Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases.

Human endogenous retroviruses (HERVs) have been implicated as causative agents in diseases characterized by inflammation and macrophage activation, such as multiple sclerosis. Because monocyte activation and differentiation influence retroviral transcription and replication, we investigated the contribution of these processes to the expression of four HERV families (HERV-W, HERV-K, HERV-E, and HERV-H) in human monocytes, and autopsied brain tissue from patients with brain diseases associated with increased macrophage activity. Reverse transcriptase-polymerase chain reaction analysis of primary macrophages and U937 monocytoid cells stimulated with phorbol-12-myristate-13-acetate or lipopolysaccharide revealed three- to ninefold increases in HERV-W, HERV-K, and HERV-H RNA levels. In addition, elevated reverse transcriptase activity and HERV RNA were detectable in supernatants from PMA-stimulated U937 cultures, properties that could be attenuated with the inhibitor of monocyte differentiation threonine-lysine-proline. In contrast, stimulation of monocytes decreased or had no effect on HERV-E expression. Compared with controls, HERV-W and HERV-K expression was increased in brain tissue from patients with multiple sclerosis or human immunodeficiency virus infection or AIDS, with concomitant elevated tumor necrosis factor-alpha levels. Similarly, elevated HERV-W levels were detected in patients with Alzheimer's dementia only when tumor necrosis factor-alpha expression was also evident (2 of 6 cases). The detection of several HERVs in inflammatory brain diseases and the capacity to augment HERV expression in monocytes with compounds that influence cellular activity suggest that increased expression of these viruses is a consequence of increased immune activity rather than causative of distinct diseases.

Idiopathic hypertrophic pachymeningitis: a report of two patients and review of the literature.

PURPOSE: We report the treatment and follow-up, including MRI, of two patients with idiopathic hypertrophic pachymeningitis and review the English language literature, with emphasis on management and outcome in this rare disorder. METHODS AND MATERIALS: The files of two patients were reviewed, with relevant histopathology and imaging (MRI). The first patient has been followed for sixteen years (the longest MRI-documented postoperative course reported for this condition) and the second for two years. The English language literature was reviewed, including a summary of all reported patients that have been followed with MRI or CT imaging. RESULTS: Despite extensive investigation, no underlying etiology was determined in either patient. Histopathological studies revealed a chronic inflammatory dural infiltrate in both patients, with granulomas in the first but not the second patient. The first patient underwent surgery twice and has remained stable for sixteen years, despite persistent neurologic deficits. The second patient was managed with dexamethasone after a surgical biopsy, and experienced complete resolution of all neurological deficits and abnormalities seen with MRI. CONCLUSIONS: Although prompt and extensive surgery has been recommended for this condition, the results from our second patient indicate that complete remission can be achieved in some patients with biopsy and steroid therapy. This also supports the view that autoimmune mechanisms underlie idiopathic hypertrophic pachymeningitis. The first patient illustrates that extensive laminectomies may be an effective therapeutic option but chronic discomfort may result. If extensive surgery must be performed, laminoplasty should be done because of the potential for reduced pain and improved long-term spinal stability.

Neurofilament and tubulin gene expression in progressive experimental diabetes: failure of synthesis and export by sensory neurons.

In human and experimental diabetes, the relationship between molecular abnormalities in perikarya of sensory neurons and structural abnormalities in their distal axons is largely unexplored. In this study we examined neurofilament (Nf) and tubulin messenger RNA (mRNA) expression and their incorporation into distal sensory axons during progressive streptozotocin-induced diabetes in rats. After 2 and 6 months of diabetes, we measured mRNA levels of all three Nf subunits, B50 [growth associated protein-43 (GAP-43)] and alpha-tubulin in L4-L6 dorsal root ganglia using Northern analysis. The same animals underwent morphometric studies of myelinated fibres by light microscopy and quantitative analysis of Nf and microtubule numbers and density within sural myelinated and unmyelinated axons. Multifibre in vivo sensory and motor conduction nerve recordings confirmed slowing of conduction velocities in diabetic rats indicating experimental neuropathy. mRNA levels for the three Nf subunits, B50 (GAP-43) and alpha-tubulin were unchanged from controls at 2 months, but were decreased by 26-46% at 6 months. These changes accompanied declines in Nf numbers and densities within large myelinated sensory axons, and Nf numbers in unmyelinated fibres by 6 months. Microtubule numbers and densities were similarly reduced in large myelinated axons, and microtubule numbers reduced in small myelinated and unmyelinated axons in diabetes at 6, but not 2 months. Axonal atrophy was observed in unmyelinated fibres at 6 months. Our findings indicate that decreased mRNA expression of cytoskeletal proteins in sensory neurons accompanies a reduction in their incorporation into distal axons. These changes imply that there is a direct link between pathological changes in the sensory neuron and alterations of its distal branches from experimental diabetes. The changes in gene expression in diabetes are unique and differ from those that develop after axotomy.

MR imaging of a hemorrhagic and granulomatous cyst of the ligamentum flavum with pathologic correlation.

Cysts of the ligamentum flavum are uncommon causes of neurologic signs and symptoms and usually are seen in persons over 50 years of age. We report a case of an epidural cyst located in the ligamentum flavum, which contributed to spinal stenosis in a 30-year-old man. Radiologic features were similar to those of a synovial cyst, but synovium was not identified histologically. The imaging and pathologic features were unusual, including hemorrhage and a fibrohistiocytic reaction with giant cells.

Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain.

Neurofibrillary tangles (NFT) in Alzheimer's disease (AD) consist largely of hyperphosphorylated tau protein. Many of the phosphorylation sites on tau are serine/threonine-proline sequences, several of which are phosphorylated in vitro by neuronal Cdc2-like kinase (Nclk), a kinase composed of Cdk5 and its activator(s). Thus, tau hyperphosphorylation in AD may result in part from deregulation of Nclk. To test this hypothesis, we examined Nclk activity in prefrontal and cerebellar cortex from 15 postmortem AD and 16 age-matched control subjects, and corrected either for Cdk5 level or for neuronal loss. The ratio of Nclk activity in prefrontal versus cerebellar cortex was then compared. When corrections were made for neuronal loss, the ratios of kinase activity in prefrontal versus cerebellar cortex were significantly higher in AD (6.45+/-0.86) than the controls (3.13+/-0.46; P = 0.003). This finding is consistent with a role for Nclk in the pathogenesis of NFT in AD.

Symptomatic hamartoma of the spinal cord associated with neurofibromatosis type 1. Case report.

The authors present a case in which a symptomatic hamartoma was found in the spinal cord of a patient with neurofibromatosis type 1 (NF-1). This 52-year-old woman presented with painful urinary incontinence. Magnetic resonance (MR) imaging revealed an intramedullary lesion within the lower thoracic spinal cord and conus medullaris, which was surgically removed. Pathological investigation showed a hamartomatous lesion consisting of glial cells, ganglion cells, abundant disoriented axons, and thin-walled vessels. This case provides a pathological correlate to the hamartomatous lesions demonstrated on MR imaging in patients with NF-1 and illustrates that these benign lesions may become symptomatic and require neurosurgical intervention.

The neuropathology of CAG repeat diseases: review and update of genetic and molecular features.

Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntington's disease, X-linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.

Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia.

Matrix metalloproteinases (MMPs) are involved in remodelling extracellular matrix. Gelatinase B (MMP-9) is an inducible 92 kDa MMP expressed by neutrophils, microglia, and endothelial cells. Gelatinase A (MMP-2) is a 72 kDa MMP, constitutively expressed in brain. Elevated MMP activity has been linked to various pathologic conditions, and the therapeutic benefit of MMP inhibitors is under study in a few experimental models. Using gelatin zymography, we have compared activities of these MMPs in infarcted and matched non-infarcted cerebral tissue from eight subjects dying at intervals of less than 2 h to several years after a stroke. Gelatinase B activity was markedly elevated in the infarcted tissue at two days post-infarction, and remained elevated in cases dying months after the event. Increases in gelatinase A activity were subtle at 2-5 days; they were marked and significant in cases dying at 4 months and later. The findings indicate distinct temporal profiles of post-ischemic gelatinase activity in human brain, with earlier but equally persistent elevation in gelatinase B when compared to gelatinase A.

Aging is associated with divergent effects on Nf-L and GFAP transcription in rat brain.

We studied the effects of advancing age on the expression of several proteins important in the structure and function of the nervous system. Brains of young (3 month), middle-aged (13 month), and old (29 month) male Fischer 344 rats were examined. Run-on transcription and Northern blot hybridizations were used to determine gene-specific transcription rates and mRNA levels, respectively. With advancing age, there was a decrement in the transcription rate and mRNA levels for neurofilament-light subunit (Nf-L), but an increment in the transcription rate and mRNA levels for glial fibrillary acidic protein (GFAP). Proteolipid protein (PLP) mRNA levels were attenuated between 3 and 13 months of age, whereas amyloid precursor protein (APP) mRNA levels were attenuated in the middle-aged but not the old animals. Transcription rates for alpha-actin and fos, and mRNA levels for alpha-actin, were unaffected. These observations indicate divergent transcriptional regulation of several genes, notably Nf-L and GFAP, in the aging mammalian forebrain.

Attenuation and recovery of nerve growth factor receptor mRNA in dorsal root ganglion neurons following axotomy.

The actions of nerve growth factor (NGF) are mediated by two receptor proteins, trk and p75. Recent evidence indicates that NGF upregulates the expression of both trk and p75 in responsive neurons including rat dorsal root ganglion (DRG) neurons. Axotomy by disconnecting the neuron from its source of target-derived NGF is predicted to lead to the downregulation of trk and p75 expression. However, previous studies of the effects of axotomy on trk and p75 mRNA expression in rat DRG have yielded discrepant results. We report that following sciatic nerve crush, trk and p75 mRNA levels in L4-L6 DRG decrease to approximately 50% of control levels at 4-14 days, return to control levels by 30 days, and are increased by approximately 30% at 60 days. Similar changes are observed following nerve transection although mRNA levels are slower in returning to normal and do not exceed control levels at later timepoints. Thus, trk and p75 expression decline early following target disconnection and later recover irrespective of target reinnervation. These observations indicate that target derived NGF is required for the maintenance of NGF receptor expression in adult rat DRG neurons and that non-target derived factors can appropriate this function following peripheral nerve injury.

SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis.

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are found in 15 to 20% of patients with familial amyotrophic lateral sclerosis (FALS). Increased levels of neurofilament subunits in transgenic mouse models of ALS also suggests a key role for these proteins in the pathogenesis of the disease. We report the coexistence of an Ile113-->Thr substitution in exon 4 of the SOD1 gene and marked neurofilamentous pathology in the same FALS patient. These observations suggest that two mechanisms, SOD1-induced toxicity and neurofilament disruption, are acting together.

Axonal atrophy in aging is associated with a decline in neurofilament gene expression.

Neurofilaments (Nfs) are major determinants of axonal caliber. Nf transcript levels increase during development and maturation, and are associated with an increase in Nf protein, Nf numbers, and caliber of axons. With aging there is axonal atrophy. In this study we asked whether the axonal atrophy of aging was associated with a decline in Nf transcript expression, Nf protein levels, and Nf numbers. Expression of transcripts for the three Nf subunits was evaluated in dorsal root ganglia (DRG) of Fischer-344 rats aged 3-32 months by Northern and in situ hybridization. There was an approximately 50% decrease in Nf subunit mRNA levels in DRG of aged (> 23 months) as compared to young and mature (3 and 12 months) rats, whereas expression of another neuronal mRNA, GAP-43, showed no decline. Western analysis showed a corresponding decrease in Nf subunit proteins and no decline in GAP-43. Morphometric analysis showed a 50% decrease in Nf numbers within axons. The decrease in Nf gene expression and Nf numbers was accompanied by a decrease in cross-sectional area and circularity of all myelinated fibers, with the largest fibers showing the most marked changes, and a shrinkage in the perikaryal area of large neurons. Furthermore, we found a concomitant decrease in the expression of transcripts for the nerve growth factor receptors trkA and p75 with aging. Although the mechanisms leading to the decrease in Nf gene expression with aging are not known, a decrease in the availability of growth factors, or the neuron's ability to respond to them, may play a role in this process.

Gene expression in Alzheimer neocortex as a function of age and pathologic severity.

Previous studies have shown a marked decline in neuronal and an increase in glial gene expression in Alzheimer's disease (AD) neocortex. Severity of pathologic changes may be greater in presenile AD (PAD) than in senile AD (SAD). We evaluated whether changes in transcript expression were altered as a function of age or pathologic severity. Northern analysis revealed a marked (> 50%) decline in expression of transcripts for the neurofilament light subunit and the major amyloid precursor protein (APP) isoforms in both PAD and SAD. Expression of these neuronal transcripts declined as a function of age in AD and control cases. Expression of the glial fibrillary acidic protein (GFAP) transcript was increased in AD, particularly in the presenile group. AD cases with larger numbers of neurofibrillary tangles had higher levels of GFAP transcript; AD cases with larger numbers of senile plaques had higher levels of APP695 transcript. We conclude that the neuronal mRNA decrements of AD are superimposed on an age-related decline. Age-related shift in expression of certain genes may account for the differences in pathologic severity of PAD and SAD.

Neuronal and glial gene expression in neocortex of Down's syndrome and Alzheimer's disease.

The association cortex of Down's syndrome (DS) predictably and prematurely undergoes neurofibrillary degeneration of Alzheimer type. Hence studies of DS are potentially useful in defining the earliest pathogenetic events in Alzheimer's disease (AD). Previous reports have described altered expression of several mRNAs in AD cortex; but the pathogenetic stage at which expression of these mRNAs begins to deviate from the norm has not been defined. We have examined this issue in neocortex of DS. Expression of mRNAs, known to be altered in AD cortex, was studied by Northern analysis, comparing frontal cortex of DS (15-45 years) with age-matched controls and with AD. Chromosome 21- and non-21-encoded mRNAs were studied, including transcripts expressed preferentially in neurons (neurofilament light subunit and amyloid precursor transcripts) and in glia (glial fibrillary acidic protein [GFAP] and S100 beta). Chromosome 21-encoded mRNAs were increased in DS cortex as expected. Except in the DS case with extensive neurofibrillary degeneration, GFAP was expressed at levels significantly below the control, suggesting that trisomy 21 exerts a suppressive effect on GFAP gene expression. We found no instance in which AD-type changes of transcript expression preceded the appearance of neurofibrillary degeneration. The findings indicate that in trisomy 21, certain changes of mRNA prevalence previously described for AD neocortex are not a necessary antecedent to neurofibrillary degeneration.