripheral nerves and 22 in the extraneural organs. The neural tumors amouted 104, comprising 82.5% of the total number of the neoplasm.Significant differences in incidence of the tumors of the brain and those in extraneural organs were demonstrated between Group I and Group II rats.According to the cytology and the pattern of predominant tumor cells, tumors of the brain and spinal cord were classified into the following types : mixed glioma (18), oligodendroglioma (18), anaplastic astrocytoma or anaplastic glioma (6), ependymoma-like tumor (5) and unclassified tumor (1). The histology of mixed glioma and oligodendroglioma were most common. 5 tumors produced in the spinal cord were classified as ependymoma-like tumor and they showed an isomorphic cell appearance with such architectural characteristics as crowns of cell nuclei around vascular vessels and pseudorosettes. No tumors were found with typical ependymal rosettes.Almost all the cranial nerve tumors were located in the trigeminal nerve and Gasserian ganglia, microscopically the majority of neurinomas were highly anaplastic with friquent mitotic figures.Besides grossly visible tumors, histological examinations of the brain and the spinal cord disclosed a total of 138 (Group I, 84 and Group II, 54) foci of glial cell hyperplasia or tumors of microscopic size. Sites of predilection for such foci or small microtumors were the subcortical white matter of the brain, the basal ganglia, the spinal cord, the hippocumpus and the periventricular areas. The predominant cell type of such lesions was either oligodendroglial or astrocytic glia. With increasing tumor size, a number of microtumors with a mixed cellular composition became frequent. There are no focus of the ependymal cell hyperplasia.The transplantation experiment demonstrated that anaplastic neurinomas were highly transplantable and capable of subsequent transfers through a number of generations.This experiment demonstrated that a single transplacental exposure of ENU was capable of inducing neuroectodermal tumors, and probably taget cells of it were the astroglia, the oligodendroglia and Schwann's sheath cells.

The diagnosis of Tay-Sachs disease.

SummaryGangliosides and neutral aminoglycolipids were determined in several organs from two subjects with classical Tay‐Sachs disease. Ganglioside GM2 was stored in all organs investigated. Of the extraneural organs, the highest concentration was found in the adrenals, spleen and liver. The rectal muscular layer had a high concentration of gangliosides. Rectal biopsy might be used for studies of the nervous ganglioside pattern.The brain tissue showed a many‐fold increase of the activities of p‐nitrophenylglycosi‐dases. The activity of ganglioside sialidase in the brain was not increased in Tay‐Sachs and some other neurometabolic diseases. Subfrac‐tionation of the glycohydrolases by ultracen‐trifugation showed no hexosaminidase activity in the supernatant fraction of the brain in Tay‐Sachs disease compared with about 2/3 of the total activity in normal human brain.A simple agarose electrophoretic method was developed for the separation of the hexosaminidases into two fractions, A and B. Hexosaminidase A was virtually absent in Tay‐Sachs disease.The known forms of gangliosidoses and their biochemical characteristics are reviewed and a scheme is given for their classification and diagnosis.

Changes in the fatty acid composition of cerebrosides and sulfatides of human nervous tissue with age

Sphingogalactolipids (galactocerebrosides and sulfatides) have been isolated in almost quantitative yields from normal human nervous tissue (mostly brain) at different ages and their fatty acid compositions have been determined by gas-liquid chromatography. The ratio of hydroxy acids to normal acids increased slightly during myelination and then remained rather constant; in adults the ratio for cerebrosides was about 2, and for sulfatides, 0.6-0.8. In adult nervous tissue the two predominant fatty acids of cerebrosides and sulfatides were the C(24) monounsaturated and 2-hydroxy saturated acids. The infant brain galactolipids had (compared with child and adult) a lower percentage of C(22)-C(26) fatty acids and a much lower percentage of monoenoic acids, both of normal and hydroxy acids. Low activities of fatty acid elongation and desaturation systems during myelination are inferred. Fatty acid changes with age were the same for cerebrosides and sulfatides but occurred later in the sulfatides, which supports the hypothesis that the cerebrosides are precursors of the sulfatides. The adult pattern of fatty acid composition with regard to degree of unsaturation and total percentage of C(22)-C(26) acids was reached as early as at 2 yr of age, but the percentage of odd-numbered (C(23) and C(25)) fatty acids continued to increase up to the age of 10-15 yr. The fatty acid composition of the galactolipids of peripheral nerves differed mainly in its lower percentages of C(25) and C(26) acids and higher percentages of C(22) and C(16) acids. This composition is thus intermediate between those of brain and of extraneural organs.