Myelin and White Matter

8/19/2019 Myelin and White Matter

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1.1 Introduction

Myelin makes up most of the substance of the whitematter in the central nervous system (CNS). It isalso present in large quantities in the peripheral ner-vous system (PNS). In both the CNS and the PNS,myelin is essential for normal functioning of thenerve fibers.

The white matter in the CNS is composed of a vastnumber of axons, which are ensheathed with myelin,which is responsible for the white color. Besidesmyelinated axons, white matter contains many cells of the neuroglia type,but no cell bodies of neurons.Theaxons it contains originate from neuronal cell bodiesin gray matter structures.

There are two main types of macroglia in the whitematter: astrocytes and oligodendrocytes. Among themany putative functions of glial cells, it is proposedthat they contribute to the structural and nutritivesupport of neurons, regulate the extracellular envi-ronment of ions and transmitters, guide migratingneurons during development, and play an importantpart in repair and regeneration. The best knownfunction of glial cells is the ensheathment of axonswith myelin by oligodendrocytes.

Gray matter contains the nerve cell bodies withtheir extensive dendritic arborization. The myelincontent of gray matter structures is much lower, but

some myelin is present around intracortical and in-tranuclear fibers. The myelin content of the thalamusand the globus pallidus is relatively high.

1.2 Morphology of Myelin

Myelin is a spiral membranous structure that is tight-ly wrapped around axons.It has a very high lipid con-tent and is soluble in fat solvents. Hence, when ordi-nary paraffin sections of the brain are prepared forlight microscopic examination, most of the myelindissolves away. After staining, the sites where myelinwas present appear as round spaces that are empty except that each has a little round dot in the center,which represents a cross section of the axon. By means of fixatives that make myelin insoluble, it ispossible to demonstrate it in paraffin sections. Osmicacid fixes myelin so that it does not dissolve in paraf-fin sections. Osmic acid itself stains myelin black.When examined under very low power, the whitematter appears black (Fig. 1.1). If the white matter isexamined under high power the myelin will be seento be arranged in small rings around each nerve fiber.There are several myelin stains that can be used oncethe tissue has been fixed by some other means. Com-monly used stains include hematoxylin, Luxol fastblue, and Oil-Red-O.

Myelin and White Matter

Chapter 1

Fig. 1.1. T2-weighted MR image compared with a

postmortem section prepared with a myelin stain,

illustrating the capability of MRI to reflect histology


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The information derived from light microscopicinvestigations is limited and is inadequate when moredetailed information about myelin structure is re-quired. Analysis of the structure of myelin began inthe 1930s, stimulated by polarization-microscopestudies and X-ray diffraction work, which led to thesuggestion that the myelin sheath was made up of layers or lamellae. The lamellar structure was con-firmed by electron microscopic studies. In electronmicrographs myelin is seen as a series of alternatingdark and less dark lines separated by unstainedzones. These lines are wrapped spirally around theaxon (Fig. 1.2). The evidence available from studiesusing polarized light, X-ray diffraction and electronmicroscopy led to the current view of myelin as a sys-tem of condensed plasma membranes with alternat-ing protein-lipid-protein-lipid-protein lamellae asthe repeating subunit.

Plasma membranes are composed predominantly of lipids and proteins, and also contain carbohydratecomponents. The lipid elements of the membranesare phospholipids, glycolipids, and cholesterol. Acommon property of these lipids is that they are am-phipathic. This means that the lipid molecules con-

tain both hydrophobic and hydrophilic regions, cor-responding to the nonpolar tails and the polar headgroups, respectively. Hydrophobic substances are in-

soluble in water, but soluble in oil. Conversely, hy-drophilic substances are insoluble in oil, but solublein water. In an aqueous environment, the amphipa-thic character of the lipids favors aggregation into mi-celles or a molecular bilayer. In a micelle (Fig. 1.3), thehydrophobic regions of the amphipathic moleculesare shielded from water, while the hydrophilic polargroups are in direct contact with water. The stability of this structure lies in the fact that significant freeenergy is required to transfer a nonpolar moleculefrom a nonpolar medium to water. Likewise, a greatdeal of energy is required to transfer a polar moiety from water to a nonpolar medium. Thus, the micelleprovides a minimal energy configuration and is ac-cordingly thermodynamically stable. The molecularbilayer, the basic structure of plasma cell membranes,also satisfies the thermodynamic requirements of amphipathic molecules in an aqueous environment.A bilayer exists as a sheet in which the hydrophobicregions of the lipids are protected from the waterwhile the hydrophilic regions are immersed in water(Fig. 1.4).As the structure of the bilayer is an inherentpart of the amphipathic character of the lipid mole-cules, the formation of lipid bilayers is essentially a

self-assembly process.In comparison with other molecular bilayers, themyelin bilayer is unique in having a very high lipid

Chapter 1 Myelin and White Matter2

Fig. 1.2. Electron micrograph of white matter with myelin sheaths

Fig. 1.3.

A micelle

Fig. 1.4.

A lipid bilayer


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content and containing chiefly saturated fatty acidswith an extraordinarily long chain length. This fatty acid composition leads to a closely packed,highly sta-ble membrane structure.The presence of unsaturatedfatty acids in a bimolecular leaflet leads to a moreloosely packed, less stable structure, as unsaturatedfatty acid chains have a kinked, hook-like configura-tion. Lipids containing such unsaturated fatty acidscannot approach neighboring molecules as closely assaturated lipids can,since the latter are rod-like struc-tures. There will be much less total interaction be-tween the tails of an unsaturated lipid and a neigh-boring molecule than between the tails of two satu-rated lipids, and the resulting binding forces will bemuch smaller. Lipids containing long-chain fatty acids are more tightly held in a membrane structurethan those containing shorter chain fatty acids, sincewith increasing length of the hydrocarbon chain thebinding interactions between the lipid molecules be-come stronger. It has also been suggested that very-long-chain fatty acids can form complexes by inter-digitation of the hydrocarbon tail on one side with thehydrocarbon tail of a lipid on the opposite side of thebimolecular leaflet. Such complexes would contributeto the stability of the myelin membrane. If this lipidcomposition is changed,as is the case in a number of demyelinating disorders, it is clear that the stability of the myelin membrane may be diminished.

The bimolecular lipid structure allows for interac-tion of amphipathic proteins with the membrane.These proteins form an integral part of the membrane,with hydrophilic regions protruding from the innerand outer faces of the membrane and connected by ahydrophobic region traversing the hydrophobic coreof the bilayer. In addition, there are peripheral pro-teins, which do not interact directly with the lipids inthe bilayer,but are bound to the hydrophilic regions of specific integral proteins. Thus,the cell membrane is a

bimolecular lipid leaflet coated with proteins on bothsides (Fig.1.5). There is inside-outside asymmetry of the lipids.In addition,integral and peripheral proteins

are asymmetrically distributed across the membranebilayer and the protein composition on the inside isdifferent from that on the outside of the bilayer.

On electron microscopic examination, a plasmamembrane is shown as a three-layered structure andconsists of two dark lines separated by a lighter inter-val. It is also revealed that the plasma membrane isnot symmetrical in form: the dark line adjacent to thecytoplasm is denser than the leaflet on the outside.

From both X-ray diffraction and electron micro-scope data it can be seen that the smallest radial sub-unit that can be called myelin is a five-layered struc-ture of protein-lipid-protein-lipid-protein (Fig. 1.6).The repeat distance is 160–180 Å. The dark lines seenin electron microscopic studies represent the proteinlayers and the unstained zones,the lipids.The unevenstaining of the protein layers results from the way themyelin sheath is generated from the plasma mem-brane. The less dark lines (so-called intraperiodlines) represent the closely apposed outer proteincoats of the original cell membrane. The dark lines(so-called major dense lines) are the fused inner pro-tein coats of the cell membrane. High-magnificationelectron micrographs show that the intraperiod lineis double in nature (Fig. 1.6).

The myelin sheath is not continuous along the en-tire length of axons, but axons are covered by seg-ments of myelin,which are separated by small regionsof uncovered axon, the nodes of Ranvier. The myelinlamellae terminate as they approach the node.The re-gion where the lamellae terminate is known as theparanode. Electron micrographs of longitudinal sec-tions of paranodal regions show that the major denselines open up and loop back upon themselves,enclos-ing cytoplasm within the loop (Fig. 1.7). In that partof the paranode most distant from the node, the in-nermost lamellae of the myelin terminate first, andsucceeding turns of the spiral of lamellae then over-

lap and project beyond the ones lying beneath. Thus,the outermost lamella overlaps all the others and ter-minates nearest the node, so that the myelin sheath

1.2 Morphology of Myelin 3

Fig. 1.5. Membrane split open to

demonstrate the layers.The lipid

bilayer is interrupted by proteins

embedded in this layer. Glycoprotein

chains rise from the surface of the

membrane


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gradually becomes thinner with increasing proximity to the node.

Schmidt-Lantermann clefts such as are describedin the PNS are rare in the CNS. These are funnel-shaped clefts within myelin sheaths.They contain cy-toplasm and extend from the soma of the myelin-forming cell to the inner end of the myelin sheath. Ina transverse section of a myelin sheath they appear asislands of cytoplasm between openings of the majordense lines.

There is considerable variation in the number of myelin lamellae in the sheaths surrounding differentaxons. Generally, the larger the diameter of the axonthe thicker its myelin sheath.In addition to this directrelationship between axon size and myelin thickness,the lengths of internodal segments also vary with thesize of the axon: the larger the nerve fiber, the greaterthe internodal length.

1.3 Oligodendrocytes

Oligodendrocytes are the key cells in myelination of the CNS.They are cells of moderate size with a smallnumber of short, branched processes. They are the

predominant type of neuroglia in white matter andare frequently found interposed between myelinatedaxons.Actual connections between oligodendrocytes

and myelin sheaths can be observed. In the gray mat-ter they aggregate closely around neuronal cell bod-ies, where they are called satellite oligodendrocytes.PNS myelin is formed by Schwann cells. The CNSmyelin membranes originate from and are part of theoligodendroglial cell membrane. The oligodendro-cytes form flat cell processes, which are wrappedaround the nerve axon in a spiral fashion (Fig. 1.8).


Fig. 1.6. The electron microscopic

picture of a myelin sheath (upper left )

reveals the five-layered structure of

myelin with major dense lines and

intraperiod lines. A higher magnifica-

tion of two myelin lamellae (lower left )

shows the periodicity of myelin even

more clearly. On the right , a schematic

representation of an electron micro-

scopic picture of a myelin sheath

surrounding an axon ( A) demonstrates

major dense lines (md ) and intraperi-

od lines (ip)

Fig. 1.7. Node of Ranvier, where the

nerve fiber between two myelinated

segments is bare.The outer myelin

layers envelope the inner layer and

cover these at the nodal junctions

Fig. 1.8. Diagram showing the axon being rolled in the myelin

sheath


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With the exception of the outer and lateral loops of the flat cell processes, the cellular cytoplasm disap-pears from these processes and the remaining cellmembranes condense into a compact structure inwhich each membrane is closely apposed to the adja-cent one. If myelin were unrolled from the axon itwould be a flat, spade-shaped sheet surrounded by atube containing cytoplasm.

Although the myelin sheath is an extension of theoligodendroglial cell membrane, the chemical com-position of myelin is quite different from that of theoligodendroglial cell membrane. The oligoden-droglial cell membrane is transformed into myelin inprocesses of modification and differentiation.

On the same axon, adjacent myelin segments be-long to different oligodendrocytes.A single oligoden-drocyte provides the myelin for many internodal seg-ments of different axons simultaneously. One oligo-dendrocyte can be responsible for the production andmaintenance of up to 40 nerve fibers (Fig. 1.9). Thishas implications for disease conditions and repara-tive processes, as the destruction of even only a few oligodendrocytes can have an extensive demyelinat-ing effect.

Together with the Schwann cells of the PNS, oligo-dendrocytes are unique in their ability to producevast amounts of a characteristic unit membrane. Theratio between cell body surface membrane andmyelin membrane is estimated at 1:620 in the case of oligodendrocytes. The deposition and maintenanceof such large expanses of membrane require optimalcoordination of the synthesis of its various lipid andprotein components and their interaction to ensureproduction of a stable membrane on the one hand

and a well-regulated and controlled breakdown andreplacement of spent components needed to supportthe myelin membrane on the other.

1.4 Astrocytes

Astrocyte functions have long been a subject of de-bate. Their major role has long been thought to be asort of skeletal function, providing packing for otherCNS components. It is becoming increasingly clearthat astrocytes are of fundamental importance inmaintaining the structural and functional integrity of neural tissue.

A well-known function of astrocytes is concernedwith repair. When damage is sustained, astrocytesproliferate, become larger, and accumulate glycogenand filaments. This state of gliosis can be total, inwhich case all other elements are lost, leaving a glialscar,or occur against a background of regenerating ornormal CNS parenchyma. Following demyelination,astrocytes synthesize growth factors thought to be in-volved in myelin repair.Astrocytes may also phagocy-tose debris in some conditions.

Astrocytes are involved in transport and in main-taining the blood–brain and CSF–brain barriers.End-feet of astrocytes form part of these barriers inperivascular and subpial regions. Endothelial tight

junctions form the primary seal of the blood–brainbarrier. The role of astrocytes in the blood–brain bar-rier is less well defined. They are physically separatedfrom endothelial cells by the basal lamina and do notcontribute directly to the physical barrier. Perivascu-lar astroglial end-feet contain many transport pro-teins, including transporters of monocarboxylates,glucose, and glutamate, as well as water. Aquaporin-4is the only known water channel in the brain and hasa localization in the astroglial end-feet.

Astrocytes play a part in the process of myelin de-

position. They promote the adhesion of oligodendro-cyte processes to axons and stimulate myelin forma-tion by local secretion of different growth factors.As-

1.4 Astrocytes 5

Fig. 1.9. Impression of the three-

dimensional structure of oligodendro-

cytes with their plasma membrane

extensions as myelin sheaths covering

the axons that cross their region


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trocytes and neurons are the sources of platelet-de-rived growth factor (PDGF), which promotes oligo-dendrocyte progenitors to proliferate, migrate, anddifferentiate. Astrocytes release basic fibroblastgrowth factor (bFGF), which promotes oligoden-droglial differentiation. Extension of oligodendro-cyte processes, a critical early step in myelin forma-tion, is facilitated by astrocytic bFGF. Insulin-likegrowth factor I (IGF-I), which plays a crucial role inoligodendrocyte development and myelin formation,is produced by various cells, including astrocytes. Itacts as an oligodendrocyte mitogen and a differentia-tion and survival factor and is one of the main regu-lators of the amount of myelin production.Astrocytesexpress neurotrophin-3 (NT-3), which promotes pro-liferation of oligodendroglial precursors and oligo-dendrocyte survival. There is evidence that NT-3 incombination with brain-derived neurotrophic factor(BDNF) can induce proliferation of endogenousoligodendrocyte progenitors and the subsequentmyelination of regenerating axons. Astrocytes andoligodendrocytes communicate via gap junction-me-diated contacts.

Astrocytes have a role in the conduction of nerveimpulses.Astrocytes and axons have an intimate rela-tionship at the node of Ranvier. Perinodal astrocytesand nodal parts of the axon have a high concentrationof sodium channels, indicating specialization of as-trocyte function at these sites.

Synthesis of the neurotransmitters glutamate andGABA (gamma aminobutyric acid) can originate ei-ther from glutamine or from α-ketoglutarate or an-other tricarboxylic acid cycle intermediate plus anamino acid as a donor of the amino group. Neuronslack the enzymes glutamine synthetase and pyruvatecarboxylase, which are present exclusively in astro-cytes. Astrocyte processes in perisynaptic regionstake up the excitatory neurotransmitter glutamatefrom the synapse and recycle it to its precursor gluta-mine. Therefore, astrocytes are important in the syn-thesis and recycling of some neurotransmitters andprotect neurons from excitotoxicity.

1.5 Biochemical Compositionof Mature Myelin and White Matter

The most conspicuous feature of the composition of myelin as opposed to other membranes is the high ra-tio of lipid to protein. It is one of the most lipid-richmembranes, lipids making up 70–80% lipid by dry weight. In comparison with other membranes, theprotein concentration of 20–30% is low. For example,

the concentration of protein in liver cell membranesis 60 %. Myelin is a relatively dehydrated structure,containing only 40% water.

CNS white matter is half myelin and half non-myelin on a dry weight basis. Owing to the highmyelin content, white matter has a relatively low wa-ter content and a high lipid content.The water contentof white matter is 72% and that of gray matter 82%.The nonmyelin portion of white matter containsabout 80% water.

Myelin is mainly responsible for the gross chemicaldifferences between white and gray matter. Myelin isrich in all lipid classes, although nonpolar lipids andglycolipids (galactolipids) are particularly well re-presented. The lipids of CNS myelin are composed of 25–28% cholesterol, 27–30% galactolipid, and 40–45% phospholipid when expressed as percentages of total lipid weight. When lipid data are expressed asmolar ratios, CNS myelin preparations contain cho-lesterol,phospholipid and galactolipid in a ratio vary-ing between 4:3:2 and 4:4:2.

The biochemical composition of mature gray andwhite matter is shown in Table 1.1. With respect towhite matter,separate figures are given for the myelinand nonmyelin portions, CNS white matter being half myelin and half nonmyelin on a dry weight basis. InTable 1.1 the lipid figures are expressed as percent-ages of total lipid weight. Since the water content andthe dry weight lipid content of gray matter and whitematter, myelin and nonmyelin, differ widely, the fig-ures expressed in this way give no direct informationabout lipid concentration in either dry or wet tissue.However, from the data presented, these concentra-tions can be calculated.

When the lipid compositions of gray and whitematter are compared, the most conspicuous differ-ence to emerge is that white matter is relatively rich ingalactolipids and relatively poor in phospholipids.Galactolipids (galactocerebroside and sulfatide) con-stitute 25–30% of the lipids in white matter, whereasthey account for only 5–10% of those in gray matter.Phospholipids account for two-thirds of the totallipids in gray matter,but less than half those in whitematter. There are, strictly speaking,no myelin-specif-ic lipids that are not found elsewhere in the brain.However, the most specific distinguishing feature of myelin lipids is the high cerebroside content, andcerebroside can be considered the most typicalmyelin lipid. During development, the concentrationof cerebroside in brain is directly proportional to theamount of myelin present.

Ethanolamine phosphoglyceride in plasmalogenform (plasmenylethanolamine) is the major myelinphospholipid. Approximately 80% of the ethanol-amine phosphoglycerides of myelin and white matterare present in plasmalogen form, and only a smallproportion are formed by phosphatidylethanol-

amine.Conversely,the plasmalogens,which comprisenearly one-third of the total phospholipids,are main-ly of the ethanolamine type with lesser amounts of



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plasmenylserine. Phosphatidylcholine is the majorcholine phosphoglyceride; only traces of cholinephosphoglyceride have the plasmalogen form.

Gangliosides are minor myelin lipids and make uponly 0.3–0.7% of total myelin lipids. They are local-ized mainly in neuronal membranes, and gray matteris 10 times as rich in gangliosides as in white matter.Gangliosides are complex sialic acids containingglycosphingolipids. GM1, a monosialoganglioside, isthe major myelin ganglioside accounting for about70 mol % of the total myelin ganglioside content.Within the CNS, the ganglioside GM4 (sialogalacto-sylceramide) is probably specific for myelin andoligodendroglia. It is a derivative of cerebroside.

Myelin lipids contain somewhat different fatty acidconstituents than other membranes.Characteristic of myelin are α-hydroxy fatty acids in cerebrosides andsulfatides and high amounts of long-chain fatty acidsin the different lipid classes. There are monounsatu-rated fatty acids, but only low amounts of polyunsat-urated fatty acids.

Table 1.2 shows the chemical structures of themain lipid constituents of myelin.

The protein composition of myelin is simpler thanthat of other membranes. Proteolipid protein andmyelin basic protein encompass approximately 60–80% of the total protein. Most myelin proteins areunique to myelin.

Proteolipid protein (PLP) and its isoform DM 20make up about 50% of the total protein in CNSmyelin.Their concentration in white matter is about 5

times that in gray matter.The proteins are encoded by the same gene and are formed by alternative splicingof the primary gene transcript. The proteins differ by a hydrophilic peptide 35 amino acids in length,whosepresence generates PLP. DM 20 is predominant in ear-ly development, whereas PLP is the major protein inmature myelin. The proteins are very hydrophobic.

There are multiple isoforms of myelin basic pro-tein (MBP),arising from different patterns of splicingof the primary gene transcript. The heterogeneity isincreased further by various posttranslational modi-fications. Myelin basic proteins account for 30–35%of the total myelin protein.MBP contains no extensiveregions of hydrophobic residues and is hydrophilic.MBP is the antigen which, when injected into an ani-mal, elicits a cellular immune response,producing theCNS autoimmune disease called experimental aller-gic encephalomyelitis.

There are several CNS myelin glycoproteins:myelin-associated glycoprotein (MAG), myelin/oligo-dendrocyte glycoprotein (MOG), and oligodendro-cyte-myelin glycoprotein (OMgp). These are high-molecular-weight proteins. They are quantitatively minor myelin components: MAG accounts for about1% of total protein and MOG, for 0.05%.

Other minor myelin proteins are oligodendrocyte-specific protein (OSP), which is a tight junctionprotein, myelin-associated oligodendrocytic basic

protein (MOBP), a small basic protein distributedthroughout compact myelin, and myelin/oligoden-drocyte-specific protein (MOSP),which is located on

1.5 Biochemical Composition of Mature Myelin and White Matter 7

Table 1.1. Composition of human CNS gray matter,white matter,myelin portion and nonmyelin portion of whole white matter.From Norton and Cammer (1984)

Gray matter White matter Myelin Nonmyelind

Watera 82 72 44 82

Total proteinb 55.3 39.0 30.0 62.2

Total lipidb 32.7 54.9 70.0 41.2

Cholesterol 22.0 27.5 27.7 14.6

Glycolipids 7.3 26.4 27.5 28.2

Cerebroside 5.4 19.8 22.7 19.9

Sulfatide 1.7 5.4 3.8 7.7

Phospholipids 69.5 45.9 43.1 51.9

Ethanolamine PG 22.7 14.9 15.6 6.8

Choline PG 26.7 12.8 11.2 16.5

Serine PG 8.7 7.9 4.8 20.4

Inositol PG 2.7 0.9 0.6 1.0

Sphingomyelin 6.9 7.7 7.9 5.6

Plasmalogensc 8.8 11.2 12.3 9.2

a Percentage of total brain weightb Figures for total protein and total lipid are percentages of dry weight; all others are percentages of total lipid weightc Plasmalogens are primarily ethanolamine phosphoglyceridesd Figures for bovine brain, which are thought to be in close agreement with those for human brain (Norton and Autilio 1966)PG phosphoglycerides


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Table 1.2. Structure of the important myelin lipids

Cerebroside sphingosine galactose

fatty acid

Sulfatide sphingosine galactose sulfate

fatty acid

Phosphatidylethanolamine fatty acid

glycerol fatty acid

phosphate ethanolamine

Phosphatidylcholine = lecithin fatty acid

glycerol fatty acid

phosphate choline

Phosphatidylserine fatty acid

glycerol fatty acid

phosphate serine

Phosphatidylinositol fatty acid

glycerol fatty acid

phosphate inositol

Ethanolamine plasmalogens *fatty acid

glycerol fatty acid

phosphate ethanolamine

Sphingomyelin sphingosine fatty acid

phosphate choline

GM3 ganglioside N-acylsphingosine

glucose

galactose N-acetylneuraminic acid


glucose


N-acetylgalactosamine


glucose


N-acetylgalactosamine

galactose

Sphingolipids of myelin are formed from sphingosine. N-acylsphingosine is termed ceramide. A phosphorylcholine group at-tached to ceramide forms sphingomyelin;glucose or galactose in glycosidic linkage forms cerebroside (most often: galactosylce-ramide).When the glucose or galactose is esterified with sulfate, sulfatide is formed.Phosphoglycerides contain two fatty acidsin ester linkage at the α and β position of glycerol and at the α’position a phosphate group to which the moiety definitive of the

class is linked. For example, a choline group defines phosphatidylcholine.The plasmalogens are similarly formed, except that atthe α position of the glycerol there is a 1:2 unsaturated ether structure ( *). Gangliosides are synthesized from N -acylsphingosineby stepwise addition of sugars and N -acetylneuraminic acid.


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the extracellular surface of oligodendrocytes andmyelin.

Highly purified myelin contains a number of en-zymes. Two of these enzymes, 2’,3’-cyclic nucleotide3’-phosphodiesterase (CNP) and a cholesterol esterhydrolase, are found at much higher specific activitiesin myelin than in brain homogenates. It appearsthat these enzymes are fairly myelin specific, and areprobably also present in oligodendroglial mem-branes. Many other enzymes are found that are notspecific to myelin but also present in other brain frac-tions. The exact function of the two enzymes is notknown.In particular,their contribution to the metab-olism of myelin constituents is not known. CNP cat-alyzes the hydrolysis of several 2’,3’-cyclic nucleotidemonophosphates, all of which are converted to thecorresponding 2’-isomer. The substrates of the en-zyme are not present in nervous tissue. CNP is one of the proteins formerly called Wolfgram proteins,a het-erogeneous group of high-molecular-weight myelinproteins named after the investigator who first sug-gested that myelin contained proteins other than pro-teolipid protein and myelin basic protein.

1.6 Molecular Architecture of Myelin

The currently accepted view of the myelin structure isthat of a double lipid bilayer, each coated on bothsides with protein. The resulting repeating subunitconsists of radial protein-lipid-protein-lipid-proteinlamellae. Some proteins are fully or partially embed-ded in the bilayer, and others are attached to the sur-face by weaker linkages.

Both proteins and lipids have an asymmetrical dis-tribution. Galactolipids, cholesterol, phosphatidyl-choline, and sphingomyelin are preferentially locatedin the former extracellular half of the bilayer (in-traperiod line). Ethanolamine plasmalogen andmyelin basic protein are preferentially located in theformer cytoplasmic half of the bilayer.

Membranes are fluid structures. Lipid moleculesdiffuse rapidly in the plane of the membrane, as doproteins, unless anchored by specific interactions.The spontaneous rotation of lipids from one side of the membrane to the other is a very slow process. Thetransition of a molecule from one membrane surfaceto the other is called transverse diffusion,or flip-flop.In view of the asymmetry of lipids in the bilayer, thetransverse mobility must be limited. The diffusionwithin the plane of the membrane is referred to aslateral diffusion.

Proteolipid protein consists of alternating hydro-philic and hydrophobic sequences with four stretches

of hydrophobic residues that are of sufficient lengthto span the lipid bilayer. It is an integral membraneprotein that passes through the bilayer four times

(four transmembrane domains). The hydrophobictransmembrane segments are linked by hydrophilicportions on both sides of the membrane. This meansthat the protein has domains in both the intraperiodand the major dense lines. Probably both isoforms,PLP and DM 20, are involved in stabilizing the in-traperiod line. Their role is described as that of ‘ad-hesive struts’ or ‘spacers,’ maintaining a set distancebetween apposed lamellae.DM 20 is the major proteo-lipid protein in early development, whereas PLP isthe major product in mature myelin. It is believed thatDM 20 has a still unidentified regulatory role in early oligodendrocyte progenitor development and differ-entiation, and that PLP plays a part later on in oligo-dendrocyte function, in the proper formation of theintraperiod line of myelin during its final elaborationand compaction.

Myelin basic protein is an extrinsic protein locatedon the cytoplasmic face of the myelin membranes atthe major dense lines. It probably stabilizes the majordense lines by keeping the cytoplasmic faces of themyelin lamellae in close apposition. Myelin-associat-ed oligodendrocytic basic protein is another smallbasic protein distributed throughout compact myelinat the major dense lines.There is evidence that MOBPreinforces the apposition of the cytoplasmic faces of the myelin sheath.

Gangliosides are located almost entirely on theexternal surface of membranes.They may have an im-portant role in cell surface recognition and signaltransduction processes such as those that occur dur-ing myelination.

Myelin glycoproteins are transmembrane proteinswith the polypeptide extending through the lipid bi-layer and the glycosylated portion of the molecule ex-posed on the outer surface of the bilayer. They are allimplicated in recognition and cell–cell interactions.

MAG is one of these proteins. Its external regioncontains immunoglobulin-like domains. Thus, MAGis a member of the immunoglobulin superfamily. It isconcentrated in the inner periaxonal membrane of the myelin sheath and absent from the compact mul-tilamellar myelin sheath.The exposed,periaxonal po-sition is compatible with its postulated involvementin oligodendrocyte–axon interaction, includingmaintenance of the structural integrity of the glia–axon adhesion in mature myelin. The observationthat the protein can be detected at the very earlieststages of myelination has led to the hypothesis thatthe protein may also play a role in mediating theoligodendrocyte-axon recognition events that pre-cede myelination and specify the initial path of myelin deposition.

MOG is another of the myelin glycoproteins. It

also belongs to the immunoglobulin superfamily. Theprotein is located at the outermost layer of the myelinsheath and the oligodendrocyte plasma membrane.

1.6 Molecular Architecture of Myelin 9


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The function of this glycoprotein is unknown. It may be involved in the adhesion between neighboringmyelinated fibers and function as glue in the mainte-nance of axon bundles in the CNS. MOG may also bea cell surface receptor that transduces signals fromthe external milieu to the inside of the oligodendro-cyte or myelin sheath.

The enzyme CNP is found in myelin and oligoden-drocytes. Within the myelin sheath it is localizedon the cytoplasmic side of noncompact regions, e.g.,periaxonally and in the paranodal loops. CNP isessential for axonal survival but not for myelin as-sembly.

1.7 Myelinogenesis

The time-course of the appearance of newly synthe-sized lipids and proteins in myelin indicates thatmyelin is not laid down as a unit. Different compo-nents are synthesized and processed in different cel-lular compartments, are transported to the sites of myelin formation by different mechanisms, and show different rates of entry into the myelin sheath. For ex-ample, MBP enters the myelin sheath with almost nolag after synthesis, whereas proteolipid protein entersmyelin with a lag-time of 30–40 min following syn-thesis. Once protein synthesis is stopped with cyclo-heximide, the entry of MBP is halted immediately, butproteolipid protein continues to be incorporated intomyelin for 30 min. These data indicate that MBP andPLP are assembled by different mechanisms, withPLP taking a longer and more circuitous routethrough the cytoplasm. Lipids also continue to be in-corporated into myelin for 4 h after protein synthesishas stopped.

MBP is synthesized on free polyribosomes nearthe plasma membrane or the adjacent myelin sheath.The myelin membrane is surrounded by and infiltrat-ed with cytoplasmic channels, called the outer loopsand longitudinal incisures of Schmidt-Lantermann,respectively. Myelin basic protein mRNA is trans-located from the nucleus to the myelin membrane viathese cytoplasmic channels. MBP synthesized here israpidly sequestered into the myelin sheath and ap-pears in the cytoplasmic leaflet of compact myelin(major dense lines). mRNAs for several other myelinproteins follow similar trafficking pathways.

Proteolipid protein and DM20 are synthesized onpolyribosomes bound to the endoplasmic reticulum.The nascent protein is inserted into the endoplasmicreticulum and passes through the Golgi apparatus tothe plasma membrane and myelin sheath via vesicu-lar transport. Inclusion in the plasma membrane

occurs by fusion of the vesicles with the plasma mem-brane. The inside of the vesicle after fusion becomesthe outside of the plasma membrane. As a conse-

quence, substances transported to the plasma mem-brane via vesicles end up in the extracellular leaflet of the myelin sheath. MAG resembles proteolipid pro-tein as far as the site of synthesis and transport to theplasma membrane are concerned.

The same two mechanisms of synthesis and trans-port can be distinguished for myelin lipids, i.e., theroutes of PLP and MBP, respectively. The endoplasmicreticulum is the site of synthesis of phosphatidyl-choline and cholesterol. The Golgi apparatus is thesite of synthesis of cerebroside, sulfatide, sphin-gomyelin, and gangliosides. The lipids are transport-ed from the Golgi apparatus to the plasma membraneby a vesicle-mediated process. Expression on the cellsurface occurs by fusion of the vesicles with the plas-ma membrane. The lipids are located predominantly in the extracellular leaflet of the myelin lamellae. Incontrast,the myelin phospholipids that predominant-ly reside on the inner leaflet, including phos-phatidylserine and ethanolamine plasmalogens, aresynthesized in the superficial cytoplasmic channelsof the myelin sheath and rapidly enter compactmyelin, possibly with phospholipid transfer proteinsas carriers. Several other phospholipids are also syn-thesized in the superficial cytoplasmic channels.

After reaching the outermost myelin layers, sub-stances penetrate to the deepest layers over a periodof a few days. This movement of substances from out-er to inner layers occurs at rates consistent with later-al diffusion along the spirally wound bilayer.

1.8 Regulationof Myelinogenesis

Elaboration of the myelin sheath involves a precisely ordered sequence of events beginning with the initialensheathment of the axon, proceeding to formationof multiple loose wrappings and eventually com-paction to form the mature multilamellar myelinsheath. These processes imply a temporally regulatedprogram of gene expression in the oligodendrocyteto ensure that the appropriate biochemical compo-nents are synthesized in the appropriate proportionsat each stage of myelinogenesis. Just before the onsetof rapid myelin membrane synthesis the expressionof genes of myelin proteins is sharply up-regulat-ed. There is evidence of a coordinated mechanismfor synchronous activation of the myelin proteingenes. This period of sharp up-regulation of ex-pression of myelin genes is the most vulnerable partof the myelination process and is called the criticalperiod.

Apparently, there are both tissue-specific and

stage-specific mechanisms controlling myelin genes.Myelin genes are only expressed in oligodendrocytesand Schwann cells. The expression of the genes is de-



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velopmentally regulated and is probably intimately associated with the stage of differentiation of thesecells. Control mechanisms are active at the transcrip-tional level. Regulatory regions, including the pro-moter regions, have been identified for myelin pro-tein genes. Key sites for tissue-specific expression of myelin proteins are clustered near the promoter re-gions,and within these clusters are several motifs thatmay be involved in coordinating the regulation of myelin-specific genes. The alternative splicing pat-terns produced from the primary myelin proteintranscripts are also developmentally regulated. Thesplicing patterns for the different proteins have beenshown to change in the course of development.

In both the CNS and the PNS, glial cells are influ-enced to produce myelin by both neuronal targetsthat they ensheathe and by a range of hormones andgrowth factors produced by neurons and astrocytes.There is a continuous oligodendrocyte-neuron-astro-cyte interaction in the process of myelination andmyelin maintenance.

Proliferation of oligodendrocyte precursor cellsdepends on electrical activity of neurons. Oligoden-drocyte number is also dependent on number of axons. Differentiation of oligodendroglia has beenshown to depend heavily on the presence and theintegrity of axons. Gene expression for myelin con-stituents is modulated by the presence of axons.Within oligodendrocytes, proteins are produced thatare thought to be involved in the induction of myeli-nation (e.g., glia-specific surface receptors for differ-entiation signals), in the initial deposition of themyelin sheath (e.g., axon-glial adhesion molecules),and in its wrapping and compaction around the nerveaxon (e.g., structural proteins of compact myelin). Aminimal axonal diameter is important for the initia-tion of myelination. Final myelin sheath thickness isalso related to axonal size. This match is reached by local control mechanisms. Therefore, a single oligo-dendrocyte can be associated with several axons of different sizes, the myelin sheaths being thicker forlarger axons. Larger axons also have longer inter-nodes.

Astrocytes are essential in the process of myelina-tion and myelin maintenance. They produce trophicfactors, including PDGF, bFGF, IGF-I,and NT-3.Thesefactors promote proliferation, migration and differ-entiation of oligodendrocyte progenitors, extensionof oligodendrocyte processes, adhesion of oligoden-drocyte processes to axons, myelin formation andmyelin maintenance.

Hormones have a dramatic effect on myelinogene-sis.A deficiency of growth hormone during the criti-cal period leads to hypomyelination. Most of the ef-

fects of growth hormone are mediated by IGF-I. Ad-ministration of this substance in early developmentleads to an increase in all brain constituents, but par-

ticularly and disproportionately in the amount of myelin produced per oligodendrocyte. Thyroid hor-mone also has an effect on myelinogenesis. Hypo-thyroidism during early development leads to hy-pomyelination, whereas hyperthyroidism acceleratesmyelination. Steroids have a complex influence. Noneof the myelin protein genes is transcriptionally regu-lated by steroids,but steroids probably act at the post-translational level,stimulating the translation of MBPand PLP mRNAs and inhibiting the translation of CNP mRNA.

The importance of iron in myelination has beenexamined. Iron and the iron mobilization proteintransferrin are localized in oligodendrocytes, andmay participate in the formation and/or maintenanceof myelin by complexing with enzymes involved inthe synthesis of myelin components.

Myelination is vulnerable to undernourishment. If there is undernourishment during the critical period

just prior to the onset of rapid myelin synthesis,myelination is more severely reduced than total brainweight, whereas the number of oligodendrocytes isunaltered.The hypomyelination is permanent.Severeundernutrition during the critical period leads to de-creased levels of IGFs and a failure in up-regulation of myelin genes.

Successful myelination is also dependent on func-tion. It is known that myelination is diminished by preventing the conduction of impulses in a nerve. Im-pulse conduction is a stimulus to myelination.Prema-ture activity accelerates myelination. Hypermyelina-tion has incidentally been noticed in cerebral anom-alies, supposedly via the stimulus of epilepsy. It hasbeen shown that oligodendrocyte progenitor cellsexpress adenosine receptors, which are activated inresponse to action potential firing. Action potentialfiring leads to the nonsynaptic release of several sub-stances from axons, including ATP and adenosine.Adenosine acts as a potent neuroglial transmitter toinhibit oligodendrocyte progenitor cell proliferation,stimulate differentiation, and promote the formationof myelin.

After formation the myelin sheath and the axon re-main mutually dependent. The myelin sheath needsan intact axon,as demonstrated by the studies on wal-lerian degeneration. On the other hand, for mainte-nance of the normal structure and function the axonrequires an intact myelin sheath. Normal astrocytesare essential for an intact myelin-axon unit.

Since myelin, once deposited, is a relatively stablesubstance metabolically, it is relatively invulnerableto adverse external factors. Generalized vulnerability of myelin to noxious agents and adverse influences islikely to be confined to the period just before and dur-

ing active myelination.

1.8 Regulation of Myelinogenesis 11


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1.9 Myelination of the Nervous System

Myelination of each of the multiple connecting fibersystems of the CNS takes place at a different time inearly development. Some fiber systems start to myeli-nate halfway through gestation or later and rapidly attain their maximal degree of myelination, whereasother systems attain their maximal degree of myeli-nation only slowly.It is, therefore, not correct to referto myelination as a singular process. There is amarked, temporal diversity in topographic patternsof myelination throughout the last half of gestationand during the first 2 postnatal years. Thus, at any time in the early development of the human brainthere are multiple separate or intermixed regionsof unmyelinated, partly myelinated, or completely myelinated tracts.

Myelination of the nervous system follows a fixedpattern consisting of ordered sequences of myelinat-ing systems apparently governed by some rules:1. The first rule, probably governing all other rules,

is that tracts in the nervous system become myeli-nated at the time they become functional.

2. Most tracts become myelinated in the direction of the impulse conduction.

3. Myelination starts in the PNS before it starts in theCNS.

4. Myelination in central sensory areas tends to pre-cede myelination in central motor areas.

5. Myelination in the brain occurs earlier in areas of primary function than in association areas.

6. Roughly speaking, myelination progresses fromcaudal (spinal cord) to rostral parts (brain) andspreads from central (diencephalon, pre- andpostcentral gyri) to peripheral parts of the brain.However, there are many exceptions to this rule.

It is important to note that the times mentioned be-low for myelination of the different tracts and struc-tures of the brain are only generalizations and ap-proximations. In the first place,there is a considerabledegree of normal variation. Secondly, the onset of myelination is difficult to define. It can be defined asthe first myelin tube found on light microscopicexamination, as the appearance of the first myelinlamella on ultrastructural examination,or as the firstevidence of the presence of myelin constituents in im-munological investigations.

In the 4th month of gestation myelin is first seen inthe anterior motor roots and soon appears in the pos-terior roots.

In the 5th month of gestation myelination starts inthe dorsal columns of the spinal cord and the anteri-or and lateral spinothalamic tracts for conduction of

somatesthetic stimuli.

In the 6th month of gestation myelination pro-ceeds rapidly cephalad in the medial lemniscus andspinothalamic tracts in the brain stem tegmentum.Myelin begins to appear in the statoacoustic tectumand tegmentum and the lateral lemniscus for the con-duction of acoustic stimuli. Myelin is seen in the in-ner, vestibulocerebellar part of the inferior cerebellarpeduncle.

In the 7th month of gestation myelination is stilllargely confined to structures outside the dien-cephalon and cerebral hemispheres. Progress of myelination is seen in the optic nerve, optic chiasmand tracts,inferior cerebellar peduncle,the parasagit-tal part of the cerebellum, the descending trigeminaltract, superior cerebellar peduncle, capsule of the rednucleus, capsule of the inferior olivary nucleus,vestibulospinal, reticulospinal and tectospinal de-scending tracts to the spinal cord and posterior limbof the internal capsule.

In the eighth month of gestation, myelinationstarts in the corpus striatum (in particular globuspallidus), anterior limb of the internal capsule, sub-cortical white matter of the post- and precentral gyri,rostral part of the optic radiation as well as corti-cospinal tracts in midbrain and pons, transpontinefibers, middle cerebellar peduncles and cerebellarhemispheres.

In the ninth month of gestation, myelination con-tinues in the thalamus (in particular ventrolateral nu-cleus), putamen, central part of the corona radiata,distal part of the optic radiation, acoustic radiation,anterior commissure,midportion of the corpus callo-sum and fornix.

However, in a child born at term,most of the struc-tures and tracts mentioned are not fully myelinatedand, in fact, in some myelination has just started.Apart from some myelin in the central tracts of thecorona radiata connected with the pre- and postcen-tral gyri, and the primary optic and acoustic radia-tions, the cerebral hemispheres are still largely un-myelinated. During the first postnatal year, myelinspreads throughout the entire brain. By the postnatalage of 12 weeks myelination is well advanced in thecorona radiata, the optic radiation and the corpus cal-losum, but the frontal and temporal white matter arestill largely unmyelinated. By the age of about 8months, the adult state is foreshadowed in that noneof the fiber systems is still completely devoid of myelin sheaths. Myelin sheaths are still sparse in thetemporal and frontal areas. It is not until the end of the second postnatal year that an advanced state of myelination is seen in all subcortical areas. Histologi-cally, myelination reaches completion in early adult-hood.



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1.10 Compositional Changesin the Developing Brain

The DNA content of brain is considered to be a reli-able indicator of cell number. The period of cellularproliferation can, therefore,be followed by measuringthe amount of DNA per brain volume. In human braintwo major periods of cell proliferation have been de-tected by measuring DNA levels. The first period be-gins at 15–20 weeks of gestation and corresponds toneuroblast proliferation. The second period begins at25 weeks of gestation and continues into the 2nd yearof postnatal life. This latter period corresponds tomultiplication of glial cells and includes a secondwave of neuronogenesis,producing mainly cerebellarneurons.

The ratio of protein to DNA indicates cell size. Thisratio increases after neuronal division ends,reflectingin part the arborization of neuronal processes. Themaximum ratio of protein to DNA is reached at2 years of age.

The outgrowth of neuronal axons and dendritesresults in a rapid increase in total ganglioside contentin the brain. Increasing lipid content indicates mem-brane formation with, in particular, an increase inquantity of axonal,dendritic,and myelin membranes.The increasing lipid content is associated with a con-comitant decrease in water content. The most rapidincrease in lipid content of the brain begins after theperiod of greatest increase of DNA and protein and isclosely related to the onset of myelination.

At birth, cerebral hemispheric white matter con-tains very little myelin and the white matter composi-tion of neonates is very different from the composi-tion of mature myelinated white matter. There is animportant overall decrease in water content of thebrain after birth and the change in water content islarger for white matter than for gray matter. The wa-ter content of neonatal gray matter is about 89% andof neonatal unmyelinated white matter about 87%,whereas the water content of adult gray matter is esti-mated to be 82% and of adult myelinated white mat-ter 72%.The lipid composition of cerebral white mat-

ter at different ages is shown in Table1.3. A majorchange is an increase in total lipid content, with a rel-ative increase in glycolipids. One of these, cerebro-side, is usually considered to be a marker for myelinas it is deposited at the same rate in the brain asmyelin. However, cerebroside is not restricted tomyelin and as much as 30% of it may be present inmembranes other than myelin. There is a relative de-crease (but absolute increase) in phospholipids in thewhite matter,which were relatively high in concentra-tion in unmyelinated white matter and are relatively low in concentration in myelin. The relative contribu-tion of cholesterol to total lipids remains constant,but the absolute cholesterol content of white matterincreases with deposition of myelin. The changes ingray matter composition are much less important.Myelin deposition in gray matter is minor.

The changes in white matter composition are notcaused only by glial cell proliferation,growth of axonsand dendrites, and myelin deposition, but also by some changes in myelin composition. The composi-tion of the myelin first deposited is somewhat differ-ent from that in adults. The most important changesare an increase in cholesterol and glycolipids as a pro-portion of total lipid and a decrease in phospholipids.In the immature brain significant amounts of glucoseare present in the glycolipids, whereas in a maturebrain glycolipids are present mainly as galactolipids.In contrast to the modest decrease in total phospho-lipids, more marked variations in the relative contri-bution of individual phospholipids are found. Sphin-gomyelin and ethanolamine phosphoglycerides in-crease, whereas choline phosphoglycerides decline.The molar ratio of galactolipids and choline phos-phoglycerides appears to be a sensitive marker of myelin maturation.

In human unmyelinated white matter much of thecholesterol present is esterified. The same is true forcholesterol in newly formed myelin. During myelinmaturation there is a decrease in the amount of cho-lesterol esters,and in adult white matter cholesterol ispresent almost entirely in the free form. The ratio of cholesterol to phospholipids in myelin increases after

1.10 Compositional Changes in the Developing Brain 13

Table 1.3. Lipid composition of human brain during development. From Svennerholm (1963)

Lipid composition of (frontal) cerebral cortex Lipid composition of (frontal) cerebral white matter

Age 2 months 1 year 5 years 2 months 1 year 5 years

Total lipidsa 28.4 31.3 29.5 29.5 49.6 58.2

Cholesterolb 21.5 19.8 19.3 26.4 25.0 24.4

Phospholipidsb 76.8 7.6 75.6 66.1 53.4 49.8

Glycolipidsb 1.8 2.6 4.1 7.5 21.6 25.8

a Expressed as percentage of dry weightb Expressed as percentage of total lipid weight


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birth and reaches the adult value at about 5 years of age.The ratio of galactolipids to phospholipids reach-es the adult value at about the same time.

During development the ganglioside compositionof myelin becomes simplified. The polysialoganglio-sides decline and the monosialoganglioside GM1 con-tent approaches about 90 % of the total gangliosideswith increasing age. The total ganglioside contentremains constant.

Maturation of myelin is accompanied by an in-crease in hydroxy fatty acids and saturated and mo-nounsaturated fatty acids.

Maturation of myelin is also accompanied by changes in the proteins.As the brain matures there isa change in occurrence of the major isoforms of themajor myelin proteins. For example, initially, early inmyelination, DM 20 is the principal isoform, whereasin adult brain DM 20 is present at much lower levelsthan the isoform PLP. With advancing developmentthe contribution of PLP and MBP to myelin proteinsshows a relative increase, whereas the high-molecu-lar-weight proteins decrease.

On the whole, the differences in chemical compo-sition of immature myelin and adult myelin are notstriking, which suggests that only subtle remodelingof myelin occurs in humans once myelination hasstarted. The major difference between white matterearly in life and in adult life seems to be the quantity of myelin rather than its quality.

1.11 Myelin Turnover

The principal features of myelin metabolism are itshigh rate of synthesis during the active stages of myelination, when each oligodendroglial cell makesmore than three times its own weight of myelin perday, and its relative metabolic stability after the com-pletion of myelination. Individual components turnover at quite different rates. There are conflicting da-ta about the precise half-lives of the various myelinlipids and proteins. This is understandable, sincethere are several variables in the experimental designthat have considerable influence on the observed,real or apparent, half-lives. However, some generalconclusions can be formulated. The concept of rela-tive long-term metabolic stability of most myelincomponents has been confirmed. Some componentsdo turn over much faster than others, and all compo-nents show both a slow- and a fast-turnover compo-nent. The data indicate that newly formed myelin iscatabolized faster than old myelin.Hence,myelin thathas been deposited early in life appears to have ahigher metabolic stability than newly synthesized

myelin.

1.12 Aging of Myelin

With increasing age, human brain weight decreasesand water content increases. Levels of DNA and num-bers of neurons in the cerebral cortex decrease signif-icantly with aging. Little change is found in some re-gions, including the brain stem.

Multiple morphological changes take place withincreasing age. The most prominent neuronalchanges are the appearance of senile plaques (areas of degenerating neuronal processes, reactive nonneu-ronal cells, and amyloid), increasing deposits of lipo-fuscin, and areas of neurofibrillary tangles. Synapsesand dendrites are lost with aging. Neurotransmittersystems are also affected by aging. Acetylcholin-esterase, choline acyltransferase, tyrosine hydroxy-lase, DOPA decarboxylase, and glutamic acid de-carboxylase, enzymes involved in cholinergic, anddopaminergic and GABA-ergic transmission, respec-tively, show appreciable decreases.

The total myelin content of white matter is reducedin old age. Low myelin concentrations of white mattermost probably reflect the continuous loss of neuronswith degeneration of axons and of the myelin sheaths.The lipid composition of myelin is quite constant dur-ing aging, with the possible exception of galac-tolipids, which tend to decline. Some differences areseen in the fatty acid composition of myelin phospho-glycerides and cerebrosides during aging.Myelin pro-teins do not undergo distinct quantitative changes intheir relative proportions during old age.

1.13 Function of Myelin

Nerve fibers transmit information to other nervefibers and to receptors of effector organs. The infor-mation is transmitted via an electric impulse calledthe action potential, which is conducted in an all-or-none way, i.e., the impulse is propagated or not. Moredetailed information is provided by temporal andspatial summation of many action potentials withinone nerve. Myelin plays an important role in the im-pulse propagation. It is an insulator, but more impor-tant is its function to facilitate conduction in axons.

In a resting nerve fiber, polarization of the mem-brane exists: the inside is charged negatively com-pared with the outside. In an excited area the situa-tion is reversed: the inside is charged positively com-pared with the outside. This is called membrane de-polarization. There is a difference in potentialbetween excited and adjacent resting fiber sectionsowing to the inversion of polarization in the excitedarea. In an effort to compensate this difference in po-

tential, local circuits of currents flow into the activeregion of the axonal membrane through the axon andout through the adjacent, polarized sections of the



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membrane. These local circuits depolarize the adja-cent section of the membrane. As soon as this depo-larization reaches the threshold of excitation, an ac-tion potential arises. These local circuits depolarizethe adjacent section of membrane in continuous se-quential fashion. Of course, the local circuits do notonly flow in the direction of the impulse conduction.However, they cause no renewed excitation in themembrane that has just been excited because a tem-porary state of inexcitability, called the refractory pe-riod exists, which ensures that the fiber conducts theaction potential in one direction and does not remainpermanently excited. In unmyelinated fibers impuls-es are propagated in this way, and the entire mem-brane surface needs to be successively excited whenan action potential travels along it.

In myelinated fibers, the excitable axonal mem-brane is only exposed to the extracellular space at thenodes of Ranvier. In the area of the node of Ranvier,the axon is rich in sodium channels.The remainder of the axolemma is covered by the myelin sheath,whichhas a much higher resistance and much lower capac-itance than the axonal membrane. When the mem-brane at the node is excited, the local circuit generat-ed cannot flow through the high-resistance sheath,and therefore flows out through the next node of Ran-vier and depolarizes the membrane there (Fig. 1.10).In this so-called saltatory conduction, the impulse

jumps from node to node, whereby the conductionvelocity is considerably increased. Saltatory nerveconduction is not only faster, but it also saves energy because only parts of the membrane need to depolar-ize and repolarize for impulse conduction. For con-duction velocities in unmyelinated fibers equivalentto those in the fastest conducting myelinating fibers,impossibly large unmyelinated fibers and energy ex-penditures several orders of magnitude greater wouldbe required.

There are several factors that influence conductionvelocity. Conduction velocity increases with increas-ing fiber diameter as a consequence of the smaller in-ternal resistance, leading to an increased flow of cur-rent and thus shortening the time necessary for theexcitation of the adjacent membrane section or thenext node of Ranvier. Increase in myelin thickness,which accompanies increase in fiber diameter, alsoincreases conduction velocity, mainly as the result of

a change in myelin sheath capacitance. The intern-odal distance influences conduction velocity. Withshorter internodal distances, the fibers behave more

and more like unmyelinated fibers while with longerinternodal distances the current density at the nextnode of Ranvier becomes smaller. Consequently,there is an optimal ratio of internode distance toaxon diameter.With increasing temperature conduc-tion velocity increases, reaching a maximum at about42 °C and decreasing thereafter.

1.14 Myelin Disorders: Definitions

‘Demyelination’ means, literally: loss of myelin andthe literal interpretation of ‘demyelinating disorders’is: disorders characterized by loss of myelin.The termdemyelination is commonly used to indicate theprocess of losing myelin, which is caused by primary involvement of oligodendroglia or myelin mem-branes. Myelin loss that is secondary to axonal lossand simultaneous loss of axons and myelin sheaths isnot usually included under the heading of demyelina-tion.

However, there is considerable confusion about themeaning of the terms demyelination and demyelinat-ing disorders. Sometimes demyelination is used tomean all conditions in which loss of myelin occurs,irrespective of whether the myelin membrane wasprimarily affected or was broken down secondary toor at the same time as axonal loss. This is probably partly because it is not always clear whether the lossof myelin is primary or secondary in nature. The mu-tual dependence of axons and myelin sheaths is animportant factor in this respect. Demyelination willeventually lead to axonal loss, and in the end axonaldegeneration will lead to loss of myelin. Hence, usinghistological examination it may be very difficult todifferentiate between primary and secondary myelinloss. Another confusing factor is that some disordersshow evidence of simultaneous primary neuronal de-generation and primary demyelination. The randomuse of related terms, such as dysmyelination,myelino-clastic disorders, white matter disorders, leuko-encephalopathies and leukodystrophies add to theconfusion.

Poser (1957) introduced the concept of ‘dysmyeli-nation.’ He proposed dividing the disorders charac-terized by primary myelin loss into ‘myelinoclasticdisorders’ and ‘dysmyelinating disorders’ (1961,

1978). He considered the myelinoclastic disorders tobe the true demyelinating disorders, in which themyelin sheath is destroyed after having been normal-

1.14 Myelin Disorders: Definitions 15

Fig. 1.10. Because of the myelin

sheath,the conduction in a myelinated

nerve fiber is saltatory,jumping from

node to node


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ly constituted. Examples are multiple sclerosis andacute disseminated encephalomyelitis. The dysmyeli-nating disorders comprise those disorders in which“myelin is not formed properly, or in which myelinformation is delayed or arrested, or in which themaintenance of already formed myelin is disturbed.”Examples are metachromatic leukodystrophy andadrenoleukodystrophy. The idea behind the conceptof dysmyelinating and myelinoclastic disorders is todistinguish between inherited disorders, especially inborn errors of metabolism, leading to disturbedmyelination and myelin loss, and acquired disorderscharacterized by primary myelin loss. However, thedefinition of dysmyelinating disorders, as formulatedby Poser, does not exclude all acquired disorders.There are many conditions characterized by a distur-bance of myelination,and most of these are caused by external factors. Moreover, myelin may have beenconstituted normally in inherited disorders, only tobe lost after many years.

There are several definitions of the term ‘leukody-strophy.’ Seitelberger (1984) defines leukodystrophiesas degenerative demyelinating processes caused by metabolic disorders. Morell and Wiesmann (1984)state that leukodystrophies are disorders affectingprimarily oligodendroglial cells or myelin. The disor-ders have to be of endogenous origin with a patterncompatible with genetic transfer of a metabolicdefect. The clinical criterion is a steadily progressivedeterioration of function. Menkes (1990) definesleukodystrophies as a group of genetically transmit-ted diseases in which abnormal metabolism of myelinconstituents leads to progressive demyelination.Common concepts in these definitions are demyeli-nation and inborn errors of metabolism. Heritability is implied.As such,the leukodystrophies are identicalwith inherited demyelinating disorders.

The terms ‘white matter disorders’ and ‘leukoen-cephalopathies’ comprise all disorders that selective-ly or predominantly involve the white matter of theCNS, irrespective of the underlying pathophysiologicmechanism and histopathologic basis. ‘White matterdisorders’ is a literal translation of leukoencephalo-pathies. Sometimes these terms are used as if they areinterchangeable with ‘demyelinating disorders,’ butusually they are used in the context of a wider rangeof disorders, characterized by either primary myelinloss or nonselective damage to myelin,axons and sup-portive tissue of the white matter. For instance, whenthe terms white matter disorder and leukoen-cephalopathy are applied in elderly people, ischemicwhite matter lesions are also implied,which do not in-volve or do not only involve a selective loss of myelin.

In this book the following definitions are used:

– ‘Demyelination’ is reserved for the process of myelin loss caused by primary and selective ab-normality of either oligodendroglia or of the

myelin membrane itself. ‘Demyelinating disor-ders’ are conditions characterized by demyelina-tion. Examples: metachromatic leukodystrophy,multiple sclerosis.

– ‘Hypomyelination’ is reserved for conditions witha significant permanent deficit in myelin deposit-ed. The most extreme variant of hypomyelinationis amyelination. Example: Pelizaeus-Merzbacherdisease.

– ‘Dysmyelination’, as the literal translation of thename implies, is reserved for conditions in whichthe process of myelination is disturbed, leading toabnormal, patchy, irregular myelination, some-times but not necessarily combined with myelinloss. Examples: some amino acidopathies, dam-aged structure of unmyelinated white matter afterperinatal hypoxia or encephalitis.

– ‘Retarded myelination’ is reserved for disordersin which the deposition of myelin is delayed,but progressing. Examples: inborn errors of me-tabolism with early onset, malnutrition, hydro-cephalus.

– ‘Myelin disorders’ comprise all the above-men-tioned conditions.

– ‘White matter disorders’ and ‘leukoencephalo-pathies’ can be defined as all conditions in whichpredominantly or exclusively white matter is af-fected. Either myelin or a combination of myelinand other white matter components is involved.Hence, white matter disorders comprise all myelindisorders,but also,for instance,white matter infec-tions and infarctions, which may affect variouswhite matter components nonselectively.

– ‘Gray matter disorders’ comprise all disorders inwhich neurons and axons are predominantly orexclusively affected.

1.15 Levels of Myelin Involvement

Both inherited and acquired myelin disorders canarise at the level of the myelin membranes or theoligodendroglial cells. As a consequence, the process-es of myelin build-up, maintenance, and turnovermay be disturbed.

The processes of myelin build-up and depositionare highly complex and require the expression of many genes, the presence of many substances, theactivity of many enzymes, optimal coordination of processes within the oligodendrocytes, and optimalcooperation with the environment. Complex and dy-namic processes are particularly vulnerable, and theprocess of active myelination is easily disturbed.Some inborn errors of metabolism lead to a shortage

of myelin components, and as a consequence to a dis-turbance of the process of myelination.An example isfound in Pelizaeus-Merzbacher disease.Acquired dis-



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orders, such as hormonal imbalances and severe mal-nutrition, can also lead to disturbed myelin build-up.

A disturbance of myelin maintenance and turn-over can lead to demyelination. In some inborn errorsof metabolism, the basic enzymatic defect involvesthe breakdown of one of the myelin components.Thiscomponent is trapped in the myelin sheath, and itsconcentration increases gradually. Finally, the myelincomposition is altered to such a degree that thestability is lost, leading to demyelination. Examplesare metachromatic leukodystrophy and globoid cellleukodystrophy. Of the acquired demyelinating disor-ders, toxic disorders in particular can lead to a distur-bance of myelin maintenance and turnover. Myelin isrich in lipids and has a long half-life. Consequently,lipophilic substances easily accumulate in myelin,disturbing the stability of the myelin membrane andleading to demyelination.

The myelin membrane may be intact and normalin appearance, biochemical composition, and func-tion until it is attacked from the outside.This appearsto be the case in several acquired demyelinatingdisorders, including inflammatory processes (e.g.,multiple sclerosis,acute disseminated encephalomye-litis), metabolic disturbances (e.g., central pontinemyelinolysis, Marchiafava-Bignami syndrome) andhypoxia (delayed posthypoxic demyelination).

Demyelinating disorders can also arise at the levelof the oligodendrocytes.Damage to oligodendrocytescan lead to disturbances of myelin build-up, main-tenance, and turnover. In some inborn errors of metabolism storage of unwanted material occurs,ultimately leading to dysfunction and death of oligo-dendrocytes. In globoid cell leukodystrophy the toxicsubstance psychosine is thought to lead to oligoden-droglial cell death and myelin loss. In acquired de-myelinating disorders, selective oligodendroglial celldeath can also occur. This is the case, for instance, inprogressive multifocal leukoencephalitis, in whichviral infection of oligodendrocytes is present.

Of course, in many disorders more than one mech-anism of myelin affection is involved.In disturbancesof myelin build-up the myelin that is laid down may have an abnormal composition and configuration.Delayed myelination, dysmyelination, and early de-myelination can occur at the same time. In other dis-orders, oligodendroglial cell death and myelin break-down independent of oligodendroglial cell deathoccur simultaneously.

1.16 Biochemical Changes Relatedto Demyelination

Demyelinating disorders can be subdivided into twolarge categories: inherited disorders due to an inbornerror of metabolism and acquired disorders sec-

ondary to adverse factors in the internal or externalenvironment.

Biochemical analysis of myelin and white matterdemonstrates an abnormal composition of the sametype in many demyelinating disorders of diverseetiology. The concept of the nonspecific process of myelin breakdown suggests that when maintenanceof normal myelin is no longer possible it follows astereotyped route to complete destruction, largely irrespective of the initiating causes. The etiologicalfactors can be wallerian degeneration,infections suchas subacute sclerosing panencephalitis, or intoxica-tions with such agents as triethyltin, but also inherit-ed metabolic diseases,e.g.,X-linked adrenoleukodys-trophy, Canavan disease,and many other demyelinat-ing diseases. In inherited diseases affecting myelinmetabolism, biochemical analysis often reveals cer-tain abnormalities superimposed on the nonspecificcompositional abnormalities. These abnormalitiesare specific for a particular disorder or type of disor-ders.For instance, an elevation of the very long-chainfatty acids of the cholesterol esters is specific for asubgroup of peroxisomal disorders, including X-linked adrenoleukodystrophy. An elevation of sul-fatide is found in the white matter of patients withmetachromatic leukodystrophy. The specific bio-chemical abnormalities of myelin in the various dis-orders are discussed in separate chapters. Here wewill limit our discussion to the nonspecific myelin ab-normalities. It should, however, be kept in mind thatthe degree of abnormality varies considerably amongdifferent diseases and among different cases of thesame disease depending on the stage of disease.

In degenerating myelin, the proportion of totalprotein to total lipid is not usually dramatically altered, but the proportions of individual lipids areabnormal. The amount of galactolipids is decreased,and cerebroside is usually much more severely affect-ed than sulfatide. Moderate decreases of ethanol-amine phosphoglycerides (mostly plasmalogen) arecommon. The amount of unesterified cholesterol isincreased,often strikingly so,constituting almost half or even more than half the total lipid content, in con-trast to approximately 27% in normal myelin. Noesterified cholesterol is found in the degeneratingmyelin sheath. Such abnormal myelin is an interme-diate form between normal myelin and completely catabolized myelin. The abnormalities are a result of partial degradation.

The compositional changes in white matter as awhole depend primarily on the extent of myelin lossand only secondarily on changes in myelin com-position. Typical white matter changes are increasedwater content and reduced lipid-to-protein ratios,

with specific decreases in such major myelin con-stituents as cholesterol, cerebroside, sulfatide, andethanolamine phosphoglycerides. In addition, there

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is an increase in cholesterol esters in whole whitematter in a number of diseases, but not in all. Thefatty acid composition of these esters is different fromthat of the small amount of esters normally present inwhite matter, but closely resembles the fatty acidslinked to the 2-position in phosphatidylcholine. It isassumed that these esters come from myelin choles-terol and phosphoglyceride fatty acids. The presenceof cholesterol esters is taken as evidence of an activephagocytosis of myelin and,as such,as an indicator of active demyelination, but the absence of cholesterolesters does not mean that there is no active demyeli-nation. The presence of cholesterol esters is reflectedin sudanophilia on histological examination. It isprobable that the mechanism of breakdown is slight-ly different in sudanophilic myelin destruction andnonsudanophilic breakdown.

1.17 Demyelination: Loss of Function

In normal myelinated nerve fibers, conduction issaltatory and internodal conduction time is fairly reg-ular. The conduction in demyelinated axons differsdramatically from that in normal fibers. The impulseconduction may be either saltatory or continuous. If the impulse conduction remains saltatory, the intern-odal conduction time varies widely from internode tointernode. The internodal conduction time is pro-longed by increased leakage of current between thenodes and by depression of excitability of the nodalmembrane. There is, therefore, a decreased currentgeneration capacity and an increased threshold forexcitation. In demyelinated fibers, a very slow contin-uous conduction (about 5% of the conduction veloc-ity of normal fibers) may be seen over short stretch-es. A so-called safety factor for impulse conductioncan be calculated. If the required minimum is notreached, impulse propagation is blocked. Further-more, the refractory period of demyelinated fibers isincreased, which leads to failure to transmit high-fre-quency trains of impulses.

It is clear that demyelination, depending on its ex-tent and severity, can lead to serious loss of function.However, damage to neurons, although not as promi-nent as destruction of myelin, may also play a part inthe functional deficit. Especially in inborn errors of metabolism, substances may also accumulate in themembranes of axons,and in this way axonal dysfunc-tion may arise, contributing to the functional loss.

1.18 Remyelination

Remyelination in the CNS is possible. Remyelinatedfibers can be recognized because the internodes aretoo short and the myelin sheath is too thin for the size

of the axon. Even with time, there is no restitution of the normal axon-to-myelin ratio. The new myelinsheath in itself is normal with normal lamellar peri-odicity.

Remyelination also occurs when the demyelinatedlesion was depleted of oligodendrocytes. The neces-sary supply of oligodendrocytes is provided by prolif-eration of remaining, mature oligodendrocytes andpossibly also by proliferation of progenitor cells fol-lowed by differentiation into myelinating oligoden-drocytes. It is often found that axons tend to be re-myelinated in clusters, suggesting that a single oligo-dendrocyte myelinates many axons in the vicinity.

Remyelination among the demyelinating disordersis variable. The most successful examples of remyeli-nation are found in those conditions in which de-myelination has occurred rapidly, irrespective of whether the condition is acute and monophasic or re-lapsing and remitting. Remyelination is much morelimited in demyelinating disorders with a protracted,chronic course. The presence of additional axonaldamage has an adverse effect on potential remyelina-tion. Some local factors, when present, may stimulateremyelination. There is evidence that epidermalgrowth factor, interleukin-2, immunoglobulins,platelet-derived growth factor and insulin growthfactors may stimulate survival and proliferation of oligodendrocytes and remyelination. In contrast, thepresence of T-CD4+ immune cells interferes withremyelination.

1.19 Retarded Myelination

The process of myelination is both complex and pro-tracted. This means that the process is vulnerable toadverse factors over a long period of time, namely from the second half of gestation up to the end of the1st or 2nd year of life. Many stress factors that act onthe incompletely myelinated brain and interfere withthe process of myelination do not have such a pro-foundly adverse effect on the mature brain. For in-stance, in the mature brain in which myelination iscomplete, stress factors such as malnutrition or hor-monal imbalances will not appreciably reduce theamount of myelin.

Well-known factors potentially leading to retarda-tion of myelination include malnutrition, hormonalimbalances (growth hormone deficiency, hypothy-roidism, hypocortisolism, hypercortisolism), prena-tal exposure to toxins (alcohol, anticonvulsants),chromosomal abnormalities, pre- and postnatal as-phyxia, cerebral infections, hydrocephalus, and in-born errors of metabolism with early onset.

It is important to realize that myelination is depen-dent on normal function and interaction of oligoden-drocytes, neurons, and astrocytes and that retarda-



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tion of myelination can be related to dysfunction of oligodendroglia and myelin, dysfunction of astro-cytes, or neuronal dysfunction. Cerebral infectionsand perinatal asphyxia may lead to disturbance of myelination through white matter damage or throughneuronal damage. In addition, inborn errors of metabolism may disturb the process of myelinationeither directly, at the level of the oligodendrocyte ormyelin sheath, or indirectly, at the level of the astro-cyte or neuron. It is important to realize that a distur-bance of myelination may also be seen in neuronaldisorders with early onset. For instance, in Menkes

disease,Alpers disease, infantile neuronal ceroid lipo-fuscinosis, infantile GM1 gangliosidosis, and infantileGM2 gangliosidosis, all of which are neuronal disor-ders, myelination is severely retarded and the whitematter looks severely abnormal on MRI, whereas inthe later onset variants of neuronal ceroid lipofusci-nosis, GM1 gangliosidosis and GM2 gangliosidosisthese white matter abnormalities do not occur.

It has been demonstrated that myelination is anexpression of the functional maturity of the brain.Retarded myelination is an expression of immaturity or dysfunction.

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The history of classifications of myelin disordersshows how each classification reflects the state of sci-entific development of its time. A revised classifica-tion based on the most recent scientific insights isproposed at the end of this chapter.

Interest in CNS myelin dates back to the nineteenthcentury. In 1854, Virchow was the first to suggest thename ‘myelin’ when he described the sheaths aroundaxons in the CNS. It is not certain when Schwann(1810–1882) first described the cells since named af-ter him, which supply the myelin sheaths around theperipheral nerve fibers. In 1878, Ranvier describedthe nodes that have since been given his name in his“Leçons sur l’histologie du système nerveux.” He be-lieved that the nodes prevented the essentially liquidmyelin from flowing to the bottom of the nerve fiber(axon).But despite this conviction,he showed consid-erable insight into the functional role of the myelinsheath,both as an insulator and as a facilitatory agentin CNS functions. It was not until 1960–1961 that therole of the oligodendrocyte in the formation of myelin in the CNS became clear, and this was due tothe work of Bunge.

During the nineteenth century and early twentiethcentury, important progress was made in the clinicaland histological description of several demyelinatingdisorders.Multiple sclerosis was recognized as a clin-ical disease entity, and the characteristic histologicalabnormalities, in the form of multiple demyelinated,sclerotic plaques within otherwise normal white mat-ter, were described.Prominent names in this develop-ment are Carswell (1838), Cruveilhier (1835–1842)and Charcot (1868).

In 1897, Heubner described a rare neurologicaldisease in children, using the name diffuse sclerosisas opposed to multiple sclerosis. The disease was his-tologically characterized by diffuse demyelination of the cerebral white matter and eventual striking hard-ening of the white matter. Since that time, the term‘diffuse sclerosis’ has commonly been used to de-scribe cerebral diseases with diffuse demyelinationand sclerotic hardening of the cerebral white matter.Pelizaeus in 1899 and Merzbacher in 1910 reported ona chronic progressive familial type of diffuse sclerosis.

In 1912, Schilder described a nonfamilial case of more acute diffuse cerebral demyelination in a child,

and he suggested the name encephalitis periaxialisdiffusa rather than diffuse sclerosis.In this case, moreprominent signs of inflammation and a less symmet-

rical distribution were observed than in the familialcases described up to that time. Schilder consideredthat this disease was a nosological and histologicalentity related to multiple sclerosis and thought therewere acute and chronic variants of diffuse sclerosis

just as there were acute and chronic types of multiplesclerosis.

Since Schilder’s time a number of familial neuro-logical disorders have been recognized, which werehistologically characterized by diffuse demyelinationand again presented under the heading of diffusesclerosis. In 1916, Krabbe described a familial infan-tile form of diffuse sclerosis.Another familial variant,with a later onset and a less rapid progression,was re-ported in 1925 by Scholz and in 1928 by Bielschowsky and Henneberg. Scholz noted that in this case themyelin breakdown products did not show the usual(orthochromatic) staining properties, but stainedmetachromatically.

In 1921, Neubürger drew attention to the fact thatthe term diffuse sclerosis was being applied to sever-al very different disease entities, and he proposed adistinction between inflammatory and degenerativeforms.In 1928, Bielschowsky and Henneberg suggest-ed the name ‘hereditary progressive leukodystro-phies’ for the degenerative forms of diffuse sclerosisand devised the following classification, based on thetime of onset of the disease and its clinical course:1. Infantile type of Krabbe2. Subacute juvenile type of Scholz3. Chronic type of Pelizaeus-Merzbacher

Hallervorden (1940) recognized that there were en-dogenous and exogenous factors causing diffuse de-myelination and that a distinction was possible be-tween disorders in which demyelination is invariably present and forms a specific part of the disease anddisorders in which demyelination occurs occasional-ly and is nonspecific. He proposed a more extendedclassification based on these subdivisions:

I. Endogenous central demyelinationA. Specific demyelinating diseasesa. Diffuse sclerosis of Krabbe and Scholzb. Pelizaeus-Merzbacher diseaseB. Nonspecific occasional demyelination

e.g. Tay-Sachs diseaseII. Exogenous central demyelinationA. Specific demyelinating diseases

Classification of Myelin Disorders

Chapter 2


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a. Inflammatory types:– Disseminated sclerosis

(= multiple sclerosis)– Diffuse sclerosis (Schilder)– Concentric sclerosis (Balò)– Neuromyelitis optica (Devic)– Encephalomyelitis disseminata– Infectious encephalitis

b. Toxic-metabolic types:– Funicular myelosis

(= vitamin B12 deficiency)– Marchiafava-Bignami disease

B. Nonspecific occasional demyelinationa. Disturbances of blood flow, e.g. subcortical

atherosclerosis (= Binswanger disease)b. Edemac. Toxic processes (carbon monoxide)d. Tumors

Until that time, distinctions between different dis-eases had been based on neuropathological and clin-ical aspects of different demyelinating disorders.From about this time onwards, histochemical meth-ods and chemical analyses became increasingly im-portant. The classification propo

Myelin and White Matter

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