RADIOLOGY IN NEURODEGENERATIVE DISORDERS
Dr. Sapna Singh*
Department of Radiology, Maulana Azad Medical College. Email : spsrailways@singhindia.com*

Neurodegenerative diseases

are complex heterogeneous brain disorders that defy easy categorization. Since many of these conditions involve myelination, either primarily or secondarily. One of the earliest attempts to classify these conditions was based on their relationship to myelin structure and function.

Demyelination

is used to describe the process in which there is breakdown of normal existing myelin. In can be due to acquired metabolic disorder, infections or inflammatory conditions. Dysmyelination, however, is used to describe the formation of an abnormal myelin structure as the result of an underlying metabolic defect in myelin formation. In either demyelination or dysmyelination the imaging characteristics on MRI might appear similar and therefore this classification is of limited value to the neuroradiologists.

Demyelination is used to describe the process in which there is a breakdown of normal existing myelin. It can be due to an acquired metabolic disorder, infections or inflammatory conditions. Dysmyelination, however, is used to describe the formation of an abnormal myelin structure as the result of an underlying metabolic defect in myelin formation.

Barkovich categorized these disorders based on whether they primarily involve white matter, grey matter or both.

Disorders that primarily affect white matter


  • Metachromatic leukodystrophy
  • Krabbe disease
  • Adrenoleukodystrophy (X linked)
  • Pelizaeus Merzbacher disease
  • Alexander disease
  • Canavan disease
  • Phenylketonuria and amino acid disorders

Disorders that primarily affect grey matter


  • Tay Sachs disease and other lipidosis
  • Hurler Syndrome and other mucopolysaccharidosis
  • Mucolipidosis and Fucosidosis
  • Glycogen Storage diseases

Disorders that affect both grey and white matter


  • Mitochondrial encephalopathy
  • Zellweger Syndrome and other peroxisomal disorders

Basal Ganglia disorders
  • Huntington disease
  • Hallervorden Spatz disease
  • Fahr disease
  • Wilson disease
Normal Myelination of the Brain
Myelination begins during the fifth fetal month with the myelination of the cranial nerves and proceeds rapidly following the order of phylogenetic development occurring first in the peripheral nerves, then the spinal cord and lastly in the brain. Myelin is composed of a bi-layer of lipids (cholesterol and glycolipids) and large proteins. Although white matter diseases affect the myelin, there are now many studies which reveal that myelin is not the only brain tissue damaged in "demyelinating disease" as the oligodendrocyte is the cell responsible for wrapping the axon concentrically to form the myelin sheath. With the addition of the magnetic resonance imaging (MRI) to the diagnostic armamentarium, it is possible to closely follow maturation and myelination of the neonatal and infant brain and understanding of the nature of diseases and a more precise histopathologic analysis is possible. Cholesterol (fat) has a short T1 and protein also decreases the T1 and an increased intensity (increased brightness) on a T1 weighted MR image. Myelin lipids are hydrophobic, hence when myelination occurs there is loss of brain water. This results in a decrease in T2 value in white matter and as a result a decreased intensity or darker appearance on T2 weighted (T2W) images.

Thus, myelination will be seen as an area of increased intensity (brighter) on T1W images and decreased intensity (darker) on T2W images.

At birth, as seen on T1W images, myelination is present in the medulla, dorsal midbrain, cerebellar peduncles, posterior limb of internal capsule and ventrolateral thalamus. Maturation proceeds from
  • Central to peripheral
  • Inferior to superior
  • Posterior to anterior

The cerebellum is myelinated at 3 months of age with an adult appearance on T2W images. The pre and post-central gyri are myelinated at 1 month and maturation of motor tracts is complete by 3 months.
The pons matures from 3-6 months with maturation proceeding rostrally along the corticospinal tracts, cerebral peduncles through the posterior limb of internal capsule and central portion of the centrum semiovale.
The optic nerves, tracts and radiations into the occipital white matter are myelinated by 3 months and the anterior limb of internal capsule by 2-3 months. The subcortical white matter maturation starts at 3 months in the occipital region and proceeds rostrally to the frontal lobe.

Myelination in the corpus callosum can be a helpful landmark when estimating myelin development. Myelination begins in the splenium posteriorly at 4 months and is complete involving the genu anteriorly at 6 months.

The early primary process of myelination from about 1-6 months is best evaluated using strongly T1W images (short TR/short TE). The T1W image will appear adult like at about 9 months. T2W images are better at depicting the associated changes of water loss that occur with myelination and may be helpful after 6 months of age.

Milestones: Normal myelination (1-6 months) (T1W images at 1.5T)
Cerebellar       white matter - 3 months
Splenium - 4 months
Genu - 6 months
Adult - 9 months


On T1W images the sequential progression of myelination is seen and myelination is identified approximately 2 months earlier than on T2W images.

Milestones : Normal myelination (T2W images at 1.5T)
Splenium - 6 months
Genu - 8 months
Anterior limb internal capsule - 11 months
Frontal white matter - 14 months
Adult pattern - 18 months
DISORDERS THAT PRIMARILY AFFECT WHITE MATTER LEUKODYSTROPHIES
Dysmyelinating diseases, or leukodystrophies, encompass a wide spectrum of inherited neurodegenerative disorders affecting the integrity of myelin in the brain and peripheral nerves.
Most of these disorders fall into one of three categories - lysosomal storage diseases, peroxisomal disorders and disease caused by unknown metabolic defect. Each leukodystrophy has distinctive clinical, biochemical, pathologic and radiological features.
Leukodystrophies result from inherited enzyme deficiency that causes abnormal formation, destruction or turnover of myelin.

LYSOSOMAL STORAGE DISEASES



Metachromatic Leukodystrophy (MLD)

Metachromatic Leukodystrophy is the most common of all the familial leukodystrophies. It is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme arylsulfatase A. The accumulation of sulfatides within glial cells and neurons causes the characteristic metachromatic reaction. The name metachromatic is derived from the neuropathologic description of metachromatic staining which consists of a brownish or reddish colour compared with the blue colour of cell nuclei when stained with cresyl violet or toluidine blue.

Clinical Features:


According to the patient age three patterns of MLD are recognized - the late infantile, juvenile and adult forms. The most common type is the late infantile variety, which usually manifests in children between 12 and 18 months of age and is characterized by motor signs of peripheral neuropathy followed by deterioration in intellect, speech and co-ordination. The disease progresses quickly and within 2 years of onset, gait disturbance, quadriplegia, blindness and decerebrate posturing may be seen. Disease progression is continuous and death occurs 6 months to 4 years of age. The clinical picture is similar to the late infantile form except that the child is old enough to manifest behavioural disturbances as well. There is impaired school performance and emotional liability. The neurological examination reveals cerebellar incoordination, pyramidal tract signs and decreased reflexes as in the lower extremities. In the uncommon adult form, patients tend to present with dementia and progress to develop motor signs.

Imaging Features:


CT appearance of MLD is a symmetrical lucency of the white matter, especially prominent in the centrum semiovale and in corpus callosum. There is no evidence of inflammation or contrast enhancement and the cortical grey matter is spared.

CT appearance of MLD is a symmetrical lucency of the white matter especially prominent in the centrum semiovale and in corpus callosum. There is no evidence of inflammation or contrast enhancement and the cortical grey matter is spared.

MR features of MLD include symmetric confluent areas of high signal within the periventricular and cerebellar white matter on T2W images. There is sparing of the subcortical U fibres until late in the disease. In the late onset (juvenile and adult forms), there is predominant involvement of the frontal white matter. In the late infantile form of MLD, the most common type, a posterior (occipital) predominance of signal abnormality has been reported with dorsofrontal progression of disease. Involvement of the corticospinal tracts may also be seen in the late infantile form of MLD. High signal intensity is seen on the long TR images along the path of corticospinal tracts in the posterior limbs of the internal capsules and brainstem. The corpus callosum is invariably affected and hypointensity may be seen within the thalami on T2W images.

Krabbe Disease/Globoid Cell Leukodystrophy (GLD)
Krabbe disease is an autosomal recessive disorder caused by a deficiency of lysosomal enzyme b-galactocerebrosidase, an enzyme that degrades cerebroside, a normal constituent of myelin.

Clinical Features
The clinical presentation of the disease varies with the age of onset. In the early onset form, presentation is either before or at the age of 2 years while the late onset form presents after age of 2 years. The early infantile form of the disease is the most common clinical form and has three phases. By 6 months of age, the infant is irritable and hypertonic with spasticity and fever. Development fails to progress and the infant regresses neurologically. The second phase is characterized by rapid deterioration in motor function with chronic opisthotonous and myoclonic jerking accompanied by hyperpyrexia. In the third phase the child appears decerebrate and has flaccid paralysis that culminates in death by 2 years of age. The late onset forms have a variable clinical presentation with a slower progression of disease.

Imaging Features
The CT findings in GLD range from white matter lucency to diffuse cerebral atrophy. The CT findings of hyperdense thalami, caudate nucleus and corona radiate are characteristic but not specific for the disease and have been shown to correspond to fine calcifications at autopsy. The most characteristic MR finding in both early and late onset forms of GLD is high signal intensity on T2W images found along the lengths of the corticospinal tracts. Additional findings in the early onset form include abnormal signal intensity within the cerebellar white matter and deep grey nuclei (dentate, basal ganglia, thalamus) with progressive involvement of the parieto-occipital white matter and posterior portion of the corpus callosum.

The CT findings of hyperdense thalami, caudate nucleus and corona radiata are characteristic but not specific for the disease and have been shown to correspond to fine calcifications at autopsy.


PEROXISOMAL DISORDERS


Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and monounsaturated fatty acids. Peroxisomal enzymes are also involved in gluconeogenesis, lysine metabolism and glutaric acid metabolism.
The first group is characterized by defects in the formation and maintenance of white matter and X-linked adrenoleukodystrophy is the prototype.

Clinical Features
The clinical features of X-linked type ALD include the onset of neurological symptoms between the ages of 5 and 9 years with behaviour problems, decreasing mental function, visual and hearing disorders progressing to motor signs and ataxia. The disease progresses to include seizures, spastic quadriplegia with death ensuring within the first few years of onset.

Imaging Features
The CT and MR appearance of adrenoleukodystrophy is somewhat specific with symmetric areas of white matter abnormality in the peritrigonal regions and extending across the splenium of the corpus callosum. Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white matter is affected. The subcortical white matter is relatively spared in the early stage but often becomes involved in the later stages.

The central or inner zone which corresponds to irreversible gliosis and scarring is moderately hypointense on T1W MR imaging and markedly hyperintense at T2W imaging. The intermediate zone corresponding to active inflammation is isointense or slightly hypo-intense and rapidly enhances after administration of contrast. The peripheral or outer zone representing the leading edge of active demyelination appears moderately hyperintense on T2W MR imaging and demonstrates no contrast enhancement. Pontomedullary corticospinal tract involvement is a common finding in adrenoleukodystrophy and is uncommon in other leukodystrophies. Atypical case of ALD with unilateral or predominantly frontal lobe involvement may occur.

Proton MR spectroscopy typically shows a decrease in NAA peak and an increase in the choline peak. The spectra may be abnormal before the conventional MR findings and studies have shown the potential of MRS for prognostic assessment of ALD.

Proton MR spectroscopy typically shows a decrease in NAA peak and an increase in the choline peak. The spectra may be abnormal before the conventional MR findings and studies have shown the potential of MRS for prognostic assessment of ALD

AMINO ACID DISORDER

Canavan Disease

Canavan disease (Canavan-van Bogaert-Bertrand disease) or spongy degeneration of the brain is an autosomal recessive disorder caused by deficiency in activity of the enzyme N-acetylaspartate, which result in accumulation of N-acetylaspartic acid in the urine, plasma and brain. This is the only known disease with a defect in NAA metabolism.

Clinical Features
It usually manifests in early infancy as hypotonia followed by spasticity, cortical blindness and macrocephaly. Macrocephaly may not be apparent in the first few months of life but the head enlarges above the ninetieth percentile within 6 months to 1 year of age. Canavan disease is a rapidly progressive illness with a mean survival time of 3 years, although protracted cases do occur. Definite diagnosis usually requires biopsy or autopsy.

Imaging Features
he CT shows diffusely decreased attenuation of the cerebral and cerebellar white matter. The MR imaging findings demonstrate diffusely decreased T1W signal and increased T2W signal within the white matter that corresponds to the CT abnormalities. Typically, there is diffuse symmetric increase signal on T2W images throughout the white matter. Unlike metachromatic leukodystrophy or Krabbe disease the subcortical U fibres also are usually involved. Occasionally there is sparing of the internal capsule, corpus callosum and putamen. Cerebral and cerebellar atrophy is a late finding.
MR spectroscopy - There is a characteristic increase in NAA peak.


WHITE MATTER DISORDERS WITH UNKNOWN METABOLIC DEFECT


Pelizaeus- Merzbacher disease, a sudanophilic leukodystrophy, is the best example of a hypo-myelinating leukoencephalopathy. PMD has been linked to a severe deficiency of myelin specific lipids caused by a lack of proteolipid protein (PLP). This myelin specific proteolipid is responsible for oligodendrocyte differentiation and survival.

Clinical Features
PMD has traditionally been divided into classic and connatal forms. Classic PMD begins during late infancy with X-linked recessive inheritance. Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy. This form has either X-linked or autosomal recessive inheritance. Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye movements, nystagmus, extrapyramidal hyperkinesias, spasticity and slow psychomotor development.

Imaging Features
CT may demonstrate only atrophy. T2W MR findings reveal a nearly total lack of normal myelination with diffuse high signal intensity that extends peripherally to involve the sub-cortical U fibres along with early involvement of the internal capsule. Sometimes, the white matter demonstrates high signal intensity with small scattered foci of more normal signal intensity - a finding that may reflect the tigroid pattern of myelination seen on histology.

T2W MR findings reveal a nearly total lack of normal myelination with diffuse high signal intensity that extends peripherally to involve the subcortical U fibres along with early involvement of the internal capsule.

MR Spectroscopy

Proton MR spectroscopy may reveal no abnormal peak consistent with the absence of sclerosis and well-preserved axons. Diffuse or focal reduction in NAA consistent with axonal damage may be seen in more severe cases.

Alexander Disease
Alexander disease or fibrinoid leukodystrophy is a rare disorder that occurs sporadically with no known pattern of inheritance.

Clinical Features
Three clinical subgroups are recognized. The infantile subgroup is characterized by early onset of macrocephaly, psychomotor retardation with seizures and death occurring within 2-3 years. The diagnosis is made on the basis of a combination of macrocephaly, early onset of clinical findings and imaging findings but definite diagnosis usually requires brain biopsy or autopsy. In the juvenile subgroup, onset of symptoms occurs between 7 and 14 years of age. Progressive bulbar symptoms with spasticity are common. In the adult subgroup, onset of symptoms and disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup.

Imaging Features
Alexander disease has a predilection for the frontal lobe white matter early in its course. CT demonstrates low attenuation in the deep frontal lobe white matter. Enhancement is often seen near the tips of the frontal horns early in the disease course. The characteristic frontal lobe areas of hyperintensity are seen on T2W MR imaging. The hyperintense areas progress posteriorly to the parietal white matter and internal and external capsules. The subcortical white matter is affected early in the disease course. In the late stages of the disease, cysts may develop in the affected regions of the brain.

Childhood Ataxia with Diffuse CNS Hypomyelination (Vanishing White Matter Disease)

This entity has been characterized in the last few years by a number of investigators. MRI demonstrates a diffuse confluent abnormality in white matter that was noted early in the course of the disease. Histopathology demonstrates a cavitating leukoencephalopathy with replacement of white matter between ependyma and U fibres that was replaced by CSF.
  • Normal or mildly delayed initial psychomotor development.
  • Neurologic deterioration with a chronic progressive and episodic course
  • Presence of cerebellar ataxia and spasticity with relative preservation of mental function. Optic atrophy and epilepsy may occur.
  • Diffuse symmetric white matter involvement on MRI with all or part of white matter exhibiting a signal intensity similar to CSF.


DISORDERS THAT PRIMARILY AFFECT GREY MATTER

Mucopolysaccharidosis



The mucopolysaccharidosis include a group of inherited metabolic disorders in which a lysosomal enzyme deficiency results in the inability to degrade the mucopolysaccharides (glycosaminoglycans) heparin sulfate, keratin sulfate and/or dermatan sulfate.

MR findings :


The finding includes poor grey-white matter differentiation with multiple patchy areas of high signal intensity on the long TR images within the periventricular white matter. Prominent cystic or dilated perivascular spaces may be seen which represents vacuolated cells distended with mucopolysaccharide. Ventricular enlargement is common. Thickening of the skull and meninges can be seen. Spinal cord compression is common especially at the foramen magnum and upper cervical canal resulting from dural thickening secondary to mucopolysaccharide deposits.

The findings include poor grey-white matter differentiation with multiple patchy areas of high signal intensity on the long TR images within the periventricular white matter


Gangliosidosis



MR findings in gangliosidosis depend on the age of presentation and thereby reflect the extent of underlying ganglioside accumulation. In infancy, there is extensive demyelination and gliosis in the white matter resulting in diffuse high signal intensity on long TR images. In the childhood form diffuse generalized cerebral and cerebellar atrophy has been described.
DISORDERS THAT PRIMARILY AFFECT GREY MATTER

Mitochondrial Disorders



Mitochondrial encephalopathy comprises a heterogeneous group of neuromuscular disorders caused by defect in the oxidative metabolic pathways of energy production owing to a structural or functional mitochondrial defect.

Mitochondrial encephalomyopathy - lactic acidosis and stroke-like symptoms (MELAS).
Imaging Features

CT and MR findings of MELAS syndrome have been reported as multiple infarct like lesions, calcification of the basal ganglia and diffuse atrophy. These infarct like lesions show low attenuation on CT and elongation of both T1 and T2 relaxation times on MR images, usually with a bilateral symmetric or asymmetric cortical and subcortical distribution. There is a posterior predilection for the lesions. The MELAS syndrome can be differentiated from cerebral infarct of vascular origin because the lesions are not restricted to a specific vascular territory and angiography reveals no vascular occlusion. During the course of the disease lesions resolve with clinical improvement or residual atrophy while new lesions appear in other regions. This finding of migrating infarct like lesions in childhood is almost unique to MELAS.

The MELAS syndrome can be differentiated from cerebral infarct of vascular origin because the lesions are not restricted to a specific vascular territory and angiography reveals no vascular occlusion

There may be generalized cerebral and cerebellar atrophy. The finding of multiple migrating infarct like lesions not limited to a specific vascular territory especially in the basal ganglia and the posterior part of the cerebral hemisphere in children suggest MELAS syndrome.

Myoclonic Epilepsy with Ragged Red Fibres (MERRF)

Unlike MELAS syndrome MERRF cause no strokes leading to cerebral infarcts. The patients usually present with myoclonus, ataxia, weakness and generalized seizures. The patients have short stature and cardiac conductive defects.
Imaging Features

The CT and MR show cerebral and cerebellar atrophy. MR findings may show hyperintense signal abnormalities in the white matter and deep grey matter. CT may show calcification of the dentate nucleus and globus pallidus.

Kearns-Sayre Syndrome

This mitochondrial disorder occurs more frequently in females and is inherited as an autosomal dominant trait.
Clinical Features
It presents as a triad of ophthalmoplegia, retinal pigmentary degeneration and complete heart block. There is short stature and frequently mental deterioration.
Imaging Features
MR findings in Kearns-Sayre syndrome reflect the pathology of spongiform degeneration and reveal signal intensity on long TR images in the white matter with a predilection for involvement of peripheral U fibres and sparing of the periventricular white matter. Symmetric high signal on T2W images can be seen in basal ganglia. The cerebellar white matter and the dorsal brainstem may also demonstrate abnormal hyperintensity. Diffuse atrophy is commonly seen involving the cerebrum and cerebellum.

Subacute Necrotizing Encephalomyopathy (Leigh Disease)
Leigh disease, or subacute necrotizing encephalomyopathy is an inherited, progressive, neurodegenerative disease of infancy or early childhood. Affected infants and children typically present with hypotonia and psycho-motor deterioration. Ataxia, ophthalmoplegia, ptosis, dystonia and swallowing difficulties inevitably ensure. Acute respiratory failure may occur.
Imaging Features
Typical MR finding in Leigh disease is the remarkably symmetrical involvement, most frequently in the putamen. The lesions are also commonly found in the globus pallidus and the caudate nucleus but never in the absence of putaminal abnormalities. Other areas of involvement include the paraventricular white matter, corpus callosum, substantia nigra, decussation of superior cerebellar peduncles, periaqueductal region, brainstem and the grey matter in the spinal cord. Loss of respiratory control in Leigh disease has been found to correlate with lower brainstem lesions (particularly situated in the periaqueductal grey matter and reticular formation of the medulla oblongata). Upper brainstem signal abnormalities are often transient and the associated respiratory difficulties resolve.
Proton MR spectroscopy with voxel placement in the basal ganglia typically demonstrates an abnormal lactate peak with a decrease in NAA/Cr.

Hallervorden-Spatz disease (HSD)
Hallervorden-Spatz disease (HSD) is a rare neurodegenerative disease. Both familial and sporadic cases have been reported. Imaging findings include iron deposits in the globus pallidus and substantia nigra.

Typical MR findings include pallidonigral low signal intensity on T2W MR scans. Sometimes smaller anteromedial high signal intensities are also present (eye-of-the-tiger sign).

Wilson Disease


Wilson disease (hepatolenticular degeneration) is an autosomal recessive inherited disorder of copper metabolism caused by a deficiency of ceruloplasmin, the serum transport protein for copper. Abnormal copper deposition occurs in various tissues, especially the liver, brain, cornea, bones and kidneys. It is associated with cirrhosis of the liver and degenerative changes in the basal ganglia. Neuroimaging studies in some cases are normal or show only mild generalized atrophy. Others show bilateral putaminal low-density lesions on NECT scans and high signal in the thalami, putamen, dentate nuclei and brainstem on T2 weighted MR scans.
Conclusion
MR imaging has continued its progress in the detection and classification of neurodegenerative diseases of the central nervous system. More recent advances in MR techniques have made assessments of tissue microstructure and function-structure correlation possible. These methodologies promise earlier and more accurate diagnosis of neurodegenerative disease and may permit distinction between age-related changes and incipient pathology.
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