Density Of Myelinated Fibers Research Articles

Inhibitory effect of troglitazone on diabetic neuropathy in streptozotocin-induced diabetic rats.

Free-radical scavengers and inhibitors of tumour necrosis factor-alpha (TNF-alpha) such as N-acetylcysteine and pentoxifylline have been shown to inhibit the development of peripheral neuropathy in streptozotocin(STZ)-induced diabetic rats. In this study we examined the effect of troglitazone, an anti-diabetic thiazolidinedione, on diabetic neuropathy, since it also is a free-radical scavenger and a TNF-alpha inhibitor. Rats were fed powder chow mixed with troglitazone at 0.5% and 0.125% ad libitum. Although blood glucose concentrations were remarkably higher and body weight lower in diabetic than in nondiabetic rats, troglitazone had no effect on these throughout the 24-week experiment. Serum lipoperoxide concentrations, tibial nerve lipoperoxide content and serum TNF-alpha activity induced by lipopolysaccharide was increased in diabetic rats, but inhibited in troglitazone-treated rats. Motor nerve conduction velocity (MNCV) of the tibial nerve slowed in diabetic rats, compared with that in nondiabetic rats. On the other hand, the slowed MNCV was (p < 0.05-0.01) inhibited after weeks 12 and 16 of the experiment in diabetic rats treated with high and low doses of troglitazone, respectively. Morphometric analysis showed that troglitazone suppressed the decrease of the myelinated fibre area (p < 0.05), axon/myelin ratio (p < 0.01) and fascicular area (p < 0.05) and suppressed the increase of myelinated fibre density (p < 0.001) in diabetic rats. These results indicate that troglitazone has a beneficial effect on peripheral neuropathy in STZ-induced diabetic rats irrespective of blood glucose concentrations.

Electrophysiological and nerve biopsy: comparative study in Friedreich's ataxia and Friedreich's ataxia phenotype with vitamin E deficiency

The authors report a comparative study of peripheral nerve conductions and nerve biopsy and somatosensory evoked potentials between 15 patients with Friedreich's ataxia and 15 patients with Friedreich's ataxia phenotype with selective vitamin E deficiency. The patients in the two groups are of similar age, age of onset, and clinical phenotype. Peripheral motor nerve action potential amplitude, and conduction velocities are within normal ranges in the two groups. In the Friedreich's ataxia group there is an early and severe peripheral sensory axonal neuronopathy, characterised by an important reduction of the amplitude of sensory action potential, and important loss of myelinated fibres with complete disappearance of large myelinated fibres without any regenerative process. In the Friedreich's ataxia phenotype with selective vitamin E deficiency group there is slight-to-moderate axonal sensory neuropathy with normal to moderate decrease of large myelinated fibre density and important regeneration in nerve biopsy. Somatosensory evoked potentials are markedly involved in the two groups asserting a severe involvement of somatosensory pathway in lumbar, thoracic and cervical spinal cord. These findings suggest that the pathological mechanism involved in the two diseases are different: central peripheral axonopathy in Friedreich's ataxia and central distal axonopathy in Friedreich's ataxia phenotype with selective vitamin E deficiency.

Fate of Schwann cells in CMT1A and HNPP: evidence for apoptosis.

The fate of Schwann cells in Charcot-Marie-Tooth (CMT) neuropathies was addressed in this study of nerve biopsies from patients with proven PMP22 duplications and deletions. In frozen sections, apoptotic nuclei were detected using the TUNEL method. In adjacent sections, anti-neurofilament 68kD antibody was used as an axonal marker, while the antibodies to NKH-1 and low-affinity nerve growth factor receptor P75NTR were used as Schwann cell markers. In addition, plastic sections were used to determine the densities of myelinated fibers and Schwann cell nuclei. In all biopsies from CMT1A, TUNEL-positive nuclei appeared in clusters. In adjacent sections, areas of TUNEL-positive nuclei matched with areas devoid of neurofilaments and NKH-1-positive Schwann cell silhouettes, suggesting that the apoptotic nuclei belonged to nonmyelinating Schwann cells. In addition, quantitative studies on plastic-embedded sections showed a significantly reduced number of total Schwann cells compared with controls, strongly favoring a loss of Schwann cell by apoptosis. In HNPP, the number of total Schwann cells was increased and a significant Schwann cell apoptosis was observed in only 2 patients. Examination of plastic sections and teased nerve preparations from these cases suggested that the Schwann cell apoptosis might be related to the regenerative state of the nerve resulting from the process of sprout pruning. No strict correlation between p75NTR expression and apoptosis was found. These studies indicate that factors regulating Schwann cell number in early postnatal development continue to be important for Schwann cell survival throughout life.

Polyneuropathy due to cobalamin deficiency in the rat

In the present study, we investigated the peripheral nervous system (PNS) (both in terms of its ultrastructure and in terms of its function) of rats made cobalamin (Cbl)-deficient either through total gastrectomy or through prolonged feeding on a Cbl-deficient diet. In both these types of Cbl-deficient neuropathies we found: (a) ultrastructurally, intramyelin and endoneural edema, with no or minimal axonal damage in the PNS, in dorsal root ganglia, and the ventral and dorsal rootlets of the spinal cord; (b) electrophysiologically, a significant reduction in the nerve conduction velocity, consistent with that reported in (a); (c) morphometrically, a significant reduction in the density of myelinated fibers both in the sciatic nerve and in the peroneal nerve. All these pathological changes were reversed by chronic postoperative administration of Cbl into totally gastrectomized (TGX)-rats, hinting at the specificity of the damage itself in relation to the permanent Cbl-deficient status of the TGX-rats. No signs of segmental demyelination or remyelination were found. We also observed a turning of type I fibers into type II fibers in the soleus muscle of all our Cbl-deficient rats, however the Cbl deficiency had been induced. This muscular change was still present in TGX- and Cbl-treated rats, and it cannot be related to a malnutrition status, since it has been observed also in rats fed a Cbl-deficient diet. All these results demonstrate that Cbl deficiency strongly affects rat PNS within different parameters.

Charcot-Marie-Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and connexin32 mutations (CMTX1).

The two most common subtypes of Charcot-Marie-Tooth (CMT) disease are CMT1A and CMTX1. To determine whether these different genetic entities display different morphological phenotypes we compared sural nerve biopsies of CMT1A patients due to PMP22 duplication with biopsies of CMTX1 patients with proven Connexin32 mutations. In CMT1A nerve biopsies we found a severe reduction in myelinated fiber density, hypermyelination as well as demyelination, and a high percentage of onion bulb formations. CMTX1 nerve biopsies showed significant differences: a higher myelinated fiber density, thinner myelin sheaths, more cluster formations, and only few onion bulb formations. Teased fibers studies in CMT1A patients showed features of demyelination and/or remyelination in almost all fibers. In contrast, teased fibers of CMTX1 patients were uniformly thinly myelinated with 5-10% active axonal degeneration and 15% segmental demyelination. Median nerve motor conduction velocities were significantly faster in CMTX1 patients (31.6+/-5.5 m/s) than in CMT1A patients (18.2+/-6.9 m/s). The possible roles of PMP22 and Connexin32 in the pathogenesis of CMT are discussed.

Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: Confirmation of a new entity

We describe two brothers, 11 and 13 years old, respectively, with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation. Electrophysiological studies showed marked reduction of motor and sensory conduction velocity and absence of sensory action potentials. Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration. Signs of demyelination were found only in the younger patient. We suggest that motorsensory neuropathy associated with deafness and mental retardation with absence of large myelinated fibers on sural nerve biopsy represents a distinct clinicopathological entity, which is transmitted in families probably as an autosomal recessive trait.

Phrenic nerves and diaphragms in sudden infant death syndrome

Disturbances of the respiratory system may be an important factor in the cascade of events leading to sudden infant death syndrome (SIDS). Even though the diaphragm is the major respiratory muscle in infants, little is known about alterations of this muscle and of the phrenic nerve in SIDS. In the present study, diaphragms and phrenic nerves of 24 SIDS infants and seven controls were analyzed. Morphometric analysis revealed only slightly larger cross sectional areas of phrenic nerve axons but no increase in myelin sheath thickness in SIDS cases. However, in one SIDS case, myelinated nerve fibre density was severely reduced. Using electron microscopy, several nerve fibres of SIDS infants showed focal accumulations of neurofilaments. Muscle fibre diameters in SIDS diaphragms were significantly larger compared to controls ( P<0.0001). However, in almost all SIDS and control cases, axons and myelin sheaths were artificially swollen, and acute segmental muscle fibre ruptures and contracture bands were found. These prominent nonspecific ultrastructural alterations should advise caution in the interpretation of morphometric data. Thus, in some cases exemplified by one case of the present series, decreased density of phrenic nerve myelinated axons might contribute to SIDS. Still, the present results indicate that development of phrenic nerves and diaphragms is not delayed in most SIDS infants.

A case-control and nerve biopsy study of CREST multiple mononeuropathy.

From 536 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis), seven were identified as having peripheral neuropathy not attributable to another cause. Peripheral neuropathy developed 0 to 25 years after their first symptoms of scleroderma. Unexplained neuropathy in CREST patients (seven patients) was more frequent than in control subjects (two patients) matched for age, sex, time of evaluation, and geographic referral region. Multiple mononeuropathy occurred significantly more frequently in the CREST group (six patients) than in the control group (0 patients). Four sural nerve biopsy specimens from the CREST patients demonstrated multifocal fiber loss and perivascular inflammation; one was diagnostic for necrotizing vasculitis and two others were highly suggestive for necrotizing vasculitis. The density of myelinated fibers in three nerves from CREST patients was significantly decreased, whereas the index of dispersion (a measure of multifocal fiber loss) was increased, and the frequency of axonal degeneration was significantly increased. Based on these clinical and pathologic findings, we conclude that in the CREST syndrome multiple mononeuropathy, although occurring infrequently, occurs more frequently than by chance and necrotizing vasculitis is the cause of this multiple mononeuropathy.

Localization in human diabetic peripheral nerve of N(epsilon)-carboxymethyllysine-protein adducts, an advanced glycation endproduct.

The present study was designed to elucidate in situ distribution of advanced glycation endproducts (AGE) in human peripheral nerve and whether the reaction products were excessive in the diabetic condition. For the detection of AGE, immunoperoxidase staining was undertaken on peripheral nerve samples obtained from 5 non-insulin-dependent diabetic patients and 5 non-diabetic control subjects. The anti-AGE antibody used in this study contained an epitope against N(epsilon)-carboxymethyllysine. Light microscopically, AGE localized in the perineurium, endothelial cells and pericytes of endoneurial microvessels as well as myelinated and unmyelinated fibers. At the submicroscopic level, AGE deposition appeared focally as irregular aggregates in the cytoplasm of endothelial cells, pericytes, axoplasm and Schwann cells of both myelinated and unmyelinated fibers. Interstitial collagens, basement membranes of the perineurium also reacted with this antibody. The AGE depositions were detected in both control and diabetic nerves, but were more intense in the latter. The excessive AGE deposition correlated with a reduction in myelinated fiber density. However, the localization of AGE was not directly associated with degeneration of nerve fibers and the link between AGE deposition and nerve fiber degeneration is yet to be determined. The present study thus demonstrated the excessive deposition of intra- and extracellular AGE in human diabetic peripheral nerve and strengthened the contention that the enhanced glycation may play a role in the development of diabetic neuropathy.

Relationship between brainstem MRI and pathological findings in progressive supranuclear palsy — study in autopsy cases

The relationship between the features of MRI in brainstem and pathological findings was investigated in eight autopsy cases with progressive supranuclear palsy (PSP). Features of T1-weighted images at midbrain level were atrophy of tegmentum and tectum, and dilatation of aqueduct. Histologically, these findings were consistent with atrophy of periaqueductal gray matter, quadrigeminal plate, and tegmentum. In these lesions, we detected neuronal loss, decrease in density of myelinated fibers, gliosis, rarefaction of tissues, and tau-positive structures such as neurofibrillary tangles (NFTs), glial fibrillary tangles (GFTs) and neuropil threads. At pons level, atrophy of tegmentum, atrophy of pontine base, and dilatation of prepontine cistern were found. Tau-positive structures were observed not only in tegmentum but also in pontine base. The density of the tau-positive structure was closely related to the severity of atrophy. Features of T2-weighted images were high intensity in the periaqueductal lesion and tegmentum in pons. In these lesions, severe histological findings were detected. The MRI features in brainstem were closely related to the histological findings as PSP.

Long-term duct-occluded segmental pancreatic autografts: absence of microvascular diabetic complications.

Current insulin therapies for control of glucose metabolism in patients with type I diabetes mellitus prevent major metabolic consequences of insulin deficiency, but none prevents or arrests long-term complications. In experimental models of canine diabetes, retinopathy, neuropathy, and nephropathy have been shown to develop within 5 years. The aim of this study was to determine in a canine model whether glucose control provided by segmental duct-occluded pancreas autografts could prevent the long-term complications of diabetes. Thirty-five outbred mongrel dogs underwent segmental pancreas autotransplantation with residual pancreatectomy. Follow-up over 5 years included endocrine, retinal fundus photography, fluorescein angiography, and nerve conduction studies. At endpoint, analysis of organ specific changes was undertaken. Long-term survival was achieved in 14 dogs for 4 to 5 years and in 3 dogs for 3 to 5 years. Glycosylated hemoglobin levels remained within normal limits, although response to glucose challenge was suboptimal. Fundus photography and fluorescein angiography demonstrated the absence of retinal vascular aneurisms, capillary leakage, and obliteration. Retinal digest showed no vascular changes and normal endothelial/pericyte ratios. Nerve conduction was normal, and histology of nerves revealed normal density of myelinated fibers and absence of intrafascicular vessels and glycogen deposits, with no change in spectrum of fiber diameters and ovoids. Renal histology revealed no evidence of nephropathy with normal glomerular basement membranes. We have demonstrated that duct-occluded segmental pancreatic autografts are capable of providing satisfactory metabolic control for up to 5 years, thereby preventing development of the long-term microvascular complications of diabetes.

De novo mutation (Arg 98→Cys) of the myelin P 0 gene and uncompaction of the major dense line of the myelin sheath in a severe variant of Charcot–Marie–Tooth disease type 1B

A point mutation (Arg 98→Cys) of exon 3 coding for the extracellular domain of the myelin protein zero (P 0) gene was found in a sporadic case of an eighteen year old Japanese man with a severe variant of Charcot–Marie–Tooth disease type 1B (CMT1B). A de novo mutation was established by parentage testing and analyses of the P 0 gene in the family. This patient showed delayed motor development, nonprogressive limb weakness and kyphoscoliosis. In addition to the nerve biopsy findings typical of CMT1B, such as segmental demyelination, marked decrease in the density of myelinated fibers, and frequent onion-bulb formation, ultrastructural examination disclosed uncompaction of the major dense lines with slight widening of the intraperiod distance in the inner layers of the myelin sheath. Although mutations in the extracellular domain of P 0 should affect homophilic adhesion between external surfaces of Schwann cell processes, resulting in the separation at the intraperiod lines, our study shows uncompacted major dense lines as a main myelin abnormality where the cytoplasmic domain of P 0 resides.

Local human sural nerve blood flow in diabetic and other polyneuropathies.

Microangiopathy is considered relevant to the pathogenesis of several forms of peripheral nerve disease, particularly diabetic polyneuropathy. In diabetes, however, it is uncertain whether reductions in mixed nerve trunk blood flow account for early features of polyneuropathy in contrast to later disease, where microvascular changes have been described. To address this issue, we measured local sural nerve blood flow in patients with mild diabetic polyneuropathy who were enrolled in a clinical trial (n = 26), patients with other polyneuropathies being studied by diagnostic sural nerve biopsy (n = 17), patients with vasculitic polyneuropathy (n = 3) and one patient with rapidly progressive severe diabetic polyneuropathy and lumbosacral plexopathies. Standardized measurements were made at 10 sites along the sural nerve of each patient prior to sural nerve resection for biopsy. We used a laser Doppler flowmetry probe sensitive to red blood cell flux to measure sural nerve blood flow. This was slightly higher in patients with mild diabetes compared with those with other polyneuropathies, but was reduced in patients with vasculitis. In patients with mild diabetes, there was no relationship between sural nerve blood flow and prebiopsy sural nerve action-potential amplitude, sural myelinated fibre density, haemoglobin A1C, duration of diabetes or age of the patient. Ten diabetic patients entered in the clinical trial had sural nerve blood flow recorded in one sural nerve, followed 1 year later by a second sural nerve blood flow measurement prior to biopsy of the contralateral sural nerve. Despite a mild trend toward decline in fibre density between the nerves over this period of time, sural nerve blood flow was similar. The patient with severe diabetic polyneuropathy and lumbosacral plexopathies had reduced sural nerve blood flow. Our findings do not provide evidence that reductions in sural nerve blood flow are associated with early peripheral neuropathy in diabetes, unlike vasculitis. The early trend toward slight rises in sural nerve blood flow may be a result of early functional microangiopathy that accompanies nerve dysfunction but does not cause it.

Ataxic neuropathy in the elderly--clinicopathological study of six cases

The combination of ataxia with peripheral neuropathy (ataxic neuropathy) is rare. Six elderly patients with peripheral neuropathy who developed ataxia were studied. Of the peripheral neuropathies, ataxic neuropathy was significantly more frequent in patients aged more than 65 years compared with younger patients. Ataxic neuropathy was associated with carcinoma (2 cases), Sjögren's syndrome (1 case), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, 1 case) and chronic idiopathic ataxic neuropathy (2 cases). The two cases of carcinomatous neuropathy initially showed ataxia, which preceded detection of the carcinomatous lesions in the lung by approximately 1 year. The study cases had many clinical features in common. In the nerve conduction study, sural nerve action potential could not be measured in five of the cases; sural nerve biopsy revealed a decreased density of myelinated fibers in all cases. In particular, the large myelinated fibers were markedly decreased. These findings were common, regardless of the underlying disease, except in the case of CIDP in which there was only a slight decrease in the number of large myelinated fibers. Differential diagnosis based on the clinicopathological features was difficult. Therefore, in cases of ataxic neuropathy, systemic evaluation is necessary to rule out the possibility of carcinoma or various systemic diseases, especially in elderly patients.

Morphophysiologic characterization of peripheral neuropathy in zinc-deficient guinea pigs.

Zinc-deficient guinea pigs develop a peripheral neuropathy characterized by abnormal posture and gait, hyperesthesia, slowed motor nerve conduction velocity (MNCV), and decreased sciatic nerve Na,K-ATPase activity. This study was designed to further investigate longitudinally the morphophysiologic features of the neuropathy. Weanling guinea pigs were fed a low-zinc (<1 mg/kg) diet ad libitum (-ZnAL), an adequate-zinc (100 mg/kg) diet ad libitum (+ZnAL), or the adequate diet restricted in intake ((+ZnRF). Electrophysiologic, morphologic, and biochemical parameters of peripheral nerves were examined at 2.5, 4.0, and 5.5 weeks. Serum zinc was significantly lower by 2.5 weeks and growth rate reduced by 4 weeks in -ZnAL animals. Postural abnormalities were first obvious at 4 weeks, although MNCVs were significantly slower in zinc-deficient animals at all time intervals. The conduction of sensory impulses, as measured by spinal cord somatosensory evoked potentials (sSSEP), was significantly slower in the -ZnAL animals at 5.5 weeks. Examination of teased preparations and histologic sections of sciatic nerves at 5.5 weeks revealed no degenerative lesions or differences in density of myelinated fibers (MF). The size frequency distribution of MF in all groups was unimodal, with a trend toward smaller myelinated nerve fibers in -ZnAL and +ZnRF animals. Sciatic nerve Na,K-ATPase activity in the -ZnAL animals was significantly reduced after 4 weeks of zinc deprivation. At 5.5 weeks, nerve concentrations of myo-inositol, glucose, fructose, and sorbitol were significantly decreased in -ZnAL animals compared with the +ZnRF and +ZnAL controls. The peripheral neuropathy associated with acute zinc deficiency is a parenchymatous axonal disorder characterized by slowed motor and sensory nerve impulse conduction and reduction in nerve Na,K-ATPase activity and nerve concentrations of simple sugars and their metabolites.

Tolrestat improves nerve regeneration after crush injury in streptozocin-induced diabetic rats

To delineate the ability of diabetic nerves to regenerate and to determine the effect of aldose reductase (AR) inhibitors (ARIs) on nerve regeneration in diabetic neuropathy, we evaluated nerve regeneration electrophysiologically and morphologically after sciatic nerve crush injury in three groups of male Sprague-Dawley rats: untreated diabetic (streptozocin [STZ]-induced, n = 16), tolrestat-treated diabetic (n = 16), and age-matched controls (n = 16). Compound muscle action potentials (CMAPs) appeared 4 weeks after crush injury in the control group and 5 weeks after injury in both diabetic groups. Motor nerve conduction velocity (MNCV) in the crushed nerves was decreased in both diabetic groups compared with the control group throughout the experiment. However, this decrease was significantly prevented at 24 weeks with tolrestat treatment. Morphologically, the density of myelinated nerve fibers (MNFs) and the number of MNFs per fascicle were significantly decreased in untreated diabetic rats, but tolrestat significantly prevented the former decrease at 5 weeks and the latter at 24 weeks. The mean diameter of large MNFs (>4 μm) was smaller in the untreated diabetic group than in the control group, but this decrease also was significantly prevented with tolrestat treatment. These results suggest that nerve regeneration is impaired in diabetic neuropathy and that tolrestat can prevent this impairment.

Sensory nerve pathology in multifocal motor neuropathy.

The nosological status of multifocal motor neuropathy remains controversial. The clinical and electrodiagnostic hallmarks suggest selective motor fiber involvement. In this study, we asked to what extent sensory nerves might be involved pathologically in multifocal motor neuropathy. Examination of sensory nerve biopsy specimens from 11 patients did reveal pathological findings in all, but they were very mild. An increased number of thinly myelinated, large-caliber fibers was the unifying feature common to each specimen. By electron microscopy, each biopsy specimen had thinly myelinated fibers surrounded by minor onion bulbs. Active demyelination, though scant, was seen in 3 nerves. Myelinated fiber density was normal. Subperineurial edema and inflammation were not present. We conclude that multifocal motor neuropathy is not an exclusively motor abnormality, although it appears to be so clinically and electrophysiologically. The frequent, albeit mild, pathological abnormalities in sensory fibers suggest that the demyelinating pathophysiology also affects sensory fibers, but to a lesser degree than motor fibers. Some investigators maintain that multifocal motor neuropathy is within the spectrum of chronic inflammatory demyelinating polyneuropathy. The very mild degree of sensory fiber involvement, the absence of inflammation or edema, and the distinctive clinical features support the concept of multifocal motor neuropathy as distinct from chronic inflammatory demyelinating polyneuropathy.

Sural nerve myelinated fiber density differences associated with meaningful changes in clinical and electrophysiologic measurements

New forms of therapy for diabetic and other neuropathies may prevent, stabilize, or ameliorate loss of nerve fibers. Clinically meaningful changes in mean Neurological Disability Score (NDS), and the associated mean change of electrophysiologic attributes have been described in diabetic polyneuropathy. It is unknown what magnitude of myelinated fiber (MF) density change is associated with these meaningful changes of clinical and electrophysiologic alterations. In 18 diabetics and 5 normal controls associations between the mean NDS, summated (ulnar, peroneal and tibial) compound muscle action potential (∑CMAP), summated (ulnar and sural) sensory nerve action potential (∑SNAP), sural SNAP, and MF density in the sural nerve, were assessed using linear regression analyses. Values were corrected for age and sex. For a decrease of: 2 points in the mean NDS (minimum clinically detectable change), MF density decreased by approximately 200 fibers/mm 2( p < 0.001) 1 mV in the mean ∑CMAP (sum of the ulnar, peroneal and tibial CMAP amplitudes), MF density decreased by 160 fibers/mm 2 ( p < 0.01) 1 μV in the mean ∑SNAP (sum of ulnar and sural SNAP amplitudes), MF density decreased by approximately 70 fibers/mm 2 ( p < 0.001) 1 μV in the mean sural SNAP, MF density decreased by approximately 150 fibers/mm 2 ( p < 0.01). Changes in sensory detection thresholds were also associated with a measurable change in the MF density. A quantifiable association exists between the magnitude of change in density of MF, and a meaningful alteration in mean NDS and various electrophysiologic parameters. Knowledge of this is needed to assess the statistical power of a clinical trial in which density of myelinated fibers is an outcome measurement.

Changes of unmyelinated nerve fibers in sural nerve in amyotrophic lateral sclerosis, Parkinson’s disease and multiple system atrophy

Quantitative changes in unmyelinated nerve fibers (UMNFs) of sural nerves in patients of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and multiple system atrophy (MSA) were evaluated using autopsy materials whose pathological diagnosis had been confirmed by careful postmortem examinations. Ordinary ALS cases demonstrated no involvement in cutaneous UMNFs; however, the patients with long survival due to the application of ventilatory support showed bimodality in UMNF diameter histograms, and a patient with involvement of systems other than motor pathways showed an abnormal value in two indices: a low percentage of subunits containing axon(s) and a high mean number of Schwann cell profiles per axon. A significant reduction of the mean value of UMNF density (21%) was found in PD patients. Because the density of myelinated nerve fibers did not show any significant decrease as compared with age-matched controls, the change of nerve fibers in peripheral nervous system was considered to be confined to UMNFs in PD. Elderly PD cases showed enhanced changes in the ageing process, as expressed by the two indices described above. In MSA, the mean value of UMNF density was significantly decreased (23%), and this decrease almost paralleled that of myelinated nerve fiber density. Abnormal values for the two indices described above were found and two out of four cases demonstrated bimodality in the diameter histogram of UMNFs. Unlike MSA, ALS and PD have not been included in the disorders with cutaneous UMNF involvement. Our results supply the first evidence of morphological changes in cutaneous UMNFs in PD cases. In ordinary ALS cases, the emergence of such morphological changes is suggested in cases with long survival.

The lateral corticospinal tract and spinal ventral horn in X-linked recessive spinal and bulbar muscular atrophy: a quantitative study.

A quantitative study was performed on spinal cord lesions in seven patients with X-linked recessive spinal and bulbar muscular atrophy. The myelinated fiber density of the lateral corticospinal tracts at the T7 cord level was well preserved for both large and small myelinated fibers. On the other hand, neurons in the L4 ventral horn were markedly depleted; marked loss was noted of the large alpha and medium-sized gamma motor neurons located in the lateral and medial nuclei as well as the small neurons in the intermediate zones of the ventral horn. These results suggest that myelinated fiber density and fiber-size distribution in the corticospinal tract are well preserved and that neuronal loss in the ventral horns is not restricted to alpha and gamma motoneurons but also involves small interneurons.