British Journal of Neurosurgery (1992) 6 , 293-296
EDITORIAL
Br J Neurosurg Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Axonal transport, imaging, and the diagnosis of nerve compression
A lower motor neuron in the L5 segment of the conus medullaris supplying extensor hallucis longus is an enormous single cell which must manage an axon almost l m in length. The nucleus of such a neuron relies on axonal transport to organize chemical and metabolic events throughout the whole length of its axon and keep it and its synapses supplied with intracellular organelles and newly synthesized proteins. Neurobiologists have been aware of the flow of proteins, vesicles, small molecules, and organelles along axons for over 40 years,’ but there have been no clinical applications of the phenomenon. When a nerve is compressed, there is evidence that interference with axoplasmic flow occurs early and may often precede interference with the transmission of electrical impulses or vascular compromise of the Indeed, the effectiveness of surgical relief of nerve compression may principally result from the restoration of normal axoplasmic flow. It is only recently that attention has been turned to the potential clinical uses of axonal transport, both for the neuroradiological diagnosis of nerve compression and to examine the effectiveness of its surgical relief. An ideal clinical application for axonal transport would be to design an imaging contrast agent which could travel up a nerve and accumulate at a site of compression. Such an agent might confirm that a herniated intervertebral disc really was impinging on a nerve root or that the superior cerebellar artery really was compressing the sensory root of the trigeminal nerve in tic douloureux. Restoration of axoplasmic flow seen on a post-operative
image could clarify which continuing symptoms were due to muscle spasm and which were due to nerve injury or continued compression.
Neurobiology underlying the rate and mechanism of axoplasmic flow Axonal transport proceeds at several different rates, but can be divided into a fast component of over 40 cm/day,4 and a slow component of only 2-3 mm/day.5 The slow component reflects gradual realignments in structural proteins along the axon as well as exchange phenomena for substances that adhere poorly to the transport machinery. Fast transport is an energy-driven process requiring a considerable amount of continuous oxidative metabolism to support a motile cross-bridge system not unlike the mechanism of muscle contraction. Two motile proteins are known to be involved, kinesin for ‘anterograde transport’ from the cell body towards the synapse, and dynein for ‘retrograde transport’ in the opposite direction, and both pull proteins and vesicles along a fixed axoskeletal framework of microtubules.6 The oxygen and glucose to support all this activity comes through the walls of the axolemma along the length of the axon, and the ATP is generated in mitochondria along the axon.
Means of introducing tracer agents T o enable the clinical use of axonal transport, the ability of nerve endings in muscle to ingest
293
Br J Neurosurg Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
294
Editorial
proteins and particles administered by intramuscular injection is exploited. The discovery of this phenomenon by Kristensson and Olsson in 19717 was proof that endocytosis and transport of exogenous proteins by intact neurons could take place in vivo. It was subsequently found that attaching specific nerve adhesion molecules to tracer labels further improved the concentration of tracer in the axon,” however, much of the large volume of subsequent research on axonal transport did not make use of this finding. The most widespread applications of axonal transport have been in mapping connections within the central nervous ~ y s t e m .Usually ~ these mapping studies involve the destruction of neural tissue at some injection site, with the objective of detecting histologically where the tracer has been carried to in 2-3 days, but evidence has been mounting that intramuscular injections can yield high intraneural concentrations of tracer with minimal spread away from the injection site.I0 Very recently it has become clear that the concentration of uptake of axonal tracers after intramuscular injection is sufficient to consider potential clinical uses. Preliminary in viva studies have revealed that labelled proteins suitable for nuclear medicine imaging can achieve useful concentrations in nerve after intramuscular injection.’ * It has been demonstrated that particles such as a colloidal gold histology label can be endocytosed and transported by nerves after intramuscular injection.I2 It is now clear that biodegradable magnetic particles can also be transported by n e r ~ e s , ~and ~ Jthat ~ they can be endocytosed after intramuscular injection with intraneural concentrations sufficient for detection with magnetic resonance imaging
(MRI).I~J~
Current areas of diagnostic difficulty A principal motive for developing these new agents are the two areas of diagnostic difficulty imposed by current techniques. Peripheral nerve entrapments are often quite difficult to localize reliably unless they occur at the carpal
tunnel, medial humeral epicondyle, or other peripheral location where it is easy to test nerve function electrically. Suspected entrapment in the brachial or lumbosacral plexus or along a deep peripheral nerve involved in an atypical pain syndrome continues to be difficult to localize with certainty. The second area of diagnostic difficulty concerns the application of MRI in low back pain. In one study, MRI scans on 67 volunteers who had never had significant back pain or sciatica were shown to neuroradiologists who did not know that the patients were asymptomatic. A diagnosis of lumbar disc herniation was made in 57% of the older v01unteers.l~Thus MRI detects disc herniations with great sensitivity, but specificity is low and it cannot confirm that the herniated disc is indeed responsible for the patient’s symptoms.
Prospects for clinical use It is likely to be some time before these novel imaging agents become routinely available for clinical use, but we should be able to look forward to a substantially enhanced ability to locate and confirm peripheral and cranial nerve compression, spinal cord injury, and possibly diffuse axonal injury in the head-injured patient. The use of this sort of tracer will require close co-operation between the neuroradiologist and the referring neurologist or neurosurgeon. The clinician will inject the tracer into muscles innervated by the nerves to be investigated and the radiologist will then evaluate images collected at various times after the injection to follow the axonal transport of the tracer. The anatomical detail visible by current generation imaging, and electrophysiological techniques to elucidate function, have greatly enhanced neurological diagnosis in the past decade. The future promise of axonal transport imaging is that the functional effects of anatomical derangement will be visible directly in the initial magnetic resonance or nuclear medicine image, and the effects of therapeutic
Editorial
intervention on anatomy and function seen directly.
295
9 Mesulam M-M. Tracing Neural Connections with
Horseradish Peroxidase. IBRO Handbook Series: Methods in the Neurosciences. Chichester: John Wiley, 1982: 251.
A. G. FILLER & B. A. BELL Atkinson Morleys' Hospital, London SW20 ONE, UK.
Br J Neurosurg Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
References 1 Weiss, PA, Hiscoe H. Experiments on the mechanism of nerve growth. J Exp Zoo1 1948; 107:315-96. 2 Weiss DG. Axoplasmic Transport. Berlin: SpringerVerlag, 1982: 477. 3 Gallant P. Blockage of fast axonal transport by mechanical compression. SOC Neurosci Abs 1991; 1759. 4 Grafstein By Forman D. Intracellular transport in neurons. Physiol Rev 1980; 60:1168-283.
5 Hoffman PN, Lasek RJ. The slow component of axonal transport: identification of major structural polypeptides and their generality among mammalian neurons. J Cell Biol 1975; 66:351-66. 6 Vallee RB, Bloom GS. Mechanisms of fast and slow axonal transport. A Rev Neurosci 1992; 1459-92. 7 Kristensson K, Olsson Y. Retrograde axonal transport of protein. Brain Res 1971; 29:363-5. 8 Brushart TM, Mesulam M-M. Transganglionic demonstration of central sensory projections from skin and muscle with HRP-lectin conjugates. Neurosci Lett 1980; 17~1-6.
10 Kramer M. Deacon T, Sokoloff A, Filler A. Organization of motorneurons innervating epaxial and hypaxial musculature in the frog, rate and monkey. SOC Neurosci Abs 1987; 13526. 11 Filler AG, Winn HR, Westrum LEYSirrotta P, Krohn K, Deacon TW. Intramuscular injection of WGA yields systemic distribution adequate for imaging of axonal transport in intact animals. SOCNeurosci Abs 1991; 17:1480. 12 Philipe E, Droz B. Calbindin-immunoreactive sensory
13 14
5
6
17
neurons of dorsal root ganglion project to skeletal muscle in the chick. J Comp Neurol 1989; 283:153-60. Brady TJ. Future prospects for MR imaging. SOCMagn Res Med Abs 1991; 102. Ghosh P, Zhou X, Lin W, Feng AS, Groman E, Lauterbur PC. Neuronal tracing with magnetic labels. SOCMagn Res Med Abs 1991; 10:1042. Filler AG, Winn HR, Howe FA, Griffiths JR, Bell BA, Deacon TW. Axonal transport of superparamagnetic metal oxide particles: potential for magnetic resonance assessments of axoplasmic flow in clinical neuroscience. SOCMagn Res Med Abs 1991; 10:985. Filler AG, Bell BA, Howe FA ,Griffiths JR, Flower My Sharma MyWinn HR, Deacon TW. Imaging of axonal transport: is the axoplasmic flow clinically relevant? J Neurol Neurosurg Psychiatry 1992; 55515-6. Boden SD, Davis DO, Dina TS, Patronas MJ, Wiesel SW. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg 1990; 72:403-8.
EDITORIAL
Br J Neurosurg Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Axonal transport, imaging, and the diagnosis of nerve compression
A lower motor neuron in the L5 segment of the conus medullaris supplying extensor hallucis longus is an enormous single cell which must manage an axon almost l m in length. The nucleus of such a neuron relies on axonal transport to organize chemical and metabolic events throughout the whole length of its axon and keep it and its synapses supplied with intracellular organelles and newly synthesized proteins. Neurobiologists have been aware of the flow of proteins, vesicles, small molecules, and organelles along axons for over 40 years,’ but there have been no clinical applications of the phenomenon. When a nerve is compressed, there is evidence that interference with axoplasmic flow occurs early and may often precede interference with the transmission of electrical impulses or vascular compromise of the Indeed, the effectiveness of surgical relief of nerve compression may principally result from the restoration of normal axoplasmic flow. It is only recently that attention has been turned to the potential clinical uses of axonal transport, both for the neuroradiological diagnosis of nerve compression and to examine the effectiveness of its surgical relief. An ideal clinical application for axonal transport would be to design an imaging contrast agent which could travel up a nerve and accumulate at a site of compression. Such an agent might confirm that a herniated intervertebral disc really was impinging on a nerve root or that the superior cerebellar artery really was compressing the sensory root of the trigeminal nerve in tic douloureux. Restoration of axoplasmic flow seen on a post-operative
image could clarify which continuing symptoms were due to muscle spasm and which were due to nerve injury or continued compression.
Neurobiology underlying the rate and mechanism of axoplasmic flow Axonal transport proceeds at several different rates, but can be divided into a fast component of over 40 cm/day,4 and a slow component of only 2-3 mm/day.5 The slow component reflects gradual realignments in structural proteins along the axon as well as exchange phenomena for substances that adhere poorly to the transport machinery. Fast transport is an energy-driven process requiring a considerable amount of continuous oxidative metabolism to support a motile cross-bridge system not unlike the mechanism of muscle contraction. Two motile proteins are known to be involved, kinesin for ‘anterograde transport’ from the cell body towards the synapse, and dynein for ‘retrograde transport’ in the opposite direction, and both pull proteins and vesicles along a fixed axoskeletal framework of microtubules.6 The oxygen and glucose to support all this activity comes through the walls of the axolemma along the length of the axon, and the ATP is generated in mitochondria along the axon.
Means of introducing tracer agents T o enable the clinical use of axonal transport, the ability of nerve endings in muscle to ingest
293
Br J Neurosurg Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
294
Editorial
proteins and particles administered by intramuscular injection is exploited. The discovery of this phenomenon by Kristensson and Olsson in 19717 was proof that endocytosis and transport of exogenous proteins by intact neurons could take place in vivo. It was subsequently found that attaching specific nerve adhesion molecules to tracer labels further improved the concentration of tracer in the axon,” however, much of the large volume of subsequent research on axonal transport did not make use of this finding. The most widespread applications of axonal transport have been in mapping connections within the central nervous ~ y s t e m .Usually ~ these mapping studies involve the destruction of neural tissue at some injection site, with the objective of detecting histologically where the tracer has been carried to in 2-3 days, but evidence has been mounting that intramuscular injections can yield high intraneural concentrations of tracer with minimal spread away from the injection site.I0 Very recently it has become clear that the concentration of uptake of axonal tracers after intramuscular injection is sufficient to consider potential clinical uses. Preliminary in viva studies have revealed that labelled proteins suitable for nuclear medicine imaging can achieve useful concentrations in nerve after intramuscular injection.’ * It has been demonstrated that particles such as a colloidal gold histology label can be endocytosed and transported by nerves after intramuscular injection.I2 It is now clear that biodegradable magnetic particles can also be transported by n e r ~ e s , ~and ~ Jthat ~ they can be endocytosed after intramuscular injection with intraneural concentrations sufficient for detection with magnetic resonance imaging
(MRI).I~J~
Current areas of diagnostic difficulty A principal motive for developing these new agents are the two areas of diagnostic difficulty imposed by current techniques. Peripheral nerve entrapments are often quite difficult to localize reliably unless they occur at the carpal
tunnel, medial humeral epicondyle, or other peripheral location where it is easy to test nerve function electrically. Suspected entrapment in the brachial or lumbosacral plexus or along a deep peripheral nerve involved in an atypical pain syndrome continues to be difficult to localize with certainty. The second area of diagnostic difficulty concerns the application of MRI in low back pain. In one study, MRI scans on 67 volunteers who had never had significant back pain or sciatica were shown to neuroradiologists who did not know that the patients were asymptomatic. A diagnosis of lumbar disc herniation was made in 57% of the older v01unteers.l~Thus MRI detects disc herniations with great sensitivity, but specificity is low and it cannot confirm that the herniated disc is indeed responsible for the patient’s symptoms.
Prospects for clinical use It is likely to be some time before these novel imaging agents become routinely available for clinical use, but we should be able to look forward to a substantially enhanced ability to locate and confirm peripheral and cranial nerve compression, spinal cord injury, and possibly diffuse axonal injury in the head-injured patient. The use of this sort of tracer will require close co-operation between the neuroradiologist and the referring neurologist or neurosurgeon. The clinician will inject the tracer into muscles innervated by the nerves to be investigated and the radiologist will then evaluate images collected at various times after the injection to follow the axonal transport of the tracer. The anatomical detail visible by current generation imaging, and electrophysiological techniques to elucidate function, have greatly enhanced neurological diagnosis in the past decade. The future promise of axonal transport imaging is that the functional effects of anatomical derangement will be visible directly in the initial magnetic resonance or nuclear medicine image, and the effects of therapeutic
Editorial
intervention on anatomy and function seen directly.
295
9 Mesulam M-M. Tracing Neural Connections with
Horseradish Peroxidase. IBRO Handbook Series: Methods in the Neurosciences. Chichester: John Wiley, 1982: 251.
A. G. FILLER & B. A. BELL Atkinson Morleys' Hospital, London SW20 ONE, UK.
Br J Neurosurg Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
References 1 Weiss, PA, Hiscoe H. Experiments on the mechanism of nerve growth. J Exp Zoo1 1948; 107:315-96. 2 Weiss DG. Axoplasmic Transport. Berlin: SpringerVerlag, 1982: 477. 3 Gallant P. Blockage of fast axonal transport by mechanical compression. SOC Neurosci Abs 1991; 1759. 4 Grafstein By Forman D. Intracellular transport in neurons. Physiol Rev 1980; 60:1168-283.
5 Hoffman PN, Lasek RJ. The slow component of axonal transport: identification of major structural polypeptides and their generality among mammalian neurons. J Cell Biol 1975; 66:351-66. 6 Vallee RB, Bloom GS. Mechanisms of fast and slow axonal transport. A Rev Neurosci 1992; 1459-92. 7 Kristensson K, Olsson Y. Retrograde axonal transport of protein. Brain Res 1971; 29:363-5. 8 Brushart TM, Mesulam M-M. Transganglionic demonstration of central sensory projections from skin and muscle with HRP-lectin conjugates. Neurosci Lett 1980; 17~1-6.
10 Kramer M. Deacon T, Sokoloff A, Filler A. Organization of motorneurons innervating epaxial and hypaxial musculature in the frog, rate and monkey. SOC Neurosci Abs 1987; 13526. 11 Filler AG, Winn HR, Westrum LEYSirrotta P, Krohn K, Deacon TW. Intramuscular injection of WGA yields systemic distribution adequate for imaging of axonal transport in intact animals. SOCNeurosci Abs 1991; 17:1480. 12 Philipe E, Droz B. Calbindin-immunoreactive sensory
13 14
5
6
17
neurons of dorsal root ganglion project to skeletal muscle in the chick. J Comp Neurol 1989; 283:153-60. Brady TJ. Future prospects for MR imaging. SOCMagn Res Med Abs 1991; 102. Ghosh P, Zhou X, Lin W, Feng AS, Groman E, Lauterbur PC. Neuronal tracing with magnetic labels. SOCMagn Res Med Abs 1991; 10:1042. Filler AG, Winn HR, Howe FA, Griffiths JR, Bell BA, Deacon TW. Axonal transport of superparamagnetic metal oxide particles: potential for magnetic resonance assessments of axoplasmic flow in clinical neuroscience. SOCMagn Res Med Abs 1991; 10:985. Filler AG, Bell BA, Howe FA ,Griffiths JR, Flower My Sharma MyWinn HR, Deacon TW. Imaging of axonal transport: is the axoplasmic flow clinically relevant? J Neurol Neurosurg Psychiatry 1992; 55515-6. Boden SD, Davis DO, Dina TS, Patronas MJ, Wiesel SW. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg 1990; 72:403-8.
